Updated Recommendations on the Use of Herpes Zoster Vaccines

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Organization: Public Health Agency of Canada

Date published: 2018-08-30

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An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)

Table of Contents

Preamble

The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to immunization.

In addition to burden of disease and vaccine characteristics, PHAC has expanded the mandate of NACI to include the systematic consideration of programmatic factors in developing evidence-based recommendations to facilitate timely decision-making for publicly funded vaccine programs at provincial and territorial levels.

The additional factors to be systematically considered by NACI include: economics, ethics, equity, feasibility, and acceptability. Over the coming years NACI will be refining methodological approaches to include these factors. Not all NACI Statements will require in-depth analyses of all programmatic factors. As NACI works towards full implementation of the expanded mandate, select Statements will include varying degrees of programmatic analyses for public health programs.

PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of PHAC’s Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.

Summary of information contained in this NACI Statement

The following highlights key information for immunization providers. Please refer to the remainder of the Statement for details.

What

Herpes Zoster Disease

  • Primary varicella zoster virus (VZV) infection causes varicella (chickenpox), and reactivated infection results in herpes zoster (shingles). Herpes zoster (HZ) is characterized by neuropathic pain and dermatomal vesicular rash.
  • Reactivation of VZV occurs with reduced cellular immune response associated with aging or immune suppression. HZ occurs most frequently among older adults (with steep increases in incidence occurring over 50 years of age) and immunocompromised persons.
  • Post-herpetic neuralgia (PHN), which can be debilitating, is the most frequent complication of HZ. Similar to incidence of HZ and hospitalization due to HZ, the risk of PHN among HZ cases increases significantly with age.

Herpes Zoster Vaccines

  • Two HZ vaccines are currently authorized for use in Canada in immunocompetent individuals ≥50 years of age. A live attenuated vaccine, Zostavax®II (Live Zoster Vaccine, LZV), has been authorized since 2008. A recombinant subunit vaccine, Shingrix®, (Recombinant Zoster Vaccine, RZV) has been authorized in October 2017. Both vaccines have been shown to be safe, immunogenic, and reduce the incidence of HZ and PHN.
  • Vaccine efficacy (VE) against HZ decreases with age and over time since vaccination with LZV whereas VE of RZV remains higher and appears to decline more slowly than VE of LZV across all age groups.
    • RZV VE against incident HZ and PHN in the three years post-immunization appears to be double that observed for LZV overall.
    • RZV VE against incident HZ in the four years post immunization remains consistent, with no significant decreases observed over time; in contrast, significant waning of protection has been observed one-year post immunization with LZV.
    • Differences in RZV four-year VE against incident HZ are non-significant across different age groups; in contrast, LZV is significantly less effective in adults over 70 years of age compared to adults 50-59 years of age.
  • Due to the adjuvant in RZV which induces a high cellular immune response to help address the natural age-related decline in immunity, this vaccine is more reactogenic than LZV.
  • Both vaccines are cost effective in those 50 years of age and older compared to no vaccination, especially in those 65-79 years of age. RZV is more cost effective than LZV.

Who

NACI makes the following recommendations for public health program level and individual level decision-making. (While in this statement, the recommendations for both levels of decision-making are essentially the same, the rationale and context are somewhat different.)

For Public Health Program Level Decision-MakingFootnote *, NACI recommends that:

  1. RZV should be offered to populations ≥50 years of age without contraindications. (Strong NACI Recommendation, Grade A evidence)
  2. RZV should be offered to populations ≥ 50 years of age without contraindications who have previously been vaccinated with LZV. (Strong NACI Recommendation, Grade A Evidence)
    1. Re-immunization with 2 doses of RZV may be considered at least one year after LZV (Discretionary NACI Recommendation, Grade I evidence)
  3. RZV should be offered to populations ≥ 50 years of age without contraindications who have had a previous episode of HZ. (Strong NACI Recommendation, Grade B Evidence)
    1. Immunization with 2 doses of RZV may be considered at least one year after the HZ episode (Discretionary NACI Recommendation, Grade I evidence)
  4. LZV may be considered for immunocompetent populations ≥50 years of age without contraindications when RZV vaccine is contraindicated, unavailable or inaccessible. (Discretionary NACI Recommendation, Grade A evidence).
  5. RZV (not LZV) may be considered for immunocompromised adults ≥50 years of age. (Discretionary NACI Recommendation, Grade I evidence). NACI will monitor results from ongoing trials in those who are immunocompromised and will reassess recommendations as evidence becomes available.
Footnote *

For public health program level decision-making, NACI recognizes that there are differences in operational contexts across Canada and suggests that provinces and territories may wish to refer to the Management Options Table 10 to consider differences between age cohorts (e.g. with respect to epidemiology and cost-effectiveness) if prioritization of targeted immunization programs is required for implementation.

Return to footnote * referrer

 

For Individual Level Decision-MakingFootnote **, NACI recommends that:

  1. RZV should be offered to individuals ≥50 years of age without contraindications. (Strong NACI Recommendation, Grade A evidence)
  2. RZV should be offered to individuals ≥ 50 years of age without contraindications who have previously been vaccinated with LZV. (Strong NACI Recommendation, Grade A Evidence)
    1. Re-immunization with 2 doses of RZV may be considered at least one year after LZV (Discretionary NACI Recommendation, Grade I evidence)
  3. RZV should be offered to individuals ≥ 50 years of age without contraindications who have had a previous episode of HZ. (Strong NACI Recommendation, Grade B Evidence)
    1. Immunization with 2 doses of RZV may be considered at least one year after the HZ episode (Discretionary NACI Recommendation, Grade I evidence)
  4. LZV may be considered for immunocompetent individuals ≥50 years of age without contraindications when RZV vaccine is contraindicated, unavailable or inaccessible. (Discretionary NACI Recommendation, Grade A evidence).
  5. RZV (not LZV) may be considered for immunocompromised adults ≥50 years of age based on a case-by-case assessment of the benefits vs risks. (Discretionary NACI Recommendation, Grade I evidence). NACI will monitor results from ongoing trials in those who are immunocompromised and will reassess recommendations as evidence becomes available.

How

RZV

  • RZV is administered intramuscularly as a two dose schedule, 2-6 months apart. To improve coverage of the 2nd dose (e.g. by simultaneous administration with another vaccine), a 0, 12-month schedule may be considered based on evidence of an acceptable safety profile and robust anti-gE immune response. 
  • RZV is contraindicated in those with a known hypersensitivity to any of the vaccine components. There is limited data in immunocompromised individuals, and no data in pregnancy and those who are breastfeeding, so RZV should be used with precaution in these populations at this time.
  • In general, inactivated vaccines may be administered concomitantly with, or at any time before or after, other inactivated vaccines or live vaccines protecting against a different disease. For concomitant parenteral injections, different injection sites and separate needles and syringes should be used. RZV may be given at the same time as unadjuvanted seasonal influenza vaccine. Studies of co-administration with pneumococcal 23-valent polysaccharide vaccine (Pneu-P-23) and Boostrix® (Tetanus, low concentration diphtheria and acellular pertussis vaccine; Tdap), are ongoing. Studies of co-administration with adjuvanted seasonal influenza vaccine (Fluad®) have not been conducted.

LZV

  • LZV is administered subcutaneously as a single dose.
  • LZV is a live vaccine and is therefore contraindicated in pregnancy and immunocompromised individuals. It is also contraindicated in individuals with a known hypersensitivity to any vaccine component. Precaution should be used when deciding to administer it to those who are breastfeeding.
  • In general, live vaccines given by the parenteral route may be administered concomitantly with other vaccines. For concomitant parenteral injections, different injection sites and separate needles and syringes should be used. If not administered concomitantly, a minimum interval of 4 weeks should be maintained between two live parenteral vaccines. LZV may be given at the same time as Pneu-P-23 based on evidence of no decrease in efficacy or increase in adverse events; no safety concerns or interference with immune response have arisen with co-administration with inactivated influenza vaccine.

Why

  • HZ is painful and can have severe complications, including long lasting nerve pain.
  • The incidence and severity of HZ and its complications increase with age.
  • Nearly one in three Canadians develops HZ during their lifetime.
  • HZ vaccines are safe, immunogenic, effective and cost-effective in preventing HZ and PHN.

Introduction

I.1 Objective of this statement

The need for this updated National Advisory Committee on Immunization (NACI) Advisory Committee Statement on the Use of Herpes Zoster (HZ) Vaccines was triggered by evidence on a newly authorized Recombinant subunit Zoster Vaccine (RZV) vaccine, Shingrix®, indicated for the prevention of HZ in individuals 50 years of age and older. The primary objective of this statement is to review current evidence and develop guidance on the use of Shingrix®, as well as to provide guidance on whether the previously authorized Live Zoster Vaccine (LZV), Zostavax®II, and/or the recently authorized RZV should be offered to Canadians ≥50 years of age and older:

  • at a population-level, in publicly funded immunization programs
  • at an individual-level, to individuals wishing to prevent HZ, or by clinicians wishing to advise individual patients about preventing HZ, with vaccines that may not currently be included in public health immunization programs.

Specific questions investigated to support the objective include:

  • Is the RZV vaccine (vs placebo and vs LZV vaccine) immunogenic, efficacious, safe, cost-effective?
  • In which age groups should HZ vaccines be offered?
  • What are the relative merits of RZV vs LZV?
  • Should RZV be offered to those who have previously been vaccinated with LZV? If offered, what should the interval between the doses be?
  • Should RZV be offered to those who have had a previous episode of HZ? If offered, what should the interval between the HZ episode and vaccination be?

NACI will review the evidence on HZ vaccines in those who are immunocompromised in a separate advisory committee statement. Studies on RZV vaccine immunogenicity, safety and efficacy in various immunocompromised groups ≥18 years of age are ongoing at the time of NACI deliberations. While RZV is not contraindicated in those who are immunocompromised, there is no indication for the use of RZV in those <50 years of age in Canada, and evidence in immunocompromised populations is limited at this time. Preliminary, non-peer-reviewed evidence presented in conference abstracts of RZV in certain immunocompromised groups suggests no significant safety or immunogenicity concerns. NACI will continue to review the evidence as it evolves and reassess recommendations.

I.2  Overview of evidence-based recommendations on the use of HZ vaccines in this statement

Based on evidence reviewed and summarized in this advisory committee statement, NACI makes the following recommendations on the use of previously recommended LZV and newly authorized RZV vaccine in populations (Table 1) and individuals (Table 2). (While in this statement, the recommendations for both public health level and individual level decision-making are essentially the same, the rationale and context are somewhat different.)

(Please note:

  • A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present.
  • A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable.

Please see Table 11 for a more detailed explanation of strength of NACI recommendations and grade of the body of evidence.)

Table 1: Summary of 2018 NACI Recommendations on the Use of HZ Vaccines for Public Health Program Level Decision-Making
(i.e. Provinces/Territories making decisions for publicly funded immunization programs)Footnote *
NACI Recommendation
(Strength of Recommendation)
Grade of Evidence
supporting recommendation
RZV
1. NACI recommends that RZV should be offered to populations ≥ 50 years of age without contraindications.
(Strong NACI Recommendation)
NACI concludes that there is good evidence to recommend immunization
(Grade A Evidence)
2. NACI recommends that RZV should be offered to populations ≥ 50 years of age without contraindications who have previously been vaccinated with LZV.
(Strong NACI Recommendation)
NACI concludes that there is good evidence to recommend immunization
(Grade A Evidence).
2a.  NACI recommends that for adults ≥ 50 years of age who have previously been immunized with LZV, re-immunization with 2 doses of RZV may be considered at least one year after LZV.
(Discretionary NACI Recommendation; based on expert opinion)
NACI concludes that there is insufficient evidence to recommend an interval between LZV and RZV
(Grade I Evidence).
3. NACI recommends that RZV should be offered to populations ≥ 50 years of age without contraindications who have had a previous episode of HZ.
(Strong NACI Recommendation)
NACI concludes that there is fair evidence to recommend immunization
(Grade B Evidence).
3a. NACI recommends that for adults ≥ 50 years of age who have had a previous episode of HZ, immunization with 2 doses of RZV may be considered at least one year after the HZ episode.
(Discretionary NACI Recommendation; based on expert opinion)
NACI concludes that there is insufficient evidence to recommend an interval between a previous episode of HZ and vaccination with RZV
(Grade I Evidence).
LZV
4. NACI recommends that LZV may be considered for immunocompetent populations ≥ 50 years of age without contraindications when RZV is contraindicated or unavailable.
(Discretionary NACI Recommendation)
NACI concludes that there is good evidence to recommend immunization
(Grade A Evidence)
RZV vs LZV in Immunocompromised Populations
5. NACI recommends that RZV (not LZV) may be considered for immunocompromised adults ≥ 50 years of age.
(Discretionary NACI Recommendation; based on expert opinion)
NACI will review the evidence as it evolves and reassess recommendations.
NACI concludes that there is insufficient evidence at this time to recommend immunization
(Grade I evidence)
Footnote *

In considering these recommendations, provinces and territories may take into account other local operational factors (e.g. current immunization programs, resources), and may wish to review differences between age cohorts (e.g. with respect to epidemiology and cost-effectiveness) outlined in the Management Options Table 10 if prioritization of targeted immunization programs is required for implementation.

Return to footnote * referrer

Table 2: Summary of 2018 NACI Recommendations on the Use of HZ Vaccines for Individual Level Decision-Making
(i.e. Individuals wishing to prevent HZ, or clinicians wishing to advise individual patients about preventing HZ with vaccines that may not currently be included in public health immunization programs)Footnote **
NACI Recommendation
(Strength of Recommendation)
Grade of Evidence
supporting recommendation
RZV
1. NACI recommends that RZV should be offered to individuals ≥ 50 years of age without contraindications.
(Strong NACI Recommendation)
NACI concludes that there is good evidence to recommend immunization
(Grade A Evidence)
2. NACI recommends that RZV should be offered to individuals ≥ 50 years of age without contraindications who have previously been vaccinated with LZV.
(Strong NACI Recommendation)
NACI concludes that there is good evidence to recommend immunization (Grade A Evidence).
2a. NACI recommends that for adults ≥ 50 years of age who have previously been immunized with LZV, re-immunization with 2 doses of RZV may be considered at least one year after LZV.
(Discretionary NACI Recommendation; based on expert opinion)
NACI concludes that there is insufficient evidence to recommend an interval between LZV and RZV
(Grade I Evidence).
3. NACI recommends that RZV should be offered to individuals ≥ 50 years of age without contraindications who have had a previous episode of HZ.
(Strong NACI Recommendation)
NACI concludes that there is fair evidence to recommend immunization
(Grade B Evidence).
3a. NACI recommends that for adults ≥ 50 years of age who have had a previous episode of HZ, immunization with 2 doses of RZV may be considered at least one year after the HZ episode.
(Discretionary NACI Recommendation; based on expert opinion)
NACI concludes that there is insufficient evidence to recommend an interval between a previous episode of HZ and vaccination with RZV
(Grade I Evidence).
LZV
4. NACI recommends that LZV may be considered for immunocompetent individuals ≥ 50 years of age without contraindications when RZV is contraindicated unavailable, or inaccessible.
(Discretionary NACI Recommendation)
NACI concludes that there is good evidence to recommend immunization
(Grade A Evidence)
RZV vs LZV in Immunocompromised Individuals
5. NACI recommends that RZV (not LZV) may be considered for immunocompromised adults ≥ 50 years of age based on a case-by-case assessment of benefits vs risks.
(Discretionary NACI Recommendation; based on expert opinion)
NACI will review the evidence as it evolves and reassess recommendations.
NACI concludes that there is insufficient evidence at this time to recommend immunization
(Grade I evidence)
Footnote **

In considering these recommendations, individuals/clinicians may wish to review the decision points outlined in the Management Options Table 9.

Return to footnote ** referrer

No studies on RZV in individuals with a previous episode of Herpes Zoster Ophthalmicus (HZO) have been conducted.Footnote 1

I.3 Background of HZ vaccines, immunization programs, and recommendations in Canada

In Canada, a live-attenuated vaccine against HZ (LZV) was initially approved for use among persons 60 years and older by the Biologics and Genetic Therapies Directorate (BGTD) of Health Canada in August 2008, and in May 2011 it was approved for use in those age 50 years and older. In 2008, only a freezer stable product (Zostavax®) was available, however in 2011, a refrigerator-stable product (Zostavax®II) replaced it.

In 2010, the National Advisory Committee on Immunization (NACI) published an advisory committee statement recommending the only available vaccine at the time (LZV) for the prevention of herpes zoster and its complications in persons 60 years and older without contraindications (e.g. immunocompromise) based on what the committee considered to be good evidence. In 2014, NACI published an updated advisory committee statement recommending that the vaccine may be used in patients aged 50-59 years based on good evidence (this recommendation was unchanged from the previous statement, but the level of evidence was upgraded as the vaccine was subsequently shown to be both safe and efficacious in this age group. However, as the duration of protection from the vaccine was unknown beyond 5 years, it was uncertain whether vaccination at younger ages would provide ongoing protection at older ages when the incidence of HZ is highest.) In the 2014 recommendations, NACI also concluded that there was insufficient evidence to recommend for or against the administration of HZ vaccine in individuals with a history of HZO. Although causality was difficult to determine, cases of HZO had been reported after administration of HZ vaccine.

NACI’s recommendations in the 2010 and 2014 Advisory Committee Statements on the Herpes Zoster vaccine authorized for use in Canada at the time (LZV) are summarized in Table 3.

Table 3: Summary of NACI Recommendations on the Use of LZV in 2010 and 2014
Population Scenarios 2010 NACI Recommendations 2014 NACI Recommendations
≥60 year olds Recommended (Grade A evidence) Recommended (Grade A evidence)
50-59 year olds May be used (Grade B evidence) May be used (Grade A evidence)
Previous episode of HZ No recommendation (Grade I evidence) May be administered (Grade B), at least one year after (expert opinion) - 2014
Previous episode of HZO   No recommendation (Grade I evidence)
Prior history of chickenpox or documented prior varicella infection Recommended (Grade A evidence)  
Immunocompromised
- HIV, post-organ or Hematopoietic Stem Cell Transplantation (HSCT) or in those receiving high dose corticosteroids, chemotherapy or immune suppressing medications   No recommendation (Grade I evidence)
- low dose immunosuppressives, anti-TNFs on a case-by-case basis   May be administered (Grade B evidence)
Co-administration
- with Trivalent Influenza Vaccine (TIV) At different site, Recommended (Grade A evidence)  
- with Pneu-P-23 ≥4 weeks apart, Recommended (Grade B evidence) Concomitantly at different site, Recommended (Grade A evidence)

In May 2014, the Canadian Immunization Committee recommended routine offering of LZV to immunocompetent adults aged 60 to 65 years and older without contraindications on the basis of the epidemiology of varicella zoster virus, zoster vaccine characteristics, disease modeling and economic analysis, as well as on the feasibility and acceptability of zoster immunization programs.Footnote 2

The live attenuated HZ vaccine has been available for private purchase, however until recently, no publicly funded immunization program has been offered in Canada. In September 2016, Ontario was the first jurisdiction to provide HZ vaccine through a publicly funded program to individuals 65-70 years of age.

In October 2017, a recombinant subunit HZ vaccine (RZV) containing VZV glycoprotein E and the AS01B adjuvant system was authorized for use in Canada.

HZ is not a reportable disease in Canada, and there are no established national targets for disease reduction or vaccination coverage goals for this vaccine preventable disease at this time.

I.4 Background of HZ vaccines, immunization programs, and recommendations worldwide

LZV was authorized for use for prevention of HZ in the United States in 2006 and recommended by the Advisory Committee on Immunization Practices (ACIP) in 2008 for immunocompetent adults 60 years of age and olderFootnote 3 . In 2006, the European Medicines Agency (EMEA) issued a marketing authorization for LZV for routine vaccination in individuals aged 60 and overFootnote 4 , and expanded its recommendation to include individuals aged 50 and older in 2007.Footnote 5  Starting in 2013, the United Kingdom National Health Service (NHS)Footnote 6  began offering LZV to individuals between 70 and 79 years of age.

Currently, the new RZV vaccine is authorized for use in Canada, the United States, Europe and Japan. On October 25, 2017, the ACIP in the United States recommended the use of RZV vaccine preferentially over LZV vaccine in immunocompetent adults age 50 years and older, including those who previously received LZV vaccine. ACIP has not yet made a recommendation for the use of RZV vaccine specifically for immunocompromised populations. LZV remains a recommended vaccine for prevention of HZ in immunocompetent adults 60 years and older in the United States.Footnote 7

II. Methods

In brief, the broad stages in the preparation of a NACI advisory committee statement are:

  1. Knowledge synthesis (retrieve and summarize individual studies, rank the level [i.e. study design] and quality of the evidence which are summarized in the Summary of Evidence Tables in the Appendix)
  2. Synthesis of the body of evidence of benefits and harms, considering the quality of the evidence and magnitude of effects observed
  3. Translation of evidence into a recommendation.

Further information on NACI’s standard evidence-based methododology is available.

For this advisory committee statement, NACI reviewed key questions for the evidence reviews as proposed by the Herpes Zoster Working Group (HZWG), including such considerations as the burden of illness and the target populations; safety, immunogenicity, efficacy, effectiveness of the HZ vaccines; vaccine schedules; economics, and other aspects of the overall immunization strategy. For the purposes of this Statement, separate strategies were used to compile evidence on the vaccine characteristics, burden of disease, and programmatic factors for HZ vaccines, which were then included in an overall knowledge synthesis by PHAC technical staff (SI, MT, OB, KE, MD, SDB) and contractor JH, supervised by the HZWG.

  • In order to assess the burden of disease, key literature was synthesized by MD in the Epidemiology section and supplemented with figures from MB based on administrative data from several Canadian jurisdictions. There is currently no surveillance program in place in Canada to monitor HZ incidence, PHN, or HZ ophthalmicus.
  • In order to assess vaccine efficacy, effectiveness, and safety, a collaboration was initiated between PHAC and the Canadian Institutes of Health Research (CIHR) Drug Safety and Effectiveness Network (DSEN). Within DSEN, the Methods and Applications Group for Indirect Comparisons (MAGIC) led a systematic review of published and unpublished studies on the safety, efficacy, and effectiveness of LZV and RZV vaccines.
    • The HZ WG provided input and guidance on the study eligibility criteria as defined by the Population, Intervention, Comparator, Outcomes and Study design (PICOS) framework (P – adults 50 years and greater, I – HZ vaccines, C – sham (or placebo vaccine), no treatment, or another HZ vaccine, O – vaccine efficacy, effectiveness, safety and quality-of-life, S – RCTs and non-randomized studies) and the literature search strategy. The literature search strategy was developed by a librarian (EC) and peer-reviewed by another librarian (JM) using the Peer Review of Electronic Search Strategies (PRESS) checklist. MEDLINE, EMBASE, and the Cochrane Library were searched from inception to January 19, 2017 and supplemented with a grey literature search (i.e. difficult to locate and unpublished documents).
    • Retrieved citations were independently screened for eligibility by pairs of MAGIC team members (WZ, RC, PK, VN, MG, RW, JPS) independently upon completion of a team calibration exercise to establish inter-rater agreement. Each relevant full text article was assessed for eligibility using a similar process. Once a list of studies that met the eligibility criteria (i.e. studies investigating efficacy, effectiveness or safety of either LZV or RZV vaccines in adults aged 50 years or older) was compiled by MAGIC, data were abstracted from each eligible article and appraised for risk of bias by two team members independently (WZ, RC, PK, VN, MG, RW, JPS) from the MAGIC team.
    • Risk of bias was assessed using The Cochrane Collaboration Risk of Bias tool for randomized controlled trials, the Newcastle Ottawa Quality Assessment Scale for cohort studies and case-control studies, and the EPOC Risk of Bias tool for nonrandomized controlled trials. Studies were also appraised according to the standard NACI methodology for inclusion in evidence tables.
    • In addition to the studies selected and appraised by MAGIC, the HZ WG included an additional 11 studies on safety and efficacy that were initially screened out by the MAGIC team as per the PICO criteria due to the lack of a comparator group. These additional studies were appraised for quality using the standard NACI methodology and downgraded where appropriate due to the lack of comparator groups. All included studies on efficacy and safety were extracted into evidence tables and synthesized into a narrative summary by technical staff at PHAC (SDB, OB, MT).
  • In order to assess the immunogenicity of HZ vaccines, a literature review was contracted by PHAC, supervised by the NACI HZWG, including summary tables with ratings of the quality of the evidence using NACI's methodological hierarchy (Tables 12 and 13) as per standard NACI methodology. The search strategy was developed with a Health Canada librarian (LG), and a search was performed on June 5, 2017 and updated on October 10, 2017 based on the following research question: P – adults 50 years and greater, I – HZ vaccines, C – sham (or placebo vaccine), no treatment, another HZ vaccine, or no comparator, O – humoral immunity and/or cell-mediated immunity (CMI).
  • In order to assess the cost effectiveness of different HZ vaccination strategies, an economic analysis was conducted by MD, ZZ, CS, PDW, VG, RA, EB, MB, under the supervision and guidance of the HZWG. The results of this model were presented to the HZ WG on January 12, 2018, and this evidence was synthesized in narrative summary by PHAC technical lead KE. Specific methods for the economic model can be found in the Economics section of this Statement.

Following a review of the synthesized body of evidence, proposed recommendations for vaccine use were developed. The Working Group chair and PHAC technical leads presented the evidence and proposed recommendations to NACI on February 7, 2018. Following thorough review of the evidence and consultation at the NACI meeting on February 7, 2018, the committee voted on specific recommendations. The description of relevant considerations, rationale for specific decisions, and knowledge gaps are described in the text.

For the analysis of vaccine safety, efficacy, effectiveness, and immunogenicity, results are presented for the “general population”. However, it should be noted that the studies informing these sections may include both immunocompetent and immunocompromised subjects, but many of the studies did not stratify the data sufficiently to allow separate analyses.

Studies specifically investigating immunocompromised populations were not included in the narrative synthesis of the body of evidence. Although these studies were not excluded from the literature reviews and are presented in evidence tables, they were not explicitly discussed in this Statement because NACI determined that specific recommendations for immunocompromised populations will be developed at a later date when more evidence is available. Several clinical trials with the RZV vaccine are currently underway in a range of immunocompromised populations including individuals with solid tumors, solid organ transplant recipients, and hematopoetic stem cell transplant recipients. NACI will continue to monitor the evidence as it evolves and perform another knowledge synthesis for this population. NACI will issue recommendations based on forthcoming studies in addition to the specific studies identified in the present literature reviews.

III. Epidemiology

III.1 Disease Description

HZ, or shingles, is a painful vesicular eruption, typically affecting a single dermatome. HZ develops due to the reactivation in the dorsal root ganglia of latent varicella zoster virus (VZV) from previous primary varicella infection when VZV-specific immunity weakens (most commonly due to age or immunocompromise). Although less contagious than primary varicella, persons with acute HZ can transmit VZV to susceptible contacts, with transmission predominantly occurring via direct contact with vesicular lesions.Footnote 8 Footnote 9 Footnote 10

Up to 40% of persons with acute HZ report at least one complication from the illness.Footnote 11 Footnote 12 Footnote 13  Common complications are potentially severe, and include postherpetic neuralgia (PHN), a prolonged and often debilitating pain following HZ infection that occurs in approximately 20% of HZ casesFootnote 14 Footnote 15 Footnote 16 , and HZ ophthalmicus (HZO), where VZV reactivation occurs in the ophthalmic division of the trigeminal nerve in 10-15% of HZ casesFootnote 17 , and can cause severe chronic pain, facial scarring, and/or loss of vision. Less common but severe HZ complications include central nervous system infections, nerve palsies including Ramsay-Hunt Syndrome, neuromuscular diseases including Guillain-Barre Syndrome, pneumonia, hepatitis and secondary bacterial infections.Footnote 18 Footnote 19 Footnote 20  In general, HZ complications are more common and may be more severe among persons who are older and/or immunocompromisedFootnote 14 Footnote 17 Footnote 21 ; children without comorbidities are less likely to experience HZ complications.Footnote 22 Footnote 23

III.2 Disease Distribution

In the absence of HZ vaccination, nearly one in three Canadians developed HZ during their lifetimeFootnote 24 , and 130,000 HZ cases, 17,000 cases of PHN, and 20 deaths from HZ were estimated to occur in Canada annually.Footnote 11  Age is the major risk factor for development of HZ, with HZ incidence sharply increasing by age among persons 50 years of age and older.Footnote 17 Footnote 25  Footnote 26  Footnote 27  Footnote 28 Footnote 29  HZ incidence also varies by sex, with females having a roughly 1.3 times greater risk of HZ relative to males.Footnote 30

Age is also the predominant risk factor for development of PHN, with each 10-year increase in age associated with a mean 1.2 to 3.1 increase in the relative odds of developing PHN.Footnote 31 The risk of PHN is particularly high among persons 50 years of age and older, with PHN risks ranging from 4% to 15% among HZ cases 50 to 59 years of age, 7% to 26% among HZ cases 60 to 69 years of age, and 14% to 29% among HZ cases 70 years of age and older, in prospective cohort studies.Footnote 17  Evidence of a relationship between PHN risk and sex is conflicting, with a recent systematic review finding differing conclusions and considerable heterogeneity across studies.Footnote 31  Unlike PHN, the risk of HZO does not vary by age.Footnote 17  In general, risk factors relating to HZO incidence, complications, and severity are largely unknown, however, it has been hypothesized they may be related to infection virulence and/or host immune response.Footnote 32

Currently, HZ is not a reportable illness in Canada, and therefore, provincial estimates of HZ incidence have largely been inferred from administrative data. Administrative databases have inherent limitations in ascertaining HZ incidence, such as the inclusion of only medically-attended HZ cases and reliance upon administrative billing codes to identify HZ medical encounters. As a result, these studies have the potential to miss and/or misclassify HZ cases. Despite limitations, these studies remain useful particularly to identify and examine underlying trends in HZ disease, provided that administrative coding practices do not change over time.Footnote 33

To date, trends in HZ incidence and rates of medical utilization have been examined via administrative data from the provinces of Alberta, British Columbia, Manitoba, Ontario, and Québec.Footnote 24 Footnote 26 Footnote 27 Footnote 28 Footnote 29 Footnote 34 Footnote 35 Footnote 36  Generally, results were similar, with crude and adjusted population incidence rates of medically-attended HZ of 3 to 5 cases per 1,000 person-years.Footnote 24 Footnote 26 Footnote 27 Footnote 28 Footnote 29 Footnote 34 Footnote 35  HZ incidence was strongly associated with age, with minimum and maximum HZ incidence consistently observed among youngest and oldest age groups, respectivelyFootnote 24 Footnote 26 Footnote 27 Footnote 28 Footnote 29 Footnote 34  (Figure 1). Similar to global estimates of HZ incidenceFootnote 17 Footnote 25 , HZ incidence among Canadian populations steeply increased among persons 50 years of age and older, with HZ incidence ranging from 4 to 6 cases per 1,000 person-years among adults 50 years of age, 6 to 9 cases per 1,000 person-years among adults 60 years of age, 7 to 11 cases per 1,000 person-years among adults 70 years of age, and 8 to 13 cases per 1,000 person-years among adults 80 years of age and older (Figure 1). Females also had a greater risk of HZ across all age strata.Footnote 26 Footnote 27 Footnote 28 Footnote 29  Approximately 2% to 4% of Canadian HZ cases were hospitalized.Footnote 26 Footnote 27  Similar to incidence, hospitalization rates were strongly associated with age, with peak rates observed among persons 65 years of age and olderFootnote 24 Footnote 26 Footnote 29 Footnote 34 Footnote 36  (Figure 2). Likewise, international data from published studies of PHN risk per case of HZ reveal a strong association with age, particularly among those 65 years of age and older (Figure 3).

Figure 1: Age-specific HZ incidence rates per 1,000 person-years reported among published studies from Canadian provinces and/or territories
Figure 1
Figure 1 - Text description

Figure 1 shows HZ incidence rate per 1,000 person-years (vertical axis) with respect to population age in years (horizontal axis). Data points are based on published studies from Canadian provinces and territories.  Among those studies where rates are reported for a range of ages, age is plotted based upon median age of the age category. For age categories that include a non-discrete age range, (i.e. ages less than or greater than a designated age), the category minimum and maximum ages are presumed to be 0 and 90 years, respectively.

Study results are plotted in distinct individual colors, differentiating between province, territory and/or time interval from which the data was obtained. The provinces and time intervals from which published data was available were Alberta (1986-2002; dark blue), Alberta (1994-2010; green); British Columbia (1994-2003; light blue); British Columbia (1997-2012; maroon); Manitoba (1979-1997; grey); Manitoba (1999-1997; yellow) and Ontario (1992-2010; orange).

All provincial data plots are intertwined, following the same trend from ages ≤ 10 up to ages ≥ 75, when studies start showing more discrepancy, with one study from Alberta (1994-2010) exhibiting a trend towards higher incidence (approx. 1-3 PYs) than average. The overall trend is a slow increase in HZ incidence from zero to ~3 cases per 1,000 person-years from the ages of zero to 45 years old.  At the age of 45, the slopes of all trend lines seem to increase, leading to HZ incidence between ~7 cases per 1,000 person-years (minimum – British Columbia 1994-2003) and ~13 cases per 1,000 person-years (maximum – Alberta 1994-2010) at age ≥ 75.

Please note: where rates were reported for a range of ages, age was plotted based upon median age of the age category. For age categories that included a non-discrete age range, (i.e. ages less than or greater than a designated age), the category minimum and maximum ages were presumed to be 0 and 90 years, respectively.

Figure 2: Age-specific HZ hospitalization rates per 100,000 person-years reported among published studies from Canadian provinces and/or territories
Figure 2
Figure 2 - Text description

Figure 2 shows HZ hospitalization rate per 100,000 person-years (vertical axis) with respect to population age in years (horizontal axis).  Data points are based on published studies from Canadian provinces and territories.  Among those studies where rates are reported for a range of ages, age is plotted based upon median age of the age category. For age categories that include a non-discrete age range, (i.e. ages less than or greater than a designated age), the category minimum and maximum ages are presumed to be 0 and 90 years, respectively.

Study results are plotted in distinct individual colors, differentiating between province, territory and/or time interval from which the data was obtained.  The provinces and time intervals from which published data was available were British Columbia (1994-2003; blue), Manitoba (1979-1997; grey) and Ontario (1992-2010; orange).

Both Manitoba and Ontario plots exhibit similar trends, i.e. a HZ hospitalization rate below 10 per 100,000 person-years for a population under the age of 45, along with a very significant slope increase starting at age 55 (Manitoba) and 65 (Ontario), increasing to maximums of ~87 HZ hospitalizations per 100,000 person-years at age 75 (Manitoba) and ~75 HZ hospitalizations per 100,000 person-years at age 85 (Ontario). The remaining plot (British Columbia) exhibits close-to-zero HZ hospitalizations per 100,000 person-years from among population aged ≤ 15, a steep increase to ~45 HZ hospitalizations per 100,000 person-years at age 45; and the lowest age ≥ 80 HZ hospitalization rate, being ~51 HZ hospitalizations per 100,000 person-years.

Please note: where rates were reported for a range of ages, age was plotted based upon median age of the age category. For age categories that included a non-discrete age range, (i.e. ages less than or greater than a designated age), the category minimum and maximum ages were presumed to be 0 and 90 years, respectively.

Figure 3: Age-specific PHN risk per case of HZ reported among published studies
Figure 3
Figure 3 - Text description

Figure 3 shows the percentage of PHN incidence per HZ case (vertical axis) with respect to population age in years (horizontal axis) among published studies. In all studies, rates were reported for a range of ages, therefore age was plotted based upon median age of the age category. For age categories that included a non-discrete age range, (i.e. ages less than or greater than a designated age), the category minimum and maximum ages were presumed to be 0 and 90 years, respectively.

Study results are plotted from data derived from published studies including a range of different study designs and methodologies. Study designs include: one RCT (Oxman et al, 2005 – orange), two analytic cohort models (Brisson et al, 2008 – light blue; Pellissier et al, 2007 – grey) and two retrospective cohort studies (H-Simpson, 1975 – dark blue; Klompas et al, 2011 – yellow).

All studies show a similar increasing trend of percentage of PHN incidence per HZ case along with age. The lowest values (below 5%) observed were among younger aged cohorts (25-45 years), and the lowest values observed among a more advanced aged cohort are shown by the plotted line from Oxman et al (2005), with a percentage of PHN incidence per HZ case of ~7% at age 65 and ~18% at age 80. The rest of the studies exhibit higher PHN incidence risk per case of HZ with advanced age, the second lowest % PHN risk per HZ case being ~12% and the highest being ~23% in the 60-65 age bracket, going all the way up to ~27% (lowest, Klompas et al 2011) to ~34% (highest, H-Simpson 1975) PHN incidence per HZ case in the ≥ 80 age bracket.

Please note: these data are derived from published studies including a range of different study designs and methodologies. Study designs include: one RCTFootnote 37 , two analytic cohort modelsFootnote 11 Footnote 38 , and two retrospective cohort studiesFootnote 13 Footnote 39 .

In all studies rates were reported for a range of ages, therefore age was plotted based upon median age of the age category. For age categories that included a non-discrete age range, (i.e. ages less than or greater than a designated age), the category minimum and maximum ages were presumed to be 0 and 90 years, respectively.

Several provincial studies have examined trends in HZ rates in relation to the adoption of childhood varicella vaccinationFootnote 26 Footnote 27 Footnote 29 Footnote 35 Footnote 36 , since it has been hypothesized that primary varicella vaccination may decrease natural boosting from circulating VZV, and result in a greater risk of VZV reactivationFootnote 40 Footnote 41 . While increases in HZ incidence or rates of clinical visits were observed over the study period in four out of five provincial studies, in two of these studiesFootnote 29 Footnote 35 , increasing HZ incidence was associated with the licensure of HZ vaccine, but not with the implementation of varicella vaccination. Based on these findings, authors hypothesized the increase in HZ incidence may be due to misclassification of visits pertaining to HZ vaccination as HZ disease. In the remaining two studies that reported an increase in HZ ratesFootnote 27 Footnote 36 , rates also increased during the pre-vaccine period making it difficult to ascertain the true relationship between HZ and primary varicella vaccination. In the remaining study, the risk of HZ during the post-publicly funded varicella vaccine program period was not statistically different from the non-publicly funded varicella vaccine period, after adjustment for potential confoundersFootnote 26. Varying trends in HZ incidence have been reported in studies of pre- and post-implementation primary varicella vaccination programs in the United States and elsewhereFootnote 17 Footnote 42 Footnote 43 . As a result, the relationship between primary varicella immunization programs and HZ incidence remains unclearFootnote 44 . 

Since primary varicella vaccine-strains can reactivate to cause HZ, examination of HZ rates among vaccinated children is also of interest in the post-varicella vaccine era. Studies from Alberta, British Columbia, Ontario, and Québec found decreases in HZ rates in the post- relative to the pre-vaccination era among children under 10 years of age who were eligible for varicella vaccinationFootnote 26 Footnote 27 Footnote 29 Footnote 36 . These data are consistent with results from other studies that found a lower HZ risk among children vaccinated with varicella vaccine compared with unvaccinated childrenFootnote 45 Footnote 46 Footnote 47 Footnote 48 . The risk of HZ among children who received varicella vaccination is an area of continued interest, particularly as vaccinated children grow into those ages that are traditionally associated with greater HZ riskFootnote 8 Footnote 49 .

III.3 High Risk Groups

Individuals who are immunocompromised either due to underlying conditions or immunosuppressive agents have an increased risk of developing HZFootnote 26 Footnote 30 Footnote 50 , and may be more likely to experience atypical and/or more severe disease and complicationsFootnote 51 Footnote 52 Footnote 53 Footnote 54 Footnote 55 . A recent systematic review and meta-analysis examined the risk of HZ among persons living with autoimmune conditions, including rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease, and found a 1.4 to 2.1 times higher risk (varying by condition) among individuals living with these conditions relative to persons without comorbiditiesFootnote 17 Footnote 30 . Another systematic review and meta-analysis estimated a 1.2 to 2.2 times higher risk of HZ among persons taking an immunosuppressive drug, such as biologics that do not target tumor necrosis factor, nonbiological disease-modifying antirheumatic drugs, or corticosteroids (with risk varying by drug), relative to persons taking placebo or no drugsFootnote 50 . Persons who are immunocompromised may also be at greater risk of developing PHN, than the general population, with higher rates of PHN observed among people who are severely immunosuppressed, people living with diabetes mellitus, or people with systemic lupus erythematosusFootnote 31. Rates of PHN lasting more than 6 months were also higher among people living with conditions presumed to affect host CMI as compared with the general population, in an administrative database study from the United StatesFootnote 55 .

III.4 Summary of HZ immunization coverage in Canada

Currently, HZ vaccine coverage is not examined via national surveys in Canada. A recent study from Alberta, however, estimated that provincial HZ vaccine coverage was approximately 8% among persons 60 years of age or older in the absence of a public HZ vaccination program and during the 4 years following HZ vaccine authorizationFootnote 56 . Given its public HZ vaccination program, provincial HZ vaccine coverage is likely higher in Ontario; however, coverage data are currently not available (author correspondence).

IV. Vaccine

IV.1 Preparations authorized for use in Canada

Two HZ vaccines are currently authorized for use in Canada in immunocompetent individuals ≥50 years of age. A live attenuated unadjuvanted vaccine, Zostavax®, has been authorized since 2008, with the newer refrigerator stable product, Zostavax®II, replacing the original freezer stable product in 2011. A recombinant adjuvanted subunit vaccine (RZV), Shingrix®, has recently been authorized in October 2017.

LZV is based on the Oka/Merck attenuated varicella virus strain which is also used for varicella vaccine productionFootnote 57 . Although zoster vaccine contains the same components as the varicella vaccine Varivax® (Merck), it has 14-fold or higher virus concentration (≥19,400 plaque forming units per dose).

RZV combines an antigen (lyophilized recombinant varicella zoster virus surface glycoprotein E, VZV gE) and adjuvant system (AS01B). This adjuvant system is composed of liposomes containing two immunostimulants (3-O-desacyl-4’-monophosphoryl lipid A [MPL]) and Quillaja saponaria Molina, fraction 21 (QS-21)Footnote 58 and has been designed to enhance the humoral immune response as well as induce a high cellular immune response to help address the natural age-related decline in immunity (immunosenescence). Similar adjuvant systems (combinations of immunostimulatory molecules to enhance protection compared to aluminum salts), are present in two licensed vaccines in Canada (AS03 in pre/pandemic vaccine Arepanrix™ H5N1; and AS04 in human papillomavirus vaccine, Cervarix™)Footnote 59 , as well as vaccines currently in clinical trials. RZV is the first vaccine authorized in Canada that includes the AS01B adjuvant system, which is also being explored in candidate malaria vaccines.

Characteristics of the HZ vaccines currently authorized for use in Canada are summarized in Table 4.

Table 4: Comparison of Herpes Zoster Vaccines Authorized for Use in Canada
Product Zostavax®IIFootnote a Shingrix®Footnote b
Manufacturer Merck Canada Inc GlaxoSmithKline Inc
Date of authorization in Canada 2008 (Zostavax®) – no longer available in Canada
2011 (Zostavax®II)
October 2017
Type of vaccine Live attenuated Recombinant subunit
Composition Active ingredient: Oka/Merck strain of VZV developed through serial passages in tissue culture.
Other ingredients: 31.16 mg of sucrose, 15.58 mg of hydrolyzed porcine gelatin, 3.99 mg of sodium chloride, 0.62 mg of monosodium L-glutamate, 0.57 mg of sodium phosphate dibasic, 0.10 mg of potassium phosphate monobasic, 0.10 mg of potassium chloride; residual components of MRC-5 cells including DNA and protein; and trace quantities of neomycin and bovine calf serum.
VZV glycoprotein E recombinant (protein found on VZV) 50 mcg
Powder (gE): dipotassium phosphate, Polysorbate 80, sodium dihydrogen phosphate dehydrate, sucrose.
Adjuvant: AS01B (liposome-based) containing 50mcg plant extract Quillaja saponaria Molina fraction 21 (QS-21) + 50 mcg 3-O-desacyl-4’-monophosphoryl lipid A (MPL) from Salmonella minnesota combined with 1mg of dioleoyl phosphatidylcholine (DOPC) and 0.25mg cholesterol.
Adjuvant suspension also contains: disodium phosphate anhydrous, potassium dihydrogen phosphate, sodium chloride, water.
Schedule 1 dose 2 doses, 2-6 months apart.
(NACI suggests that a 0, 12 months schedule may be considered to improve coverage of the 2nd dose through simultaneous administration with another vaccine based on an acceptable safety profile of this schedule and robust anti-gE immune response, though it was not non-inferior to a 0, 2-month schedule) Footnote c
Route of Administration Subcutaneous Intramuscular
Indications Prevention of HZ in individuals ≥ 50 years Prevention of HZ in individuals
≥ 50 years
Contraindications - History of hypersensitivity to any component of the vaccine, including gelatin and neomycin
- Immunosuppression or immunodeficiency
- Pregnancy
-Known hypersensitivity to the active substance or to any component of the vaccine
Precautions - Breastfeeding - Pregnancy (no data in humans)
- Breastfeeding (no data)
- Immunocompromised individuals (limited data)
Storage Requirements Zostavax®II: Refrigerator – stable
(Zostavax® -- no longer available in Canada: Freezer- stable)
Refrigerator – stable
Footnote a

Merck Canada Inc. PRODUCT MONOGRAPH ZOSTAVAX® II; 2017.

Return to footnote a referrer

Footnote b

GlaxoSmithKline Inc. Product Monograph: Shingrix: Herpes Zoster vaccine; October 2017.

Return to footnote b referrer

Footnote c

Lal H, Poder A, Campora L, Geeraerts B, Oostvogels L, Vanden Abeele C, et al. Immunogenicity, reactogenicity and safety of 2 doses of an adjuvanted herpes zoster subunit vaccine administered 2, 6 or 12 months apart in older adults: Results of a phase III, randomized, open-label, multicenter study. Vaccine. 2018 https://www.ncbi.nlm.nih.gov/pubmed/29174683;36(1):148-154.

Return to footnote c referrer

IV.2 Efficacy and Effectiveness

IV.2.1 Efficacy and effectiveness of LZV in the general population

There were 14 studies that assessed single-dose live zoster vaccine efficacy (VE) and effectiveness in the general population. Of these, 3 were good quality studies and 11 were rated as fair quality (Refer to Summary of Evidence Tables, Appendix A).

Efficacy of LZV in preventing HZ among adults 50-59 years of age was reported in a large RCT involving over 22,000 individualsFootnote 61 . Within 1.5 years of immunization, VE was estimated to be 69.8% (95% CI: 54.1%-80.6%). Lower vaccine effectiveness within one year of immunization (50.34% [95% CI: 36.01-51.55%]) in this age group was reported following an analysis of observational dataFootnote 62.

While comparable protective effects against incident HZ were reported in adults 60-69 years of age, a decline in vaccine effectiveness was generally observed with age. In the largest clinical trial that assessed vaccine protection in adults over 60 years of age, three-year efficacy was highest in adults less than 70 years of age (63.9% [95% CI: 55.5%-79.9%] vs. 37.6% [95% CI: 25%-48.1%] in adults 70 years of age and olderFootnote 37 Footnote 63  (overall trial VE 51.3% [95% CI: 44.2%-57.6%]). Although the sample population from the shingles prevention efficacy study (Department of Veterans Affairs Collaboration) might not provide a complete representation of the general population, the estimates were consistent with observational studies in which three-year effectiveness ranged from 48% (95% CI: 39%-56%) to 55% (95% CI: 52%- 58%)Footnote 62 Footnote 64 Footnote 65 Footnote 66 Footnote 67 Footnote 68  for adults over 60 years of age and from 33% (95% CI: 32%-35%) to 49.8% (95% CI: 46.6%-52.8%) for adults 70 years of age and older. In addition to the observed waning of protection with age, reviewed studies also reported continuous declines in effectiveness over time, with little or no protection observed beyond 6 years post-immunizationFootnote 61 Footnote 66 .

Immunization with LZV was also found to be protective against PHN and recurrent HZ. In clinical trials, three year effectiveness against PHN was reported to be 65.7% (95% CI: 20.4%-86.7%) in adults 60-69 years of age and 66.8% (95% CI: 43.3%-81.3%) in adults 70 years of age and olderFootnote 37 Footnote 63 . These estimates were similar to those reported in observational studiesFootnote 68 Footnote 70 . In individuals with previous HZ, protection within three years of immunization was only observed among adults less than 70 years of age (61% [95% CI: -3.45%-95%]), but not in those 70 years of age and older (-0.05% [95% CI: -1.09%-70%Footnote 69 ]).

IV.2.2 Efficacy and effectiveness of RZV in the general population

Estimates of RZV VE (two doses) were available from two pivotal clinical trials that recruited over 28,000 adults over 50 years of age. Both were rated as good quality studiesFootnote 71 Footnote 72  (See Summary of Evidence Tables). Among adults 50 to 59 years of age, three year efficacy was estimated to be 96.6% (95% CI: 89.6%-99.3%) for incident HZ and 100% (95% CI: 40.8%-100%) against PHN. In adults 60-69 years of age, efficacy against HZ was reported to be 97.4% (95% CI: 90.1%-99.7%). For adults 70 years of age and older, using pooled data from both studies, VE against incident HZ was estimated to be 91.3% (95% CI: 86.8%-94.5%). For adults 80 years of age and older, using pooled data from both studies, VE against incident HZ was estimated to be 91.4% (95% CI: 80.2%-97.0%).  Although a decrease in efficacy in this age group was observed over a four-year post immunization period, differences between year one (97.6% [95% CI% 90.9%-99.8%]) and year four (84.7% [95% CI: 69%-93.4%]) were not found to be statistically significant. Overall VE against PHN was 91.2% (95% CI: 75.9-97.7) in adults 50 years of age and older, and 88.8% (95% CI: 68.7%-97.1%) in adults 70 years of age and older.

IV.3 Immunogenicity

Traditionally, studies of HZ vaccines have used anti-VZV antibodies to assess humoral immunity and a variety of cellular assays to assess CMI. More recently, to assess humoral immunity, pivotal trials of the RZV vaccine have specifically measured anti-gE antibodies in addition to anti-VZV antibodies. Some studies have reported only anti-gE antibodies. Equivalency between anti-VZV and anti-gE antibody responses following vaccination or infection has not been established in the literature, but manufacturer data on file report good correlation between anti-gE and anti-VZV antibodies.

There are currently no established humoral and/or cellular correlates of protection against herpes zoster or PHN among patients who have had primary VZV infection or prior vaccinationFootnote 73 Footnote 74 . Therefore, all studies evaluating the immunogenicity of zoster vaccination must be interpreted with caution. It does appear that CD4+ and CD8+ cells play a central role in preventing VZV reactivationFootnote 71 Footnote 75 ; and one studyFootnote 76  has suggested that CMI (as measured by IFN-gamma producing T-cells) at the time of zoster onset was associated with reduced disease severity and reduced likelihood of PHN, whereas humoral immunity (as measured by anti-VZV antibodies) was notFootnote 77 .

Many immunogenicity studies reviewed did not include control groups where patients did not receive any vaccination, and the overall quality of evidence for most studies was fair or poor (See Summary of Evidence Table, Appendix B).

IV.3.1 Immunogenicity of LZV in the general population

All reviewed studies used LZV (there were no other live vaccines in this population group). Studies generally all assessed humoral immunity through anti-VZV antibody levels, and many also assessed CMI through VZV-specific IFN-gamma spot-forming cells with ELISPOT or through responder cell frequency assays measuring counts per minute of H3-thymidine incorporation in peripheral blood mononuclear cells stimulated with VZV. LZV was found to be immunogenic (i.e. there were significant increases in antibody or T-cell levels) in all studies.

The duration of follow-up ranged from 4 weeks to up to 3 years (except for studies looking at those who were receiving a booster shot). In general, immunity as measured by antibody levels and T-cell counts peaked at 6 weeks and declined afterwards. One studyFootnote 76 , rated as good quality, suggested that CMI (as measured by IFN-gamma positive T-cells) at the time of zoster onset was associated with reduced disease severity and likelihood of PHN, whereas humoral immunity (as measured by anti-VZV antibodies) was not. Another study, rated as good quality, suggested that the rise in antibody titres up to 6 weeks post-vaccination was correlated with VE whereas antibodies levels after 6 weeks was notFootnote 77 .

Immune responses to LZV appeared to decline with age.One studyFootnote 78 , rated as good quality, suggested that the humoral response among those 50-59 years old was slightly higher than among those 60 years and older. Another fair quality study suggested that the CMI response was higher in those 60-69 years of age compared to those over 70 years of age.

In terms of the mechanism of administrationFootnote 79 , one fair quality study suggested that intradermal administration of LZV was associated with higher and more persistent increases in humoral immunity than traditional subcutaneous administration. Another fair-quality study did not find any differences in intramuscular versus subcutaneous administrationFootnote 80 . In terms of the number of doses required, two studiesFootnote 81 Footnote 82  suggested there were no differences in immunogenicity between 1 and 2-dose administrations of LZV. Regarding booster doses, one fair quality and one poor quality study assessed the effect of a booster dose among those older than 70 years of age compared to those who were being vaccinated for the first time. For those receiving boosters, there appeared to be a greater CMI response but no difference in humoral responseFootnote 83 Footnote 84 .

IV.3.2 Immunogenicity of RZV in the general population

Studies reviewed on immunogenicity of RZV generally all assessed humoral immunity through anti-gE antibody levels and many also assessed CMI, usually through CD4+ T-cells with at least two activation markers (including expression of IFN-gamma, IL-2, TNF-alpha, or CD40 ligand). RZV was found to be immunogenic in all studies.

With respect to duration of protection, one study available only as an abstract at the time of NACI deliberations found that measures of humoral and cell mediated immunity were still elevated from baseline at 9 years post-vaccination, with anti-gE and T-cell levels plateauing between years 4 and 9 post-vaccinationFootnote 85 . Another study, rated as poor quality, found that while humoral and CMI peak at month 3, anti-gE and CD4+ T-cells were elevated from baseline at 72 months post-vaccinationFootnote 86 .

Levels of immunity did not appear to vary by age. One study rated as poor quality, found that similar levels of CMI and humoral immunity were elicited across those aged 50-59, 60-69, and 70 years or overFootnote 105 . Among patients with prior zoster infection, the subunit vaccine was found to generate a robust humoral response that was similar for all age groups over 50Footnote 87  years in another study rated as poor quality. This study had limitations that precluded definitive evaluation of a prior episode of HZ.

One abstract (of a study which has since been published) suggested that prior vaccination with live vaccine at least 5 years prior did not appear to change the baseline measures of humoral or cell mediated immunity while vaccination with RZV led to a similar response in patients with and without a prior history of vaccination with live zoster vaccineFootnote 88 . Similarly, one study rated as poor quality demonstrated that among patients with a history of herpes zoster, RZV elicited a robust humoral immune response that was similar for all age groups over 50Footnote 87  years of age.

IV.3.3 Head-to-head comparisons of LZV versus RZV

Only one study by Weinberg et al. has compared immunogenicity between the live and subunit vaccines in a head-to-head fashion, and it is currently available only as an abstract that could not be rated for qualityFootnote 89 . This study suggests that there is a higher memory CD4+ and CD8+ response among those receiving RZV than those receiving the live vaccine. These results suggest that the RZV is more immunogenic than the live vaccine.

IV.4 Vaccine Administration and Schedule

IV.4.1 Vaccine administration and schedule for LZV

LZV is given as a subcutaneous injection, preferably in the deltoid region. It should be reconstituted immediately upon removal from the refrigerator. Please see the product monograph for details on reconstitution of the vaccine prior to administration.

Individuals should receive a single dose consisting of the entire content of the reconstituted vial (approximately 0.65 mL).

The need for a booster dose following primary vaccination has not been established.

IV.4.2 Vaccine administration and schedule for RZV

RZV is given as an intramuscular injection, preferably in the deltoid muscle. The vaccine is supplied as a vial of lyophilized recombinant varicella zoster virus surface glycoprotein E (VZV gE) which is reconstituted at the time of use with the accompanying vial of AS01B adjuvant suspension. Please see the product monograph for details on reconstitution of the vaccine prior to administration.

The primary vaccination schedule is a two dose series (0.5 mL/dose) with the second dose administered between 2 and 6 months after the first dose. Two doses of RZV administered 2 months apart have been shown to be immunogenic and efficacious against HZ. Immunogenicity studies that looked at alternative dosing schedules demonstrated that 0, 6months was non-inferior to 0, 2 months. However, non-inferiority of the 0, 12 months schedule was not demonstrated. The small study of 346 participants found that two doses of RZV elicited robust anti-gE immune responses in adults ≥50 years of age with 0-2, 6 and 12- month schedules with no safety concerns identified in any of the three schedules. Immune responses to RZV administered at months 0 and 6 were non-inferior to those elicited by a 0, 2-month schedule. Non-inferiority in terms of anti-gE humoral immune responses 1 month post-dose 2 was not demonstrated for the 0, 12-month schedule. This may have been due to a small number of participants with markedly lower anti-gE antibody levels post-vaccination, not observed in the other groups. No explanation for the low anti-gE antibody levels post-vaccination of these 9 participants in the 0, 12-month schedule could be identified by the investigators.

While the recommended interval between two doses of RZV is 2-6 months, a minimum interval between two doses of RZV (below which the second dose is considered invalid and should be repeated) of 1 month (4 weeks) should be maintained. Initial results from studies in immunocompromised populations using a one month interval between doses of RZV suggest no safety, immunogenicity, or efficacy concernsFootnote 61 . If an interval longer than 6 or 12 months after the first dose has elapsed, the vaccine series need not be restarted, however individuals may remain at risk of HZ during a longer than recommended interval between doses 1 and 2.

The need for a booster dose following the primary vaccination schedule has not been established.

IV.5 Serological Testing

Serologic testing is not recommended before or after HZ vaccination. There are no accepted correlates of protection following immunization against varicella and zoster using tests for humoral antibody or cell mediated immunity. HZ vaccination of healthy individuals who are VZV susceptible is not associated with any known safety risk. If, in the rare circumstance, an individual aged 50 years or older is known to be susceptible to VZV, two doses of univalent varicella vaccine should be administered rather than HZ vaccineFootnote 90. Immune protection against HZ cannot be readily tested therefore there is no role for post-immunization testing of antibody titres.

IV.6 Storage Requirements

IV.6.1 Storage requirements for LZV

During shipment, LZV must be maintained at a temperature between -50°C and +8°C to ensure that there is no loss of potency. LZV should be stored in a refrigerator at a temperature of +2°C to +8°C or colder until it is reconstituted for injection. The diluent should be stored separately at room temperature (+20 to +25°C) or in the refrigerator (+2 to +8°C). Before reconstitution, it should be protected from light. After reconstitution, the vaccine should not be frozen. If reconstituted vaccine is not used within 30 minutes, it should be discardedFootnote 57 .

IV.6.2 Storage requirements for RZV

The lyophilized gE vial and the adjuvant solution vial should both be stored in a refrigerator at a temperature of +2°C to +8°C in the original package (to protect from light). Neither vial should be frozen. After reconstitution, the vaccine should be used promptly. If this is not possible, it should be stored in a refrigerator at a temperature of +2°C to +8°C. If reconstituted vaccine is not used within 6 hours, it should be discardedFootnote 58 .

IV.7 Simultaneous Administration with Other Vaccines

Simultaneous administration of vaccines can be beneficial by decreasing the required number of patient visits and increasing compliance with recommended vaccines.

IV.7.1 Simultaneous administration of LZV with other vaccines

In general, live vaccines given by the parenteral route may be administered concomitantly with other vaccinesFootnote 91 . For concomitant parenteral injections, different injection sites and separateFootnote 91  needles and syringes should be used. If not administered concomitantly, a minimum interval of 4 weeks should be maintained between two live parenteral vaccines.

In 2014, NACI recommended that pneumococcal 23-valent polysaccharide vaccine (Pneu-P-23) may be administered concomitantly with LZV at a different body injection site, based on good evidence from a study that showed no increase in cases of HZ in those who received concomitant vs. sequential administration of vaccinesFootnote 69 .

Concomitant administration of LZV with quadrivalent influenza vaccine has been found to be non-inferior according to pre-specified criteria (GMT ratio 0.87) to non-concomitant administration and led to an anti-VZV antibody GMFR of 1.9Footnote 92 .

Among individuals who received LZV together with an inactivated influenza or Pneu-23 vaccine, co-administration did not results in an increase in AEs compared to separate vaccine administration.

IV.7.2 Simultaneous administration of RZV with other vaccines

In general, inactivated vaccines may be administered concomitantly with, or at any time before or after, other inactivated vaccines or live vaccines protecting against a different disease. For concomitant parenteral injections, different injection sites and separate needles and syringes should be usedFootnote 93 Footnote 94 .

A study of concomitant administration of RZV with quadrivalent influenza vaccine reveals no evidence of safety concerns or interference in immune responses for either vaccineFootnote 94 . Concomitant administration was found to be non-inferior (GMC ratio control to concomitant was 1.08) for both RZV and the influenza vaccine as measured by GMC ratios at 1 month post-vaccination.

Studies of simultaneous administration with Pneu-P-23 and Boostrix ® (Tetanus, low concentration diphtheria and acellular pertussis vaccine) are ongoing. The safety and efficacy of administration of two adjuvanted vaccines (e.g., RZV and adjuvanted influenza vaccine Fluad®) either concomitantly or at other intervals, have not been evaluated.

IV.8 Adverse Events

IV.8.1 Adverse events with LZV in the general population

In total, 21 studies reported on short and long term vaccine safety following the administration of LZV of different potencies. Of these 11 were good quality studies, 8 were fair quality studies and 2 were poor quality studies (See Summary of Evidence Tables, Appendix C).

In adults less than 60 years of ageFootnote 61 Footnote 95 , injection site reactions were the most commonly reported AEs, the majority of which (>95%) were rated mild or moderate in intensity. In the pivotal clinical trial in which over 11,000 adults 50-59 years of age received LZV, injection site AE were reported by 63.9% of vaccine recipients (49.5% [95% CI: 48.4%–50%] risk difference compared to placebo). In the same trial, vaccine-related systemic AEs within one to 42 days following immunization were reported in 6.7% of individuals (2% [95% CI: 1.4%–2.6%] increased risk of systemic AEs compared to placebo). Among individuals less than 60 years of age, only one vaccine-related AE was reported in the reviewed studies.

Compared to adults less than 60 years of ageFootnote 63 Footnote 79 Footnote 80 Footnote 81 Footnote 82 Footnote 95 Footnote 96 Footnote 97 Footnote 98 Footnote 99 Footnote 100 , adults 60 years of age and older generally reported fewer injection site AEs. The majority (>95%) of these events were rated mild or moderate in intensity and were of less than 2 days duration. In observational studies, erythema, pain, tenderness, and swelling were the most common symptoms reported by one quarter to one third of individuals. In a pivotal clinical trial that assessed vaccine safety in over 3,300 adults over 60 years of age, injection site AEs were reported by 56.6% of study participants 60-69 years of age (37.7% [34.6%-40.6%] risk difference compared to placebo), and 39.2% of study participants 70 years of age and older (25.4% [22.5%-28.4%] ) risk difference compared to placebo).

In adults 60 years of age and older, systemic vaccine-related AEs within 42 days following immunization were reported by less than 8% of individuals. In a pivotal clinical trial that assessed vaccine safety in over 3,300 adults, vaccine-related systemic events were reported by 6.3% of study participants (1.4% [95% CI: 0.3%-2.5%] risk difference compared to placebo). Vaccine-related SAEs in this age group were rarely reported, with only an increase in the rate of allergic reactions being observed among LZV recipients. There was no increase in vaccine-related SAEs (e.g. measured by an increase in hospitalization and emergency department admission rates) reported in the reviewed observational studiesFootnote 46 Footnote 69 Footnote 101 Footnote 102 . Studies that assessed the safety of LZV administration in individuals over 60 years of age with prior HZFootnote 83 Footnote 103 Footnote 104  reported similar rates of AEs as those reported in previously LZV unimmunized individuals.

IV.8.2 Adverse events with RZV vaccine in the general population

Vaccine safety of RZV vaccine was investigated in seven randomized studiesFootnote 71 Footnote 72 Footnote 86 Footnote 105 Footnote 106 Footnote 107 Footnote 108 . The largest studies were two pivotal trials in which over 14,000 adults over 50 years of age received two doses of RZV vaccine. Of studies identified through the literature search, 4 were good quality studies and 3 were rated as fair quality studies (See Summary of Evidence Tables, Appendix C).

Injection site AEs were commonly reported by participants, with approximately 80% reporting injection-site pain and approximately 30% reporting redness at the site of injection. In a pivotal trial that assessed vaccine safety in over 15,400 adults 50 years of age and older, Grade 3 injection site reactions (AEs that were severe enough to prevent normal activities) were reported by 9.5% (96% CI: 8.7%–10.4%) of vaccine recipients compared to 0.4% (95% CI: 0.2%–0.6%) of placebo recipients. Among adults 70 years of age and older, Grade 3 injection site AEs were reported by 8.5% (95% CI: 6.2%–11.3%) of vaccine and 0.2% (95% CI: 0–1.1%) of placebo recipients. Pain was generally more commonly reported by participants less than 70 years of age compared to those who were 70 years of age and older. The median duration of reported injection site AEs was 2 to 3 days.

The most frequently reported systemic AEs in clinical trials were fatigue and myalgia (reported by up to half of vaccine recipients) as well as headache (reported by up to 40% of vaccine recipients). In a pivotal trial that assessed vaccine safety in over 15,400 adults over 50 years of age, Grade 3 systemic reactions were reported by 11.4% (95% CI: 10.5%–12.4%) of vaccine recipients compared to 2.4% (95% CI: 2%–2.9%) of placebo recipients. In adults 70 years of age and older, Grade 3 systemic AEs were reported by 6% (95% CI: 4.1%–8.4%) of vaccine and 2% (95% CI: 1–3.6%) of placebo recipients. Systemic events that included Grade 3 reactions were more frequently reported after the receipt of the second RZV vaccine dose. The median duration of reported systemic AEs was 1 to 2 days.

Overall, the rates of SAEs in the reviewed studies were similar between the intervention and control groups, with none of the SAEs considered to be vaccine-related by the study investigators based on the plausibility and time since vaccination. The rates of reported vaccine-related SAEs and immune-mediated diseases were similar in the vaccine and the placebo group up to 9 years post immunization.

IV.9 Contraindications and Precautions

IV.9.1 Contraindications and precautions for LZV

LZV is contraindicated in individuals with a history of hypersensitivity to any component of the vaccine, including gelatin, or an anaphylactic/anaphylactoid reaction to neomycin (present in trace quantities in the vaccine).

As it is a live vaccine and may result in disseminated disease in individuals who are immunosuppressed or immunodeficient, LZV is contraindicated in individuals with primary and acquired immunodeficiency states. It is not contraindicated in those receiving topical or inhaled corticosteroids, low-dose systemic corticosteroids, or in those receiving corticosteroids as replacement therapy (e.g. for adrenal insufficiency). LZV is contraindicated in active untreated tuberculosis.

LZV is contraindicated in pregnancy, and pregnancy should be avoided for three months after vaccine administration. While no studies have been conducted in this population, naturally occurring VZV infection is known to cause fetal harm in some cases.

Caution should be taken when LZV is administered to those who are breastfeeding as it is not known whether VZV is secreted in breast milk. In the presence of fever >+38.5°C, deferral of vaccination should be consideredFootnote 57 .

IV.9.2 Contraindications and precautions for RZV

RZV is contraindicated in individuals with a known hypersensitivity to any component of the vaccine.
This vaccine should be used with precaution in those who are pregnant (as there are no data on its use in this population), or breastfeeding (as the effect on breast-fed infants of vaccination in those who are breastfeeding has not been studied). The safety and efficacy in individuals younger than 18 years of age has not been studied, and there are limited data on its use in immunocompromised individuals 50 years of age and olderFootnote 58 .

V. Economics

V.1 Economic model description

To estimate the cost-effectiveness of Herpes Zoster (HZ) vaccination, a Cost Utility Analysis (CUA) was adapted from Brisson et al 2008Footnote 11  to compare the clinical and economic outcomes of different vaccination options. In the aforementioned study the authors compared LZV to no vaccination in a cohort through different phases of HZ. In this study the model was extended to include vaccination with RZV. Therefore, this CUA 1) evaluated the cost-effectiveness of vaccination against HZ using one of the two vaccines (LZV and RZV) compared to the absence of vaccination and 2) compared the cost-effectiveness between LZV and RZV. In brief, the model follows a cohort of individuals through different phases of HZ. As depicted in Figure 4, different HZ disease phases are represented by the boxes and arrows indicate the transition along the disease. Individuals in the cohort start off without HZ and may develop HZ and progress to PHN. Death is also associated for each health state. Cases of HZ and PHN are characterized according to their pain severity: no pain, mild/moderate pain, and severe pain. The model compares the incidence of HZ and PHN, healthcare resource use, costs and Quality Adjusted Life Years (QALY) lost to HZ and PHN between cohorts of vaccinated and unvaccinated individuals.

The study perspective is that of the health care system, which includes all direct medical costs of treating the disease. The societal perspective which considers costs outside of the health care system, such as lost productivity, was not examined because these costs fall outside of vaccination programs and the health care system. The base case has vaccination of 65-year-olds. Additional analyses also examined vaccination between 50 and 85 years of age. The cohort is modelled over a lifetime with costs and benefits discounted at 3%.

Figure 4: Model outcomes associated with HZ
Figure 4
Figure 4 - Text description

Figure 4 shows different HZ disease phases. Each disease phase is depicted by a box. There are boxes to represent phases for No HZ, HZ, PHN and Death. Tryearsition from one disease phase to another is shown with arrows. At the phase of No HZ, the arrows show that disease can tryearsition to HZ or PHN or Death. At the phase of HZ, the arrows show that disease can tryearsition to PHN or Death or revert to No HZ. At the phase of PHN the arrows show that disease can tryearsition to Death or revert to No HZ. Reverting to No HZ occurs after treatment of the disease.

V.2 Model parameters: epidemiological, vaccine characteristics, and economic

The model parameters can be classified by the epidemiology, vaccine characteristics and economics (see Table 5). Vaccine characteristics on the efficacy for RZV and LZV were based on clinical trialsFootnote 61 Footnote 63 Footnote 71 Footnote 72 . Epidemiological data on age specific incidence of HZ and age specific incidence of hospitalization was obtained from administrative databases in QuebecFootnote 109 Footnote 110  and a literature review. Articles identified in the literature review are from OntarioFootnote 29 , BCFootnote 26 , and AlbertaFootnote 27 . The study considered the minimum and maximum values of these data sources and the base case is the mean of the minimum and maximum values identified. Other data on the length of stay, consultations per case, and PHN per case were derived from the literatureFootnote 11 Footnote 24 Footnote 63 Footnote 111  and MedEchoFootnote 110  and RAMQFootnote 109 . Economic data on the costs were inflated to 2015 Canadian dollars and obtained from the literature. Utility weights for each health state were used in the estimation of QALYs. These data were collected from the Monitoring and Assessing Shingles Through Education and Research (MASTER) studyFootnote 112  and from Brisson et alFootnote 11 .

Table 5: Model Parameters
Parameters Data Source
Epidemiology and health care resource use
Incidence of HZ RAMQ 2001-2015, Brisson et al 2008, Tanuseputro et al 2011, Marra et al 2016, Russell et al 2014.
Hospitalizations MedEcho 2001-2015, Brisson et al 2008, Tanuseputro et al 2011, Brisson et al 2001.
Consultations (per case) RAMQ 2001-2005, Brisson et al 2008, Najafzadeh et al 2009
Length of Stay (days) MedEcho 2001-2015, Brisson et al 2001, Najafzadeh et al 2009
Case Fatality Brisson et al 2008
PHN (per case) Oxman et al 2005, Brisson et al 2008
Vaccine Characteristics
Shingrix® (RZV)  
ZOE-50 Lal et al 2015
ZOE-70 Cunningham et al 2016
Zostavax® (LZV)  
SPS Oxman et al 2005
STPS Schmader et al 2012
Economic
Unit costs (Canadian inflated to $2015)  
HZ GP consultation Friesen et al 2017Footnote a, Najafzadeh et al 2009, Brisson et al 2008
HZ Hospitalization Friesen et al 2017Footnote a, Najafzadeh et al 2009, Brisson et al 2008
Treatment per HZ episode Friesen et al 2017Footnote a, Najafzadeh et al 2009, Brisson et al 2008
Treatment per PHN episode Friesen et al 2017Footnote a, Najafzadeh et al 2009, Brisson et al 2008
Utility weights (QALY estimates) Brisson et al 2008, Drolet et al 2010
Footnote a

Friesen KJ, Chateau D, Falk J, Alessi-Severini S, Bugden S. Cost of shingles: Population based burden of disease analysis of herpes zoster and postherpetic neuralgia. BMC Infect Dis. 2017;17(1).

Return to footnote a referrer

V.2.1 Model parameters: vaccine characteristics

The vaccine characteristics were defined by the VE and waning rate. The VE reflects the proportion of individuals protected following immunization and the degree to which they are protected. The waning rate is the rate at which protection conferred by the vaccine diminishes over time. VE parameter values of the two vaccines were estimated by fitting the age-specific annual incidence of HZ predicted by the model with that observed in the vaccinated arm of the randomized clinical trials using 6 different functions of waning efficacy over time (Linear, 1-Exponential, Power, Exponential, Log, and 1-Power). This method, based on previous modeling studiesFootnote 11 Footnote 113  makes it possible to estimate both the short-term VE and waning efficacy from clinical trials, and explore the uncertainty surrounding the long-term efficacy of the two vaccines. Figure 5 shows the calibration results of the predicted VE to randomized clinical trials data (efficacy against HZ according to age, efficacy against HZ according to the years since vaccination, efficacy against PHN according to age).

Age specific VE parameter values were modelled. At each age RZV had higher VE compared to LZV. For LZV the VE against PHN was estimated to be higher than VE against HZ for individuals older than 70 y ears old (as seen in Brisson et al 2008). For RZV, trials did not show any significant difference in VE against HZ and PHN and the model assumed that both initial VE and waning efficacy were the same for HZ and PHN endpoints. The base case presumes full compliance for the RZV 2-dose series.

Figure 5: Fitted VE to vaccine clinical trial data

A) Efficacy against HZ, by age
Figure 5a
Figure 5A - Text description

Figure 5A shows line graphs depicting the estimated vaccine efficacy by age.

The horizontal axis contains the age at vaccination from age 60 to 85 years old at 5 year age increments.  The vertical axis in the left has the vaccine efficacy in percentage from 0% to 100% at 10% intervals.  

Red lines for RZV show the estimated vaccine efficacy whereas blue lines show LZV.  RZV and LZV each has six lines based on six different estimations of vaccine efficacy.

Along the line graphs for RZV and LZV there are dots and confidence intervals representing the vaccine efficacy from clinical trials for all ages in order to demonstrate the accuracy of the estimated line graphs.

RZV vaccine efficacy for all six estimated lines is similar.  At age 60 years the vaccine efficacy is over 95% and dCSlines to nearly 90% at age 85 years.

LZV vaccine efficacy for all six estimated lines is similar but the rate of dCSline is different after age 75 years.  At age 60 years the vaccine is around 70% and dCSlines to around 10% to 30% at age 85 years.

B) Efficacy against HZ, over time since vaccination
Figure 5b
Figure 5B - Text description

Figure 5B shows line graphs depicting the estimated vaccine efficacy over time since vaccination. 

The horizontal axis displays time since vaccination from years 1 to 8 in yearly increments.  The vertical axis in the left has the vaccine efficacy in percentage from 0% to 100% at 10% intervals.  

Red lines for RZV show the estimated vaccine efficacy whereas blue lines show LZV.  RZV and LZV each has six lines based on six different estimations of vaccine efficacy.

Along the line graphs for RZV and LZV there are dots and confidence intervals representing the vaccine efficacy from clinical trials in years 1 to 4 in order to demonstrate the accuracy of the estimated line graphs.  RZV vaccine efficacy for all 6 lines is similar from years 1-4, in which the vaccine efficacy remains around 90%.  After the fourth year, five out of six estimated lines remain similar, showing vaccine efficacy between 70 to 85% after 8 years. Notably, the sixth estimated lines dCSlines all the way down to  around 10% efficacy after 8 years post-vaccination.

LZV vaccine efficacy for all six estimated lines is similar but differentiate after the 5-year mark. The vaccine efficacy dCSreases from  around 60% to 40% within the first 5 years, after which the lines reach a maximum of  around 40% and a minimum of  10% at the 8-year mark, with the remaining lines in between those values.

C) Efficacy against PHN, by age
Figure 5c
Figure 5C - Text description

Figure 5C shows line graphs depicting the estimated vaccine efficacy against PHN by age. 

The horizontal axis contains the age at vaccination from age 60 to 85 years old at 5 year age increments.  The vertical axis in the left has the vaccine efficacy in percentage from 0% to 100% at 10% intervals.  

Red lines for RZV show the estimated vaccine efficacy whereas blue lines show LZV.  RZV and LZV each has six lines based on different estimations of vaccine efficacy.

Along the line graphs for RZV and LZV there are dots and confidence intervals representing the vaccine efficacy from clinical trials for all ages in order to demonstrate the accuracy of the estimated line graphs.

RZV vaccine efficacy for all six estimated lines is similar from 90% to nearly 100% for ages 60-80.  At age 80 years the vaccine efficacy around 90% remains constant for 4 out of 6 estimated lines, whereas two lines show a dCSrease in efficacy reaching near 75% at age 85 years. LZV vaccine efficacy for all six estimated lines are similar, exhibiting a slow but steady dCSrease from around 75% efficacy at age 60 years, down to  around 65% at age 85.

V.2.2 Model parameters: epidemiological and health care resource use estimates

Parameters for epidemiology and health care resource use are presented in Table 6. For all parameters, the parameters from Brisson et al 2008 were examined and updated with literature reviews and specific analysis of available data sources. Parameters on the incidence, consultations, hospitalizations and deaths from HZ were updated through a systematic review and data extraction from Quebec administrative databases (Regie de l’Assurance Maladie du Quebec (RAMQ) and hospitalization database Med-Echo). The parameters in Table 6 represent the minimum and maximum values identified in the literature and from an unpublished Quebec administrative database analysis. The base case was assumed to be the mean of the minimum and maximum values. PHN was defined as a clinically significant pain persisting more than 90 days after rash onset. The proportion of HZ cases developing PHN used the minimum and maximum values from Brisson et al 2008, which were based on data from the Shingles Prevention StudyFootnote 63  and Edmunds et al 2001Footnote 114 . Case fatality values were based on studies from England and Wales given the lack of Canadian data of HZ related mortality.

Table 6: Epidemiological parameters
Age Range Base Min Max Reference
Herpes zoster incidence (per 1,000 person-year)
50-54 years 3.8 3.5 4.2 RAMQ 2001-2015
Brisson et al 2008 Tanuseputro et al 2011
Russell et al 2014
Marra et al 2016
55-64 years 6.0 5.1 6.9
65-74 years 8.6 7.3 10.0
75+ years 9.9 8.0 11.8
Hospitalizations (per case)
50-54 years 1.1% 0.5% 1.6% MedEcho 2001-2015
Brisson et al 2008
Tanuseputro et al 2011
Brisson et al 2001
55-64 years 1.6% 0.7% 2.5%
65-74 years 3.3% 1.5% 5.1%
75+ years 9.9% 4.1% 15.6%
Consultations (per case)
50-54 years 1.7 1.0 2.4 RAMQ 2001-2015
Brisson et al 2008
Najafzadeh et al 2009
55-64 years 2.0 1.0 2.9
65-74 years 2.3 1.0 3.5
75+ years 2.6 1.0 4.2
Length of Stay (days)
50-54 years 9.3 5.9 12.7 MedEcho 2001-2015
Brisson et al 2001
Najafzadeh et al 2009
55-64 years 11.1 6.2 15.9
65-74 years 12.6 8.3 16.9
75+ years 18.0 12.4 23.6
Case-fatality
50-54 years 0.000% 0.000% 0.002% Brisson et al 2008
55-64 years 0.000% 0.000% 0.002%
65-74 years 0.012% 0.012% 0.083%
75+ years 0.076% 0.040% 0.083%
PHN risk (per case)
50-54 years 9.4% 6.9% 11.9% Oxman et al 2005
Brisson et al 2008
55-64 years 9.4% 6.9% 11.9%
65-74 years 26.0% 18.5% 33.4%
75+ years 27.7% 22.0% 33.4%

V.2.3  Model parameters: economics

Parameter values for the economic inputs in the model were classified according to costing information and QALY estimates derived using utility weights (Tables 7 and 8). Costs represented expenditures on health care utilization to treat HZ using the mean costs from collected data sources and adjusted to 2015 according to the Consumer Price Index. This includes general practitioner (GP) consultation, hospitalization, prescription costs and costs of treating PHN based on data from the literature—see Table 7. Vaccine costs were both the price plus administrative costs. These costs considered the uncertainty of prices for RZV and LZV in publicly funded programs and also the variability of costs to administer a vaccine across provinces and territories. In Canada, the publicly available prices are the “list price”, or retail price, which are both typically higher than negotiated prices with provincial and territorial vaccine programs through the bulk procurement program or individual contracts with jurisdictions. Given the uncertainty and confidentiality of negotiated prices and the variability in administrative costs, the base case instead investigated vaccine costs of $140 and $200 (price plus administration). Utility weights were used in the estimation of QALYs. These weights are anchored from 0 to 1 where 0 represents death and 1 is full health (or no disability). Weights valued between the anchors represent morbidity at a different health capacity. The QALYs lost per case (whether HZ or PHN) is the difference in the utility weights with and without disease over time. Utility weight data were obtained from the MASTER studyFootnote 112  and Brisson et al 2008Footnote 11 . The base case was assumed to be the mean of the minimum and maximum—see Table 8.

Table 7: Economic cost parameters
Parameters Costs (2015 $CAN) Reference
Base Case Scenario Min Max
Hospitalizations $876 $473 $1,419 Friesen et al 2017Footnote a
Najafzadeh et al 2009
Brisson et al 2008
Consultations $27 $23 $108 Friesen et al 2017Footnote a
Najafzadeh et al 2009
Brisson et al 2008
Treatment per HZ episode $129 $52 $244 Friesen et al 2017Footnote a
Najafzadeh et al 2009
Brisson et al 2008
Treatment per PHN episode $1,515 $924 $2,591 Friesen et al 2017Footnote a
Najafzadeh et al 2009
Brisson et al 2008

Min: Minimum values identified in literature; Max: Maximum values identified in literature; Base Case: Values from Friesen et al 2017

Footnote a

Friesen KJ, Chateau D, Falk J, Alessi-Severini S, Bugden S. Cost of shingles: Population based burden of disease analysis of herpes zoster and postherpetic neuralgia. BMC Infect Dis. 2017;17(1).

Return to footnote a referrer

Table 8: QALYs lost (utility values)
Age Range QALYs lost (utility values) Reference
Base Case Scenario Min Max
HZ
50 to 59 years old 0.009 0.006 0.012 Brisson et al 2008
Drolet et al 2010
60 to 69 years old 0.010 0.006 0.013
70+ years old 0.010 0.007 0.014
PHN
50 to 59 years old 0.041 0.032 0.052 Brisson et al 2008
Drolet et al 2010
60 to 69 years old 0.192 0.103 0.290
70+ years old 0.234 0.191 0.290

Min: Minimum values identified in literature; Max: Maximum values identified in literature; Base Case: Values from Friesen et al 2017

V.3 Results

All model estimates were based on 30,000 simulations and presented with the median and 90% Uncertainty Intervals (UI) which show the 5th and 95th percentile of the distribution of simulation results. To obtain these estimates, each parameter was assigned a triangular probability distribution and combinations of these parameter values were drawn using Latin hypercube sampling. The maximum and minimum values of the triangular distribution are the maximum and minimum values identified from the literature, and the median is the base case values found in Tables 6, 7, 8.

V.3.1 Results: Cost-effectiveness

The base case results examined 65 year olds (Figure 6). RZV has median ICERs ranging from cost savings to $6,356 per QALY at different vaccine costs ($100-$200). LZV has higher median ICERs ranging from $7,673 per QALY to $37,249 per QALY and less cost effective than RZV.

Figure 7 displays the results for all age groups at various vaccine costs (price plus administration). Compared to LZV, RZV has lower cost per QALYs for all age groups and vaccine costs and therefore more cost effective than LZV. At ages 65-79, RZV is the most cost-effective compared to other age groups because of higher burden of illness with age (increased risk of hospitalization and PHN per HZ case) and the likeliness that the vaccine will be effective during the years when burden of illness is high (unless VE wanes more quickly than anticipated).

Figure 6: Cost effectiveness of vaccination versus no vaccination (65 year olds)
Figure 6
Figure 6 - Text description
Figure 6: Cost effectiveness of vaccination versus no vaccination (65 year olds)
Age at vaccination/ Vaccine Cost LZV
Percentiles of model predictions
RZV
Percentiles of model predictions
5th 25th Median 75th 95th 5th 25th Median 75th 95th
65 years
100 $ CS CS 7 673 14 224 22 710 CS CS CS CS 11 778
120 $ CS 1 688 13 647 21 334 31 929 CS CS CS CS 18 187
140 $ CS 5 828 19 576 28 434 41 349 CS CS CS 2 922 24 715
160 $ 1 064 9 960 24 486 35 614 50 822 CS CS 488 6 359 31 295
180 $ 4 686 14 139 31 345 42 810 60 345 CS CS 3 414 9 874 37 839
200 $ 8 235 18 344 37 249 49 994 70 059 CS 1 507 6 356 13 433 44 382
Figure 7: Cost effectiveness of vaccination versus no vaccination (for all age groups)
Figure 7
Figure 7 - Text description
Figure 7: Cost effectiveness of vaccination versus no vaccination (for all age groups)
Age at vaccination/ Cost of vaccination LZV
Percentiles of model predictions
RZV
Percentiles of model predictions
5th 25th Median 75th 95th 5th 25th Median 75th 95th
50 years
100 $ CS CS 48 218 126 144 190 174 CS CS CS 40 129 188168
120 $ CS 4 595 65 295 160 411 239 776 CS CS 5 018 54 585 238517
140 $ CS 9 938 82 335 194 883 289 253 CS 288 10 391 68 986 289570
160 $ 3 777 15 269 99 362 229 146 339 041 CS 4 266 15 704 83 534 339960
180 $ 7 995 20 713 116 389 263 419 388 706 1 320 8 214 21 128 97 972 390442
200 $ 12 200 26 172 133 416 297 892 438 704 5 067 12 164 26 651 112450 441319
60 years
100 $ CS CS 16 723 32 160 50 672 CS CS CS 2 673 35 736
120 $ CS 3 348 24 494 43 291 66 795 CS CS CS 7 667 48 432
140 $ CS 7 844 32 343 54 540 83 021 CS CS 1 401 12 826 61 003
160 $ 2 621 12 440 40 077 65 819 99 318 CS CS 4 888 17 876 73 565
180 $ 6 458 17 052 47 905 76 965 115 451 CS 2 353 8 431 22 972 86 128
200 $ 10 151 21 691 55 856 88 191 131 697 CS 5 398 11 995 28 126 98 793
65 years
100 $ CS CS 7 673 14 224 22 710 CS CS CS CS 11 788
120 $ CS 1 688 13 647 21 334 31 920 CS CS CS CS 18 187
140 $ CS 5 828 19 576 28 434 41 349 CS CS CS 2 922 24 715
160 $ 1 064 9 960 25 486 35 614 50 822 CS CS 488 6 359 31 295
180 $ 4 686 14 139 31 345 42 810 60 345 CS CS 3 414 9 874 37 839
200 $ 8 235 18 344 37 249 49 994 70 059 CS 1 507 6 356 13 433 44 382
70 years
100 $ CS CS 6 489 11 977 18 662 CS CS CS CS 6 578
120 $ CS 3 517 12 759 19 026 26 835 CS CS CS CS 12 122
140 $ CS 8 287 19 014 26 071 35 096 CS CS CS 1 531 17 638
160 $ 2 884 12 982 25 241 33 217 43 540 CS CS CS 4 794 23 262
180 $ 6 983 17 770 31 446 40 397 51 967 CS CS 2 322 8 142 28 963
200 $ 11 097 22 509 37 651 47 589 60 467 CS 498 5 345 11 513 34 667
75 years
100 $ CS CS 217 6 431 14 717 CS CS CS CS CS
120 $ CS CS 6 649 13 531 22 971 CS CS CS CS 2 327
140 $ CS 5 272 13 078 20 750 31 439 CS CS CS CS 7 122
160 $ CS 11 006 19 604 28 101 40 086 CS CS CS 1 436 12 127
180 $ 4 492 16 696 26 148 35 515 48 764 CS CS CS 5 109 17 214
200 $ 9 457 22 290 32 659 42971 57 628 CS CS 2 260 8 805 22 435
80 years
100 $ CS 1 440 8 414 14 995 24 843 CS CS CS CS 1 238
120 $ CS 8 904 16 492 24 060 35 479 CS CS CS CS 6 616
140 $ 4 739 16 314 24 594 33 231 46 389 CS CS CS 2 807 12 147
160 $ 11 471 23 585 32 758 42 483 57 379 CS CS 1 175 7 203 17 856
180 $ 18 038 30 791 40 952 51 828 68 355 CS CS 5 253 11 661 23 675
200 $ 24 461 38 023 49 162 61 164 79 723 CS 2 717 9 281 16 146 29 630
85 years
100 $ 1 538 12 753 20 428 28 498 41 271 CS CS CS CS 6 854
120 $ 10 580 22 376 31 013 40 526 55 661 CS CS CS 4 826 13 360
140 $ 19 343 31 855 41 575 52 584 70 095 CS CS 4 392 10 394 20 133
160 $ 27 814 41 316 52 256 64 758 84 823 CS 3 158 9 522 16 053 26 970
180 $ 36 051 50 716 62 889 77 032 99 751 CS 8 061 14 643 21 784 34 035
200 $ 44 151 60 056 73 533 89 362 114 693 2 694 12 894 19 800 27 617 41 170

V.3.2 Results: Epidemiology

The number needed to vaccinate (NNV) – the number of people that should be vaccinated to prevent a single case of HZ, PHN, ophthalmic HZ and hospitalization – was calculated as the number of people vaccinated divided by the number of events prevented. Fewer vaccinations were required for RZV compared to LZV across all ages. Figure 8 displays the NNV to reduce a case of HZ, PHN, ophthalmic HZ and hospitalization. At different ages, the NNV is relatively stable for RZV for all outcomes. LZV requires more people to be vaccinated to prevent a case of HZ, PHN and ophthalmic HZ at older ages (≥80 years old). For hospitalization, LZV requires relatively more people to be vaccinated for ages 50-65 and ≥80 years compared to 70-75 year olds.

Figure 8: Number needed to vaccinate to prevent 1 case of HZ, 1 case of PHN, 1 case of ophthalmic HZ and 1 hospitalization
Figure 8
Figure 8 - Text description
Figure 8: Number needed to vaccinate to prevent 1 case of herpes zoster (HZ), 1 case of post-herpetic neuralgia (PHN), 1 hospitalization, 1 death, and 1 ophtalmic HZ according to age (vaccination vs no vaccination)
Age at vaccination LZV
Percentiles of model predictions
RZV
Percentiles of model predictions
5th 25th Median 75th 95th 5th 25th Median 75th 95th
50 years
Herpes zoster 6 6 15 26 28 5 5 7 14 26
PHN 26 37 106 225 341 22 26 36 105 288
Hospitlization 103 162 638 1511 2419 84 108 171 742 2061
Herpes zoster Ophthalmic 34 43 103 173 230 29 36 49 9626 193
60 years
Herpes zoster 9 10 18 26 28 6 7 8 11 21
PHN 31 41 78 116 150 23 27 33 51 128
Hospitlization 119 178 463 771 1136 84 111 149 275 947
Herpes zoster Ophthalmic 56 74 122 168 229 34 43 54 76 150
65 years
Herpes zoster 13 14 21 28 31 6 7 8 10 18
PHN 33 41 64 77 93 23 27 31 38 73
Hospitlization 124 179 335 491 700 82 107 137 191 613
Herpes zoster Ophthalmic 76 102 138 185 285 37 46 57 75 138
70 years
Herpes zoster 21 24 28 39 43 7 9 9 11 19
PHN 42 50 73 83 96 27 31 35 40 73
Hospitlization 133 191 289 374 494 83 106 130 173 385
Herpes zoster Ophthalmic 123 157 196 251 362 43 54 65 85 139
75 years
Herpes zoster 32 35 42 53 63 9 10 11 12 19
PHN 51 62 78 89 102 31 36 40 46 71
Hospitlization 126 172 215 267 378 75 95 116 152 226
Herpes zoster Ophthalmic 171 230 295 386 586 48 61 77 103 161
80 years
Herpes zoster 47 54 75 106 125 11 13 14 15 22
PHN 68 82 97 109 126 40 45 50 57 80
Hospitlization 169 221 269 333 466 95 119 145 184 267
Herpes zoster Ophthalmic 257 365 523 721 1136 60 77 96 125 190
85 years
Herpes zoster 67 80 142 273 380 15 17 18 20 25
PHN 94 110 124 140 164 52 59 66 74 94
Hospitlization 229 290 351 421 604 125 156 188 234 328
Herpes zoster Ophthalmic 377 590 983 1801 3133 79 101 124 159 237

V.3.3 Results: Sensitivity analysis

Univariate sensitivity analyses were performed for the key model parameters (e.g. percentage of HZ cases developing PHN, QALYs lost to PHN). To do so, the model fixed one key parameter value to its minimum or maximum value and varied all other parameters using triangular probability distribution. This procedure was repeated for all key parameters. This was performed at different vaccine costs (price plus administration) of $140 and $200 for both vaccines.

Epidemiological parameters

Key parameters varied in the univariate sensitivity analyses are: percentage of HZ cases developing PHN cases, PHN QALY lost, HZ incidence, hospitalization and percentage of all events among immunocompetent individuals (Figures 9, 10, 11 and 12). A low burden of illness from the minimum parameter values resulted in worse cost effectiveness (more cost per QALY), compared to the base case, because there are fewer cases to prevent. On the other hand, the maximum parameter values demonstrated a higher burden of illness translating to more prevented cases and therefore better cost effectiveness (lower cost per QALY). Nonetheless the magnitude of the ICERs, and conclusions, was not largely different than the base case ICER for both vaccines. However for LZV at $200 (price plus administration) which is more than the retail price and the negotiated price may be lower, the ICER was approximately $50,000 (base case approximately $37,000) when minimum values (lower burden) were used for key epidemiological parameters except hospitalisations.

Economic parameters

Key economic parameters varied were: cost of treatment per PHN episode, hospitalization, consultations, HZ treatment per episode and on the discount rate (Figures 13, 14, 15 and 16). The minimum and maximum values of each parameter resulted in stable median ICERs, and did not change conclusions, compared to the base case for LZV and RZV.

Figure 9: Sensitivity analysis of epidemiological parameters for LZV at $140 (price + administration)
Figure 9
Figure 9 - Text description
Figure 9: Sensitivity analysis of epidemiological parameters for LZV at $140 (price + administration)
Parameters varied LZV
Percentiles of model predictions
5th 25th Median 75th 95th
Base Case Scenario CS 5 828 19 576 28 434 41 349
Proportion PHN min CS 9 486 27 840 39 188 54 900
Proportion PHN max CS 3 509 14 760 21 436 31 088
QALYs lost PHN min CS 7 591 27 518 39 594 52 996
QALYs lost PHN max CS 4 625 15 656 21 406 28 413
HZ incidence min 3 218 11 871 28 217 38 193 53 451
HZ incidence max CS 1 346 13 697 21 196 31 535
Hospitalizations min 6 207 12 380 24 725 33 084 46 842
Hospitalizations max CS CS 14 320 23 787 36 491
Immunocompetent min 6 873 15 610 32 836 44 548 62 448
Immunocompetent max CS 7 827 22 135 31 635 45 684

CS : cost-saving; HZ : Herpes Zoster; PHN : Post-herpetic neuralgia

Figure 10: Sensitivity analysis of epidemiological parameters for RZV at $140 (price + administration)
Figure 10
Figure 10 - Text description
Figure 10: Sensitivity analysis of epidemiological parameters for RZV at $140 (price + administration)
Parameters varied RZV
Percentiles of model predictions
5th 25th Median 75th 95th
Base Case Scenario CS CS CS 2 922 24 715
Treatment/PHN episode min CS CS CS 5 673 33 889
Treatment/PHN episode max CS CS CS 1 166 18 191
Hospitalizations min CS CS CS 3 933 33 849
Hospitalizations max CS CS CS 2 359 17 604
Consultations min CS CS 1 835 7 831 32 990
Consultations max CS CS CS CS 17 994
Treatment/HZ episode min CS 752 3 671 8 287 28 213
Treatment/HS episode max CS CS CS CS 21 080
Discount rate 0% CS 564 4 716 11 010 39 464
Discount rate 5% CS 7 827 CS 4 543 27 629

CS : cost-saving; HZ : Herpes Zoster; PHN : Post-herpetic neuralgia

Figure 11: Sensitivity analysis of epidemiological parameters for LZV at $200 (price + administration)
Figure 11
Figure 11 - Text description
Figure 11: Sensitivity analysis of epidemiological parameters for LZV at $200 (price + administration)
Parameters varied LZV
Percentiles of model predictions
5th 25th Median 75th 95th
Base Case Scenario 8235 18344 37249 49994 70059
Proportion PHN min 12597 25247 50803 66789 90787
Proportion PHN max 5364 13608 29242 38783 53821
QALYs lost PHN min 10892 23615 52727 69056 87860
QALYs lost PHN max 6527 14250 29869 37398 47227
HZ Incidence min 15987 27073 49431 63973 87371
HZ Incidence max 2915 11854 28962 39538 55750
Hospitalizations min 16308 25248 42407 54724 75753
Hospitalizations max 218 11174 31893 45208 64856
Immunocompetent min 19877 31785 55579 72709 99659
Immunocompetent max 10555 20949 40773 54485 75968

CS : cost-saving; HZ : Herpes Zoster; PHN : Post-herpetic neuralgia

Figure 12: Sensitivity analysis of epidemiological parameters for RZV at $200 (price + administration)
Figure 12
Figure 12 - Text description
Figure 12: Sensitivity analysis of epidemiological parameters for RZV at $200 (price + administration)
Parameters varied RZV
Percentiles of model predictions
5th 25th Median 75th 95th
Base Case Scenario CS 1507 6356 13433 44382
Treatment/ PHN episode min CS 3909 9990 18902 59157
Treatment/ PHN episode max CS CS 3945 9643 34022
Hospitalizations min CS 1985 8183 17458 60081
Hospitalizations max CS 1187 5066 10460 31386
Consultations min 933 7384 12525 20625 56469
Consultations max CS CS 1786 7999 34829
Treatment/ HZ episode min 4535 8761 12631 19245 48011
Treatment/ HZ episode max CS CS CS 7469 40679
Discount rate 0% 4473 10703 15969 24885 65366
Discount rate 5% CS 3438 8350 15653 48629

CS : cost-saving; HZ : Herpes Zoster; PHN : Post-herpetic neuralgia

Figure 13: Sensitivity analysis of economic parameters for LZV at $140 (price + administration)
Figure 13
Figure 13 - Text description
Figure 13: Sensitivity analysis of economic parameters for LZV at $140 (price + administration)
Parameters varied LZV
Percentiles of model predictions
5e 25e Median 75e 95e
Base Case Scenario CS 5828 19 576 28 434 41 349
Treatment/PHN episode min 450 8 695 22 420 31 447 45 143
Treatment/PHN episode max CS 2 180 16 166 24 674 37 176
Hospitalizations min 5 135 11 257 24 081 32 450 45 865
Hospitalizations max CS CS 14 572 23 994 36 329
Consultations min CS 7 228 21 417 30 385 44 082
Consultations max CS 3 262 16 340 24 622 36 548
Treatment/HZ episode min CS 7 744 21 383 30 461 43 845
Treatment/HZ episode max CS 3 662 17 478 26 170 38 812
Discount rate 0% CS CS 9 830 19 036 29 650
Discount rate 5% 3 356 12 449 26 593 35 586 50 347

CS : cost-saving; HZ : Herpes Zoster; PHN : Post-herpetic neuralgia

Figure 14: Sensitivity analysis of economic parameters for RZV at $140 (price + administration)
Figure 14
Figure 14 - Text description
Figure 14: Sensitivity analysis of economic parameters for RZV at $140 (price + administration)
Parameters varied RZV
Percentiles of model predictions
5e 25e Median 75e 95e
Base Case Scenario CS CS CS 2 922 24 715
Treatment/PHN episode min CS CS 276 5 657 27 801
Treatment/PHN episode max CS CS CS CS 20 600
Hospitalizations min CS CS 2 656 7 348 27 565
Hospitalizations max CS CS CS CS 21 331
Consultations min CS CS CS 4 289 26 717
Consultations max CS CS CS 192 20 543
Treatment/HZ episode min CS CS CS 5 322 27 488
Treatment/HZ episode max CS CS CS 105 21 583
Discount rate 0% CS CS CS CS 18 384
Discount rate 5% CS CS 1 843 7 551 29 093

CS : cost-saving; HZ : Herpes Zoster; PHN : Post-herpetic neuralgia

Figure 15: Sensitivity analysis of economic parameters for LZV at $200 (price + administration)
Figure 15
Figure 15 - Text description
Figure 15: Sensitivity analysis of economic parameters for LZV at $200 (price + administration)
Parameters varied LZV
Percentiles of model predictions
5th 25th Median 75th 95th
Base Case Scenario 8235 18344 37249 49994 70059
Treatment/PHN episode min 11065 21263 40092 53000 73737
Treatment/PHN episode max 4850 14530 33893 46110 65627
Hospitalizations min 15269 24124 41754 54103 74649
Hospitalizations max 1182 11199 32165 45385 64497
Consultations min 9506 19601 39027 51930 72707
Consultations max 5882 15627 33903 46144 65000
Treatment/HZ episode min 9986 20303 39014 52045 72402
Treatment/HZ episode max 6210 16056 35141 47641 66898
Discount rate 0% CS 5898 23111 35918 52175
Discount rate 5% 16370 28123 47368 60865 83201

CS : cost-saving; HZ : Herpes Zoster; PHN : Post-herpetic neuralgia

Figure 16: Sensitivity analysis of economic parameters for RZV at $200 (price + administration)
Figure 16
Figure 16 - Text description
Figure 16: Sensitivity analysis of economic parameters for RZV at $200 (price + administration)
Parameters varied RZV
Percentiles of model predictions
5th 25th Median 75th 95th
Base Case Scenario CS 1507 6356 13433 44382
Treatment/PHN episode min CS 4324 9088 16285 47551
Treatment/PHN episode max CS CS 2887 9756 40539
Hospitalizations min 3401 7687 11653 18246 47322
Hospitalizations max CS CS CS 7437 40807
Consultations min CS 2822 7670 14870 46550
Consultations max CS CS 3773 10539 40173
Treatment/HZ episode min CS 3930 8719 15900 47400
Treatment/HZ episode max CS CS 3553 10461 41206
Discount rate 0% CS CS CS 4605 34648
Discount rate 5% 1289 7694 12754 20575 51280

CS : cost-saving; HZ : Herpes Zoster; PHN : Post-herpetic neuralgia

V.4 Study Limitations

The model used data on health care costs of HZ and PHN that are incomplete for Canada. Although Canada has variability in healthcare costs thus leading to uncertainty in cost parameters, sensitivity analysis did not find that these costs have an impact on model conclusions. The baseline results presumed 100% compliance for 2 doses of RZV reflecting the clinical trials, however post-market realities are not likely to yield such a high compliance rate for both doses. The study did not take into account the potential impact of varicella vaccination on HZ incidence. It has been suggested that by reducing primary varicella incidence through varicella vaccination, universal varicella vaccination will lead to a short to medium term increase in zoster incidence among age groups that do not receive varicella vaccinationFootnote 11 Footnote 112 . If this occurs, the results in this study will be conservative and underestimate the cost effectiveness of a HZ vaccinationFootnote 11 .

VI. Recommendations

Following the review of available evidence summarized above and in the Management Options Table below (Table 9) comparing the HZ vaccines currently authorized for use in Canada, NACI makes the following recommendations for public health level and individual level decision-making. (While in this statement, the recommendations for both levels of decision-making are essentially the same, the rationale and context are somewhat different.)
Please note:

  • A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present.
  • A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable.

Please see Table 11 for a more detailed explanation of strength of NACI recommendations and grade of the body of evidence.

NACI will continue to monitor the scientific developments related to Herpes Zoster vaccines, including studies related to immunocompromised populations, and will update recommendations as evidence evolves.

VI.1 Recommendations for Public Health Program Level Decision-Making

(i.e. Provinces/Territories making decisions for publicly funded immunization programs)

In considering these recommendations and for the purposes of publicly funded program implementation, provinces and territories may take into account other local operational factors (e.g. current immunization programs, resources). Recognizing that there are differences in operational contexts across Canada, jurisdictions may wish to refer to Management Options Table 10 below for a summary of the relative merits of vaccinating different age cohorts (e.g. with respect to epidemiology and cost-effectiveness) if prioritization of targeted immunization programs is required for implementation.

RZV: Recommendations for Public Health Program Level Decision-Making

1. NACI recommends that Recombinant Zoster Vaccine should be offered to populations ≥ 50 years of age without contraindications. (Strong NACI Recommendation)

NACI concludes that there is good evidence to recommend immunization (Grade A Evidence)

Summary of Evidence and Rationale:

  • Age is the predominant risk factor for the development of HZ and PHN, and hospitalization among HZ cases. Steep increases in HZ incidence and PHN risk per HZ case occur over 50 years of age. Peak hospitalization rates for HZ and PHN risk per HZ case are observed among persons 65 years of age and older.
  • Protection against HZ decreases with age at, and time since, vaccination with Live Zoster Vaccine (LZV) whereas VE of the newly authorized Recombinant Zoster Vaccine (RZV) remains higher and appears to decline more slowly than VE of LZV across all age groups.
    • RZV VE against incident HZ and PHN in the three years post-immunization appears to be double that observed for LZV overall.
    • RZV VE against incident HZ in the four years post immunization remains consistent, with no significant decreases observed over time; in contrast, significant waning of protection has been observed one-year post immunization with LZV.
    • Four-year VE against incident HZ does not vary significantly across age groups for RZV; in contrast, LZV is significantly less effective in adults over 70 years of age compared to adults 50-59 years of age.
  • Both vaccines are safe in immunocompetent individuals. Due to the adjuvant in RZV, which induces a high cellular immune response and helps address the natural, age-related decline in immunity, the RZV vaccine is more reactogenic than LZV. Grade 3 local and systemic reactions (i.e. severe enough to interfere with normal activities) have been more frequently reported following the receipt of RZV than LZV, but these reactions have been transient (lasting 2-3 days).
  • Both LZV and RZV are immunogenic (though there are no established correlates of protection and study results must be interpreted with caution). For LZV, immune response appears more robust for those 50-59 years of age than for older age groups, but remains the same across all age groups over 50 years for RZV. Immunogenicity has been demonstrated up to 9 years post-vaccination with RZV compared to 3 years post-vaccination with LZV.
  • Both LZV and RZV are cost effective compared to no vaccination (determined through a Cost Utility Analysis), and are most cost effective (lowest cost/QALY) in those 65-79 years of age. RZV was found to be more cost effective than LZV, even taking into account possible reactogenicity of RZV and non-compliance of a second dose of the vaccine.
  • From a program implementation perspective, resources will be required to implement a 2-dose schedule (at 0, 2-6 months) for RZV (vs. a 1-dose schedule for LZV), and provide counseling on the reactogenicity of the RZV vaccine. Public health programs may consider a 0, 12-month schedule if it will improve coverage of the 2nd dose by simultaneous administration with other adult vaccines. Though in a small studyFootnote 60 this schedule did not meet non-inferiority criteria to a 0, 2-month schedule (as the 0, 6-month schedule did), it was found to have an acceptable safety profile and robust anti-gE immune response.

NACI considered various factors related to the HZ vaccines currently authorized for use in Canada (outlined in the Management Options Table 9). Both LZV and RZV are safe, immunogenic, and effective in preventing HZ and PHN. On balance, NACI felt that the higher efficacy of the RZV vaccine in adults 50 years of age and older, with minimal waning of protection, and factoring in cost-effectiveness of the immunization, all supported a public health program level recommendation to vaccinate populations ≥ 50 years of age. This population is at higher risk of HZ and PHN and will likely continue to be protected with RZV at older ages as the risk of HZ and PHN continues to increase. From a public health program level perspective, RZV has been shown to be more cost effective than LZV. Programs will require strategies (e.g. education, recalls/reminders) to ensure adherence to the two-dose schedule for RZV (as VE and duration of protection is unclear after only one dose), and provide counseling on short-term reactogenicity of the vaccine. If, due to operational constraints, prioritization of targeted immunization programs is required for implementation, jurisdictions may wish to refer to Management Options Table 10 below for a summary of the relative merits of vaccinating different age cohorts (e.g. with respect to epidemiology and cost-effectiveness).

2. NACI recommends that Recombinant Zoster Vaccine should be offered to populations ≥ 50 years of age without contraindications who have previously been vaccinated with Live Zoster Vaccine. (Strong NACI Recommendation)

NACI concludes that there is good evidence to recommend immunization (Grade A Evidence).

2a. NACI recommends that for adults ≥ 50 years of age who have previously been immunized with LZV, re-immunization with 2 doses of RZV may be considered at least one year after LZV. (Discretionary Recommendation)

NACI concludes that there is insufficient evidence to recommend an interval between LZV and RZV (Grade I Evidence). Therefore this recommended interval is based on expert opinion.

Summary of Evidence and Rationale:

  • For the reasons outlined above, including good evidence on higher VE of RZV across all age groups (especially among older age groups) and minimal waning of protection after vaccination with RZV compared to LZV (which is particularly important given the increased incidence of HZ and PHN with age), NACI concludes that prior recipients of LZV will benefit from increased protection with RZV.
  • VE of LZV wanes after the first year post-immunization.
  • At this time, there is limited evidence on minimal and recommended intervals between LZV and RZV. A recently published study of adults ≥65 years of age vaccinated with RZV revealed comparable immunogenicity and reactogenicity in those who were vaccinated with LZV at least 5 years previously vs those who had never received LZV. No safety concerns were evident within 1 month of the completed 2-dose RZV schedule. Shorter intervals between the 2 vaccines have not been studied.
  • In general, inactivated vaccines may be administered concomitantly with, or at any time before or after, other live vaccines protecting against a different disease. There are no guidelines for intervals between an inactivated and live vaccine protecting against the same diseaseFootnote 91 .
  • The minimum interval shown to be safe and effective between doses of RZV is 2 months; similar data do not exist regarding minimum intervals between LZV and RZV.

Prior recipients of LZV vaccine will derive additional protection from completion of the 2-dose series of RZV given higher and more durable VE across age groups. Comparable safety, reactogenicity and immunogenicity have been demonstrated between those who have previously been vaccinated with LZV and those who have not. For those who have previously been vaccinated with LZV, consideration of the interval between LZV and RZV vaccination will depend on age of vaccination with LZV (since VE decreases with age), as well as time since LZV vaccination (since efficacy wanes after the first year). Based on limited evidence summarized above, NACI suggests re-immunization with 2 doses of RZV after one year post LZV administration due to rapidly declining LZV effectiveness after the first year post-vaccination. While the only published study to date investigating immunization with RZV following LZV used an interval of at least 5 years, there is no reason to believe that a shorter interval would be harmful.

3. NACI recommends that Recombinant Zoster Vaccine should be offered to populations ≥ 50 years of age without contraindications who have had a previous episode of HZ. (Strong NACI Recommendation)

NACI concludes that there is fair evidence to recommend immunization (Grade B Evidence).

3a.NACI recommends that for adults ≥ 50 years of age who have had a previous episode of HZ, immunization with 2 doses of RZV may be considered at least one year after the HZ episode. (Discretionary Recommendation)

NACI concludes that there is insufficient evidence to recommend an interval between previous episode of HZ and vaccination with RZV (Grade I Evidence). Therefore this recommended interval is based on expert opinion.

Summary of Evidence and Rationale:

  • In its 2014 Advisory Committee Statement, NACI recommended that LZV may be administered to individuals with a previous episode of HZ (based on Grade B evidence), at least one year after the HZ episode (based on expert opinion). Please see the 2014 NACI statement for a summary of this evidence.
  • As summarized in the 2014 NACI statement on HZ, recurrent episodes of HZ have been confirmed in immunocompetent individuals and some studies suggest that the risk of HZ in those with a prior history is comparable to the risk in those without a history of HZ. Therefore this population is still at risk for HZ and is likely to benefit from the protection afforded by vaccinationFootnote 60.
  • A reported history of a previous occurrence of HZ may be incorrect as no laboratory evaluations to confirm a diagnosis exist.
  • Currently there is only one study (rated as poor quality) that investigated immunogenicity and safety of RZV among patients with prior HZ infection. In this study, immune responses to, and the safety profile of RZV in adults ≥ 50 years with a physician-documented history of HZ were consistent with those observed in those ≥50 years without a documented history of HZ. No formal comparisons by time since prior HZ episode were made in this study.
  • In its 2014 recommendations, NACI concluded that there was insufficient evidence to recommend for or against the administration of HZ vaccine in individuals with a history of HZO. Although causality was difficult to determine, cases of HZO had been reported after administration of LZV.

Similar to its 2014 recommendation for LZV, NACI recommends immunization with RZV in individuals with a prior episode of HZ. Individuals with a prior episode of HZ are still at risk of HZ, and a history of HZ is unreliable, therefore vaccination with RZV in those who report a prior history of HZ may be beneficial. Furthermore, one study has shown no differences in safety or immunogenicity of RZV in individuals with a prior episode of HZ. In the absence of evidence on an appropriate interval, NACI maintains its previous suggestion of waiting at least one year post HZ episode prior to the administration of herpes zoster vaccine. No studies on RZV in individuals with a previous episode of Herpes Zoster Ophthalmicus (HZO) have been conducted.

LZV: Recommendations for Public Health Program Level Decision-Making

4. NACI recommends that Live Zoster Vaccine may be considered for immunocompetent populations ≥ 50 years of age without contraindications, when Recombinant Zoster Vaccine is contraindicated or unavailable. (Discretionary NACI Recommendation)

NACI concludes that there is good evidence to recommend immunization (Grade A Evidence)

Summary of Evidence and Rationale:

  • NACI concludes (as it has in previous Herpes Zoster advisory committee statements) that there is good evidence to recommend immunization with LZV in adults aged ≥60 years (Grade A Evidence). However, the recommendation on the use of this vaccine in immunocompetent populations ≥ 60 years of age is now “Discretionary” due to the comparative evidence on higher efficacy, longer duration of protection, and relative cost effectiveness of the newly authorized RZV vaccine (summarized above and in the Management Options Table 9).
  • Although LZV is safe and efficacious in 50-59 year olds and was previously recommended by NACI on a discretionary basis for this age group, waning protection of the vaccine means that it may not provide optimal ongoing protection at older ages where the risk of HZ and PHN are greatest. With the newly authorized RZV vaccine and its higher efficacy and longer duration of protection in this age group, NACI now strongly recommends that RZV be used in 50-59 year olds in addition to adults ≥60 years without contraindications.
  • LZV vaccine may still be considered in individuals in whom RZV vaccine is contraindicated (i.e. known hypersensitivity to any component of the vaccine), or if RZV is not available. LZV has been authorized in Canada since 2008 and has been shown to be safe, immunogenic, and effective.

Other recommendations regarding the use of LZV vaccine in the 2014 NACI Statement on the Use of Herpes Zoster Vaccine (recommendations #3-5 and #9 regarding administration of LZV in those with a previous episode of HZ or HZO, booster dose, and co-administration with Pneu-P-23) are still relevant, and may be found on the Statement on the Use of Herpes Zoster Vaccine.

RZV vs LZV in Immunocompromised Populations: Recommendations for Public Health Program Level Decision-Making

5. NACI recommends that Recombinant Zoster Vaccine (not Live Zoster Vaccine) may be considered for immunocompromised adults ≥ 50 years of age. (Discretionary NACI Recommendation)

NACI concludes that there is insufficient evidence at this time to recommend immunization (Grade I Evidence). Therefore, this recommendation is based on expert opinion.

Summary of Evidence and Rationale:

  • Individuals who are immunocompromised, either due to underlying conditions or immunosuppressive agents, have an increased risk of developing HZ and may be more likely to experience atypical and/or more severe disease and complications.
  • Although, in general, immunocompromised individuals should not receive live vaccines because of the risk of disease caused by the vaccine strains, NACI has previously recommended the use of LZV in individuals on low dose immunosuppressive therapy and anti-TNF biologics on a case-by-case basis. The recommendation was made in the absence of an inactivated vaccine and on the assumption that individuals have existing immunity to varicella-zoster virus.
  • In immunocompromised individuals, because antigens in the vaccine cannot replicate, NACI generally recommends the use of inactivated vaccines over live vaccines.
  • The magnitude and duration of vaccine-induced immunity are often reduced in immunocompromised individuals.
  • In general, experts in immunodeficiency recommend vaccines like RZV to patients with immunodeficiency even when the efficacy in this population is uncertain. This is based on the assumption that the vaccine will not do any harm and may do some good, and that immunocompromised individuals are not homogeneous and often will have some responsiveness.
  • Immunocompromise is a contraindication for LZV. While there are currently limited peer-reviewed, published data specifically supporting the use of RZV in immunocompromised populations, immunocompromise is not a contraindication for the use of RZV.

Unlike with LZV, immune compromise is not a contraindication for RZV. Based on the burden of illness of HZ in immunocompromised individuals and general guidance on the use of inactivated vaccines versus live vaccines in those who are immunocompromised (summarized above), NACI feels that the benefits of considering vaccination with RZV (instead of LZV) in those who are immunocompromised outweighs the risks at this time.

NACI will monitor the evidence as it evolves and will reassess individual level and public health program level recommendations in immunocompromised individuals and populations as soon as the evidence from ongoing trials (in different immunocompromised populations ≥18 years of age with differing 2- and 3-dose schedules) becomes available.

VI.2 Recommendations for Individual Level Decision-Making

(i.e. Individuals wishing to prevent HZ, or clinicians wishing to advise individual patients about preventing HZ with vaccines that may not currently be included in public health immunization programs.)

RZV: Recommendations for Individual Level Decision-Making

1. NACI recommends that Recombinant Zoster Vaccine should be offered to individuals ≥ 50 years of age without contraindications. (Strong NACI Recommendation)

NACI concludes that there is good evidence to recommend immunization (Grade A Evidence)

Summary of Evidence and Rationale:

(See points above in Recommendation #1 for Public Health Program Level Decision-Making)

On balance, NACI felt that the higher efficacy of the RZV vaccine in adults 50 years of age and older, and minimal waning of protection supports an individual-level recommendation to vaccinate individuals ≥ 50 years of age who are at higher risk of HZ and PHN and will likely continue to be protected with RZV at older ages as the risk of HZ and PHN continues to increase. From an individual level perspective, individuals wishing to prevent HZ or clinicians wishing to advise patients should consider the decision points outlined in the Management Options Table 9 when making a decision as well as the individual cost of RZV vs LZV vaccines. Individuals should be prepared to adhere to a 2 dose schedule for the RZV vaccine (as VE and duration of protection is unknown after only one dose), and understand that they may experience more short term reactogenicity from the RZV vaccine. Management Options Table 10 outlines the relative merits of vaccinating with RZV at different ages, primarily from a health care system perspective.

2. NACI recommends that Recombinant Zoster Vaccine should be offered to individuals ≥ 50 years of age without contraindications who have previously been vaccinated with Live Zoster Vaccine. (Strong NACI Recommendation)

NACI concludes that there is good evidence to recommend immunization (Grade A Evidence).

2a. NACI recommends that for adults ≥ 50 years of age who have previously been immunized with LZV, re-immunization with 2 doses of RZV may be considered at least one year after LZV. (Discretionary Recommendation)

NACI concludes that there is insufficient evidence to recommend an interval between LZV and RZV (Grade I Evidence). Therefore this recommended interval is based on expert opinion.

Summary of Evidence and Rationale:

(See points above in Recommendation #2 and 2a for Public Health Program Level Decision-Making)

Prior recipients of LZV vaccine will derive additional protection from the completion of a 2-dose series of RZV given higher and more durable VE across age groups. Comparable safety, reactogenicity and immunogenicity have been demonstrated between those who have previously been vaccinated with LZV and those who have not. For those who have previously been vaccinated with LZV, consideration of the interval between LZV and RZV vaccination will depend on age of vaccination with LZV (since VE decreases with age), as well as time since LZV vaccination (since efficacy wanes after the first year). Based on limited evidence summarized above, NACI suggests re-immunization with 2 doses of RZV at least one year year post LZV administration due to rapidly declining LZV effectiveness after the first year post-vaccination. While the only published study to date investigating immunization with RZV following LZV used an interval of at least 5 years, there is no reason to believe that a shorter interval would be harmful.

3. NACI recommends that Recombinant Zoster Vaccine should be offered to individuals ≥ 50 years of age without contraindications who have had a previous episode of HZ. (Strong NACI Recommendation)

NACI concludes that there is fair evidence to recommend immunization (Grade B Evidence).

3a. NACI recommends that for adults ≥ 50 years of age who have had a previous episode of HZ, immunization with 2 doses of RZV may be considered at least one year after the HZ episode. (Discretionary Recommendation)

NACI concludes that there is insufficient evidence to recommend an interval between previous episode of HZ and vaccination with RZV (Grade I Evidence). Therefore this recommended interval is based on expert opinion.

Summary of Evidence and Rationale:

(See points above in Recommendation #3 and 3a for Public Health Program Level Decision-Making)

HZ vaccination is still beneficial in individuals who report a prior history of HZ since individuals with a prior episode of HZ are still at risk of HZ. Furthermore, one study has shown no differences in safety or immunogenicity of RZV in individuals with a prior episode of HZ. In the absence of evidence on an appropriate interval, NACI maintains its previous suggestion of waiting at least one year post HZ episode prior to the administration of herpes zoster vaccine.

LZV: Recommendations for Individual Level Decision-Making

4. NACI recommends that Live Zoster Vaccine may be considered for immunocompetent individuals ≥ 50 years of age without contraindications, when Recombinant Zoster Vaccine is contraindicated, unavailable or inaccessible. (Discretionary NACI Recommendation)

NACI concludes that there is good evidence to recommend immunization (Grade A Evidence)

Summary of Evidence and Rationale:

(See points above in Recommendation #4 for Public Health Program Level Decision-Making)

LZV vaccine may be considered in individuals in whom RZV vaccine is contraindicated, unavailable, or in individuals who prefer this vaccine over RZV vaccine after reviewing the decision points as outlined in the Management Options Table 9 (e.g. individuals who will not complete the 2-dose schedule for RZV vaccine, or for whom RZV is too expensive). LZV has been authorized in Canada since 2008 and has been shown to be safe, immunogenic, and effective. However, based on comparative evidence on higher efficacy and longer duration of protection against HZ with the newly authorized RZV vaccine, especially in older age groups as the risk of HZ and PHN increase, NACI’s recommendation for LZV is “discretionary” (see Table 11 for a description of the strength of NACI recommendations).

Other recommendations regarding the use of LZV vaccine in the 2014 NACI Statement on the Use of Herpes Zoster Vaccine (recommendations #3-5 and #9 regarding administration of LZV in those with a previous episode of HZ or HZO, booster dose, and co-administration with Pneu-P-23) are still relevant, and may be found here.

RZV vs LZV in Immunocompromised Individuals: Recommendations for Individual Level Decision-Making

5. NACI recommends that Recombinant Zoster Vaccine (not Live Zoster Vaccine) may be considered for immunocompromised adults ≥ 50 years of age based on a case-by-case assessment of benefits vs risks. (Discretionary NACI Recommendation)

NACI concludes that there is insufficient evidence at this time to recommend immunization (Grade I Evidence). Therefore, this recommendation is based on expert opinion.

(See points above in Recommendation #5 for Public Health Program Level Decision-Making)

Immune compromise is a contraindication for the use of LZV, but not for the use of RZV. Based on the burden of illness of HZ in immunocompromised individuals and general guidance on the use of inactivated vaccines versus live vaccines in those who are immunocompromised (summarized above), NACI feels that the benefits of considering vaccination with RZV (vs LZV) in immunocompromised individuals on a case-by-case basis outweighs the risks at this time.

NACI will monitor the evidence as it evolves and will reassess individual level and public health program level recommendations in immunocompromised individuals and populations as soon as the evidence from ongoing trials (in different immunocompromised populations ≥18 years of age with differing 2- and 3-dose schedules) becomes available.

VI.3 Management Options

There are two vaccines authorized for use in Canada for the prevention of HZ in those 50 years of age and older. The decision on which vaccine option is preferable depends on the key considerations for each vaccine, and a comparison of the relative merits of both, as summarized in Table 9 below.

Management Options Table 9: Comparing Herpes Zoster Vaccines authorized for use in Canada
Options
LZV vs RZV
Factors for Consideration Decision Points
1. LZV Efficacy against HZ (VE [95%CI])
Based on clinical trial data:

Efficacy against PHN (VE [95% CI]
Based on clinical trial data:

  • 60-69yo: 65.7% [20.4-86.7]
  • ≥ 70yo: 66.8% [43.3-81.3%]Footnote c

- VE against HZ 51% in ≥60 year olds; decreases with age at receipt of vaccine
- VE against PHN 67% in ≥60 year olds

Duration of protection against HZ
- VE drops by first year after vaccination (15-25%)
- VE <35% by 6th year post-vaccination
- VE negligible by 10th year post-vaccination

Effectiveness against HZ [95% CI]
- Canadian data in ≥50 year olds reveal effectiveness drops from 50% [44.71%, 54.83%] one year post vaccination to 14% [-20.99%, 38.88%] 5 years post vaccination.Footnote d

Immunogenicity
-demonstrated up to 3 years post-vaccination
-immune response among those aged 50-59 appears more robust than those over the age of 60(e)

Safety
- SAE: No significant differences between vaccinated and placebo recipients in 8 RCTs with 36,868 participants; vaccine-related SAE reported among 0-8% of vaccine recipients
- Most common AE in 3 clinical trials were injection site reactions (48% vaccine recipients vs 17% placebo); Grade 3 moderate/severe injection site reactions in 0-4% of vaccine recipients in 4 studies
- Rarely, LZV vaccine strain has reportedly caused HZ and disseminated rash in immunocompetent recipients.
- LZV is a live vaccine therefore there is a theoretical risk of transmission from vaccinated to susceptible individuals (though no cases have been documented)
- Contraindicated in immunocompromised populations except those on low doses of some immunosuppressants (e.g. methotrexate, Imuran) and early, well-controlled HIV

Economics
- Compared to no vaccination, LZV (in the base case at 65 years old) has median ICERs ranging from $7,673 to $37,249 per QALY at different vaccine costs.

Feasibility/Acceptability
- refrigerator-stable
- one dose schedule
- LZV has been used around the world for a decade

- LZV has been authorized for use in Canada and elsewhere (e.g. U.S. Europe, UK) for over a decade and NACI recommendations for the use LZV have been in place since 2010. RZV has recently been authorized for use in Canada and the U.S. in October 2017.

Epidemiology
- Age is the major risk factor for development of HZ and PHN. Incidence sharply increases among persons 50 years of age and older.
Efficacy
- Estimates of efficacy against HZ and PHN for RZV are higher than for LZV across all age groups studied, and especially among those ≥ 70 years of age
- VE against HZ decreases with age at receipt of LZV (51% in ≥60 year olds and 38% in ≥70 year olds)
- VE against PHN is higher than for HZ with LZV, and roughly the same with RZV

Duration of Protection
- Waning of protection against HZ appears to occur at a slower rate for RZV compared to LZV over the first 4 years after vaccination
- Real world VE data reveal uncertain protection by 5 years post vaccination with LZV; real world VE of RZV still pending

Unknowns:
- VE and waning after only 1 dose of RZV
- VE of RZV beyond 4 years
- waning of VE against PHN over time

Immunogenicity
- Both LZV and RZV are immunogenic
- Immune response is more robust for those 50-59 years of age for LZV, but the same across all age groups above 50 yrs for RZV
- Immunogenicity has been demonstrated up to 9 years post-vaccination with RZV vs 3 years post-vaccination with LZV

Unknowns:
- Established correlates of protection

Safety
- Both vaccines are safe in immunocompetent individuals
- RZV uses a new adjuvant and is more reactogenic than LZV, leading to more Grade 3 reactions (severe enough to prevent normal activities) following vaccination
- LZV is a live attenuated vaccine which can cause HZ in rare circumstances, and has been reported to cause vaccine-related VZV in a small number of cases
- LZV is contraindicated in immunocompromised populations, in whom incidence of HZ is higher

Unknowns:
- The adjuvant in RZV is new, so long-term data are not yet available.
- Further study on the use of HZ vaccines in individuals with a prior history of HZO is needed.

Economics
Based on Cost Utility Analysis:
- Both HZ vaccines are cost-effective compared to no vaccination for adults ≥50 years.
- RZV is more cost effective than LZV.

- The additional dose required for the RZV immunization schedule will require additional administrative costs
- Increased reactogenicity of RZV may result in additional use of health care resources

Feasibility/Acceptability
- Vaccination with RZV is a 2 dose schedule vs LZV which is a 1 dose schedule. Increased reactogenicity in RZV may affect compliance with second dose. Consideration to improve adherence and acceptability to the 2nd dose of RZV, as well as additional operational costs for the administration of the 2nd dose would be required.
- LZV has been used around the world for longer than RZV. Real world experience with RZV and the AS01B adjuvant is limited and may affect acceptability.

Unknowns:
- It is unknown what the adherence to the complete 2-dose vaccination schedule with RZV will be in ≥50 year-olds.

2. RZV Efficacy against HZ (VE [95%CI])
(Based on 2 large Phase 3 RCT)
  • 50-59y: 96.6% [89.6, 99.3]
  • 60-69y: 97.4% [90.1-99.7]
  • 70-79y: 91.3% [86.0-94.9]
  • ≥80y: 91.4% [80.2-97.0]Footnote fFootnote g

Efficacy against PHN (VE [95%CI])
(based on 2 large Phase 3 RCT)

  • ≥50y: 91.2 [77.9-97.7]
  • ≥70y: 88.8 [68.7-97.1]Footnote g

Duration of protection against HZ
(based on 2 large Phase 3 RCT)
- Minimal waning of VE for 4 years following vaccination (≥85% for all 4 years)

Immunogenicity
- demonstrated up to 9 years post-vaccination with >3 fold rise of CD4+ T cell response above baseline.
-similar across all adults over 50 years of age.

Safety
- AS01B adjuvant in RZV vaccine induces high cellular response which is important in HZ because of increased incidence with decreased cellular immunity, however this causes increased reactogenicity.

(The following based on 2 large Phase 3 RCT and smaller studies)Footnote fFootnote g
- Grade 3 reactions (severe enough to prevent normal activities) more commonly reported in vaccinated vs placebo recipients (16.5 vs 3.1%), lasting 1-2 days
- Grade 3 injection site reactions more commonly reported in vaccinated vs placebo recipients (9.4 vs 0.3%)
- Grade 3 systemic reactions more commonly reported in vaccinated vs placebo recipients (10.8 vs 2.4%)
- No significant differences reported in SAE in vaccinated vs placebo (12.6 vs 13%)

  • In clinical trials, reactions to dose 1 did not strongly predict reactions to dose 2.

Cost-Effectiveness
- Compared to no vaccination, RZV (in the base case at 65 years old) has median ICERs ranging from cost savings to $6,356 per QALY at different vaccine costs.

Feasibility/Acceptability Issues
- refrigerator-stable
- 2 doses required (phase 2 clinical trial in adults ≥60 years revealed 2 doses induced higher immune response than one dose)Footnote h
-higher reactogenicity than LZV

Footnote a

Schmader KE, Oxman MN, Levin MJ, Johnson G, Zhang JH, Betts R, et al. Persistence of the efficacy of zoster vaccine in the shingles prevention study and the short-term persistence substudy. Clin Infect Dis. 2012;55(10):1320-8.

Return to footnote a referrer

Footnote b

Oxman MN, Levin MJ, Arbeit RD, Barry P, Beisel C, Boardman KD, et al. Vaccination against herpes zoster and postherpetic neuralgia. J Infect Dis. 2008;197(SUPPL. 2):S228-36.

Return to footnote b referrer

Footnote c

Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. New Engl J Med. 2005;352(22):2271,2284+2365.

Return to footnote c referrer

Footnote d

McDonald BM, Dover DC, Simmonds KA, Bell CA, Svenson LW, Russell ML. The effectiveness of shingles vaccine among Albertans aged 50 years or older: A retrospective cohort study. Vaccine. 2017;35(50):6984-9.

Return to footnote d referrer

Footnote e

Sutradhar SC, Wang WWB, Schlienger K, Stek JE, Chan JXSF, Silber JL. Comparison of the levels of immunogenicity and safety of zostavax in adults 50 to 59 years old and in adults 60 years old or older. Clin Vaccine Immunol. 2009;16(5):646-52.

Return to footnote e referrer

Footnote f

Lal H., Cunningham A.L., Godeaux O., Chlibek R., DiezDomingo J., Hwang S.J., et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med. 2015 28 May 2015;372(22):2087-96.

Return to footnote f referrer

Footnote g

Lal H., Cunningham A.L., Kovac M, Chlibek R, Hwang S-, Díez-Domingo J, et al. Efficacy of the herpes zoster subunit vaccine in adults 70 years of age or older. New Engl J Med. 2016;375(11):1019-32.

Return to footnote g referrer

Footnote h

Chlibek R., Smetana J., Pauksens K., Rombo L., Van den Hoek J.A.R., Richardus J.H., et al. Safety and immunogenicity of three different formulations of an adjuvanted varicella-zoster virus subunit candidate vaccine in older adults: A phase II, randomized, controlled study. Vaccine. 2014 26 Mar 2014;32(15):1745-53.

Return to footnote h referrer

Management Options Table 10 summarizes the relative merits of vaccinating different age cohorts if prioritization of targeted immunization programs is required for implementation.

Management Options Table 10 : Comparing options of vaccinating different age cohorts with RZV
Options
Age Cohorts
Factors for Consideration Decision Points
50-64 year olds

Efficacy against HZ (VE [95%CI])
(Based on 2 large Phase 3 RCT)

  • 50-59y: 96.6% [89.6, 99.3]
  • 60-69y: 97.4% [90.1-99.7]
  • 70-79y: 91.3% [86.0-94.9]
  • ≥80y: 91.4% [80.2-97.0]Footnote aFootnote b

Efficacy against PHN (VE [95%CI])
(based on 2 large Phase 3 RCT)

  • ≥50y: 91.2 [77.9-97.7]
  • ≥70y: 88.8 [68.7-97.1]Footnote b

Epidemiology
- Age is the major risk factor for development of HZ and PHN. Incidence sharply increases among persons 50 years of age and older.

(The following numbers related to HZ incidence, hospitalization and PHN risk are baseline parameter values used in the economic analysis, derived from the literature)

HZ Incidence (per 1,000 person-yrs [min, max]) Footnote c Footnote d Footnote e Footnote f Footnote g Footnote h

  • 50-54y: 3.8 [3.5, 4.2]
  • 55-64y: 6.0 [5.1, 6.9]
  • 65-74y: 8.6 [7.3, 10.0]
  • ≥75y: 9.9 [8.0, 11.8]

HZ Hospitalizations (per case [min, max]) Footnote c Footnote f Footnote i

  • 50-54y: 1.1% [0.5%, 1.6%]
  • 55-64y: 1.6% [0.7%, 2.5%]
  • 65-74y: 3.3% [1.5%, 5.1%]
  • ≥75y: 9.9% [4.1%, 15.6%]

PHN Risk (per case [min,max]) Footnote c Footnote j

  • 50-54y: 9.4% [6.9%, 11.9%]
  • 55-64y: 9.4% [6.9%, 11.9%]
  • 65-74y: 26.0% [18.5%, 33.4%]
  • ≥75y: 27.7% [22.0%, 33.4%]

Economics
Based on Cost Utility Analysis:
-RZV is cost-effective compared to no vaccination for adults ≥50 years. Best cost effectiveness found to be among 65-79 year olds.

Higher Incremental Cost Effectiveness Ratio (ICER) implies lower cost effectiveness. i.e. pay more per unit of QALY

Median ICER (cost per QALY) for RZV

  • 50-59y: $26,651
  • 60-64y: $11,995
  • 65-69y: $6,356
  • 70-74y: $5,345
  • 75-79y: $2,260
  • 80-84y: $9,281
  • ≥85: $19,800
50-64 year olds
  • RZV is efficacious, safe, immunogenic, cost effective in this group
  • Least cost effective compared to other age cohorts because of the possible risk that VE will wane by the time this cohort is at highest risk of HZ incidence, hospitalization, and PHN.
  • Lower burden of illness compared to older age groups.
  • Unknown duration of protection with RZV, so VE may wane when burden of illness is highest in older age groups. However, if lifelong immunity persists, vaccinating earlier offers maximum prevention potential over the longest period of time.
65-79 year olds 65-79 year olds
  • RZV is efficacious, safe, immunogenic, cost effective in this group
  • Most cost effective compared to other age cohorts because of higher burden of illness with age (increased risk of hospitalization and PHN per HZ case especially ≥65 years of age) and the likelihood that the vaccine will be effective during the years when burden of illness is high (unless VE wanes quickly).
  • Longer life expectancy than the older age cohort therefore benefits of vaccination accrue over a longer period of time.
  • May simultaneously administer with other adult vaccines to improve coverage and reduce operational costs
≥80 year olds ≥80 year olds
  • RZV is efficacious, safe, immunogenic, cost effective in this group
  • Less cost effective compared to 65-79 year olds because the benefits of vaccination accrue over a shorter period of time due to a shorter life expectancy.
  • Highest burden of illness (highest incidence of HZ and risk of hospitalization and PHN per HZ case.)
Footnote a

a. Lal H., Cunningham A.L., Godeaux O., Chlibek R., DiezDomingo J., Hwang S.J., et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med. 2015 28 May 2015;372(22):2087-96.

Return to footnote a referrer

Footnote b

Lal H., Cunningham A.L., Kovac M, Chlibek R, Hwang S-, Díez-Domingo J, et al. Efficacy of the herpes zoster subunit vaccine in adults 70 years of age or older. New Engl J Med. 2016;375(11):1019-32.

Return to footnote b referrer

Footnote c

Brisson M, Pellissier JM, Camden S, Quach C, De Wals P. The potential cost-effectiveness of vaccination against herpes zoster and post-herpetic neuralgia. Hum vaccin. 2008 May-Jun;4(3):238-45.

Return to footnote c referrer

Footnote d

Marra F, Chong M, Najafzadeh M. Increasing incidence associated with herpes zoster infection in British Columbia, Canada. BMC Infect Dis. 2016;16(1).

Return to footnote d referrer

Footnote e

Russell ML, Dover DC, Simmonds KA, Svenson LW. Shingles in Alberta: Before and after publicly funded varicella vaccination. Vaccine. 2014;32(47):6319-24.

Return to footnote e referrer

Footnote f

Tanuseputro P, Zagorski B, Chan KJ, Kwong JC. Population-based incidence of herpes zoster after introduction of a publicly funded varicella vaccination program. Vaccine. 2011;29(47):8580-4.

Return to footnote f referrer

Footnote g

Marra F, Lo E, Kalashnikov V, Richardson K. Risk of Herpes Zoster in Individuals on Biologics, Disease-Modifying Antirheumatic Drugs, and/or Corticosteroids for Autoimmune Diseases: A Systematic Review and Meta-Analysis. Open Forum Infect Dis. 2016(eCollection 2016 Oct.):3(4):ofw205.

Return to footnote g referrer

Footnote h

Régi de l'assurance maladie [Internet].: Gouvernment du Québec; 2018 [cited 2017]. Available from: http://www.ramq.gouv.qc.ca/en/Pages/home.aspx.

Return to footnote h referrer

Footnote i

Sources de données et métadonnées [Internet].: Santé et Services Sociaux du Québec; 2016 [updated 26 juillet 2016; cited 2017]. Available from: http://www.msss.gouv.qc.ca/professionnels/documentation-sources-de-donnees-et-indicateurs/sources-de-donnees-et-metadonnees/med-echo/.

Return to footnote i referrer

Footnote j

Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. New Engl J Med. 2005;352(22):2271,2284+2365.

Return to footnote j referrer

VII. Research priorities

Research to address the following outstanding questions is encouraged:

New and emerging research priorities

  • What is the vaccine effectiveness and duration of protection after one dose of RZV vaccine?
  • What is the duration of protection after two doses of RZV vaccine (beyond 4 years)?
  • What is the vaccine immunogenicity, efficacy, effectiveness, and safety of RZV vaccine in immunocompromised populations <50 years of age and >50 years of age?
  • How will vaccination with RZV affect individuals with a prior history of HZO?
  • How do LZV and RZV vaccines compare in head to head trials?
  • What will HZ vaccine effectiveness, efficacy, immunogenicity and safety be in cohorts vaccinated with varicella vaccine in childhood (and not exposed to wild type VZV)?
  • What is the immunological correlate of protection against herpes zoster disease and PHN?
  • What is the immunogenicity of a 0, 12-month schedule of RZV? (Additional studies with larger study populations would be helpful.)
  • What is the safety, immunogenicity, and efficacy of an interval shorter than 5 years between a dose of RZV and LZV in those who have been previously vaccinated with LZV?
  • Are there safety, efficacy or immunogenicity concerns with co-administration of RZV and other vaccines such as Pneu-P-23, Tdap, adjuvanted influenza?

Standing research priorities

From the 2014 NACI Statement on LZV:

  • Persistence of VE in persons >50 years of age.
  • The need for booster doses of HZ vaccine in the long-term.
  • Efficacy of immunization on persons with prior history of HZ.
  • Assessing safety of HZ vaccine in individuals with a prior history of HZO and the association of HZ vaccine with the recurrence of HZO.
  • What are the vaccine efficacy, effectiveness, and safety of HZ vaccines in immunocompromised populations?
  • Further study on co-administration of HZ vaccine and Pneu-P-23.

VIII. Surveillance issues

Ongoing and systematic data collection, analysis, interpretation and timely dissemination is fundamental to planning, implementation, evaluation, and evidence-based decision-making. To support such efforts, NACI encourages surveillance improvements in the following areas:

  1. Epidemiology
    • Examination of the Canadian burden and epidemiology of herpes zoster and its complications over time in the general population, and among cohorts vaccinated with varicella vaccine in childhood
    • Evaluation of the impact of HZ vaccination in provinces and territories on HZ burden, complications, and epidemiology
  2. Vaccine (coverage, adverse events)
    • HZ vaccination coverage among adults 50 years and older in provinces and territories
    • Compliance rate of 2nd dose of RZV vaccine
    • Long term safety of RZV vaccine
  3. Attitudes and behaviours
    • Impact of reactogenicity of RZV on attitudes and behaviours of patients and providers

Tables

Summary of Evidence Tables for primary studies can be found in the Appendices.

Table 11: NACI Recommendations: Strength of Recommendation and Grade of Evidence
STRENGTH OF NACI RECOMMENDATION
Based on factors not isolated to strength of evidence (e.g. public health need)
GRADE OF EVIDENCE
Based on assessment of the body of evidence

Strong
“should/should not be offered”

  • Known/Anticipated advantages outweigh known/anticipated disadvantages (“should”),

OR Known/Anticipated disadvantages outweigh known/anticipated advantages (“should not”)

  • Implication: A strong recommendation applies to most populations/individuals and should be followed unless a clear and compelling rationale for an alternative approach is present
A – good evidence to recommend
B – fair evidence to recommend
C – conflicting evidence, however other factors may influence decision-making
D – fair evidence to recommend against
E – good evidence to recommend against
I – insufficient evidence (in quality or quantity), however other factors may influence decision-making

Discretionary
“may be considered”

  • Known/Anticipated advantages closely balanced with known/anticipated disadvantages, OR uncertainty in the evidence of advantages and disadvantages exists
  • Implication: A discretionary recommendation may be considered for some populations/individuals in some circumstances. Alternative approaches may be reasonable.
A – good evidence to recommend
B – fair evidence to recommend
C – conflicting evidence, however other factors may influence decision-making
D – fair evidence to recommend against
E – good evidence to recommend against
I – insufficient evidence (in quality or quantity), however other factors may influence decision-making
Table 12: Ranking Individual Studies: Levels of Evidence Based on Research Design
Level Description
I Evidence from randomized controlled trial(s).
II-1 Evidence from controlled trial(s) without randomization.
II-2 Evidence from cohort or case-control analytic studies, preferably from more than one centre or research group using clinical outcome measures of VE.
II-3 Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence.
III Opinions of respected authorities, based on clinical experience, descriptive studies and case reports, or reports of expert committees.
Table 13: Ranking Individual Studies: Quality (internal validity) Rating of Evidence
Quality Rating Description
Good A study (including meta-analyses or systematic reviews) that meets all design-specific criteriaFootnote * well.
Fair A study (including meta-analyses or systematic reviews) that does not meet (or it is not clear that it meets) at least one design-specific criterionFootnote * but has no known "fatal flaw".
Poor A study (including meta-analyses or systematic reviews) that has at least one design-specificFootnote * "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations.
Footnote *

General design specific criteria are outlined in Harris RP, Helfand M, Woolf SH, et al. Current methods of the US Preventive Services Task Force: a review of the process. Am J Prev Med 2001;20:21-35.

Return to footnote * referrer

List of abbreviations

AE
Adverse Effect
AS
Adjuvant System
BGTD
Biologics and Genetic Therapies Directorate
BOI
Burden of Illness
CUA
Cost Utility Analysis
CIHR
Canadian Institutes of Health Research
CMI
Cell-Mediated Immunity
CI
Confidence Interval
CKD
Chronic Kidney Disease
DSEN
Drug Safety and Effectiveness Network
GM
Geometric Mean
GMR
Geometric Mean Ratio
GMRI
Geometric Mean Ratio Increase
GP
General Practitioner
HR
Hazard Ratio
HSCT
Hematopoietic Stem Cell Transplantation
HZ
Herpes Zoster
HZWG
Herpes Zoster Working Group
HZO
Herpes Zoster Ophthalmicus
ICER
Incremental Cost-Effectivness Ratio
IM
Intramuscular Administration
IR
Incidence Rate
LZV
Live Zoster Vaccine
MAGIC
Methods and Applications Group for Indirect Comparisons
NACI
National Advisory Committee on Immunization
NNV
Number Needed to Vaccinate
PHN
Post-Herpetic Neuralgia
PICOS
Population, Intervention, Comparator, Outcomes and Study design
Pneu-P-23
Pneumococcal polysaccharide 23-valent vaccine
PY
Person Years
QALY
Quality Adjusted Life Years
RAMQ
Regie de l’Assurance Maladie du Quebec
RCF
Responder Cell Frequency
RR
Relative Risk
RZV
Recombinant Zoster Vaccine
SAE
Serious Adverse Effect
SAAE
Serous Autoimmune Adverse Event
SC
Subcutaneous Administration
SFC
Spot Forming Cells
SPS
Shingles Prevention Study
STPS
Short-Term Persistence Substudy
TIV
Trivalent Influenza Vaccine
UI
Uncertainty Intervals
VE
Vaccine Efficacy
VZV
Varicella Zoster Virus

Acknowledgments

This statement was prepared by: Dr. S. Ismail, Dr. M. Tunis, Dr. O. Baclic, Dr. M. K. Doll, Dr. J. Hu, Dr. R. Warrington, Mr. K. Eng, Mr. S. Duchesne-Belanger, and approved by NACI.

Herpes Zoster Working Group Members: Dr. R. Warrington (Chair), Dr. S. Deeks, Dr. P. De Wals, Dr. K Dooling, K. Eng, Dr. J. Gallivan, Dr. S. Ismail, M. Landry, Dr. C. Rotstein, Dr. C Sauvageau, Dr. S. E Straus, Dr. M. Tunis.

NACI Members: Dr. C. Quach (Chair), Dr. W. Vaudry (Vice-Chair), Dr. N. Dayneka, Dr. P. De Wals, Dr. S. Deeks, Dr. V. Dubey, Dr. R. Harrison, Dr. M. Lavoie, Dr C. Rotstein, Dr. M. Salvadori, Dr. B. Sander, Dr. N. Sicard, Dr. R. Warrington.

Liaison Representatives: Dr. J. Brophy (Canadian Association for Immunization Research and Evaluation [CAIRE]), Dr. E. Castillo (Society of Obstetricians and Gynaecologists of Canada), Dr. A. Cohn (Centers for Disease Control and Prevention, United States), Ms. T. Cole (Canadian Immunization Committee), Dr. J. Emili (College of Family Physicians of Canada), Dr. K. Klein (Council of Chief Medical Officers of Health), Dr. C. Mah (Canadian Public Health Association), Dr. D. Moore (Canadian Paediatric Society), Dr. A. Pham-Huy (Association of Medical Microbiology and Infectious Disease [AMMI] Canada).

Ex-Officio Representatives:, Dr. (LCdr) K. Barnes (National Defence and the Canadian Armed Forces), Ms. G. Charos (Centre for Immunization and Respiratory Infectious Diseases [CIRID], Public Health Agency of Canada [PHAC]), Dr. G. Coleman (Biologics and Genetic Therapies Directorate [BGTD], Health Canada [HC]), Dr. J. Gallivan (Marketed Health Products Directorate [MHPD], HC), Ms. J. Pennock (CIRID, PHAC), Mr. G. Poliquin (National Microbiology Laboratory), Dr. T. Wong (First Nations and Inuit Health Branch [FNIHB], HC).

NACI gratefully acknowledges the contribution of: The team from University of Laval, Centre de recherché du CHU de Quebec, and INSPQ for contributions to the economic analysis including Dr. M. Brisson, Dr. Z. Zhou, Dr. M. Drolet, Dr. C. Sauvageau, Dr. P. De Wals, Dr. V. Gilca, Dr. JF. Laprise, and Dr. R. Amini. This team, however, are not the authors of the economic section in the Statement.

Ms. J. Chor, Ms. A. Fleurant, and Ms. C. Mauviel (CIRID, PHAC), Ms. L. Gamble (Health Library, HC) for supporting the immunogenicity search strategy, and the MAGIC team for their contribution to the safety, effectiveness, and efficacy analysis including Dr. A. C. Tricco, Dr. S. E. Straus, Ms. W. Zarin, Dr. R. Cardoso, Dr. A.A. Veroniki, Dr. P. A. Khan, Dr. V. Nincic, Mr. M. Ghassemi, Ms. R. Warren, Ms. J. Sharpe and Dr. A. Page. The safety, effectiveness, efficacy literature search strategy was developed and peer-reviewed by librarians Dr. E. Cogo and Dr. J. McGowan.

Appendices: Summary of Evidence Tables

(See Tables 12 and 13 of the NACI Advisory Committee Statement on Updated Recommendations on the Use of Herpes Zoster for details on the ranking of level of evidence and quality of individual studies as summarized in the Summary of Evidence Tables, below.)

Appendix A: Summary of Evidence Related to Efficacy and Effectiveness of Herpes Zoster Vaccines

  • LZV (Zostavax®)
    • Immunocompetent individuals
    • Immunocompromised individuals
  • RZV (Shingrix®)
    • Immunocompetent Individuals

Appendix B: Summary of Evidence Related to Immunogenicity of Herpes Zoster Vaccines

  • LZV (Zostavax®)
    • General population
    • Immunocompromised
  • RZV (Shingrix®)
  • Head to Head Comparison of LZV and RZV
  • Concomitant Administration with Other Vaccines

Appendix C: Summary of Evidence Related to Safety of Herpes Zoster Vaccines

  • LZV (Zostavax®)
    • Immunocompetent individuals
  • RZV (Shingrix®)
  • Immunocompetent individuals

Appendix A: Summary of Evidence Related to Efficacy and Effectiveness of Herpes Zoster Vaccines

Live Zoster Vaccine (Zostavax®) efficacy and effectiveness among immunocompetent individuals
Study Details Summary
Study Vaccine Study Design Participants Summary of Key Findings Using Text or Data Level of Evidence Quality
Langan et al, 2013 Zostavax®  

Age
Individuals aged 65 years or older

Number (immunocompetent):
625,409

Antiviral definition group:
Definition requiring antiviral administration within 7 days before or after the diagnostic code for HZ.

General definition group:
A strict definition for HZ was used and therefore misclassification of incident HZ is not likely, although it is not possible to completely exclude misclassification.

Analyses were adjusted for age, gender, race, low income, immunosuppression, and important comorbidities associated with zoster, and then stratified by immunosuppression status. Cohort was followed for a total of 1,233,333 Person Years (PY).

Results:

Zoster vaccine effectiveness against incident HZ:

Antiviral definition:
Unvaccinated:

  • Events: 11,398
  • PY: 1,291.8
  • Incidence rate (IR) /1000 PY (95% Confidence interval(CI): 10.0 (9.8-10.2)

Vaccinated:

  • Events: 130
  • PY: 26.3
  • IR /1000 PY (95% CI): 4.9 (4.2–5.9)
  • Crude Hazard Ratio (HR) (95% CI): 0.53 (0.44–0.63)
  • Adj. HR (95% CI): 0.49 (0.41–0.59)

General definition:
Unvaccinated:

  • Events: 17,110
  • PY: 1,202.3
  • IR /1000 PY (95% CI): 14.2 (14.0–14.4)

Vaccinated:

  • Events: 289
  • PY: 25.8
  • IR /1000 PY (95% CI): 11.2 (10.0–12.6)
  • Crude HR (95% CI): 0.80 (0.71–0.90)
  • Adj. HR (95% CI): 0.75 (0.67–0.84)

Zoster vaccine effectiveness against incident PHN after 30 days (adjusted for age, gender, race, immunosuppression status, low income, COPD, IBD, kidney disease, diabetes mellitus, rheumatoid arthritis, and SLE):

Antiviral definition:

Unvaccinated:

  • Events: 1,665
  • PY: 2,563.4
  • IR /1000 PY (95% CI): 0.65 (0.62–0.68)

Vaccinated:

  • Events: 16
  • PY: 71.4
  • IR /1000 PY (95% CI): 0.22 (0.14–0.36)
  • Crude HR (95% CI): 0.39 (0.24–0.64)
  • Adj. HR (95% CI): 0.38 (0.23–0.63)

General definition:

Unvaccinated:

  • Events: 2,241
  • PY: 2,507.0
  • IR /1000 PY (95% CI): 0.89 (0.86–0.93)

Vaccinated:

  • Events: 29
  • PY: 70.1
  • IR /1000 PY (95% CI): 0.41 (0.29–0.59)
  • Crude HR (95% CI): 0.52 (0.36–0.76)
  • Adj. HR (95% CI): 0.52 (0.36–0.76)

Zoster vaccine effectiveness against incident PHN after 90 days (adjusted for age, gender, race, immunosuppression status, low income, COPD, IBD, kidney disease, diabetes mellitus, rheumatoid arthritis, and SLE):

Antiviral definition:

Unvaccinated:

  • Events: 871
  • PY: 2,616.5
  • IR /1000 PY (95% CI): 0.33 (0.31–0.35)

Vaccinated:

  • Events: na
  • PY: na
  • IR /1000 PY (95% CI): na
  • Crude HR (95% CI): 0.42 (0.22–0.81)
  • Adj. HR (95% CI): 0.41 (0.21–0.79)

General definition:

Unvaccinated:

  • Events: 1,220
  • PY: 2,581.0
  • IR /1000 PY (95% CI): 0.47 (0.45–0.50)

Vaccinated:

  • Events: 19
  • PY: 70.9
  • IR /1000 PY (95% CI): 0.27 (0.17-0.42)
  • Crude HR (95% CI): 0.64 (0.40–1.00)
  • Adj. HR (95% CI): 0.62 (0.39–0.97)
II-2 Fair
Langan et al, 2016 Zostavax® Cohort study (5% random sample of adults enrolled in US Medicare from 2007 to 2009)

Age
Adults aged 65 years or older.

Number:
N = 766,330

Comorbidities:
None, chronic kidney disease (CKD), diabetes mellitus.

Analysis conducted on total of 1,320,100 PYs of follow-up. CKD was present in 24% of individuals (183,762).

Zoster vaccine effectiveness against incident HZ, adjusted for age, gender, race, low income, immunosuppression, immune-mediated disorders and COPD:

Overall:

Unvaccinated:

  • Events: 12,958
  • PY: 1291.8
  • IR /1000 PY (95% CI): 10.0 (9.8–10.2)
  • Crude HR (95% CI): 1.0
  • Adj. HR (95% CI): 1.0

Vaccinated:

  • Events: 154
  • PY: 28.3
  • IR /1000 PY (95% CI): 5.4 (4.6–6.4)
  • Crude HR (95% CI): 0.55 (0.47–0.64)
  • Adj. HR (95% CI): 0.52 (0.44–0.61)

With Chronic Kidney Disease:

Unvaccinated:

  • Events: 3438
  • PY: 302.0
  • IR /1000 PY (95% CI): 11.4 (11.0–11.8)
  • Crude HR (95% CI): 1.0
  • Adj. HR (95% CI): 1.0

Vaccinated:

  • Events: 28
  • PY: 4.4
  • IR /1000 PY (95% CI): 6.4 (4.4–9.2)
  • Crude HR (95% CI): 0.56 (0.39–0.81)     
  • Adj. HR (95% CI): 0.51 (0.35–0.74) 

With Diabetes Mellitus:

Unvaccinated:

  • Events: 5181
  • PY: 509.2
  • IR /1000 PY (95% CI): 10.2 (9.9–10.4)
  • Crude HR (95% CI): 1.0
  • Adj. HR (95% CI): 1.0

Vaccinated:

  • Events: 46
  • PY: 8.4
  • IR /1000 PY (95% CI): 5.4 (4.1–7.3)
  • Crude HR (95% CI): 0.54 (0.40–0.72)  
  • Adj. HR (95% CI): 0.50 (0.38–0.67)

With CKD and Diabetes Mellitus:

Unvaccinated:

  • Events: 1926
  • PY: 174.9
  • IR /1000 PY (95% CI): 11.0 (10.5–11.5)
  • Crude HR (95% CI): 1.0
  • Adj. HR (95% CI): 1.0

Vaccinated:

  • Events: 14
  • PY: 2.2
  • IR /1000 PY (95% CI): 6.5 (3.8–10.9)
  • Crude HR (95% CI): 0.59 (0.35–1.00)
  • Adj. HR (95% CI): 0.54 (0.32–0.91)
II-2 Fair
Marin et al, 2015 Zostavax® Matched case-control study

Age
60 years or older

Number
N = 628 (n=266 HZ cases and n=362 controls)

Pre-Exposure History: Vaccinated and not vaccinated

Vaccination was associated with 54% (95% CI:32%-69%) reduction in HZ incidence, 58% (95% CI:31%-75%) reduction in HZ
prodromal symptoms, and 70% (95% CI:33%-87%) reduction in medically-attended prodrome at an average of 3 years following vaccination.

HZ vaccine was statistically significant effective at preventing postherpetic neuralgia (PHN) measured at 30 days after rash onset, 61% (95% CI: 22%-80%).

Among persons who developed HZ, no differences were found by vaccination status in severity or duration of HZ pain after rash onset.

Vaccine effectiveness against Herpes Zoster (HZ) overall and by age at vaccination and against other HZ-related outcomes:

Case-patient vs Controls; Vaccine Efficacy (VE) (95% CI)

  • All participants: 266 VS 362; 54.2% (32.0%-69.2%)
  • HZ by age at vaccination:
    -   Unvaccinated:
    189 VS 195; Reference
    -   Vaccinated age 60-69 yrs:
    34 VS 82; 67.1% (42.6%-81.2%)
    -   Vaccinated age 70+:
    38 VS 82; 38.3% (0%-64.2%)
  • HZ prodrome:
    177 VS 250; 58.0% (30.8%-74.5%)
  • HZ-medically attended prodrome:
    95 VS 138; 70.0% (32.8%-86.6%)
  • PHN
    -   Pain at 30 d:
    108 VS 152; 60.5% (22.0%-80.0%)
    -   Pain at 60 d:
    40 VS 55; 69.1% (0%-91.4%)
    -   Pain at 90 d:
    20 VS 27; 55.2% (0%-91.6%)
II-2 Fair
Oxman et al, 2005

Vaccine: live attenuated Oka/Merck
VZV vaccine 18,700 to 60,000
PFUs per dose (>90% received <32,300 PFUs)

Placebo: not stated

Randomized, placebo-controlled, double-blind clinical trial (SPS study)

Age
60 years or older

Number
387,546

Pre-Exposure History:
Eligible subjects had a history of varicella or had resided in the continental United States for at least 30 years.

During the mean duration of HZ surveillance of 3.13 years, reduction in the Burden of Illness (BOI) due to HZ was estimated to be 61.1% (51.1–69.1), PHN 66.5% (47.5–79.2), and HZ incidence 51.3% (44.2-57.6).

Results:

The Effect of Zoster Vaccine on the BOI in HZ in the Modified Intention-to-Treat Population:

Vaccine Group:

All subjects:

  • No. of cases/subjects: 315/19,254
  • BOI Score: 2.21
  • Incidence per 100 PY: 5.42

60-69 yr:

  • No. of cases/subjects: 122/10,370
  • BOI Score: 1.50
  • Incidence per 100 PY: 3.90

70 yr:

  • No. of cases/subjects: 193/8,884
  • BOI Score: 3.47
  • Incidence per 100 PY: 7.18

Male:

  • No. of cases/subjects: 181/11,390
  • BOI Score: 2.09
  • Incidence per 100 PY: 5.30

Female:

  • No. of cases/subjects: 134/7,864
  • BOI Score: 2.34
  • Incidence per 100 PY: 5.58

Placebo Group:

All subjects:

  • No. of cases/subjects: 642/19,247
  • BOI Score: 5.68
  • Incidence per 100 PY: 11.12

60-69 yr:

  • No. of cases/subjects: 334/10,356
  • BOI Score: 4.33
  • Incidence per 100 PY: 10.79

70 yr:

  • No. of cases/subjects: 308/8,891
  • BOI Score: 7.78
  • Incidence per 100 PY: 11.50

Male:

  • No. of cases/subjects: 361/11,337
  • BOI Score: 5.81
  • Incidence per 100 PY: 10.65

Female:

  • No. of cases/subjects: 281/7,910
  • BOI Score: 5.47
  • Incidence per 100 PY: 11.79

The Effect of Zoster Vaccine on PHN in the Modified Intention-to-Treat Population:

Vaccine Group:

All subjects (n=19,254):

  • No. of Confirmed Cases of HZ with PHN: 27
  • Incidence/1000 PY: 0.46

60-69 yr (n=10,370):

  • No. of Confirmed Cases of HZ with PHN: 8
  • Incidence/1000 PY: 0.26

70 yr (n=8,884):

  • No. of Confirmed Cases of HZ with PHN: 19
  • Incidence/1000 PY: 0.71

Male (n= 11,390):

  • No. of Confirmed Cases of HZ with PHN: 19
  • Incidence/1000 PY: 0.56

Female (n=7,864):

  • No. of Confirmed Cases of HZ with PHN: 8
  • Incidence/1000 PY: 0.33

30-day Persistence of PHN among all subjects:

  • No. of Confirmed Cases of HZ with PHN: 81
  • Incidence/1000 PY: 1.39

60-day Persistence of PHN among all subjects:

  • No. of Confirmed Cases of HZ with PHN: 45
  • Incidence/1000 PY: 0.77

90-day Persistence of PHN among all subjects:

  • No. of Confirmed Cases of HZ with PHN: 27
  • Incidence/1000 PY: 0.46

120-day Persistence of PHN among all subjects:

  • No. of Confirmed Cases of HZ with PHN: 17
  • Incidence/1000 PY: 0.29

182-day Persistence of PHN among all subjects:

  • No. of Confirmed Cases of HZ with PHN: 9
  • Incidence/1000 PY: 0.16

Placebo Group:

All subjects (n=19,247):

  • No. of Confirmed Cases of HZ with PHN: 80
  • Incidence/1000 PY: 1.38

60-69 yr (n=10,356):

  • No. of Confirmed Cases of HZ with PHN: 23
  • Incidence/1000 PY: 0.74

70 yr (n=8,891):

  • No. of Confirmed Cases of HZ with PHN: 57
  • Incidence/1000 PY: 2.13

Male (n= 11,337):

  • No. of Confirmed Cases of HZ with PHN: 51
  • Incidence/1000 PY: 1.50

Female (n=7,910):

  • No. of Confirmed Cases of HZ with PHN: 29
  • Incidence/1000 PY: 1.22

30-day Persistence of PHN among all subjects:

  • No. of Confirmed Cases of HZ with PHN: 196
  • Incidence/1000 PY: 3.39

60-day Persistence of PHN among all subjects:

  • No. of Confirmed Cases of HZ with PHN: 113
  • Incidence/1000 PY: 1.96

90-day Persistence of PHN among all subjects:

  • No. of Confirmed Cases of HZ with PHN: 80
  • Incidence/1000 PY: 1.38

120-day Persistence of PHN among all subjects:

  • No. of Confirmed Cases of HZ with PHN: 54
  • Incidence/1000 PY: 0.93

182-day Persistence of PHN among all subjects:

  • No. of Confirmed Cases of HZ with PHN: 33
  • Incidence/1000 PY: 0.57
I Good
Oxman et al, 2008

Vaccine: live attenuated Oka/Merck
VZV vaccine 18,700 to 60,000
PFUs per dose (>90% received <32,300 PFUs)

Placebo: not stated

Randomized, placebo-controlled, double-blind clinical trial (SPS study)

Age:
60 years or older

Number:
N = 387,546

Pre-Exposure History:
Subjects were to have no prior HZ or varicella vaccination.

During the mean duration of HZ surveillance of 3.13 years, HZ vaccine reduced the HZ BOI by 61.1% (95% [CI], 51.1%–69.1%; P < .001) and reduced the incidence of PHN by 66.5% (95% CI, 47.5%–79.2%; P < .001). The incidence of HZ was also reduced by 51.3% (95% CI, 44.2%–57.6%; P < .001).

Results:

HZ VE for the HZ BOI:

All subjects (95% CI):

  • Efficacy: 61.1% (51.1%-69.1%)
  • Vaccine (n=19,247): 2.21%
  • Placebo (n=19,254): 5.68%

60-69 yr:

  • Efficacy: 65.5% (51.5%-75.5%)
  • Vaccine (n=10,356): 1.50%
  • Placebo (n=10,370): 4.33%

70 yr or more:

  • Efficacy: 55.4% (39.9%-66.9%)
  • Vaccine (n=8,891): 3.47%
  • Placebo (n=8,884): 7.78%3

HZ VE for the incidence of HZ:

All subjects (95% CI):

  • Efficacy: 51.3% (44.2%-57.6%)
  • Vaccine (n=19,247): 5.4%
  • Placebo (n=19,254): 11.1%

60-69 yr:

  • Efficacy: 65.5% (55.5%-70.9%)
  • Vaccine (n=10,356): 3.9%
  • Placebo (n=10,370): 10.7%

70 yr or more:

  • Efficacy: 55.4% (25.0%-48.1%)
  • Vaccine (n=8,891): 7.2%
  • Placebo (n=8,884): 11.5%

HZ VE for the Incidence of PHN:

All subjects (95% CI):

  • Efficacy: 66.5% (47.5%-79.2%)
  • Vaccine (n=19,247): 0.46%
  • Placebo (n=19,254): 1.38%

60-69 yr:

  • Efficacy: 65.7% (20.4%-86.7%)
  • Vaccine (n=10,356): 0.26%
  • Placebo (n=10,370): 0.74%

70 yr or more:

  • Efficacy: 66.8% (43.3%-81.3%)
  • Vaccine (n=8,891): 0.71%
  • Placebo (n=8,884): 2.13%
I Good
Schmader et al, 2012

Vaccine: Zostavax®

Placebo: all Zostavax® vaccine constituents except VZV or virus components

Randomized, double-blind, placebo-controlled study

Age
50-59 years

Number
N= 22,439

Pre-Exposure History:
History of varicella or residence in a VZV-endemic area for ≥ 30 years.

The ZV reduced the incidence of HZ (30 cases in vaccine group, 1.99/1000 PYs vs. 99 cases in placebo group, 6.57/1000 PYs). VE   against incident HZ over an average of 1.3 years follow-up was 69.8% (95% CI, 54.1–80.6).

Results:
Zoster Vaccine Group (n= 11,211)

ITT entire study duration (n=11,211):

  • HZ Cases:30
  • Total follow-up in PYs: 15,042.85
  • Estimated incidence/1000 PY: 1.99
  • VE (95% CI): 69.8% (54.1–80.6)

ITT 0.0-0.5 years (n= 11,186):

  • HZ Cases: 9
  • Total follow-up in PYs: 5,536.77
  • Estimated incidence/1000 PY: 1.62
  • VE (95% CI): 76.9% (51.5–90.2)

ITT >0.5-1.0 years (n=10,954):

  • HZ Cases: 13
  • Total follow-up in PYs: 5,420.64
  • Estimated incidence/1000 PY: 2.40
  • VE (95% CI): 64.0% (30.4–82.5)

ITT >1.0-1.5 years (n= 10,747):

  • HZ Cases: 7
  • Total follow-up in PYs: 3,513.60
  • Estimated incidence/1000 PY: 2.00
  • VE (95% CI): 65.2% (14.3–87.6)

ITT >1.5 years (n= 3,743):

  • HZ Cases: 1
  • Total follow-up in PYs: 571.84
  • Estimated incidence/1000 PY: 1.75
  • VE (95% CI): 75.3% (2149.5–99.5)

MITT (n=11,165):

  • HZ Cases: 26
  • Total follow-up in PYs: 14,124.16
  • Estimated incidence/1000 PY: 1.84
  • VE (95% CI): 72.4% (57.0–82.9)

Placebo Group (n= 11,228)

ITT entire study duration (n=11,228):

  • HZ Cases: 99
  • Total follow-up in PYs: 15,009.62
  • Estimated incidence/1000 PY:6.60

ITT 0.0-0.5 years (n= 11,210):

  • HZ Cases: 39
  • Total follow-up in PYs: 5,541.08
  • Estimated incidence/1000 PY: 7.04

ITT >0.5-1.0 years (n=10,953):

  • HZ Cases: 36
  • Total follow-up in PYs: 5,407.72
  • Estimated incidence/1000 PY: 6.66

ITT >1.0-1.5 years (n= 10,712):

  • HZ Cases:,20
  • Total follow-up in PYs: 3,496.06
  • Estimated incidence/1000 PY: 5.72

ITT >1.5 years (n= 3,728):

  • HZ Cases: 4
  • Total follow-up in PYs: 564.76
  • Estimated incidence/1000 PY: 7.08

MITT (n=11,189):

  • HZ Cases: 94
  • Total follow-up in PYs: 14,091.27
  • Estimated incidence/1000 PY: 6.67
I Good
Schmader et al, 2012

Vaccine: live attenuated Oka/Merck
VZV vaccine 18,700 to 60,000
PFUs per dose (>90% received <32,300 PFUs)

Placebo: not stated

Follow-up to SPS double-blind randomized controlled trial (STPS study)

Age
60 years or older

Number
N= 14,270-38,546

Pre-Exposure History:
Eligible subjects had a history of varicella or had resided in the continental United States for at least 30 years.

In the STPS analysis of 16,500 PYs follow-up involving over 14,000 adults, as compared to the SPS, VE for HZ BOI decreased from 61.1% to 50.1%, VE for the incidence of PHN decreased from 66.5% to 60.1%, and VE for the incidence of HZ decreased from 51.3% to 39.6%, although the differences were not statistically significant. Analysis of VE in each year after vaccination for all 3 outcomes showed a decrease in VE after year 1, with a further decline thereafter. VE was statistically significant for the incidence of HZ and the HZ BOI through year 5.

Summary of Study Outcomes, by Year After Vaccination, in the Shingles Prevention Study (SPS) Population, the Short-Term Persistence Substudy (STPS) Population, and the Combined SPS and STPS Populations:

Zoster Vaccine Group (n= 19,270):

One year since randomization (n= 19,254):

  • HZ cases: 69
  • PYs: 17 584
  • HZ Incidence /1000 PYs: 3.9
  • PHN Incidence /1000 PYs: 0.28
  • HZ BOI: 0.49
  • VE for HZ BOI, % (95% CI): 79.2 (66.8–86.9)
  • VE for Incidence of PHN, % (95%CI): 83.4 (56.7–95.0)
  • VE for Incidence of HZ, % (95% CI): 62.0 (49.6–71.6)

Two years since randomization (n= 19,024):

  • HZ cases: 102
  • PYs: 18,869
  • HZ Incidence /1000 PYs: 5.4
  • PHN Incidence /1000 PYs: 0.37
  • HZ BOI: 0.82
  • VE for HZ BOI, % (95% CI): 54.9 (32.0–70.1)
  • VE for Incidence of PHN, % (95%CI): 69.8 (27.3–89.1)
  • VE for Incidence of HZ, % (95% CI): 48.9 (34.7–60.1)

Three years since randomization (n= 18,692):

  • HZ cases: 92
  • PYs: 15 181
  • HZ Incidence /1000 PYs: 6.1
  • PHN Incidence /1000 PYs: 0.66
  • HZ BOI: 1.04
  • VE for HZ BOI, % (95% CI): 44.4 (17.6–62.5)
  • VE for Incidence of PHN, % (95%CI): 38.3 (−44.7 to 75.0)
  • VE for Incidence of HZ, % (95% CI): 46.8 (31.1–59.2)

Four years since randomization (n= 11,689):

  • HZ cases: 49
  • PYs: 6264
  • HZ Incidence /1000 PYs: 7.8
  • PHN Incidence /1000 PYs: 0.64
  • HZ BOI: 0.98
  • VE for HZ BOI, % (95% CI): 66.9 (37.5–82.5)
  • VE for Incidence of PHN, % (95%CI): 60.7 (−36.3 to 91.0)
  • VE for Incidence of HZ, % (95% CI): 44.6 (20.5–61.8)

Five years since randomization (n= 7,197):

  • HZ cases: 26
  • PYs: 3,180
  • HZ Incidence /1000 PYs: 8.2
  • PHN Incidence /1000 PYs: 0.63
  • HZ BOI:0.72
  • VE for HZ BOI, % (95% CI): 74.9 (48.6–87.7)
  • VE for Incidence of PHN, % (95%CI): 73.8 (−37.8 to 97.3)
  • VE for Incidence of HZ, % (95% CI): 43.1 (5.1–66.5)

Six years since randomization (n= 7,086):

  • HZ cases: 48
  • PYs: 4,850
  • HZ Incidence /1000 PYs: 9.9
  • PHN Incidence /1000 PYs: 0.82
  • HZ BOI:1.82
  • VE for HZ BOI, % (95% CI): 23.6 (−58.1 to 63.1)
  • VE for Incidence of PHN, % (95%CI): 32.0 (−100.0 to 87.3)
  • VE for Incidence of HZ, % (95% CI): 30.6 (−6.0 to 54.6)

Seven years since randomization (n= 4,054):

  • HZ cases: 13
  • PYs: 2,243
  • HZ Incidence /1000 PYs: 5.8
  • PHN Incidence /1000 PYs: 0.89
  • HZ BOI:1.44
  • VE for HZ BOI, % (95% CI): 72.5 (9.9–91.6)
  • VE for Incidence of PHN, % (95%CI): 60.0 (−4.5 to 97.1)
  • VE for Incidence of HZ, % (95% CI): 52.8 (−16.5 to 80.5)

SPS Years 0-4.9 (n= 19,254):

  • HZ cases: 315
  • PYs: 58,203
  • HZ Incidence /1000 PYs: 5.4
  • PHN Incidence /1000 PYs: 0.46
  • HZ BOI:0.73
  • VE for HZ BOI, % (95% CI): 61.1 (51.1–69.1)
  • VE for Incidence of PHN, % (95%CI): 66.5 (47.5–79.2)
  • VE for Incidence of HZ, % (95% CI): 51.3 (44.2–57.6)

Short-Term Persistence Study Years (STPS) 3.3-7.8 (n= 7,320):

  • HZ cases: 84
  • PYs: 9,967
  • HZ Incidence /1000 PYs: 8.4
  • PHN Incidence /1000 PYs: 0.70
  • HZ BOI:1.42
  • VE for HZ BOI, % (95% CI): 50.1 (14.1–71.0)
  • VE for Incidence of PHN, % (95%CI): 60.1 (−9.8 to 86.7)
  • VE for Incidence of HZ, % (95% CI): 39.6 (18.2–55.5)

SPS + STPS Years 0-7.8 (n= 19,254):

  • HZ cases: 399
  • PYs: 68,171
  • HZ Incidence /1000 PYs: 5.9
  • PHN Incidence /1000 PYs: 0.50
  • HZ BOI: 0.89
  • VE for HZ BOI, % (95% CI): 58.6 (48.6–66.6)
  • VE for Incidence of PHN, % (95%CI): 64.9 (47.4–77.0)
  • VE for Incidence of HZ, % (95% CI): 48.7 (42.0–54.7)

Placebo Group (n= 19,276):

One year since randomization (n= 19,247):

  • HZ cases: 181
  • PYs: 17,539
  • HZ Incidence /1000 PYs: 10.3
  • PHN Incidence /1000 PYs: 1.71
  • HZ BOI: 2.11

Two years since randomization (n= 18,948):

  • HZ cases: 198
  • PYs: 18,731
  • HZ Incidence /1000 PYs: 10.6
  • PHN Incidence /1000 PYs: 1.23
  • HZ BOI: 1.84

Three years since randomization (n= 18,494):

  • HZ cases: 171
  • PYs: 14,998
  • HZ Incidence /1000 PYs: 11.4
  • PHN Incidence /1000 PYs: 1.07
  • HZ BOI: 1.80

Four years since randomization (n= 11,474):

  • HZ cases: 87
  • PYs: 6,158
  • HZ Incidence /1000 PYs: 14.1
  • PHN Incidence /1000 PYs: 1.62
  • HZ BOI: 2.42

Five years since randomization (n= 6,887):

  • HZ cases: 42
  • PYs: 2,921
  • HZ Incidence /1000 PYs: 14.4
  • PHN Incidence /1000 PYs: 2.40
  • HZ BOI: 2.71

Six years since randomization (n= 6,055):

  • HZ cases: 47
  • PYs: 3,295
  • HZ Incidence /1000 PYs: 14.3
  • PHN Incidence /1000 PYs: 1.21
  • HZ BOI: 2.39

Seven years since randomization (n= 2,237):

  • HZ cases: 11
  • PYs: 896
  • HZ Incidence /1000 PYs: 12.3
  • PHN Incidence /1000 PYs: 2.23
  • HZ BOI: 3.59

SPS Years 0-4.9 (n= 19,247):

  • HZ cases: 642
  • PYs: 57,736
  • HZ Incidence /1000 PYs: 11.1
  • PHN Incidence /1000 PYs: 1.39
  • HZ BOI: 1.89

Short-Term Persistence Study Years (STPS) 3.3-7.8 (n= 6,950):

  • HZ cases: 95
  • PYs: 6,802
  • HZ Incidence /1000 PYs: 14.0
  • PHN Incidence /1000 PYs: 1.76
  • HZ BOI: 2.69

SPS + STPS Years 0-7.8 (n= 19,247):

  • HZ cases: 737
  • PYs: 64,538
  • HZ Incidence /1000 PYs: 11.4
  • PHN Incidence /1000 PYs: 1.43
  • HZ BOI: 2.05
II-3 Fair
Morrison et al, 2015

Vaccine: live attenuated Oka/Merck
VZV vaccine 18,700 to 60,000
PFUs per dose (>90% received <32,300 PFUs)

Placebo: not stated

Follow-up to SPS double-blind randomized controlled trial
(LTPS study)

Age
60 years or older

Number
N= 6,043

Seven years since randomization (nPYs= 6,865):

  • VE for HZ BOI, % (95% CI): 47.7 (20.9–65.5)
  • VE for Incidence of PHN, % (95%CI): 26.3 (−40.0 to 66.3)
  • VE for Incidence of HZ, % (95% CI): 46.0 (28.4–60.2)

Eight years since randomization (nPYs= 6,564):

  • VE for HZ BOI, % (95% CI): 46.2 (25.8–61.0)
  • VE for Incidence of PHN, % (95%CI): 27.5 (−37.5 to 66.9)
  • VE for Incidence of HZ, % (95% CI): 31.1 (11.2–47.6)

Nine years since randomization (nPYs= 6,280):

  • VE for HZ BOI, % (95% CI): 27.6 (4.5–45.1)
  • VE for Incidence of PHN, % (95%CI): 60.5 (7.7–87.2)
  • VE for Incidence of HZ, % (95% CI): 6.8 (−16.5 to 26.4)

Ten years since randomization (nPYs= 5,005):

  • VE for HZ BOI, % (95% CI): 33.3 (1.5–54.8)
  • VE for Incidence of PHN, % (95%CI): 44.2 (−21.5 to 79.5)
  • VE for Incidence of HZ, % (95% CI):  44.2 (−21.5 to 79.5)

Eleven years since randomization (nPYs= 1,470):

  • VE for HZ BOI, % (95% CI): 7.9 (−48.6 to 42.9)
  • VE for Incidence of PHN, % (95%CI):  11.5 (−100.0 to 81.7)
  • VE for Incidence of HZ, % (95% CI):   −1.7 (−57.1 to 37.9)
II-3 Fair
Tseng et al, 2011 Zostavax® Retrospective cohort study

Age
60 years or older

Number
N= 303,044

Immune status:
The study excluded immunocompromised patients

Pre-Exposure History:
No history
of HZ

Analysis conducted for a total of 486,074 PYs.

Comparison of HZ Incidence in Study Cohorts by Vaccination Status (adjusted for age, sex, race, health care utilization, and chronic disease in the model):

Vaccinated Cohort (n= 75,761):

Age 60-64 years (n= 23,195):

  • No. of cases: 204
  • PYs: 38,405
  • Incidence/1000 PYs (95% CI): 5.3 (4.6-6.1)
  • Adjusted HZ (95% CI): 0.50 (0.43-0.58)

Age 65-69 years (n= 20,166):

  • No. of cases: 197
  • PYs: 34,975
  • Incidence/1000 PYs (95% CI): 5.6 (4.9-6.5)
  • Adjusted HZ (95% CI): 0.40 (0.34-0.47)

Age 70-74 years (n=15,426):

  •  No. of cases: 202
  • PYs: 27,635
  • Incidence/1000 PYs (95% CI): 7.3 (6.3-8.4)
  • Adjusted HZ (95% CI): 0.46 (0.39-0.53)

Age 75-79 years (n= 10,978):

  • No. of cases: 146
  • PYs: 19,894
  • Incidence/1000 PYs (95% CI): 7.3 (6.2-8.6)
  • Adjusted HZ (95% CI): 0.45 (0.38-0.54)

Age 80 or more years (n= 5,996):

  • No. of cases: 79
  • PYs: 9,506
  • Incidence/1000 PYs (95% CI): 8.3 (6.6-10.4)
  • Adjusted HZ (95% CI): 0.44 (0.35-0.56)

Overall (n= 75,761):

  • No. of cases: 828
  • PYs: 130,415
  • Incidence/1000 PYs (95% CI): 6.4 (5.9-6.8)
  • Adjusted HZ (95% CI): 0.45 (0.42-0.48)

Unvaccinated Cohort (n= 227,283):

Age 60-64 years (n= 69,585):

  • No. of cases: 1,027
  • PYs: 105,700
  • Incidence/1000 PYs (95% CI): 9.7 (9.1-10.3)

Age 65-69 years (n= 60,498):

  • No. of cases: 1,206
  • PYs: 94,835
  • Incidence/1000 PYs (95% CI): 12.7 (12.0-13.5)

Age 70-74 years (n=46,278):

  • No. of cases: 1,090
  • PYs: 74,532
  • Incidence/1000 PYs (95% CI): 14.6 (13.8-15.5)

Age 75-79 years (n=32,934):

  • No. of cases: 824
  • PYs: 54,074
  • Incidence/1000 PYs (95% CI): 15.2 (14.2-16.3)

Age 80 or more years (n= 17,988):

  • No. of cases: 459
  • PYs: 26,518
  • Incidence/1000 PYs (95% CI): 17.3 (15.8-19.0)

Overall (n= 227,283):

  • No. of cases: 4,606
  • PYs: 35,659
  • Incidence/1000 PYs (95% CI): 13.0 (12.6-13.3)
II-2 Fair
Tseng et al, 2012 Zostavax® Retrospective cohort study

Age
60 years or older

Number:
N= 6,216  Keiser Permanente insurance membres

Vaccinated cohort: immunized between January 2007 and December 2010 and with
HZ diagnosis 180-730 days prior to vaccination.

Unvaccinated cohort:
randomly sampled members who were matched 5:1 to the vaccinated cohort on the basis of birth date (±1 year) were identified.

The average period from the initial HZ episode to the end of follow-up was 3.3 years. Adjusted HRs comparing incidence of recurrent HZ between the vaccinated and the unvaccinated cohort (confirmed case):
Age < 70: 0.39 (.05–4.45)
Age ≥70: 1.05 (.30–3.69)
Overall: 0.73 (.25–2.09)

Vaccinated Cohort (n= 1,036)
Confirmed case:

Age <70 years (n= 533):

  • Cases: 1
  • PYs: 1,006.46
  • Incidence/1000 PYs (95% CI): 0.99 (.02–5.54)
  • Rate Ratio: 0.45 (.06–3.51)

Age 70 or more (n= 503):

  • Cases: 3
  • PYs: 1,098.41
  • Incidence/1000 PYs (95% CI): 2.73 (.56–7.98)
  • Rate Ratio: 1.05 (.30–3.65)

Total (n= 1,036):

  • Cases: 4
  • PYs: 2,104.87
  • Incidence/1000 PYs (95% CI): 1.90 (.52–4.87)
  • Rate Ratio: 0.79 (.28–2.27)

Confirmed, probable and possible case:

Age < 70 years (n= 533):

  • Cases: 2
  • PYs: 1,004.77
  • Incidence/1000 PYs (95% CI): 1.99 (.24–7.19)
  • Rate Ratio: 0.62 (.14–2.71)

Age 70 or more (n= 503):

  • Cases: 3
  • PYs: 1,098.41
  • Incidence/1000 PYs (95% CI): 2.73 (.56–7.98)
  • Rate Ratio: 0.92 (.27–3.15)

Total (n= 1,036):

  • Cases: 5
  • PYs: 2,103.17
  • Incidence/1000 PYs (95% CI): 2.38 (.77–5.55)
  • Rate Ratio: 0.77 (.30–1.98)

Diagnosis code (electronic record):

Age < 70 years (n= 533):

  • Cases: 10
  • PYs: 989.8
  • Incidence/1000 PYs (95% CI): 10.10 (4.84–18.58)
  • Rate Ratio: 1.32 (.66–2.64)

Age 70 or more (n= 503):

  • Cases: 10
  • PYs: 1,088.08
  • Incidence/1000 PYs (95% CI): 9.19 (4.41–16.90)
  • Rate Ratio: 1.25 (.63–2.51)

Total (n= 1,036):

  • Cases: 20
  • PYs: 2,077.88
  • Incidence/1000 PYs (95% CI): 9.63 (5.88–14.87)
  • Rate Ratio: 1.29 (.79–2.11)

Unvaccinated Cohort (n= 5,180)
Confirmed case:

Age < 70 years (n= 2,665):

  • Cases: 11
  • PYs: 5,009.35
  • Incidence/1000 PYs (95% CI): 2.20 (1.10–3.93)

Age 70 or more (n= 2,515):

  • Cases: 14
  • PYs: 2.62 (1.43–4.39)
  • Incidence/1000 PYs (95% CI): 1.05 (.30–3.65)

Total (n= 5,180):

  • Cases: 25
  • PYs: 10,358.76
  • Incidence/1000 PYs (95% CI): 2.41 (1.56–3.56)

Confirmed, probable and possible case:

Age < 70 years (n= 2,665):

  • Cases: 16
  • PYs:5,003.81
  • Incidence/1000 PYs (95% CI): 3.20 (1.83–5.19)

Age 70 or more (n= 2,515):

  • Cases: 16
  • PYs: 5,349.21
  • Incidence/1000 PYs (95% CI): 2.99 (1.71–4.86)

Total (n= 5,180):

  • Cases: 32
  • PYs: 10,353.02
  • Incidence/1000 PYs (95% CI): 3.09 (2.11–4.36)

Diagnosis code (electronic record):

Age < 70 years (n= 2,665):

  • Cases: 38
  • PYs: 4,972.96
  • Incidence/1000 PYs (95% CI): 7.64 (5.41–10.49)

Age 70 or more (n= 2,515):

  • Cases: 39
  • PYs: 5,320.14
  • Incidence/1000 PYs (95% CI): 7.33 (5.21–10.02)

Total (n= 5,180):

  • Cases: 77
  • PYs: 10,293.1
  • Incidence/1000 PYs (95% CI): 7.48 (5.90–9.35)
II-2 Fair
Tseng et al, 2015 Zostavax® Retrospective cohort study

Age
60 years or older

Number
N= 2,310

Overall, PHN risk was 40% lower in vaccinated adults (adjusted RR, 0.59; 95% CI, .41–.85).Thirty vaccinated women (4.2%) experienced PHN, compared with 75 unvaccinated women (10.4%), with an adjusted relative risk of 0.41 (95% CI, .26–.64). PHN occurred in 26 vaccinated men (6.0%) versus 25 unvaccinated men (5.8%), with an adjusted relative risk of 1.06 (.58–1.94). These associations did not differ significantly by age.

Results:
Vaccinated Group (n= 1,155):

Male patients aged 60-69 years (n= 162):

  • PHN cases, (%): 8 (4.94)
  • Unadjusted RR (95% CI): 1.07 (.40–2.85)
  • Adjusted RR (95% CI): 1.16 (.36–3.73)

Male patients aged 70 or more (n= 270):

  • PHN cases, (%): 18 (6.67)
  • Unadjusted RR (95% CI): 1.02 (.52–1.97)
  • Adjusted RR (95% CI): 0.93 (.44–1.94)

Total male patients (n= 432):

  • PHN cases, (%): 26 (6.02)
  • Unadjusted RR (95% CI): 1.04 (.60–1.8)
  • Adjusted RR (95% CI): 1.06 (.58–1.94)

Female patients aged 60-69 years (n= 293):

  • PHN cases, (%): 7 (2.39)
  • Unadjusted RR (95% CI): 0.28 (.12–.64)
  • Adjusted RR (95% CI): 0.30 (.12–.74)

Female patients aged 70 or more (n= 430):

  • PHN cases, (%): 23 (5.35)
  • Unadjusted RR (95% CI): 0.45 (.28–.75)
  • Adjusted RR (95% CI): 0.40 (.25-.64)

Total female patients (n= 723):

  • PHN cases, (%): 30 (4.15)
  • Unadjusted RR (95% CI): 0.40 (.26–.61)
  • Adjusted RR (95% CI): 0.41 (.26–.64)

All patients aged 60-69 years (n= 455):

  • PHN cases, (%): 15 (3.30)
  • Unadjusted RR (95% CI): 0.46 (.25–.84)
  • Adjusted RR (95% CI): 0.53 (.27–1.02)

All patients aged 70 or more (n= 700):

  • PHN cases, (%): 41 (5.86)
  • Unadjusted RR (95% CI): 0.60 (.41–.89)
  • Adjusted RR (95% CI): 0.63 (.41–.96)

Total patients (n= 1 155):

  • PHN cases, (%): 56 (4.85)
  • Unadjusted RR (95% CI): 0.56 (.40–.78)
  • Adjusted RR (95% CI): 0.59 (.41–.85)

Unvaccinated Group (n= 1 155):

Male patients aged 60-69 years (n= 173):

  • PHN cases, (%): 8 (4.62)

Male patients aged 70 or more (n= 259):

  • PHN cases, (%): 17 (6.56)

Total male patients (n= 432):

  • PHN cases, (%): 25 (5.79)

Female patients aged 60-69 years (n= 316):

  • PHN cases, (%): 27 (8.54)

Female patients aged 70 or more (n= 407):

  • PHN cases, (%): 48 (11.79)

Total female patients (n= 723):

  • PHN cases, (%): 75 (10.37)

All patients aged 60-69 years (n= 489):

  • PHN cases, (%): 35 (7.16)

All patients aged 70 or more (n= 666):

  • PHN cases, (%): 65 (9.76)

Total patients (n= 1 155):

  • PHN cases, (%): 100 (8.66)
II-2 Fair
Tseng et al, 2016 Zostavax® Retrospective cohort study

Age
Individuals aged 60 years or older

Number:
N = 176,078

Pre-exposure history:
Members having a diagnosis of HZ during the 1 year prior to
and 30 days after the index date were excluded from analysis.

The effectiveness of HZ vaccine decreased from 68.7% (95% CI, 66.3%–70.9%) in the first year to 4.2% (95% CI, −24.0% to 25.9%) in the eighth year.

Results:

Effectiveness and 95% CI of ZV, by Year After Vaccination:

60-69 years old:

  • 0-<1: 69.9 (66.8-72.8)
  • 1-<2: 52.1 (47.0-56.8)
  • 2-<3: 43.8 (36.7-50.1)
  • 3-<4: 36.6 (26.7-45.2)
  • 4-<5: 39.7 (28.1-49.5)
  • 5-<6: 38.2 (24.4-49.5)
  • 6-<7: 19.4 (-2.7-36.7)
  • 7-<8: -18.3 (-76.1-20.5)

70 years and older:

  • 0-<1: 66.9 (63.1-70.3)
  • 1-<2: 47.0 (41.1-52.4)
  • 2-<3: 33.9 (25.7-41.2)
  • 3-<4: 33.3 (23.4-41.9)
  • 4-<5: 34.3 (22.6-44.3)
  • 5-<6: 28.1 (13.2-40.5)
  • 6-<7: 13.3 (-9.7-31.4)
  • 7-<8: 18.1 (-17.3-42.8)

Total:

  • 0-<1: 8.7 (66.3-70.9)
  • 1-<2: 49.5 (45.7-53.1)
  • 2-<3: 39.1 (33.8-43.9)
  • 3-<4: 35.2 (28.3-41.4)
  • 4-<5: 37.1 (29.1-44.2)
  • 5-<6: 32.9 (23.1-41.5)
  • 6-<7: 16.5 (1.4-29.3)
  • 7-<8: 4.2 (-24.0-25.9)

Comparison of HZ incidence in study cohorts by HZ vaccination status:

Vaccinated (n= 176,078)

Age 60-64 (n= 72,553):

  • No. of cases: 1,506
  • PYs:  239,507
  • Incidence/1000 PYs (95% CI): 6.3 (96.0-6.6)
  • Rate Ratio (95% CI): 0.50 (0.47-0.53)

Age 65-69 (n= 41,276):

  • No. of cases: 1,216
  • PYs: 156,331
  • Incidence/1000 PYs (95% CI): 7.8 (7.4-8.2)
  • Rate Ratio (95% CI): 0.56 (0.53-0.60)

Age 70-74 (n= 25,278):

  • No. of cases:  974
  • PYs: 108,619
  • Incidence/1000 PYs (95% CI):  9.0 (8.4-9.5)
  • Rate Ratio (95% CI): 0.58 (0.54-0.62)

Age 75-79 (n= 18,915):

  • No. of cases:  826
  • PYs:  83,867
  • Incidence/1000 PYs (95% CI): 9.8 (9.2-10.5)
  • Rate Ratio (95% CI): 0.58 (0.54-0.63)

Age 80 or more (n= 18,056):

  • No. of cases: 717
  • PYs:  65,411
  • Incidence/1000 PYs (95% CI): 11.0 (10.2-11.8)
  • Rate Ratio (95% CI): 0.64 (0.59-0.70)

Unvaccinated (n= 528,234)

Age 60-64 (n= 219,165):

  • No. of cases: 6,124
  • PYs: 487,546
  • Incidence/1000 PYs (95% CI): 12.6 (12.3-12.9)

Age 65-69 (n= 122,248):

  • No. of cases: 4,657
  • PYs: 337,160
  • Incidence/1000 PYs (95% CI): 13.8 (13.4-14.2)

Age 70-74 (n= 75,614):

  • No. of cases: 3,710
  • PYs: 239,958
  • Incidence/1000 PYs (95% CI): 15.5 (15.0-16.0)

Age 75-79 (n=56,809):

  • No. of cases: 3,117
  • PYs: 184,864
  • Incidence/1000 PYs (95% CI): 16.9  (16.3-17.5)

Age 80 or more (n= 54,398):

  • No. of cases: 2,573
  • PYs: 151,189
  • Incidence/1000 PYs (95% CI): 17.0  (16.4-17.7)
II-2 Fair
Tseng et al, 2016 Zostavax® Retrospective cohort study

Age
60 years or older

Number
N= 3,492

Comorbidities:
End-stage Renal Disease (ESRD)

The number of HZ cases was 16 in 1373 PYs (11.7 per 1000 PYs; 95% CI, 7.1–19.0) among the vaccinated and 126 in 5644 PYs (22.3 per 1000 PYs; 95% CI, 18.7–26.6) among the unvaccinated. The 36-month cumulative risk of incident HZ was 4.1% and 6.6%, respectively. HZ vaccination was associated with a reduced risk of HZ (adjusted HR = 0.49; 95% CI, .29–.85). The reduced risk seems more prominent if the vaccine is given within two years of dialysis initiation.

Comparison of HZ incidence in ESRD patients by HZ vaccination status:

Vaccinated Group (n= 582):

Aged < 70 years (n= 331):

  • No. of cases: 9
  • PYs: 755
  • Incidence/1000 PYs (95% CI): 11.9 (6.2- 22.9)
  • Rate Ratio (95% CI): 0.6 (0.3-1.1)
  • Unadjusted HR (95% CI): 0.48 (0.23-0.98)
  • Adjusted HR: (95% CI): 0.43 (0.29-0.85)

Aged 70 or more years (n= 251):

  • No. of cases:  7
  • PYs: 618
  • Incidence/1000 PYs (95% CI): 11.3 (5.4- 23.8)
  • Rate Ratio (95% CI): 0.5  (0.2-1.0)
  • Unadjusted HR (95% CI): 0.52 (0.23-1.15)
  • Adjusted HR: (95% CI): 0.45 (0.19-1.07)

Hemodialysis (n= 496):

  • No. of cases: 15
  • PYs: 1190
  • Incidence/1000 PYs (95% CI): 12.6 (7.6- 20.9)
  • Rate Ratio (95% CI): 0.6 (0.3-1.0)
  • Unadjusted HR (95% CI): 0.57 (0.32-0.99)
  • Adjusted HR: (95% CI): 0.58 (0.32-1.04)

Peritoneal dialysis (n= 86):

  • No. of cases: 1
  • PYs: 183
  • Incidence/1000 PYs (95% CI): 5.5 (0.8- 38.8)
  • Rate Ratio (95% CI): 0.2 (0.0-1.3)

< 2 years on dialysis before index date (n= 256):

  • No. of cases: 7
  • PYs: 658
  • Incidence/1000 PYs (95% CI): 10.6 (5.1- 22.3)
  • Rate Ratio (95% CI): 0.5 (0.2-1.0)
  • Unadjusted HR (95% CI): 0.37 (0.16-0.89)
  • Adjusted HR: (95% CI): 0.28 (0.10-0.73)

2 or more years on dialysis before index date (n= 326):

  • No. of cases: 9
  • PYs: 715
  • Incidence/1000 PYs (95% CI): 12.6 (6.6- 24.2)
  • Rate Ratio (95% CI): 0.6 (0.3-1.1)
  • Unadjusted HR (95% CI): 0.59 (0.28-1.24)
  • Adjusted HR: (95% CI): 0.64 (0.29-1.40)

Total (n= 582):

  • No. of cases: 16
  • PYs: 1,373
  • Incidence/1000 PYs (95% CI): 11.7 (7.1- 19.0)
  • Rate Ratio (95% CI): 0.5 (0.3-0.9)
  • Unadjusted HR (95% CI): 0.49 (0.29-0.84)
  • Adjusted HR: (95% CI): 0.49 (0.29-0.84)

Unvaccinated Group (n= 582):

Aged < 70 years (n= 1 655):

  • No. of cases: 67
  • PYs: 3,230
  • Incidence/1000 PYs (95% CI): 20.7 (16.3- 26.4)

Aged 70 or more years (n= 1255):

  • No. of cases: 59
  • PYs: 2,414
  • Incidence/1000 PYs (95% CI): 24.4 (18.9- 31.5)

Hemodialysis (n= 2,574):

  • No. of cases: 108
  • PYs: 5,066
  • Incidence/1000 PYs (95% CI): 21.3 (17.7- 25.7)

Peritoneal dialysis (n= 336):

  • No. of cases: 18
  • PYs: 578
  • Incidence/1000 PYs (95% CI): 31.1 (19.6- 49.4)

< 2 years on dialysis before index date (n= 1320):

  • No. of cases: 59
  • PYs: 2,603
  • Incidence/1000 PYs (95% CI):  22.7 (17.6- 29.3)

2 or more years on dialysis before index date (n= 1590):

  • No. of cases: 67
  • PYs: 3,041
  • Incidence/1000 PYs (95% CI): 22.0 (17.3- 28.0)

Total (n= 2910):

  • No. of cases: 126
  • PYs: 5,644
  • Incidence/1000 PYs (95% CI):  22.3 (18.7- 26.6)
II-2 Fair
McDonald et al, 2017 Zostavax® Retrospective cohort Study Age
50 years of age and older
Number
1,094,236 (1,005,869 immunocompetent; 636,581 50-59 years of age)

Among 1,094,236 individuals identified in the Alberta Health Care Insurance Plan Registry (AHCIP) cohort (2009-2015), 85,439 (7.80%) received Zostavax®. HZ IR was 9.03 [95% CI: 8.95, 9.11] cases per 1,000 PY (49,243 cases).

Vaccine Effectiveness from Years 1-5 since vaccination (95% CI):

  • One year since vaccination 50+: 50.02% (44.71%, 54.83%)
  • One year since vaccination 50–59: 50.34% (36.01%, 61.55%).
  • Two years since vaccination (n=57,752): 34.50% (44.71%, 54.83%)
  • Three years since vaccination (n=38,972): 31.45% (21.80%, 39.91%)
  • Four years since vaccination (n=16,669): 30.46% (13.86%, 44.32%)
  • Five years since vaccination (n= 3,696): 14.00% (-20.99%, 38.88%)
II-2 Fair
Subunit Vaccine (Shingrix®) efficacy among immunocompetent individuals
Study Details Summary
Study Vaccine Study Design Participants Summary of Key Findings Using Text or Data Level of Evidence Quality
Cunningham et al. 2016

Vaccine: Shingrix®

Placebo: 0.9% saline
Randomized, placebo-controlled, phase 3 trials (ZOE-50 and ZOE-70)

Age
Adults 70 years or older

Number:
N = 16,596

Participants received two doses of RZV or
placebo (assigned in a 1:1 ratio) intramuscularly 2 months apart.

RZV Group:
Overall (n = 8,250)
70-79 yr (n = 6,468)
≥80 yr (n = 1,782)

Placebo Group:
Overall (n = 8,346)
70-79 yr (n = 6,554)
≥80 yr (n = 1,792)

Results:

HZ

  • VE % [95% CI] :
    Overall : 91.3% [86.8-94.5](n=16,596)
    - 70-79yr: 91.3% [86.0-94.9](n=13,022)
    - ≥80 yr : 91.4% [80.2-97.0] (n=3,574)
  • Four-year follow-up:
    -   Year 1 VE (n=16,596): 97.6 [90.0-99.8]
    -   Year 2 VE (n=16,063): 92.0 [82.8-96.9]
    -   Year 3 VE (n=15,397): 84.7 [69.0-93.4]
    -   Year 4 VE (n=14,693): 87.9 [73.3-95.4]

RZV Group

  • Overall (n = 8,250):
    -   HZ cases: 25
    -   PY: 30,725.5
    -   IR: 0.8
  • 70-79 yr (n = 6,468)
    -   HZ cases: 19
    -   PY: 24,410.9
    -   IR: 0.8
  • ≥80 yr (n = 1,782)
    -   HZ cases: 6
    -   PY: 6,314.6
    -   IR: 1.0

Placebo Group:

  • Overall (n = 8,346):
    -   HZ cases: 284
    -   PY: 30,414.7
    -   IR: 9.3
  • 70-79 yr (n = 6,554)
    -   HZ cases: 216
    -   PY: 24,410.9
    -   IR: 8.9
  • ≥80 yr (n = 1,792)
    -   HZ cases: 68
    -   PY: 6,151.9
    -   IR: 11.1

Postherpetic Neuralgia (PHN)

  • VE % [95% CI] :
    ≥70 yr: 88.8% [68.7-97.1] (n=16,596)
    ≥50 yr: 91.2% [75.9-97.7] (n=27,916)

RZV Group

  • Overall (n = 8,250):
    -   PHN cases: 4
    -   PY: 30,760.3
    -   IR: 0.1

Placebo Group:

  •  Overall (n = 8,346):
    -   PHN cases: 36
    -   PY: 30,942.0
    -   IR: 1.2

Vaccine effectiveness against PHN among 3,491 individuals 50-59 years of age was also reported: 100% (40.8%-100%)

I Good
Lal et al, 2015

Vaccine: Shingrix®

Placebo:0.9% saline solution
Randomized, placebo-controlled, phase 3 study (ZOE-50)

Age
adults ≥50 years of age

Number
15,411 partici-pants received at least one dose of vaccine
(7,698) or placebo (7,713).

Modified vaccinated cohort (n=14,759): Participants received 2 doses of vaccine 2 months apart

Total vaccinated cohort (n=15,411): Participants received at least 1 vaccine. During a mean follow-up of 3.2 years, HZ was confirmed in 6 participants in the vaccine group and in 210 participants in the placebo group (IR, 0.3 vs. 9.1 per 1000PYs).

Modified vaccinated cohort:

  • VE % [95% CI] :
    - Overall: 97.2% [93.7-99.0] (n=14,759)
    - 50-59 yr: 96.6% [89.6-99.3] (n=7,017)
    - 60-69yr: 97.4% [90.1-99.7](n=4,307)
    - ≥70 yr : 97.9% [87.9-100.0] (n=3,435)

RZV Group:

  • Overall (n = 7,344):
    -   HZ cases: 6
    -   PY: 23,297.0
    -   IR: 0.3
  • 50-59 yr (n = 3,492)
    -   HZ cases: 3
    -   PY: 11,161.3
    -   IR: 0.3
  • 60-69 yr (n = 2,141)
    -   HZ cases: 2
    -   PY: 7,007.9
    -   IR: 0.3
  • ≥70 yr (n = 1,711)
    -   HZ cases: 1
    -   PY: 5,127.9
    -   IR: 0.2

Placebo Group:

  • Overall (n = 7,415):
    -   HZ cases: 210
    -   PY: 23,170.5
    -   IR: 9.1
  • 50-59 yr (n = 3,525)
    -   HZ cases: 87
    -   PY: 11,134.7
    -   IR: 7.8
  • 60-69 yr (n = 2,166)
    -   HZ cases: 75
    -   PY: 6,952.7
    -   IR: 10.8
  • ≥70 yr (n = 1,724)
    -   HZ cases: 48
    -   PY: 5,083.0
    -   IR: 9.4

Total vaccinated cohort:

  • VE % [95% CI] :
    - Overall: 96.2% [92.7-98.3] (n=15,411)
    - 50-59 yr: 96.9% [90.6-99.4] (n=7,289)
    - 60-69yr: 94.1% [85.6-98.1](n=4,490)
    - ≥70 yr : 98.3% [89.9-100.0] (n=3,632)

RZV Group:

  • Overall (n = 7,698):
    -   HZ cases: 9
    -   PY: 25,584.5
    -   IR: 0.4
  • 50-59 yr (n = 3,645)
    -   HZ cases: 3
    -   PY: 12,244.9
    -   IR: 0.2
  • 60-69 yr (n = 2,244)
    -   HZ cases: 5
    -   PY: 7,674.1
    -   IR: 0.7
  • ≥70 yr (n = 1,809)
    -   HZ cases: 1
    -   PY: 5,665.5
    -   IR: 0.2

Placebo Group:

  • Overall (n = 7,713):
    -   HZ cases: 235
    -   PY: 25,359.9
    -   IR: 9.3
  • 50-59 yr (n = 3,644)
    -   HZ cases: 95
    -   PY: 12,162.5
    -   IR: 7.8
  • 60-69 yr (n = 2,246)
    -   HZ cases: 83
    -   PY:  7,581.8
    -   IR: 10.9
  • ≥70 yr (n = 1,823)
    -   HZ cases: 57
    -   PY: 5,615.6
    -   IR: 10.2
I Good

Appendix B: Summary of Evidence Related to Immunogenicity of Herpes Zoster Vaccines

Live vaccine studies in the general population (n=22)
Study Details Summary
Study Vaccine Study Design Participants Summary of Key Findings Using Text or Data Level of Evidence Quality

Gilbert et al, 2014

Zostavax® among 50-59 year olds

Randomized controlled trial (subset of ZEST trial) to assess correlates of protection

n=2491

n=1218 (vaccine group)

n=1273 (placebo group)

Anti-VZV antibodies using gpELISA measured at baseline and 6 weeks

GMT in vaccine group increased from 284 (95% CI 267,303) to 662 (95% CI 627, 698); GMFR was 2.31 (95% CI 2.20, 2.43)

GMT and GMFR were unchanged in placebo group

Level I

Good

Levin et al, 2013

Zostavax® among 50-59 year olds

Randomized, double-blind, placebo-controlled multicentre study

n=2269 (subset of ZV efficacy trial n=22,439)

n=1136 (vaccine group)

n=1133 (placebo group)

Anti-VZV antibodies through gpELISA at baseline and week 6

GMT increase from 293.1 to 660.0 from baseline to week 6 in vaccine group, a GMFR of 2.31 while antibodies were unchanged in placebo group

Level I

Good

Levin et al, 2008

Zostavax® among 60 years and older

Randomized, double-blind, placebo-controlled trial

Denver and San Diego

n=1395 (subset of SPS n=38,546)

n=691 (vaccine group)

n=704 (control group)

CMI: Responder cell frequency (RCF) assay and spot forming cells (SFCs) (IFN-gamma) via ELISPOT at baseline, week 6, and years 1, 2, and 3

Humoral immunity: Anti-VZV antibodies with gpELISA at baseline, week 6, and years 1, 2, and 3

CMI (both measures) and humoral immunity were higher among those who received vaccine, an effect that persisted up to 3 years. RCF & SCF GMTs and Anti-VZV antibodies peaked at 6 weeks and decreased afterwards

Level I

Good

Vermeulen et al, 2011

Zostavax®  among 60 years and older

Randomized, placebo-controlled, double-blind, trial

n=210 (all ≥60 years)

n=104 (2 doses of Zostavax® 6 weeks apart)

n=105 (placebo)

CMI: IFN-gamma SFCs through ELISPOT at baseline, 2 and 6 weeks after each dose), and 6 months post-vaccination

GMCs were higher among the vaccine group and peaked at 2 weeks post-vaccination 1; by 6 months post-vaccination 2, GMCs were higher than baseline but lower than peak levels

Humoral immunity: Anti-VZV antibodies through gpELISA at baseline and 2 and 6 weeks after immunization

Anti-VZV antibodies were higher among the vaccine group and peaked at 2 weeks post-vaccination 1

In general, a second dose of Zostavax® did not boost VZV-specific immunity

Level I

Good

Weinberg et al, 2009

Zostavax®

Randomized, double-blind, placebo-controlled, trial

n=2,343 (from SPS trial)

n=981 (developed zoster)

n=1,362 (no zoster)

CMI (IFN-gamma through ELISPOT) corresponded with zoster morbidity whereas humoral immunity (Anti-VZV antibodies through gpELISA) did not correspond as strongly with morbidity

Level I

Good

Beals et al, 2016

Zostavax® (in various doses intradermally and subcutaneously)

Randomised, partially-blinded  parallel group study (there were concomitant placebo given)

3 clinics in Colorado and Florida

n=223

6 groups (full dose & 1/3 dose subcutaneous; full dose, 1/3 dose, 1/10 dose, and 1/27 dose intradermal)

≥ 50 with a history of varicella or residing in a varicella endemic country for 30 years or more

Anti-VZV antibodies (GMT through gpELISA, GMC through ELISPOT) pre-vaccination and at 6 weeks and 18 months

Full dose subcutaneous (SC) resulted in GMFR of 1.74 (90% CI 1.48, 2.04) post 6-weeks compared to 3.25 (90% CI 2.68, 3.94) for intradermal. GMFR persisted for intradermal but not SC administration at 18 months.

Level I

Fair (no control group that did not receive vaccine, imbalance in gender distribution for some of the groups)

Diez-Domingo et al, 2015

Zostavax® (administered subcutaneous-ly and intramuscular IM)

Open-label non-inferiority trial
Germany, Spain

n=354

n=177 (IM group)

n=177 (SC group)

CMI: ELISPOT assay measured for a subset of participants using at baseline and 4 weeks post-vaccination

CMI was comparable between IM and SC groups

Humoral immunity: VZV antibody titres measured for all participants at baseline and 4 weeks post-vaccination

Humoral immunity was comparable between IM and SC groups.

Level I

Fair (No control group that did not receive vaccine, CMI was measured only for a subset of study population)

Gilderman et al, 2008

Zostavax® (refrigerator-stable versus frozen formulation)

Double-blind, randomized controlled trial

n=368 initial enrollment

n=182 (refrigerated vaccine)

n=185 (frozen vaccine)

Anti-VZV antibodies using gpELISA measured at baseline and 28 days

GMT and GMFR for refrigerator and frozen formulations were similar

Level I

Fair (on control group without vaccine)

Sutradhar et al, 2009

Zostavax®

Randomized, double-blind, clinical trial

n=1122 (from two separate multicentre trials)

n=389 (50-59y years)

n=733 (≥60 years)

Anti-VZV antibodies through gpELISA at baseline and 4 weeks

GMTS and GMFRs were higher among both groups following vaccination, but slightly higher among 50-59 age group – adjusting for pre-vaccination titers, GMFR ratio for 50-59 versus ≥60 was
1.13 (95% CI 1.02, 1.25)

Level I

Fair (no control group that did not receive vaccine)

Vesikari et al, 2013

Zostavax® (1 dose and 2 doses at 0 and 1 months or 0 and 3 months)

Phase 3, open-label, randomized trial

n=759 (all ≥70 years)

n=243 (1 dose)

n=203 (2 doses 1 month apart)

n=198 (2 doses 3 months apart)

Anti-VZV antibodies through gpELISA at baseline and 4-weeks post-dose 1 and 2 and 12 months post last dose

GMCs were similar between the 1 and 2-dose schedules at all time points

Level I

Fair (no control group that did not receive vaccine)

Levin et al, 2016

Zostavax® (second dose administered 10 years after first dose)

Non-randomized controlled study

n=600

n=201 (prior Zostavax®, ≥70 years)

n=199 (no prior Zostavax®, ≥70 years) 

n=100 (no prior Zostavax®, 60-70 years)

n=100 (no prior Zostavax®, 50-60 years)

CMI: SFCs (IFN-gamma & IL-2) via ELISPOT at baseline and weeks 1, 6, and 52

SFCs were significantly higher at baseline and up to 52 weeks after re-vaccination for those previously vaccinated compared to other groups, suggesting a residual effect of CMI that is enhanced by booster

Humoral immunity: Anti-VZV antibodies with gpELISA at baseline and weeks 1, 6, and 52

All groups developed an increase in GMT at week 1 which peaked at week 6 while by week 52 GMTs were not significantly higher than baseline

In general, baseline levels of CMI and humoral immunity were higher among younger people

Level II-1

Fair (no randomization, not all outcome measures were compared)

Arnou et al, 2011

Zostavax® (one dose)

Phase IV Open-label non-randomized study of Zostavax® within 6 months of expiration

6 centres in France

n=96

n=50 between 50-59 years; n=46 ≥ 60 years

Anti-VZV antibodies through gpELISA pre-vaccination and 28-35 days after vaccination

GMFR for the 50-59 age group was 3.9 (95% CI 3.0, 5.1) compared to 2.6 (95% CI 2.0, 3.4).

Level II-2

Poor (no control group, patient characteristics not reported, no description of withdra-wals)

Choi et al, 2016

Zostavax® (one dose) in Korean Adults

Open-label, single-arm Phase 4 study

n=180

VZV antibody GMT and GMFR at baseline and 4 weeks

GMT increased from baseline of 66.9 (95% CI 59.2, 75.5) to 185.4 (95% CI 167.0, 205.9), representing GMFR of 2.8 (95% CI 2.3-3.1)

GMFR for ≥60 was 2.6 while for 50-59 was 2.9

Level II-2

Poor (no control group, protocol deviation in 14 or 7.8% of subjects)

Laing et al, 2015

Zostavax®

Cohort

n=12

Magnitude and breadth of CD4+ T-cell response at baseline and 2, 4, and 26 weeks post-vaccination

Essentially, vaccination increased the magnitude (2.3 times) and breadth (4.2 times) of CD4+ cells at one-month, although levels declined by 6 months

Level II-2

Poor (non-randomized, small sample size)

Macaladad et al, 2006

Zostavax® among seronegative and low-seropositive adults

Cohort study (initially conceived of as RCT, but enrollment too low)

n=21 (adults ≥ 30 years)

n=18 (vaccine group)

n=3 (placebo group)

Anti-VZV antibodies through gpELISA at baseline and week 6

Antibody response was higher in vaccine group compared to placebo, but higher among low-seropositive (GMT=25.7 units/mL) than among seronegative (GMT=12.0 units/mL)

Level II-2

Poor (small sample size, very small control group)

Patterson-Bartlett et al, 2007

Zostavax®

Cohort study for phenotypic and functional characterization of T-cells

n=25 (20 of whom are ≥ 60 years)

n=10 (vaccine group)

n=10 (placebo group)

n=5 (young adult controls)

Vaccine significantly increased VZV-specific Th1, memory, early effector, and cutaneous homing receptor-bearing T-cells

Level II-2

Poor

Qi et al, 2016

Zostavax®

Cohort study to assess defective T-memory cell differentiation

n=39

IFN-gamma ELISPOT at baseline, and day 8, 14, and 28 post-vaccination and Anti-VZV antibodies through ELISA at baseline and 28-days post-vaccination

IFN-gamma T-cells increased peaked at 10 times baseline between 8 and 14 days and declined to 3 times baseline by day 28; correlation between increases in Anti-VZV antibodies and T-cell frequencies did not reach significance, suggesting these responses are independent

Level II-2

Poor

Sei et al, 2015

Zostavax®

Cohort study to assess breadth, magnitude, and quality of ex vivo CD4+ & CD8+ response

n=21

The response of multiple antigens to multiple types of T-cells was assessed. Authors postulate that an increase in poly-functional CD4+ and ORF9-specific CD8+ cells contribute to efficacy

Level II-2

Poor

Weinberg et al, 2017

Zostavax®

Cohort study to assess differences in immune response between younger and older adults

n=58

n=25 (25-40 years old)

n=33 (60-80 years old)

Older adults appear to have higher proportion of senescent and exhausted VZV-specific T-cells, leading to overall poor effector response to a VZV challenge.

Level II-2

Poor

Yao et al, 2015

Zostavax® among Taiwanese adults

Cohort study

n=150

Anti-VZV antibodies through gpELISA were higher 4 weeks post-vaccination, with a GMFR of 3.05 (95% CI 2.6, 3.6)

Level II-2

Poor

Sullivan et al, 2013

Zostavax®

Cohort study comparing B and T-cell proliferation among young and old

n=39

n=16 (25-40 years old)

n=23 (60-79 years old)

There was a transient increase in B-cell proliferation in both groups, but a significant reduction in the elderly group. There were no differences in proliferation of CD4+ or CD8+ T-cells between young and old

Level II-2

N/A pending full methods

Weinberg et al, 2015 [abstract]

Zostavax®

Cohort study

n=400 (all ≥70 years)

n=201 (Zostavax® ≥10 years prior)

n=199 (no prior Zostavax®)

Anti-VZV antibodies increased following vaccination and GMCs were similar across both groups

IFN-gamma cell counts were higher in previously vaccinated group at week 6 (peak response) and year 1

Level II-2

N/A pending full methods

Live vaccine studies in immunocompromised populations (n=12)
Study Details Summary
Study Vaccine Study Design Participants Summary of Key Findings Using Text or Data Level of Evidence Quality

Mullane et al, 2013

ZVHT administered four times 30 days apart in  populations with solid tumor malignancy, hematologic malignancy, HIV with CD4 <200, autologous HSCT,  and allogenic HSCT

Randomized, double-blind, placebo-controlled multicentre study

n=262 (vaccine group)

n=79 (placebo group)

Anti-VZV antibodies through gpELISA and IFN-gamma ELISPOT counts pre-vaccination and 28 days after 4 doses

GMFR for anti-VZV antibodies ranged from 0.9 to 2.4 depending on type of immunosuppression; For allogenic and autologous HSCT patients there were no changes in GMFR for anti-VZV antibodies.

GMFR for IFN-gamma ELISPOT ranged from 0.2 to 9.0 depending on type of immunosuppression; For allogenic HSCT patients there was a significant decline in GMFR for IFN-gamma.

Level I

Good

Russell et al, 2015

Zostavax® in patients on chronic / maintenance corticosteroids

Randomized, double-blind, placebo-controlled, multicentre study

n=314 (initial enrollment, (adults ≥60 years)

n=206 (VZV group)

n=101 (placebo group)

Anti-VZV antibodies through gpELISA at baseline and 6 weeks

GMFR among vaccine group was 2.3 (95% CI 2.0, 2.7), higher than that of placebo group with a GMFR of 1.1 (95% CI 1.0, 1.2)

Level I

Good

Winthrop et al, 2017

Zostavax® among rheumatoid arthritis patients on methotrexate with and without Tofacitinb

Randomized controlled trial

n=112

n=55 (Tofacitinib group started 2- weeks post-vaccination)

n=57 (no Tofactinib group)

Both CMI and humoral immunity were similar among those receiving Tofacitinb and placebo at 6 weeks post vaccination: The GMFR for Anti-VZV antibodies was 2.11 in the Tofacitinib group versus 1.74 in the placebo group while the GMFR for IFN-gamma SFCs was 1.50 in the Tofacitinib group versus 1.29 in the placebo group .

The magnitude of the humoral response was comparable to those seen in patients without rheumatoid arthritis while the CMI response was slightly less than in patient without rheumatoid arthritis.

Level I

Fair (no control group that did not receive vaccine, small sample size)

Camacho et al, 2010
[Abstract]

ZVHT administered four times 30 days apart in adults with hematologic malignancy

Phase I randomized, double-blind, placebo-controlled study

n=80

n=61 received  ZVHT

n=19 received placebo

Anti-VZV antibodies through gpELISA and IFN-gamma ELISPOT counts pre-vaccination and 28 days after 4 doses

GMFR for anti-VZV antibodies was 1.3 (90% CI 1.1, 1.5) and 2.2 (90% CI 1.4, 3.5) for IFN-gamma ELISPOT.

Level I

N/A
pending full methods

McAdam et al, 2013 [abstract]

Inactivated Varicella Zoster Virus vaccine - ZVin (4 doses, 30 days apart) among patients with autoimmune disease on and not on biologics

Randomized, double-blind, placebo-controlled trial

n~340

n~180 (ZVin at lower Ag level)

n~100 (ZVin at higher Ag level)

n~60 (placebo)

Anti-VZV antibodies through gpELISA and IFN-gamma through ELISPOT at baseline, postdose 2 (half of patients), postdose 3 (other half of patients), and 4 weeks after last dose

At 28 days, there were statistically significant increases for both gpELISA (GMFR 1.57) and ELISPOT (GMFR 2.01) assays

Level I

N/A pending full methods

Winston et al, 2011 [abstract]

Heat-treated zoster vaccine (ZVHT) among patients with allogenic or autologous HSCT

Randomized, double-blind, placebo-controlled trial

n=100

n=40 (vaccine group allogenic HSCT)

n=10 (no vaccine allogenic HSCT)

n=40 (vaccine group autologous HSCT)

n=10 (no vaccine autologus HSCT)

Humoral immunity as measured through VZV-specific antibodies declined among patients with allogenic and autologous HSCT.

CMI as measured through IFN-gamma response were elicited among autologous HSCT patients (GMFR 7.6 at post-dose 4) but not among allogenic HASCT patients (GMR 0.2 at post-dose 4)

Level I

N/A pending full methods

Wasan et al, 2016

Zostavax® among IBD patients on low-dose immunomo-dulators or    5-ASA or no therapy

Cohort study of patients immunosuppressed and not

n=39

n=14 (immunosuppressed – i.e. low-dose immunomodulators)

n=25 (not immunosuppressed – i.e. 5-ASA or no therapy)

Immunosuppressed patients had a weaker immune response (both CMI & humoral) compared those not immunosuppressed, but their response was still significant at 2 and 6 weeks post-vaccination.

Level II-2

Fair (control group present, but small sample size and no randomization)

Hata et al, 2013

Zostavax® among diabetes mellitus patients

Cohort study

n=20

n=10 (healthy volunteers)

n=10 (diabetic patients)

CMI: IFN-gamma through ELISPOT at baseline and months 3 and 6
SFC ratios at 6 months versus baseline were 2.3 for diabetic patients and 3.3 for healthy volunteers (not significantly different)

Humoral immunity: Antibodies through immunoadherence hemagglutination (IAHA) test at baseline and months 3 and 6

No significant difference in antibody titres at 6 months between the two groups

Level II-2

Poor (non-randomized trial, small sample size)

Irwin et al, 2013

Zostavax® among patients with major depressive disorder (MDD)

Cohort study

n=92 (subset of the SPS study population)

n=40 (MDD stratified by those on and not on antidepressant medications)

n=52 (never mentally ill)

CMI: VZV-RCF and IFN-gamma ELISPOT at baseline and 6, 52, and 104 weeks

Among those with MDD who were treated, VZV-RCF levels at 6 weeks were similar to non-depressed controls; Among those with MDD who were not treated, VZV-RCF at 6 weeks was unchanged from baseline; no significant differences in IFN-gamma levels across time and age groups

Humoral immunity: Anti-VZV antibodies using gpELISA at baseline and 6, 52, and 104 weeks 

No significant differences in VZV-antibody levels across time and age groups

Level II-2

Poor (non-randomized, outcome reporting unclear, 12 of 52 initially selected in MDD group refused to participate)

Parrino et al, 2017

Inactivated zoster vaccine (ZVin 4 dose regimen) among patients with hematologic malignancies with anti-CD20 monoclonal antibody treatment

Open-label, single-arm Phase 1 study

n=80 (adults ≥ 18 years)

VZV IFN-gamma ELISPOT assay at baseline and 28-35 days postdose 4

GMFR 28-35 days postdose 4 was 4.34 (90% CI 3.0, 6.2)

Level II-2

Poor (no control group)

Kho et al, 2016 [abstract]

Zostavax® among patients with end-stage renal disease awaiting transplant

Cohort study

n=53

n=26 (ESRD patients)

n=27 (gender and age-matched kidney donors)

VZV-specific IgG titres measured at baseline and 1, 3, and 12 months post-vaccination

IgG titers among ESRD patients and controls were comparable and higher at all time points after baseline

Level II-2

N/A pending full methods

Wasan et al, 2012

Zostavax® among IBD patients on methrotrexate or thiopurines

Cohort study of patients ≥50 years

n=17

n=8 (low dose immunosuppres-sive therapy)

n=9 (no immunosuppresive therapy)

Immunocompetent patients with IBD were able to mount a significant humoral and CMI response while immunosuppressed patients did not mount a significant humoral response but did mount a significant but reduced CMI response.

Level II-2

N/A pending full methods

Subunit (RZV) vaccine studies in the general population (n=10)
Study Details Summary
Study Vaccine Study Design Participants Summary of Key Findings Using Text or Data Level of Evidence Quality

Chlibek et al, 2013

RZV (Two 50 ug doses 2 months apart with different amounts and types of adjuvant)

Phase 2 randomized controlled trial

Czech Republic, Spain, United States

n=410 initial enrolment

n=150 (RZV + AS01B)
n=149 (RZV + ASO1E)
n=73 (RZV + saline)

n=38 (saline alone)

CMI: CD4+ T-cells with at least two activation markers) at baseline, 1, and 3 months

Response highest in those with AS01B, then AS01E, then saline

Humoral immunity: Serum anti-gE and Anti-VZV antibodies at baseline, 1, and 3 months

Response highest in those with AS01B, then AS01E, then saline

Similar immunogenicity was noted across 50-59, 60-69, and ≥70 age groups for those given AS01B

Level I

Good

Leroux-Roels et al, 2012

RZV (two doses 2 months apart), Varilrix (two doses 2 months apart), or both

Phase 1/2 open-label, randomized, parallel-group study

Belgium

n=155

n=135 (age 50-70) – 45 each in the RZV, Varilrix, and RZV + Varilrix groups

n=20 (age 18-30) – 10 each in RZV and RZV + Varilrix groups

CMI: CD4+ T-cells with at least 2 immune markers at baseline and months 1, 2, 3, and 12 for all patients; older adults who received RZV alone and met certain criteria were also sampled at months 30 and 42

Up to 12 months, CD4+ T-cells were higher with RZV than with Varilrix and not different between RZV and RZV + Varilrix groups

By 42 months, CD4+ T-cells were lower than at 12 months but higher than baseline

Humoral immunity: Anti-VZV and anti-gE titres at baseline and months 1, 2, 3, and 12 for all patients; older adults who received RZV alone and met certain criteria were also sampled at months 30 and 42

Up to 12 months, anti-VZV GMCs were higher with RZV than with Varilrix and not different between RZV and RZV + Varilrix groups; the anti-gE humoral response rate was higher than for anti-VZV

By 42 months, antibody levels were lower than at 12 months but higher than baseline

Level I

Fair (no control group that did not receive vaccine)

Lal et al, 2017

RZV (2 50 ug doses at 0/2, 0/6, and 0/12 months to assess for non-inferiority of different schedules)

Phase 3 randomized, open-label non-inferiority trial

n=354 initial enrollment

n=117 (0/2 month group)

n=116 (0/6 month group)

n=113 (0/12 month group)

Humoral immunity: Anti-gE antibodies at 1 month post-dose 2 for all groups.

GMC ratios were 1.16 (97.5% CI 0.98, 1.39) and 1.19 (97.5% CI 0.93, 1.53) for the 0/2 month group to the 0/6 and 0/12 month groups respectively

Authors state that non-inferiority was demonstrated for the 0/6 month administration but not the 0/12 month administration

Level I

Fair (open-label, no control group without vaccine)

Vink et al, 2017

RZV (2 doses two months part IM and SC administration) among Japanese adults

Phase3, open-label, randomized trial

n=60

n=30 (subcutaneous)

n=30 (IM)

Anti-gE antibodies through ELISA at baseline and 1 and 12 months post-dose 2

There was a decline in anti-gE antibodies between 1 and 12 months post-dose 2, but an increase in levels above baseline; there was no difference between SC versus IM injection

Level I

Fair (small sample size)

Diez-Domingo et al, 2016 [abstract]

RZV (two doses 2 months apart) among European adults

Randomized clinical trial

n=23,289 ≥50 years (from ZOE-50 and ZOE-70 studies)

Humoral response: anti-gE GMC at baseline and 1-month post-second dose

38.0 times increase in anti-gE above baseline

CMI: CD4+ T-cell frequencies with two activation markersat baseline and 1-month post-second dose

21.2 times increase in CD42+ frequency above baseline

Level I

N/A pending full methods

Grupping et al, 2017 (ID week poster)

RZV in patients previously vaccinated (5 years ago or more) with live vaccine

Phase 3, matched, open-label, prospective trial

n=430

n=215 (previously vaccinated)

n=215 (not previously vaccinated)

CMI: CD4+ T-cells with at least two activation markers at baseline, 1 month post-dose 1, and 1 month post-dose 2

Humoral immunity: anti-gE antibody concentrations baseline, 1 month post-dose 1, and 1 month post-dose 2

Measure of CMI and humoral immunity were similar at baseline for the two groups; by 1 month post-dose 2, they had increased significantly.

Level I

N/A pending full methods

Chlibek et al, 2016

RZV (Two 50 ug doses 2 months apart)

Phase 2 open-label, single-group trial

Czech Republic, Germany, Sweden, Netherlands

n=166 initial enrollment

n=129 at month 48

n=119 at month 72

CMI: CD4+ T-cells with at least two activation markers) at 48, 60, 72 months

CD4 counts peaked at month 3 and then declined, but higher than pre-vaccination levels – Pre-vaccination:119.4 (Q1-3, 67.8,  286.9); at 36 months 640.0 (Q1-3 403.0-1,405.4); at 72 months 477.3 (Q1-3 231.4, 1,037.0)

Humoral immunity: Anti-gE antibody concentrations at 48, 60, 72 months

Anti-gE antibodies peaked at month 3 and then declined, but higher than pre-vaccination levels – Pre-vaccination: 1,121.3 mIU/mL (Q1-3 624.2, 2,309.0); at 72 months 8,159.0 (Q1-3 5,451.2, 12,212.4)

Level II-2

Poor (no control group – at least for the 72 month arm – initial study at control groups but only measured to 36 months)

Godeaux et al, 2017

RZV (two doses 2 months apart) among adults with a prior history of herpes zoster

Phase III, non-randomized trial

n=96 initial enrollment divided equally across 50-59, 60-69, and ≥70

Anti-gE GMCs and mean geometric increase at baseline and 28 days post-second dose

GMC across all participants increased from 2398 (95% CI 1,779 3,233) to 47,759 (95% CI 42,259, 53, 794); mean geometric increase was 19.9

Level II-2

Poor (no
control group, limited methods section)

Lal et al, 2013

RZV (two doses 2 months apart)

Phase 1, open-label study

Conducted in Australia but all patients were ethnically Japanese

n=39

n=20 (age 18-30)

n=19 (age 50-69)

Anti-gE antibodies and Anti-VZV antibodies
at baseline and months 1 and 3

Among the older patients, anti-gE GMC increased from 2,123 to 65,589 (31-fold increase) while anti-VZV GMC increased from 1,284 to 12,883 (11-fold increase); response was higher among those aged 18 to 30

Level II-2

Poor (no control group, small sample size)

Pauksens et al, 2017 (ID week poster)

RZV

Phase 3b, open-label, long-term extension cohort study with 9 years follow-up

n=70

CMI (CD4+ cells with at least two activation markers) and humoral immunity (anti-gE antibody levels) peaked at month 3 but at 9 years was still higher than baseline (3.4 times for CMI and 7.4 times for humoral). Levels plateaued between years 4 and 9

Level II-2

N/A pending full methods

Subunit vaccine studies in immunocompromised populations (n=5)

Berkowitz et al, 2015

RZV (three doses at 0, 2, 6 months) in HIV+ patients

Phase ½, randomized, placebo controlled study

3 cohorts of HIV positive patients
n=123
n=94 on ART, CD4,≥200
n=14 on ART, CD4 50-199
n=15 ART-naïve, CD4,≥500

n=112 completed 18 month follow-up (67 in RZV group, 45 in control group)

Mean age 46, range 23-74

CMI: CD4+ T-cells expressing at least 2 activation markers at baseline ad months 1, 2, 3, 6, 7, and 18

Among the ART, high CD4 and ART-naive high CD4 patients, Geometric mean ratio was higher for RZV than placebo: 21.95 (70% CI 12.97, 38.02); increases persisted to month 18

Humoral immunity: Anti-gE antibody concentrations pre-vaccination and at months 1, 2, 3, 6, 7, and 18

Among the ART, high CD4 and ART-naive high CD4 patients, Geometric mean ratio at 7 months was higher for RZV than placebo: 46.22 (70% CI 33.63, 63.53); increases persisted to month 18

No benefit to third dose

 

Level I

Good

Stadtmauer et al, 2014

RZV (2 and 3-dose regimes) in autologous HSCT transplant patients

Phase 1/2a randomized, observer-blind placebo-controlled trial

n=121 (initial enrollment) – n=99 remained by month 15

n=30 (3 doses AS01B)

n= 29 (3 doses AS01E)

n=31 (2 doses AS01B)

n=30 (3 doses saline)

CMI: CD4+ & CD8+ cells with at least 2 activation markers at baseline, month 4, and month 15

CMI was higher among all vaccine groups compared to saline, a response that persisted to the end of the study

Humoral immunity: anti-gE antibody concentrations at baseline, month 4, and month 15

GMCs were higher among all vaccine groups compared to saline, a response that persisted for at least one year after last vaccination; GMCs decreased between 29-46% from month 4 to 15

Combined CMI & humoral response was superior in 3-dose AS01B compared to AS01E (p<0.25) and compared to 2-dose AS01B (p<0.15)

Level I

Fair (fairly high dropout rate by end of study, not all outcome comparison done)

Oostovegels, 2017 (ID Week poster)

RZV in patients with hematologic malignancy

Phase 3 observer-blind, placebo-controlled trial

n=562

n=415 in humoral immunogenicity group (vaccine =217, placebo=198)

n=132 in cell-mediated immunogenicity group (vaccine =69, placebo=16)

CMI: CD4+ T-cells expressing at least two activation markers at baseline, 1-2 months post-dose 1, and 1 month post-dose 2 (n=132)

CMI VRR was ~80% compared to <10% in vaccine vs. placebo 1 month post-dose 2

Humoral immunity:  anti-GE antibody levels at baseline, 1-2 months post-dose 1, and 1 month post-dose 2 (n=415)

Humoral VRR was 80% compared to around 0% in vaccine vs. placebo 1 month post-dose 2

Level I

N/A pending full methods – study is ongoing

Vink 2017 (ID Week Poster)

RZV in patients with solid tumors before & after immunosuppressive therapy

Phase 2/3 observer-blind, placebo-controlled trial

n=232

n=117 (vaccine group, 90 pre-chemo, 27 on chemo)

n=115 (placebo group, 91 pre-chemo, 24 on chemo)

CMI: CD4+ T-cells expressing at least two activation markers at baseline and months 1, 2, 6, and 12 post-vaccination in patients yet to start chemotherapy

Adjusted GM frequency ratio was 9.9 (95% CI 3.6-27.2) at month 2 between vaccine & placebo group; 17.6% (month 12) and 50.0% (month 2) of the pre-chemo group met criteria for CMI vaccine response

Humoral immunity: Anti-GE antibody levels at baseline and months 1, 2, 6, and 12 post-vaccination in all patients

Adjusted GMC ratio was 23.2 (95% CI 17.9-30.0) at month 2 between vaccine & placebo group; While GMC declined with time in vaccine group, it was higher for vaccine group than placebo group at all points of follow-up

Level I

N/A pending full methods

Vink (2), 2017 (ID Week Poster)

RZV in renal transplant patients on chronic immunosuppression

Phase 2/3 observer-blind, placebo-controlled trial

n=264

n=132 (vaccine group)

n=132 (placebo group)

CMI was assessed in 72 patients (36 in each group): CD4+ T-cells expressing at least two activation markers at baseline, 1-2 months post-dose 1, and 1 month post-dose 2

Adjusted GM frequency ratio was 17 (95% CI 5.9, 20.4) at 1 month post-dose 2

Humoral immunity was assessed in 240 patients (121 vaccine, 119 placebo):  anti-GE antibody levels at baseline, 1-2 months post-dose 1, and 1 month post-dose 2

Adjusted GMC ratio was 14.0 (95% CI 10.9, 18.0) at 1 month post-dose 2

Level I

N/A pending full methods

 

Head-to-head comparisons of live and subunit vaccines (n=1)
Study Details Summary
Study Vaccine Study Design Participants Summary of Key Findings Using Text or Data Level of Evidence Quality

Weinberg et al, 2017 (abstract)

Zostavax vs. RZV

Unclear

Unknown – patients were either 50-70 with no vaccine or 70+ who had received Zostavax® at least 5 years ago; at entry they received Zostavax® or RZV

CMI & humoral immunity measured at days 0, 30, 90, and 365.

Higher memory CD4+ & CD8+ response detected in RZV group

Unknown

N/A

Concomitant administration with other vaccines (n=3)
Study Details Summary
Study Vaccine Study Design Participants Summary of Key Findings Using Text or Data Level of Evidence Quality

MacIntyre et al, 2010

Zostavax® with concomitant administration of Pneumovax 23 vaccine

Randomized, double-blind, placebo-controlled trial

n=473 (initial enrollment)

n=237 (concomitant vaccination)

n=236 (Pneumovax Day 0, Zostavax® Day 28)

Anti-VZV antibodies through gpELISA at baseline and week 8

GMT ratio (concomitant to non-concomitant) was 0.70 (95% CI 0.61, 0.80), suggesting lower response for concomitant administration; however, the estimated GMFR for concomitant administration did meet acceptable antibody response in absolute terms

Level I

Good

Levin et al, 2017

Zostavax® with concomitant administration of influenza vaccine

Randomized, double-blinded, placebo-controlled trial

n=882 (all ≥50 years)

n=441 received Zostavax® and influenza vaccine concurrently

n=441 received Zostavax® 4 weeks after influenza

Anti-VZV antibodies through gpELISA, measured at baseline and 4 weeks post-vaccination

Post-vaccination, GMT were non-inferior according to authors in concomitant administration group versus non-concomitant group: GMT ratio 0.87 (95% CI 0.80, 0.95); GMFR in concomitant group was 1.9 (95% CI 1.76, 2.05)

Level I

Good

Schwarz et al, 2017

RZV with concomitant administration of influenza vaccine

Phase 3, randomized, open-label, multicentre clinical trial

n=828 (all ≥50 years)

n=413 (Coadministrat-ion – received RZV at day 0 and month 2; flu vaccine at day 0)

n=415 (Control – received RZV su at month 2 & 4; flu vaccine at day 0)

Anti-gE antibodies measured at baseline, day 21, and months 2, 3, and 5

The GMC ratio of control to concomitant administration groups was 1.08 (95% CI 0.97, 1.20) demonstrating non-inferiority of RZV. Non-inferiority was also demonstrated for all four influenza vaccine strains.

Level I

Fair (non-blinded)

Appendix C: Summary of Evidence Related to Safety of Herpes Zoster Vaccines

Live Zoster Vaccine (Zostavax®)  safety among immunocompetent individuals
Study Details Summary
Study Vaccine Study Design Participants Summary of Key Findings Using Text or Data Level of Evidence Quality

Arnou et. al, 2011

Zostavax®, refrigerator-stable

Open-label, single-arm study

Age:
50 years or older.

Number (N=):
96

Adverse events (AEs) reported within 28-days post-immunization

Results n (%):

Any injection-site reactions or systemic AEs related to the vaccine: 52 (54.2%);  at least one systemic AE reported by 22.9% of study participants

Injection-site reactions (day 0–28): 50 (52.1)

  • Solicited: (day 0–4) 50 (52.1)
    Erythema: 36 (37.5)
    Swelling: 21 (21.9)
    Pain 39 (40.6)
  • Spontaneously reported: (day 0–28) 4 (4.2)
    Pruritus: 4 (4.2)

Systemic AEs related to the vaccine (day 0–28): 8 (8.3)
Asthenia: 2 (2.1)
Headache: 2 (2.1)
Keratitis: 1 (1.0)
Pyrexia: (body temperature ≥38.3°C) 1 (1.0)
Rash of interes: 2 (2.1)
HZ: 1 (1.0)
Vesicular rash: 1 (1.0)
Paresthesia: 1 (1.0)

II-2

Poor

Baxter et al, 2012

Zostavax®

Cohort study (insurance claims data)

Rate of diagnosis codes for days 1–42 following LZV administration

compared to codes days 91–180 post vaccination (vaccinees used as their own “controls”)

Age:
60 years or older.

Number (N=):
29,010

AEs observed during a 42-day port-immunization period. No increased RR observed in 382 comparisons performed for the main analysis

4 comparisons which had an increased RR with a nominal (unadjusted) p-value ≤0.05 were further investigated and after record reviews found to be no longer statistically significant.

Allergic reactions in the 1–7 days window in the outpatient and ED settings was the only significantly increased risk identified in the study.

II-2 Fair

Beals et al, 2016

Zostavax®

Randomized, partly blinded trial (dosing study)

Intradermal injection provided using NanoPass MicronJet600 device (microneedles, 0·60 mm in length)

Age:
50 (mean 60.8) years or older.

Number (N=):
223 (56% female)

AEs observed during a 42-day port-immunization period.

Results:
SC administration:

Full dose (N = 52 ) :

  • ≥1 injection site AEs: 27 (52%)
  • Erythema: 16 (31%)
  • Pain: 15 (29%)
  • Swelling: 13 (25%)
  • Induration: 5 (10%)
  • Pruritus: 1 (2%)
  • Hematoma, anesthesia, rash, scab:     3 (6%)

1/3 dose (N = 34 ) :

  • ≥1 injection site AEs: 7 (21%)
  • Erythema: 5 (15%)
  • Pain: 4 (12%)
  • Swelling: 4 (12%)
  • Induration: 2 (6%)
  • Pruritus: 2 (6%)
  • Hematoma, anesthesia, rash, scab: 0

Intradermal administration:

Full dose (N= 34):

  • ≥1 injection site AEs: 27 (79%)
  • Erythema: 26 (77%)
  • Pain: 8 (24%)
  • Swelling: 13 (35%)
  • Induration: 12 (35%)
  • Pruritus:4 (12%)
  • Hematoma, anesthesia, rash, scab: 2 (6%)

1/3 dose (N= 35 ):

  • ≥1 injection site AEs: 22 (63%)
  • Erythema: 21 (60%)
  • Pain: 9 (26%)
  • Swelling: 8 (23%)
  • Induration: 12 (34%)
  • Pruritus: 4 (12%)
  • Hematoma, anesthesia, rash, scab: 1 (3%)

1/10 dose (N= 34):

  • ≥1 injection site AEs: 19 (56%)
  • Erythema: 16 (47%)
  • Pain: 5 (15%)
  • Swelling: 6 (18%)
  • Induration: 11 (32%)
  • Pruritus: 1 (3%)
  • Hematoma, anesthesia, rash, scab: 0

1/27 dose (N = 34):

  • ≥1 injection site AEs: 19 (56%)
  • Erythema: 18 (53%)
  • Pain: 6 (18%)
  • Swelling: 7 (21%)
  • Induration: 10 (30%)
  • Pruritus: 1 (3%)
  • Hematoma, anesthesia, rash, scab: 0

Placebo (N = 39):

  • ≥1 injection site AEs: 5 (13%)
  • Erythema: 4 (10%)
  • Pain: 0
  • Swelling: 2 (5%)
  • Induration: 1 (3%)
  • Pruritus: 0
  • Hematoma, anesthesia, rash, scab: 0

No SAEs or temperatures greater than 38°C were reported in the study

I Fair

Choi et al, 2016

Zostavax®

Open label, single arm

Age
adults aged ≥50 years

Number
N=180

Results n (%, 95% CI)

One or more AEs: 113 (62.8; 55.3-69.9)

  • One or more injection site AEs: 96 (53.3)
  • Systemic AEs: 44 (24.4)

AEs related to the vaccine: 97 (53.9; 46.3-61.3)

  • One or more injection site AEs: 95 (52.8)
  • Systemic AEs: 10 (5.6)

One or more SAEs: 3 (1.7; 0.4-4.8)
SAEs related to the vaccine: 0

The injection-site AEs were more frequently reported by adults 50 to 59 years of age (58.4%) than those 60 years of age and older (48.4%).

The majority of AEs in the study were of less than 2 days duration

II-2 Fair

Diez-Domingo et al, 2014

Zostavax®

Open-label, randomised, comparative, study (IM vs. SC administration)

Age
adults aged ≥50 years

Number
N=177 (SC group)

Results n (%):

  • AE (Days 0–28): 123 (69.5)
  • Vaccine-related AE (Days 0–28): 118 (66.7)
  • Injection site reaction (Days 0–28): 114 (64.4)
  • Solicited injection site reaction (Days 0–4) : 110 (62.1)
  • Unsolicited injection site reaction (Days 0–28): 14 (7.9)
  • Systemic AE (Days 0–28): 40 (22.6)
  • Vaccine-related systemic AE (Days 0–28): 13 (7.3)
  • Injection site rash (Days 0–28): 0
  • Non-injection site rash (Days 0–28): 0
  • SAE:  2 (1.1)
  • Vaccine-related SAE: 0
  • Withdrawal due to an AE: 0
I Fair

Gilderman et al 2008

Vaccine 1: Zostavax® (refrigerator stable formulation)

Vaccine 2: Zostavax® (frozen formulation)

Randomized, controlled, double-blind

Age
50 to 59 (n=135)
60 to 69 (n=140)
70+ (n=92)

Number:
N = 367

Mean age: 63 years

Results during a 28-day follow-up period: n (%)

Group 1 (n = 180):

  • One or more AEs: 82 (45.6)
    - Injection-site AEs: 64 (35.6)
    - Systemic AEs: 34 (18.9)
  • Vaccine-related AEs: 68 (37.8)
    - Injection-site AEs: 64 (35.6)
    - Systemic AEs: 10 (5.6)
  • Subjects with SAEs: 1 (0.6)
    - Vaccine-related SAE: 0 (0.0)
    -  Death: 0 (0.0)
  • Discontinued due to any AE: 0 (0.0)
  • Discontinued due to a vaccine-related AE: 0 (0.0)

Group 2 (n=183):

  • One or more AEs: 101 (55.2)
    - Injection-site AEs: 85 (46.4)
    - Systemic AEs: 39 (21.3)
  • Vaccine-related AEs: 87 (47.5)
    - Injection-site AEs: 85 (46.4)
    - Systemic AEs: 11 (6.0)
  • Subjects with serious adverse event (SAE): 0 (0.0)
    - Vaccine-related SAE: 0 (0.0)
    - Death: 0 (0.0)
  • Discontinued due to any AE: 0 (0.0)
  • Discontinued due to a vaccine-related AE: 0 (0.0)

All AE were generally mild.

I Good

Hata et al 2016

Vaccine:
varicella zoster vaccine, containing an estimated 50 000 pfu per dose

Placebo:
sterile

purified distilled water for injection

All study participants received  PPSV23 concomitantly with LZV or placebo

Double-blind randomized placebo-controlled study

Age
60-70 years.

Number
N = 54

Immune status:
All participants with DM (mean HbA1c 7.2%)

PPSV23 was provided simultaneously.

Results n (%):

Zoster vaccine group (n = 27)

  • One or more AE: 5 (18.5)
  • Vaccine-related AE: 3 (11.1)
  • Injection-site AEs: 2 (7.4)
    -  Erythema: 0 (0.0)
    -  Pain: 2 (7.4)
    -  Pruritus: 0 (0.0)
    -  Swelling: 1 (3.7)
    -  Warmth: 1 (3.7)
  • Systemic AEs: 1 (3.7)
    -  Malaise: 1 (3.7)
    -  Pruritus: 1 (3.7)
  • Severe AE: 0 (0.0)
  • Vaccine-not related AEs: 2 (7.4)

Placebo  group (n = 27)

  • One or more AE: 6 (22.2)
  • Vaccine-related AE: 4 (14.8)
  • Injection-site AEs: 3 (11.1)
    -   Erythema: 1 (3.7)
    -   Pain: 1 (3.7)
    -   Pruritus: 2 (7.4)
    -   Swelling: 0 (0.0)
    -   Warmth: 1 (3.7)
  • Systemic AEs: 1 (3.7)
    -   Malaise: 1 (3.7)
    -   Pruritus: 2 (7.4)
  • Severe AE: 0 (0.0)
  • Vaccine-not related AEs: 3 (11.1)
I Fair

Kerzner et al, 2007

Vaccines:
Zostavax® and Fluzone

Placebo:
not specified

Randomized, double-blinded clinical trial

Concomitant group received ZVL and IIV

on Day 1 and placebo at Week 4.

Nonconcomi-tant group received IIV and placebo on Day 1 and ZVL at Week 4.

Age
Adults aged 50 or older

Number
Total (n=762)

concomitantly vaccinated (n=382)

Sequentially vaccinated (n=380)

.

Results Days 1-28 Post vaccination:
n (%)

Concomitant Group (n=382)

All vaccinated subjects with follow-up (n=378):

  • ≥1 AEs: 243 (64.3)
    -  Injection-site AEs: 195 (51.6)
    -   Systemic AEs: 125 (33.1)
  • Vaccine-related AEs: 172 (45.5)
    -   Injection-site AEs: 169 (44.7)
    -   Systemic AEs: 17 (4.5)
  • SAEs: 6 (1.6)
    -   Serious vaccine-related AE: 0 (0.0)
    -   Death: 0 (0.0)
    -   Discontinued because of a vaccine-related AE: 0 (0.0)

Subjects aged ≥ 50 with follow-up (n=125)

  • ≥1 AEs: 88 (70.4)
    -  Injection-site AEs: 74 (59.2)
    -   Systemic AEs: 43 (34.4)
  • Vaccine-related AEs: 69 (55.2)
    -   Injection-site AEs: 67 (53.6)
    -   Systemic AEs: 7 (5.6)
  • SAEs: 1 (0.8)
    -   Serious vaccine-related AE: 0 (0.0)
    -   Death: 0 (0.0)
    -   Discontinued because of a vaccine-related AE: 0 (0.0)

Subjects aged ≥ 60 with follow-up (n=253)

  • ≥1 AEs: 155 (61.3)
    - Injection-site AEs: 121 (47.8)
    -  Systemic AEs: 82 (32.4)
  • Vaccine-related AEs: 103 (40.7)
    -  Injection-site AEs: 102 (40.3)
    -  Systemic AEs: 10 (4.0)
  • SAEs: 5 (2.0)
    - Serious vaccine-related AE:  0 (0.0)
    - Death:  0 (0.0)
    - Discontinued because of a vaccine-related AE:  0 (0.0)

Nonconcomitant Group (n=380)

All vaccinated subjects with follow-up (n=376):

  • ≥1 AEs: 220 (58.5)
    -  Injection-site AEs: 180 (47.9)
    -  Systemic AEs: 124 (33.0)
  • Vaccine-related AEs: 150 (39.9)
    -  Injection-site AEs: 144 (38.3)
    -  Systemic AEs: 18 (4.8)
  • SAEs: 5 (1.3)
    -  Serious vaccine-related AE: 0 (0.0)
    -  Death: 0 (0.0)
    -  Discontinued because of a vaccine-related AE: 0 (0.0)

Subjects aged ≥ 50 (n=127)

  • ≥1 AEs: 84 (66.1)
    -  Injection-site AEs: 72 (56.7)
    -   Systemic AEs: 47 (37.0)
  • Vaccine-related AEs: 60 (47.2)
    - Injection-site AEs: 58 (45.7)
    - Systemic AEs: 11 (8.7)
  • SAEs: 2 (1.6)
    - Serious vaccine-related AE: 0 (0.0)
    - Death: 0 (0.0)
    - Discontinued because of a vaccine-related AE:  0 (0.0)

Subjects aged ≥ 60 (n=249)

  • ≥ 1 AEs: 136 (54.6)
    -  Injection-site AEs: 108 (43.4)
    -  Systemic AEs: 77 (30.9)
  • Vaccine-related AEs: 90 (36.1)
    - Injection-site AEs: 86 (34.5)
    - Systemic AEs: 7 (2.8)
  • SAEs: 3 (1.2)
    - Serious vaccine-related AE: 0 (0.0)
    - Death: 0 (0.0)
    - Discontinued because of a vaccine-related AE: 0 (0.0)
I Good

Lai et al, 2015

Zostavax®

Case-control study

Cases and controls identified from 18,534 events in VAERS reported after LZV

Age
50 years or older

Number
102 serious autoimmune AEs (SAAEs) reported between May 2006 and November 2014

No increased risk of SAAEs identified except for alopecia and arthritis (OR: 2.2 [95% CI:1.2-4.3] and 2.7 (1.7-4.3], respectively)

In total 40 cases of alopecia and 61 cases of arthritis reported in VAERS during the study period with a median of 4 days between vaccination and symptom onset.

II-2

Poor

Levin et al, 2016

Zostavax®

Non-randomized controlled study

Age
50 years or older

Number
Overall: n=600

Pre-Exposure History:
Subjects either had a history of varicella or had resided in the United States for ≥30 years with no history of HZ

The vaccine was generally well tolerated in all groups (Table 2). As many as 57% of subjects in groups 1 and 2 and 75% of subjects in groups 3 and 4 reported ≥1 adverse experience through week 52. Most of the AEs were injection site reactions (pain and erythema) occurring 1–5 days after ZV receipt. Only 6 subjects reported injection-site adverse experiences from day 6 to week 6 after ZV receipt. The higher rate of AEs in groups 3 and 4 was primarily related to a higher rate of injection site reactions. Vaccine-related non–injection site reactions occurred in 3%–8% of subjects ≤6 weeks after ZVL receipt.

Group 1 (n = 200):
Subjects ≥70 years who received ZV  ≥10 years previously

Group 2 (n= 200):
Subjects ≤70 years who never received ZV and were matched to group 1 subjects by 5-yr age increments.

Group 3 (n=100):
Subjects 60 to < 70 years who never received ZVL.

Group 4 (n= 100):
Subjects ≥ 50 to < 60 years who never received ZVL.

Results:
AEs Among Participants, by Study Group:

Group 1 (n=200), Participants, No. (%):

  • ≥ AE: 115 (57)
  • Injection-site AE: 69 (34)
  • Non-injection site AE: 82 (41)
  • Vaccine-related non-injection site AE:  7 (3.5)
  • SAE: 29 (14)
  • Vaccine-related AE: 0

Group 2 (n=200), Participants, No. (%):

  • ≥ AE: 109 (55)
  • Injection-site AE: 61 (31)
  • Non-injection site AE: 74 (37)
  • Vaccine-related non-injection site AE:  6 (3)
  • SAE: 29 (15)
  • Vaccine-related AE: 0

Group 3 (n=100), Participants, No. (%):

  • ≥ AE: 75 (75)
  • Injection-site AE: 56 (56)
  • Non-injection site AE: 68 (38)
  • Vaccine-related non-injection site AE:  4 (4)
  • SAE: 6 (6)
  • Vaccine-related AE: 0

Group 4 (n=100), Participants, No. (%):

  • ≥ AE: 74 (74)
  • Injection-site AE: 57 (57)
  • Non-injection site AE: 40 (40)
  • Vaccine-related non-injection site AE:  8 (8)
  • SAE: 2 (2)
  • Vaccine-related AE: 0

II-1

Fair

MacIntyre et al, 2010

Vaccines: Zostavax® and PPV23

Placebo: not specified

Randomized, double-blind, placebo-controlled study

At Day 1, all adults received open-label PPV23 while administration of ZVL or placebo at Day 1 and Week 4 was blinded

Concomitant group received ZVL and PPV23 on Day 1 and placebo at Week 4.

Nonconcomitant group received PPV23 and placebo on Day 1 and ZVL at Week 4.

Age
60 years or older

Number
N= 473

Postvaccination of ZVL, clinical AEs were numerically but not significantly higher in nonconcomitant group. The incidence of injection-site AEs was similar in both groups. All 6 reported SAEs were deemed not related to study vaccine.

Results: no. cases (estimated risk %):

Concomitant group (n=235):

AEs Summary

  • Subjects with follow-up: 235 (100)
    - With one or more AE: 153 (65.1)
    - Injection-site AEs: 136 (57.9)
    - Systemic AEs: 70 (29.8)
  • Vaccine-related AEs: 139 (59.1)
    -   Injection-site AEs: 136 (57.9)
    -   Systemic AEs: 16 (6.8)
  • SAEs: 2 (0.9)
    -  Vaccine related: 0 (0.0)
    -   Death: 0 (0.0)
    -   Discontinued due to AE: 1 (0.4)
    -   Discontinued due to vaccine-related AE: 1 (0.4)
    -   Discontinued due to SAE:        0 (0.0)
    -   Discontinued due to serious vaccine-related AE: 0 (0.0)

Injection-site AEs

Injection site for ZOSTAVAX®:

  • Subjects with follow-up: 235
  • With ≥1 injection-site AE: 103 (43.8)
    -   Erythema: 72 (30.6)
    -   Induration: 2 (0.9)
    -   Pain: 73 (31.1)
    -   Pruritus: 11 (4.7)
    -   Swelling: 66 (28.1)

Injection site for Placebo:

  • Subjects with follow-up: 230
  • With ≥1 injection-site AE: 10 (4.3)
    -   Erythema: 1 (0.4)
    -   Pain: 8 (3.5)
    -   Swelling: 3 (1.3)

Non-concomitant group (n= 236) :

AEs Summary

  • Subjects with follow-up: 236 (100)
  • With one or more AE: 165 (69.9)
  • Injection-site AEs: 141 (59.7)
  • Systemic AEs: 74 (31.4)
  • Vaccine-related AEs: 146 (61.9)
    -   Injection-site AEs: 141 (59.7)
    -   Systemic AEs: 13 (5.5)
  • SAEs: 4 (1.7)
    -  Vaccine related: 0 (0.0)
    -   Death: 0 (0.0)
    -   Discontinued due to AE: 1 (0.4)
    -   Discontinued due to vaccine-related AE: 0 (0.0)
    -   Discontinued due to SAE: 1 (0.4)
    -   Discontinued due to serious vaccine-related AE: 0 (0.0)

Injection-site AEs

Injection site for ZOSTAVAX®:

  • Subjects with follow-up: 234
  • With ≥1 injection-site AE: 84 (35.9)
    -   Erythema: 69 (29.5)
    -   Induration: 3 (1.3)
    -   Pain: 66 (28.2)
    -   Pruritus: 7 (3.0)
    -   Swelling: 61 (26.1)

Injection site for Placebo:

  • Subjects with follow-up: 236
  • With ≥1 injection-site AE: 27 (11.4)
    -   Erythema: 7 (3.0)
    -   Pain: 21 (8.9)
    -   Swelling: 5 (2.1)
I Good

Mills et al, 2010

Vaccine: LZV ~89,000 PFUs

Placebo: not stated

Randomized Controlled Trial

Age
50 years or older

Number
N = 101

Pre-Exposure History:
HZ history-positive adults

In HZ history-positive adults ≥50 years of age, zoster vaccine was well tolerated.

Randomized Group1 (n=51):
On day 1, subjects in Group 1 were administered zoster vaccine and received placebo at week 4.

Randomized Group2 (n=50):
On day 1, subjects in Group 2 were administered placebo and received placebo at week zoster vaccine.

Results n (%):

Zostavax®

Overall per-protocol summary:

  • N = 100
  • N with follow-up: 98 (98.0)
  • One or more AE: 51 (52.0)
    -  Local AEs: 45 (45.9)
    -  Systemic AEs: 15 (15.3)
  • Vaccine-related systemic AEs: 2 (2.0)
  • SAE: 0 (0.0)
    - Vaccine-related: 0 (0.0)
    - Death: 0 (0.0)
  • Discontinued due to vaccine-related AE: 0 (0.0)

Subjects with 5-9 years since prior HZ episodes:

  • N = 70
  • N with follow-up: 68 (97.1)
  • One or more AE: 37 (54.4)
    -  Local AEs: 32 (47.1)
    -  Systemic AEs: 9 (13.2)
  • Vaccine-related systemic AEs: 1 (1.5)

Subjects with ≥10 years since prior HZ episodes:

  • N = 30
  • N with follow-up: 30 (100)
  • One or more AE: 14 (46.7)
    -  Local AEs: 13 (43.3)
    -  Systemic AEs: 6 (20.0)
  • Vaccine-related systemic AEs: 1 (3.3)

Subjects 50-59 years of age:

  • N = 20
  • N with follow-up: 19 (95.0)
  • One or more AE: 9 (47.4)
    -  Local AEs: 9 (47.4)
    -  Systemic AEs: 1 (5.3)
  • Vaccine-related systemic AE: 0 (0.0)

Subjects ≥60 years of age:

  • N = 80
  • N with follow-up: 79 (98.8)
  • One or more AE: 42 (53.2)
    -  Local AEs: 36 (45.6)
    -  Systemic AEs: 14 (17.7)
  • Vaccine-related systemic AEs: 2 (2.5)

Placebo:

Overall per-protocol summary:

  • N = 101
  • N with follow-up: 96 (95.0)
  • One or more AE: 17 (17.7)
    -  Local AEs: 4 (4.2)
    -  Systemic AEs: 13 (13.5)
  • Vaccine-related systemic AE: 0 (0.0)
  • SAE: 0 (0.0)
    -  Vaccine-related: 0 (0.0)
    -  Death: 0 (0.0)
  • Discontinued due to vaccine-related AE: 0 (0.0)

Subjects with 5-9 years since prior HZ episodes:

  • N = 71
  • N with follow-up: 66 (93.0)
  • One or more AE: 15 (22.7)
    -  Local AEs: 3 (4.5)
    -  Systemic AEs: 12 (18.2)
  • Vaccine-related systemic AE: 0 (0.0)

Subjects with ≥10 years since prior HZ episodes:

  • N =30
  • N with follow-up: 30 (100)
  • One or more AE: 2 (6.7)
    -  Local AEs: 1 (3.3)
    -  Systemic AEs: 1 (3.3)
  • Vaccine-related systemic AE: 0 (0.0)

Subjects 50-59 years of age:

  • N = 20
  • N with follow-up: 19 (95.0)
  • One or more AE: 5 (26.3)
    -  Local AEs: 1 (5.3)
    -  Systemic AEs: 4 (21.1)
  • Vaccine-related systemic AE: 0 (0.0)

Subjects ≥60 years of age:

  • N = 81
  • N with follow-up: 77 (95.1)
  • One or more AE: 12 (15.6)
    -  Local AEs: 3 (3.9)
    -  Systemic AEs: 9 (11.7)
  • Vaccine-related systemic AE: 0 (0.0)
I Good

Morrison et al, 2013

Vaccine: Zostavax®

Case-control

Age
60 years or older

Among SPS placebo recipients who received LZV, there were 420 with documented

HZ during the SPS and 13,261 individuals without prior HZ (comparator group)

LZV provided at mean 3.6 years following a prior HZ episode

A total of 4 SAEs were reported among 4/ 420 adults with prior HZ, and 111 SAEs among 88/13,261 adults with no history of HZ.

No differences in SAEs were found in the proportion of vaccine recipients with and without prior HZ, and no unexpected injection site AEs were reported by the study participants in the 28 days post vaccine administration.

II-2 Good

Murray et al, 2010

Vaccine: Zostavax®

Placebo: Zostavax® vaccine stabilizer without VZV or virus components

Randomized, placebo-controlled trial

Age
60 years or older

Number
N = 11,999

No statistically significant differences found in SAEs among vaccine and placebo recipients in the 42-day or 182-day observation period

Zoster Vaccine Group (n= 5,983):

Primary Safety Follow-up Period (Day 1 to Day 42 Postvaccination):

  • With follow-up: 5,979 (99.9)
  • With SAEs: 84 (1.4)
  • Blood/Lymphatic Disorders: 1 (0.0)
  • Cardiac Disorders: 19 (0.3)
  • Ear/Labyrinth Disorders: 0 (0.0)
  • Eye Disorders: 1 (0.0)
  • Gastrointestinal  Disorders: 8 (0.1)
  • General  Disorders: 8 (0.1)
  • Hepatobiliary Disorders: 3 (0.1)
  • Infections and Infestations: 11 (0.2)
  • Injury, Poisoning and Procedural Complications: 5 (0.1)
  • Metabolism and Nutrition Disorders: 1 (0.0)
  • Musculoskeletal and Connective Tissue  Disorders: 6 (0.1)
  • Neoplasms: 15 (0.3)
  • Nervous System  Disorders: 5  (0.1)
  • Psychiatric  Disorders: 2 (0.0)
  • Renal and Urinary  Disorders: 4 (0.1)
  • Reproductive System Disorders: 1 (0.0)
  • Respiratory, Thoracic and Mediastinal  Disorders: 6  (0.1)
  • Skin  Disorders: 1 (0.0)
  • Vascular  Disorders: 4 (0.1)
  • Vaccine-related SAEs: 2 (0.0)
  • Death: 6 (0.1)

Secondary Safety Follow-Up Period (Day 1 To Day 182 Postvaccination)

  • With follow-up: 5,979 (99.9)
  • With SAEs: 340 (5.7)
  • Blood/Lymphatic Disorders: 5 (0.1)
  • Genetic Disorders: 0 (0.0)
  • Cardiac Disorders: 73 (1.2)
  • Ear/Labyrinth Disorders: 0 (0.0)
  • Endocrine Disorders: 2 (0.0)
  • Eye Disorders: 2 (0.0)
  • Gastrointestinal Disorders: 37 (0.6)
  • General Disorders: 26 (0.4)
  • Hepatobiliary Disorders: 7 (0.1)
  • Immune System Disorders: 1 (0.0)
  • Infections and Infestations: 57 (1.0)
  • Injury, Poisoning and Procedural Complications: 26 (0.4)
  • Investigations: 0 (0.0)
  • Metabolism and Nutrition Disorders: 13 (0.2)
  • Musculoskeletal and Connective Tissue Disorders: 30 (0.5)

Placebo Group (n= 5,997):

Primary Safety Follow-up Period (Day 1 to Day 42 Postvaccination):

  • With follow-up: 5,990 (99.9)
  • With SAEs: 67 (1.1)
  • Blood/Lymphatic Disorders: 0 (0.0)
  • Cardiac Disorders: 19 (0.3)
  • Ear/Labyrinth Disorders: 1 (0.0)
  • Eye Disorders: 0 (0.0)
  • Gastrointestinal  Disorders: 6 (0.1)
  • General  Disorders: 4 (0.1)
  • Hepatobiliary Disorders: 2 (0.0)
  • Infections and Infestations: 13 (0.2)
  • Injury, Poisoning and Procedural Complications: 5 (0.1)
  • Metabolism and Nutrition Disorders: 4 (0.1)
  • Musculoskeletal and Connective Tissue  Disorders: 5 (0.1)
  • Neoplasms: 9 (0.2)
  • Nervous System Disorders: 7 (0.1)
  • Psychiatric  Disorders: 2 (0.0)
  • Renal and Urinary Disorders: 1 (0.0)
  • Reproductive System  Disorders: 2 (0.0)
  • Respiratory, Thoracic and Mediastinal  Disorders: 4 (0.0)
  • Skin  Disorders: 0 (0.0)
  • Vascular  Disorders: 4 (0.1)
  • Vaccine-related SAE: 0 (0.0)
  • Death: 5 (0.1)

Secondary Safety Follow-Up Period (Day 1 To Day 182 Postvaccination)

  • With follow-up: 5,990 (99.9)
  • With SAEs: 300 (5.0)
  • Blood/Lymphatic Disorders: 4 (0.1)
  • Genetic Disorders: 1 (0.0)
  • Cardiac Disorders: 72 (1.2)
  • Ear/Labyrinth Disorders: 4 (0.1)
  • Endocrine Disorders: 0 (0.0)
  • Eye Disorders: 1 (0.0)
  • Gastrointestinal Disorders: 29 (0.5)
  • General Disorders: 22 (0.4)
  • Hepatobiliary Disorders: 8 (0.1)
  • Immune System Disorders: 1 (0.0)
  • Infections and Infestations: 59 (1.0)
  • Injury, Poisoning and Procedural Complications: 26 (0.4)
  • Investigations: 2 (0.0)
  • Metabolism and Nutrition Disorders:   12 (0.2)
  • Musculoskeletal and Connective Tissue Disorders: 24 (0.4)
I Good

Oxman et al, 2005

Vaccine: live attenuated Oka/Merck
VZV vaccine 18,700 to 60,000
PFUs per dose (>90% received <32,300 PFUs)
Placebo: not stated

Randomized, placebo-controlled, double-blind clinical trial (SPS study)

Age
60 years or older

Number
38,546

Vaccine Group
All Subjects (n= 19,270):

From day of vaccination to end of study:

  • Death: 793 (4.1)
  • Death 60-69 yr: 218 (2.1)
  • Death ≥70 yr: 575 (6.5)
  • Vaccine-related SAE: 2 (<0.1)

From day of vaccination to day 42:

  • Death: 14 (0.1)
  • One or more SAEs: 255 (1.4)
  • Varicella-like rash at injection site: 20 (0.1)
  • Varicella-like rash not at injection site: 18 (0.1)
  • HZ-like rash: 17 (0.1)
  • Rash unrelated to HZ: 595 (3.2)
  • Confirmed case of HZ: 7 (<0.1)

Subjects in the AE substudy (n= 3345):

From day of vaccination to end of study:

  • Subjects hospitalized: 1,137 (34.0)
  • Hospitalization related to HZ: 5 (0.2)

From day of vaccination to day 42:

  • ≥1 SAEs: 64 (1.9)
  • ≥1 AEs: 1,929 (58.1)
  • ≥1 systemic: 820 (24.7)
  • ≥1 vaccine-related systemic AEs: 209 (6.3)
  • Temperature ≥38.3oC: 27 (0.8)
  • Self-reports of feeling abnormal temperature: 231 (7.2)
  • ≥ Local AEs: 1,604 (48.3)
  • Erythema: 1,188 (35.8)
  • Pain/Tenderness: 1,147 (34.5)
  • Swelling: 871 (26.2)
  • Pruritus: 237 (7.1)
  • Warmth: 57 (1.7)
  • Hematoma: 53 (1.6)
  • Rash: 10 (0.3)

Placebo Group:

All Subjects (n= 19,276):

From day of vaccination to end of study:

  • Death: 795 (4.1)
  • Death 60-69 yr: 246 (2.4)
  • Death ≥70 yr: 549 (6.2)
  • Vaccine-related SAE: 3 (<0.1)

From day of vaccination to day 42:

  • Death: 16 (0.1)
  • One or more SAEs: 254 (1.4)
  • Varicella-like rash at injection site: 7 (0.04)
  • Varicella-like rash not at injection site: 14 (0.1)
  • HZ-like rash: 36 (0.2)
  • Rash unrelated to HZ: 620 (3.3)
  • Confirmed case of HZ: 24 (0.1)

Subjects in the AE substudy (n= 3271):

From day of vaccination to end of study:

  • Subjects hospitalized: 1,115 (34.1)
  • Hospitalization related to HZ: 6 (0.2)

From day of vaccination to day 42:

  • ≥1 SAEs: 41 (1.3)
  • ≥1 AEs: 1,117 (34.4)
  • ≥1 systemic: 768 (23.6)
  • ≥1 vaccine-related systemic AEs: 160 (4.9)
  • Temperature ≥38.3oC: 27 (0.9)
  • Self-reports of feeling abnormal temperature: 190 (6.0)
  • ≥ Local AEs: 539 (16.6)
  • Erythema: 227 (7.0)
  • Pain/Tenderness: 278 (8.5)
  • Swelling: 147 (4.5)
  • Pruritus: 33 (1.0)
  • Warmth: 11 (0.3)
  • Hematoma: 46 (1.4)
  • Rash: 3 (0.1)
I Good

Schmader et al, 2012

Vaccine: Zostavax®

Placebo: all Zostavax® vaccine constituents except VZV or virus components

Randomized, double-blind, placebo-controlled study

Age
50-59 years

Number
N= 22,439

AEs were reported by 72.8% of subjects in the ZV group and 41.5% in the placebo group, with the difference primarily due to higher rates of injection-site AEs and headache. The proportion of subjects reporting SAEs occurring within 42 days postvaccination (ZV, 0.6%; placebo, 0.5%) and 182 days postvaccination (ZV, 2.1%; placebo, 1.9%) was similar between groups.

Results no. (%):
Zoster Vaccine Group (11,094):

  • With >1 AE: 8,080 (72.8)
    - Injection-site AEs: 7,089 (63.9)
    - Systemic AEs: 3,932 (35.4)
  • With vaccine-related AEs: 7,213 (65.0)
    - Injection-site AEs: 7,089 (63.9)
    - Systemic AEs: 746 (6.7)
  • With SAEs: 69 (0.6)
    - Serious vaccine-related AEs:1 (0.0)
    - Death:1 (0.0)

Placebo Group (n=11,116):

  • With >1 AE: 4,613 (41.5)
    - Injection-site AEs: 1,596 (14.4)
    - Systemic AEs: 3,722 (33.5)
  • With vaccine-related AEs: 1,988 (17.9)
    - Injection-site AEs: 1,596 (14.4)
    - Systemic AEs: 526 (4.7)
  • With SAEs: 61 (0.5)
    - Serious vaccine-related AE: 0 (0.0)
    - Death: 3 (0.0)
I Good

Simberkoff et al, 2010

Vaccine: live attenuated Oka/Merck
VZV vaccine 18,700 to 60,000
PFUs per dose (>90% received <32,300 PFUs) Placebo: not stated

Randomized, placebo-controlled,

double-blind clinical trial (SPS study)

Age
60 years or older

Number
N= 6,616

After inoculation, 255 (1.4%) vaccine recipients and 254 (1.4%) placebo recipients reported EIG. Local inoculation-site side effects were reported by 1,604 (48%) vaccine recipients and 539 (16%) placebo recipients in the substudy. A total of 977 (56.6%) of the vaccine recipients reporting local side effects were aged 60 to 69 years, and 627 (39.2%) were older than 70 years. After inoculation, HZ occurred in 7 vaccine recipients versus 24 placebo recipients. Long-term follow-up (mean,

3.39 years) showed that rates of hospitali-zation or death did not differ between vaccine and placebo recipients.

Aged 60-69 Years:

HZ Group no. (risk%) (n=1,726):

  • >1 injection-site AE: 977 (56.6)
    -  %risk difference (95% CI): 37.7 (34.6 to 40.6)
    -  %risk difference between age strata (95% CI): 16.4 (13.1 to 19.8)
  • Erythema: 718 (41.6)
    -  %risk difference (95% CI): 33.8 (31.2 to 36.5)
    -  %risk difference between age strata (95% CI): 11.1 (8.0 to 14.3)
  • Swelling: 559 (32.4)
    -  %risk difference (95% CI): 27.1 (24.7 to 29.6)
    -  %risk difference between age strata (95% CI): 12.2 (9.2 to 15.1)
  • Pain/tenderness: 743 (43.0)
    -  %risk difference (95% CI): 32.9 (30.2 to 35.7)
    -  %risk difference between age strata (95% CI): 17.1 (13.9 to 20.2)
  • Rash: 12 (0.7)
    -  %risk difference (95% CI): 0.6 (0.2 to 1.2)
    -  %risk difference between age strata (95% CI): 0.2 (-0.5 to 0.8)
  • Pruritus: 164 (9.5)
    - %risk difference (95% CI): 8.5 (7.1 to 10.1)
    - %risk difference between age strata (95% CI): 4.6 (2.9 to 6.4)
  • Hematoma: 23 (1.3)
    - %risk difference (95% CI): -0.5 (-1.3 to 0.4)
    -  %risk difference between age strata (95% CI): -0.5 (-1.5 to 0.3)
  • Mass: 22 (1.3)
    -  %risk difference (95% CI): 1.2 (0.7 to 1.9)
    -  %risk difference between age strata (95% CI): 0.8 (0.2 to 1.6)
  • Warmth: 39 (2.3)
    -  %risk difference (95% CI): 1.9 (1.1 to 2.8)
    -  %risk difference between age strata (95% CI): 1.0 (0.2 to 2.0)
  • Other AE: 20 (1.2)
    -  %risk difference (95% CI): 0.6 (-0.1 to 1.3)
    -  %risk difference between age strata (95% CI): 0.3 (-0.4 to 1.1)

Placebo Group (n= 1,709)

  • >1 injection-site AE: 326 (19.1)
  • Erythema: 136 (8.0)
  • Swelling: 92 (5.4)
  • Pain/tenderness: 174 (10.2)
  • Rash: 1 (0.1)
  • Pruritus: 18 (1.1)
  • Hematoma: 31 (1.8)
  • Mass: 1 (0.1)
  • Warmth: 7 (0.4)
  • Other AE: 10 (0.6)

Aged 70 Years or more:

HZ Group no. risk% (n=1,600):

  • >1 injection-site AE: 627 (39.2)
    -  %risk difference (95% CI): 25.4 (22.5 to 28.4)
  • Erythema: 470 (29.4)
    -  %risk difference (95% CI): 23.6 (21.1 to 26.2)
  • Swelling: 312 (19.5)
    -  %risk difference (95% CI): 16.0 (13.9 to 18.2)
  • Pain/tenderness: 404 (25.3)
    -  %risk difference (95% CI): 18.5 (16.0 to 21.0)
  • Rash: 8 (0.5)
    -  %risk difference (95% CI): 0.2 (-0.4 to 0.7)
  • Pruritus: 73 (4.6)
    -  %risk difference (95% CI): 3.6 (2.5 to 4.8)
  • Hematoma: 30 (1.9)
    -  %risk difference (95% CI): 0.9 (0.1 to 1.8)
  • Mass: 8 (0.5)
    -  %risk difference (95% CI): 0.1 0.4 (0.1 to 1.0)
  • Warmth: 18 (1.1)
    -  %risk difference (95% CI): 0.3 0.9 (0.3 to 1.6)
  • Other AE: 13 (0.8)
    -  %risk difference (95% CI): 0.5 (0.1 to 1.1)

Placebo Group (n= 1540)

  • >1 injection-site AE: 213  (13.8)
  • Erythema: 91  (5.9)
  • Swelling: 55  (3.6)
  • Pain/tenderness: 104  (6.8)
  • Rash: 5  (0.3)
  • Pruritus: 15  (1.0)
  • Hematoma: 15  (1.0)
  • Mass: 1  (0.1)
  • Warmth: 4  (0.3)
  • Other AE: 5 (0.3)
I Good

Tseng et al, 2012

Zostavax®

Observational study using a cohort analysis  by case-centered and  self-controlled case series designs

Age
50 years and older

Number
N= 193,083

Risk of SAEs in the 42 days following vaccination was not statistically different compared to the historical comparison period.

Allergic reactions in the 1–7 days window in the outpatient and emergency department settings were higher compared to the historical comparison period (RR  = 2.13, 95% CI: 1.87–2.40 by case-centred method and RR = 2.32, 95% CI: 1.85–2.91 by SCCS)

II-2 Fair

Tyring et al, 2007

Vaccine 1: LZV~207,000
PFUs

Vaccine 2: LZV~58,000
PFUs

Randomized clinical trial

Age
50 years and older (median 64)

Number
N= 698

No serious vaccine-related AEs were reported. Similar AE rates were observed in the higher and lower potency groups (overall systemic AEs: 37.5 and 39.3%, vaccine-related systemic AEs: 10.9 and 13.2%, injection-site AEs: 63.0 and 59.8%). Rates for a combined endpoint of moderate or severe injection-site pain/tenderness/soreness and swelling were 17.2% (95% CI 13.9, 21.0) and 9.0% (95% CI 5.6, 13.4), respectively. Most combined endpoint events were reported as moderate in intensity.

Higher Potency Group (n=459)

Aged 50-59 years (n= 123):

  • Vaccine-related AEs: 102 (82.9)
  • Injection-site AE: 102 (82.9)
  • Erythema: 83 (67.5)
  • Pain: 84 (68.3)
  • Swelling: 73 (59.3)
  • Pruritus:  25 (20.3)
  • Systemic AE: 17 (13.8)
  • SAEs: 2 (1.3)
  • Depression: 1 (0.8)
  • Angina pectoris: 0 (0.0)
  • Enteritis: 1 (0.8)
  • Coronary artery disease: 0 (0.0)
  • Small cell lung cancer: 0 (0.0)
  • Vaccine-related SAE: 0 (0.0)
  • Deaths: 0 (0.0)

Aged 60 years or more (n= 336):

  • Vaccine-related AEs: 198 (58.9)
  • Injection-site AE: 187 (55.7)
  • Erythema: 142 (42.3)
  • Pain: 132 (39.3)
  • Swelling: 115 (34.2)
  • Pruritus:  32 (9.5)
  • Systemic AE: 33 (9.8)
  • SAEs: 2 (0.6)
  • Depression: 0 (0.0)
  • Angina pectoris: 1 (0.3)
  • Enteritis: 0 (0.0)
  • Coronary artery disease: 1 (0.3)
  • Small cell lung cancer: 0 (0.0)
  • Vaccine-related SAE: 0 (0.0)
  • Deaths: 0 (0.0)

Total (n= 459):

  • Vaccine-related AEs: 300 (65.4)
  • Injection-site AE: 289 (63.0)
  • Erythema: 225 (49.0)
  • Pain: 216 (47.1)
  • Swelling: 188 (41.0)
  • Pruritus:  57 (12.4)
  • Systemic AE: 50 (10.9)
  • SAEs: 4 (0.9)
  • Depression: 1 (0.2)
  • Angina pectoris: 1 (0.2)
  • Enteritis: 1 (0.2)
  • Coronary artery disease: 1 (0.2)
  • Small cell lung cancer: 0 (0.0)
  • Vaccine-related SAE: 0 (0.0)
  • Deaths: 0 (0.0)

Lower Potency Group (n=234)

Aged 50-59 years (n= 62):

  • Vaccine-related AEs: 46 (74.2)
  • Injection-site AE: 43 (69.4)
  • Erythema: 35 (56.5)
  • Pain: 32 (51.6)
  • Swelling: 27 (43.5)
  • Pruritus: 4 (6.5)
  • Systemic AE: 13 (21.0)
  • SAEs: 1 (1.6)
  • Depression: 0 (0.0)
  • Angina pectoris: 0 (0.0)
  • Enteritis: 0 (0.0)
  • Coronary artery disease: 0 (0.0)
  • Small cell lung cancer: 1 1.6
  • Vaccine-related SAE: 0 (0.0)
  • Deaths: 0 (0.0)

Aged 60 years or more (n= 172):

  • Vaccine-related AEs: 99 (57.6)
  • Injection-site AE: 97 (56.4)
  • Erythema: 76 (44.2)
  • Pain: 59 (34.3)
  • Swelling: 50 (29.1)
  • Pruritus: 15 (8.7)
  • Systemic AE: 18 (10.5)
  • SAE: 0 (0.0)
  • Depression: 0 (0.0)
  • Angina pectoris: 0 (0.0)
  • Enteritis: 0 (0.0)
  • Coronary artery disease: 0 (0.0)
  • Small cell lung cancer: 0 (0.0)
  • Vaccine-related SAE: 0 (0.0)
  • Deaths: 0 (0.0)

Total (n= 234):

  • Vaccine-related AEs: 145 (62.0)
  • Injection-site AE: 140 (59.8)
  • Erythema: 111 (47.3)
  • Pain: 91 (38.9)
  • Swelling: 77 (32.9)
  • Pruritus: 19 (8.1)
  • Systemic AE: 31 13.2
  • SAEs: 1 0.4
  • Depression: 0 (0.0)
  • Angina pectoris: 0 (0.0)
  • Enteritis: 0 (0.0)
  • Coronary artery disease: 0 (0.0)
  • Small cell lung cancer: 1 (0.4)
  • Vaccine-related SAE: 0 (0.0)
  • Deaths: 0 (0.0)
I Fair

Vermeulen et al, 2012

Vaccine: LZV ~23,000 PFUs

Placebo: Not stated

Randomized  controlled trial

Vaccine administration provided on days 0 and 42

Age
60 years or older

Number
N= 209

No serious vaccine-related AEs occurred in 42-day period following immunization.

Results no. cases (%):
Zoster Vaccine Group:

Postvaccination 1 (n=104):

  • With one or more AE: 74 (71.2)
  • With vaccine-related AEs: 55 (52.9)
  • Injection-site AE: 51 (49.0)
  • Erythema: 42 (40.4)
  • Pain: 38 (36.5)
  • Pruritus: 10 (9.6)
  • Swelling: 32 (30.8)
  • Warmth: 3 (2.9)
  • Systemic AE: 13 (12.5)
  • Pruritus: 3 (2.9)
  • With SAE: 0 (0.0)
  • Discontinued due to a vaccine-related AEb: 2 (1.9)

Postvaccination 2 (n=98):

  • With one or more AE: 75 (76.5)
  • With vaccine-related AEs: 62 (63.3)
  • Injection-site AE: 60 (61.2)
  • Bruising: 2 (2.0)
  • Erythema: 53 (54.1)
  • Pain: 37 (37.8)
  • Pruritus: 11 (11.2)
  • Swelling: 43 (43.9)
  • Systemic AE: 5 (5.1)
  • Rash: 2 (2.0)
  • With SAE: 5 (5.1)
  • Discontinued due to a vaccine-related AE: 0 (0.0)

Placebo Group:

Postvaccination 1 (n=105):

  • With one or more AE: 46 (43.8)
  • With vaccine-related AEs: 12 (11.4)
  • Injection-site AE: 11 (10.5)
  • Erythema: 7 (6.7)
  • Pain: 2 (1.9)
  • Pruritus: 2 (1.9)
  • Swelling: 4 (3.8)
  • Warmth: 0 (0.0)
  • Systemic AE: 1 (1.0)
  • Pruritus: 0 (0.0)
  • With SAE: 0 (0.0)
  • Discontinued due to a vaccine-related AEb: 0 (0.0)

Postvaccination 2 (n=101):

  • With one or more: 40 (39.6)
  • With vaccine-related: 12 (11.9)
  • Injection-site AE: 7 (6.9)
  • Bruising: 0 (0.0)
  • Erythema: 1 (1.0)
  • Pain: 5 (5.0)
  • Pruritus: 1 (1.0)
  • Swelling: 0 (0.0)
  • Systemic AE: 6 (5.9)
  • Rash: 1 (1.0)
  • With SAE: 0 (0.0)
  • Discontinued due to a vaccine-related AE: 0 (0.0)
I Good

Vesikari et al, 2013

Zostavax®

Randomized Controlled Trial

Single dose of LZV provided on - day 0 (visit 1) only; or
- day 0 (visit 1) and day 28–35
- day 0 (visit 1) and day 81–97

Age
70 years or older (mean 76.1y)

Number
N= 759

HZ vaccine was generally well tolerated, with no evidence of increased AE incidence after the second dose with either schedule.

Results no. cases (%):
Post-dose 1, pooled data from single and 2-dose schedules (n= 749):

  • AE: 433 (57.8)
  • Vaccine related: 353 (47.1)
  • Injection-site reaction: 341 (45.5)
  • Solicited injection-site reaction: 338 (45.1)
  • Erythema: 298 (39.8)
  • Pain: 171 (22.8)
  • Swelling: 162 (21.6)
  • Unsolicited injection-site reaction: 28 (3.7)
  • Sys: 210 (28.0)
  • Vaccine-related: 48 (6.4)
  • Rash of interest: 2 (0.3)
  • Varicella/varicella-like: 0
  • HZ/zoster-like: 2 (0.3)
  • SAE: 9 (1.2)
  • Withdrawal due to AE: 9 (1.2)
  • Vaccine-related: 7 (0.9)
  • Non-serious vaccine-related: 7 (0.9)

Post-dose 2, 1-month schedule (n= 232):

  • AE: 123 (53.0)
  • Vaccine related: 100 (43.1)
  • Injection-site reaction: 98 (42.2)
  • Solicited injection-site reaction: 98 (42.2)
  • Erythema: 90 (38.8)
  • Pain: 39 (16.8)
  • Swelling: 54 (23.3)
  • Unsolicited injection-site reaction: 3 (1.3)
  • Systemic AE: 48 (20.7)
  • Vaccine-related: 8 (3.4)
  • Rash of interest: 1 (0.4)
  • Varicella/varicella-like: 1 (0.4)
  • HZ/zoster-like: 0
  • SAE: 2 (0.9)
  • Withdrawal due to AE: 1 (0.4)
  • Vaccine-related: 0
  • Non-serious vaccine-related: 0

Post-dose 2, 3-month schedule (n= 221):

  • AE: 107 (48.4)
  • Vaccine related: 95 (43.0)
  • Injection-site reaction: 94 (42.5)
  • Solicited injection-site reaction: 93 (42.1)
  • Erythema: 85 (38.5)
  • Pain: 44 (19.9)
  • Swelling: 49 (22.2)
  • Unsolicited injection-site reaction: 7 (3.2)
  • Systemic AE: 34 (15.4)
  • Vaccine-related: 6 (2.7)
  • Rash of interest: 1 (0.5)
  • Varicella/varicella-like: 1 (0.5)
  • HZ/zoster-like: 0
  • SAE: 2 (0.9)
  • Withdrawal due to AE: 0 (0)
  • Vaccine-related: 0
  • Non-serious vaccine-related: 0
I Good
Subunit Vaccine (Shingrix®) safety among immunocompetent individuals
Study Details Summary
Study Vaccine Study Design Participants Summary of Key Findings Using Text or Data Level of Evidence Quality

Chlibek et al. 2013

Vaccine: Shingrix®

Placebo: saline

Randomized control trial

Age
adults ≥50 years of age

Number (N=):
183

Results:
Percent of Subjects in Each Treatment Group Reporting Solicited General and Local Reactions:  % [95% CI]

gE/AS01b (n=150)

  • Any symptom:
    Any: 87.3 [80.9, 92.2]
    Grade 3: 9.3 [5.2, 15.2]
  • General symptoms:
    -   Any:
    Any:  63.3 [55.1, 71.0]
    Grade 3: 8.7 [4.7, 14.4]
    -   Fatigue:
    Any: 48.0 [39.8, 56.3]
    Grade 3: 6.0 [2.6, 11.1]
    -   Fever:
    Any: 16.7 [11.1, 23.6]
    Grade 3: 0.0 [0.0, 2.4]
    -   Gastrointestinal:
    Any: 11.3 [6.7, 17.5]
    Grade 3: 0.0 [0.0, 2,4]
    -   Headache:
    Any: 37.3 [29.6, 45.6]
    Grade 3: 3.3 [1.1, 7.6]
    -   Myalgia:
    Any: 41.3 [33.4, 49.7]
    Grade 3: 4.7 [1.9, 9.4]
  • Local Symptoms
    -   Any:
    Any: 84.0 [77.1, 89.5]
    Grade 3: 5.3 [2.3, 10.2]
    -   Pain:
    Any: 83.3 [76.4, 88.9]
    Grade 3: 4.0 [1.5, 8.5]
    -   Redness:
    Any: 29.3 [22.2, 37.3]
    Grade 3: 1.3 [0.2, 4.7]
    -  Swelling:
    Any: 15.3 [10.2, 22.1]
    Grade 3: 0.7 [0.0, 3.7]

Placebo (n=38)

  • Any symptom:
    Any:  21.1 [9.6, 37.3]
    Grade 3: 5.3 [0.6, 17.7]
  • General symptoms:
    -  Any:
    Any: 18.4 [7.7, 34.3]
    Grade 3: 5.3 [0.6, 17.7]
    -  Fatigue:
    Any: 18.4 [7.7, 34.3]
    Grade 3:  2.6 [0.1, 13.8]
    -  Fever:
    Any: 2.6 [0.1, 13.8]
    Grade 3: 0.0 [0.0, 9.3]
    -  Gastrointestinal:
    Any:  7.9 [1.7, 21.4]
    Grade 3: 2.6 [0.1, 13.8]
    -  Headache:
    Any: 10.5 [2.9, 27.8]
    Grade 3: 0.0 [0.0, 9.3]
    -  Myalgia:
    Any: 5.3 [0.6, 17.7]
    Grade 3: 2.6 [0.1, 13.8]
  • Local Symptoms
    -  Any:
    Any: 7.9 [1.7, 21.4]
    Grade 3: 0.0 [0.0, 9.3]
    -  Pain:
    Any: 7.9 [1.7, 21.4]
    Grade 3: 0.0 [0.0, 9.3]
    -  Redness:
    Any: 0.0 [0.0, 9.3]
    Grade 3: 0.0 [0.0, 9.3]
    -  Swelling:
    Any: 0.0 [0.0, 9.3]
    Grade 3: 0.0 [0.0, 9.3]
I Good

Chlibek et al. 2014

Shingrix®

Randomized control trial

Age
≥60 years

Number=
166

Subjects randomized to receive two doses of different HZsu formulations; only AEs for currently licenced product presented

Results: percentage %  [95% CI]

Shingrix® (50 µg gE/AS01B) (N=166):

Local Symptoms:

Overall cohort

  • Pain :
    Any : 72.9% [65.5–79.5]
    Grade 3a: 1.8% [0.4–5.2]
  • Redness:
    Any : 39.8% [32.3–47.6]
    Grade 3b : 3.0% [1–6.9]
  • Swelling:
    Any : 19.9% [14.1–26.8]
    Grade 3b : 1.2% [0.1–4.3]

60-69 years

  • Pain :
    Any : 90.9% [75.7–98.1]
    Grade 3a: 0% [0–10.6]
  • Redness:
    Any : 39.4% [22.9–57.9]
    Grade 3b: 3% [0.1–15.8]
  • Swelling:
    Any : 18.2% [7–35.5]
    Grade 3b : 3% [0.1-15.8]

≥70 years

  • Pain :
    Any : 68.4% [59.8–76.2]
    Grade 3a: 2.3% [0.5–6.5]
  • Redness:
    Any : 39.8% [31.5–48.7]
    Grade 3b : 3% [0.8–7.5]
  • Swelling:
    Any : 20.3% [13.8–28.1]
    Grade 3b : 0.8% [0–4.1]

General Symptoms:

Overall Cohort

  • Fatigue:
    Any : 51.2% [43.3–59.0]
    Grade 3a : 4.2% [1.7–8.5]
  • Fever :
    Any (c) : 10.8 [6.6–16.6]
    Grade 3d : 0.6% [0.0–3.3]
  • Headache:
    Any : 35.5% [28.3–43.3]
    Grade 3a : 1.8% [0.4–5.2]
  • Myalgia :
    Any : 53.6% [45.7–61.4]
    Grade 3a : 4.8% [2.1–9.3]

Grade 3a: Defined as preventing normal everyday activities

Grade 3b: Defined as a diameter of > 100mm

Any (c): Defined as an oral/axillary temperature of ≥37.5°C.

Grade 3d: Defined as an oral/axillary temperature of > 39°C.

I Fair

Chlibek et al. 2016

Shingrix®

Follow-up to, randomized controlled trial

Age
≥60 years

Number=
Results available for 119 adults at month 72 following the receipt of two doses of HZsu vaccine

All SAEs developed by study participants were considered unrelated to vaccination by the study investigators

II-2 Good

Cunningham et al. 2016

Vaccine: Shingrix®

Placebo:  0.9% saline solution

Randomized, placebo-controlled trial (ZOE-70)  

Participants received two doses of RZV or placebo administered intramuscularly 2 months apart.

Age

Adults 70 years or older

Number:

1,010

Results: n/ntot, % [95% CI]

RZV Group
Within 7 days after vaccination in the reactogenicity subgroup (ntot = 505):

  • Any: 399, 79.0% [75.2–82.5]
  • Grade 3: 60, 11.9% [9.2–15.0]
  • Local: 374, 74.1% [70.0–77.8]
    -   Pain: 347, 68.7% [64.5–72.7]
    -   Redness: 198, 39.2% [34.9–43.6]
    -   Swelling: 114, 22.6% [19.0–26.5]
  • Grade 3 local: 43, 8.5% [6.2–11.3]
  • Systemic: 267, 53.0% [48.5–57.4]
    -   Fatigue: 166, 32.9% [28.8–37.2]
    -   Myalgia: 157 , 31.2% [27.1–35.4]
    -   Headache: 124, 24.6% [20.9–28.6]
    -   Shivering: 75, 14.9% [11.9–18.3]
    -   Fever: 62, 12.3% [9.6–15.5]
    -  Gastro.: 55, 10.39% [8.3–14.0]
  • Grade 3 systemic: 30, 6.0% [4.1–8.4]

Throughout the study period in the total vaccinated cohort (ntot = 6950)

  • SAE: 1153, 16.6% [15.7–17.5]
  • SAE related to vaccination: 12, 0.2% [0.1–0.3]
  • Potential immuned-mediated disease: 92, 1.3% [1.1–1.6]
  • Death: 426, 6.1% [5.6–6.7]

Placebo Group
Within 7 days after vaccination in the reactogenicity subgroup (ntot = 505):

  • Any: 149, 29.5% [25.6–33.7]
  • Grade 3: 10, 2.0% [1.0–3.6]
  • Local: 50, 9.9% [7.4–12.8]
    -   Pain: 43, 8.5% [6.2–11.3]
    -   Redness: 5, 1.0% [0.3–2.3]
    -   Swelling: 2, 0.4% [0.0–1.4]
  • Grade 3 local: 1, 0.2% [0.0–1.1]
  • Systemic: 127, 25.1% [21.4–29.2]
    -   Fatigue: 77, 15.2% [12.2–18.7]
    -   Myalgia: 41, 8.1% [5.9–10.9]
    -   Headache: 55, 10.9% [8.3–13.9]
    -   Shivering: 22, 4.4% [2.7–6.5]
    -   Fever: 13, 2.6% [1.4–4.4]
    -  Gastro.: 40, 7.9% [5.7–10.6]
  • Grade 3 systemic: 10, 2.0% [1.0–3.6]

Throughout the study period in the total vaccinated cohort (ntot = 6950)

  • SAE: 1214, 17.5% [16.6–18.4]
  • SAE related to vaccination: 8, 0.1% [0.0–0.2]
  • Potential immuned-mediated disease: 97, 1.4% [1.1–1.7]
  • Death: 459, 6.6% [6.0–7.2]
I Good

Lal et al, 2015

Vaccine: Shingrix®,

Placebo:  0.9% saline solution

Randomized, placebo-controlled trial (ZOE-50)

Age
Adults ≥50 years of age.

Number: 15,411;  reactogenicity subgroup: 8,926

SAE recorded in all participants for up to 12 months after the second dose

Results: n/ntot, % (95% CI):

RZV Group

Reactogenicity Group (n=4460)

Within 30 days after vaccination:

  • Unsolicited report of AE:  1308, 29.3% (28.0–30.7)
  • Grade 3 unsolicited report of AE: 208, 4.7% (4.1–5.3)

Within 7 days after vaccination:

  • Solicited or unsolicited report of AE:  3765, 84.4% (83.3–85.5)
  • Grade 3 solicited or unsolicited report of AE:
    760, 17.0% (15.9–18.2)
  • Grade 3 solicited or unsolicited report of vaccine-related AE:
    694, 15.6% (14.5–16.7)
  • Solicited report of injection-site reaction (ntot = 4382): 3,571,  81.5% (80.3–82.6)
    -   Pain: 3,464, 79.1% (77.8–80.2)
    -   Redness: 1,664, 38.0% (36.5–39.4)
    -   Swelling: 1.153, 26.3% (25.0–27.6)
  • Grade 3 solicited report of injection-site reaction: 417, 9.5% (8.7–10.4)
  • Solicited report of systemic reaction (ntot=4375): 2.894, 66.1% (64.7–67.6)
    -   Myalgia: 2.025, 46.3% (44.8–47.8)
    -   Fatigue: 2.008, 45.9% (44.4–47.4)
    -   Headache:1.716, 39.2% (37.8–40.7)
    -   Shivering: 1.232, 28.2% (26.8–29.5)
    -   Fever: 939, 21.5% (20.3–22.7)
    -   Gastrointestinal: 788, 18.0% (16.9–19.2)
  • Grade 3 solicited report of systemic reaction: 498 11.4% (10.5–12.4)

Total vaccinated cohort (n=7,698):
Throughout study period:

  • SAE: 689, 9.0% (8.3–9.6)
  • Potential immune-mediated disease: 78, 1.0% (0.8–1.3)
  • Death: 167, 2.2% (1.9–2.5)

Within 30 days after vaccination:

  • SAE: 87, 1.1% (0.9–1.4)
  • Serious vaccine-related AE: 1, 0.0 (0.0–0.1)
  • Death: 8, 0.1 (0.0–0.2)

Placebo Group

Reactogenicity Group (n=4,466)

Within 30 days after vaccination:

  • Unsolicited report of AE:
    1,226, 27.5% (26.1–28.8)
  • Grade 3 unsolicited report of AE: 151, 3.4% (2.9–4.0)

Within 7 days after vaccination:

  • Solicited or unsolicited report of AE:
    1,689, 37.8% (36.4–39.3)
  • Grade 3 solicited or unsolicited report of AE: 145, 3.2% (2.7–3.8)
  • Grade 3 solicited or unsolicited report of vaccine-related AE:
    83, 1.9% (1.5–2.3)
  • Solicited report of injection-site reaction (ntot=4377): 522, 11.9% (11.0–12.9)
    -   Pain: 490, 11.2% (10.3–12.2)
    -   Redness: 59, 1.3% (1.0–1.7)
    -   Swelling: 46, 1.1% (0.8–1.4)
  • Grade 3 solicited report of injection-site reaction: 16, 0.4% (0.2–0.6)
  • Solicited report of systemic reaction(ntot=4378): 1,293, 29.5% (28.2–30.9)
    -   Myalgia: 530, 12.1% (11.2–13.1)
    -   Fatigue: 728, 16.6% (15.5–17.8)
    -   Headache: 700, 16.0% (14.9–17.1)
    -   Shivering: 259, 5.9% (5.2–6.7)
    -   Fever: 132, 3.0% (2.5–3.6)
    -   Gastrointestinal: 387, 8.8% (8.0–9.7)
  • Grade 3 solicited report of systemic reaction: 106, 2.4% (2.0–2.9)

Total vaccinated cohort (n=7713):
Throughout study period:

  • SAE: 686, 8.9% (8.3–9.6)
  • Potential immune-mediated disease:   97, 1.3% (1.0–1.5)
  • Death: 174, 2.3% (1.9–2.6)

Within 30 days after vaccination:

  • SAE: 97, 1.3% (1.0–1.5)
  • Serious vaccine-related AE: 3, 0.0% (0.0–0.1)
  • Death: 7, 0.1% (0.0–0.2)
I Good

Leroux-Roels et al, 2012

Vaccines: Shingrix® and LZV

Randomized, parallel-group trial

HZsu or LZV or HZsu+LZV provided at months 0 and 2

Age
Between 18 and 30 years or between 50 and 70 years of age.

Number
N = 155

Few grade 3 events and no SAE were reported. Fatigue, myalgia, headache, and injection site pain were the most common solicited reactions for RZV and occurred more frequently than with LZV

Results no. (%) 95% CI:

Percentage of Subjects
Experiencing Local and General Solicited Reactions During the 7-day Postvaccination Period Following Any vaccine Dose:

Adults aged 50-70 years (n = 135)

LZV only group (n=45):

General reactions:

  • Fatigue:
    -  Any: 6 (13.3) 5.1–26.8
    -  Grade 3: 0 (0.0) 0.0–7.9
  • Fever:
    -  Any: 0 (0) 0.0–7.9
    -  Grade 3: 0 (0) 0.0–7.9
  • Gastrointestinal:
    -  Any: 9 (17.8) 8.0–32.1
    -  Fever: 1 (2.2) 0.1–11.8
  • Headache:
    -  Any: 11 (24.4) 12.9–39.5
    -  Grade 3: 0 (0) 0.0–7.9
  • Myalgia:
    -  Any: 7 (15.6) 6.5–29.5
    -  Grade 3: 0 (0) 0.0–7.9

Local reactions:

  • Pain:
    -  Any: 23 (51.1) 35.8–66.3
    -  Grade 3: 0 (0.0) 0.0–7.9
  • Redness:
    -  Any: 28 (62.2) 46.5–76.2
    -  Grade 3: 2 (4.4) 0.5–15.1
  • Swelling:
    -  Any: 20 (44.4) 29.6–60.0
    -  Grade 3: 2 (4.4) 0.5–15.1

RZV only group (n=45):

General reactions:

  • Fatigue:
    -  Any: 28 (62.2) 46.5–76.2
    -  Grade 3: 3 (6.7) 1.4–18.3
  • Fever:
    -  Any: 9 (20) 9.6–34.6
    -  Grade 3: 0 (0) 0.0–7.9
  • Gastrointestinal:
    -  Any: 8 (17.8) 8.0–32.1
    -  Fever: 2 (4.4) 0.5–15.1
  • Headache:
    -  Any: 27 (60) 44.3–74.3
    -  Grade 3: 3 (6.7) 1.4–18.3
  • Myalgia:
    -  Any: 30 (66.7) 51.0–80.0
    -  Grade 3: 3 (6.7) 1.4–18.3

Local reactions:

  • Pain:
    -  Any: 40 (88.9) 75.9–96.3
    -  Grade 3: 2 (4.4) 0.5–15.1
  • Redness:
    -  Any: 15 (33.3) 20.0–49.0
    -  Grade 3: 9 (20.0) 9.6–34.6
  • Swelling:
    -  Any: 8 (17.8) 8.0–32.1
    -  Grade 3: 4 (8.9) 0.5–15.1

RZV + LZV group (n=45):

General reactions:

  • Fatigue:
    -  Any: 25 (55.6) 40.0–70.4
    -  Grade 3: 2 (4.4) 0.5–15.1
  • Fever:
    -  Any: 7 (15.6) 6.5–29.5
    -  Grade 3: 0 (0) 0.0–7.9
  • Gastrointestinal:
    -  Any: 15 (33.3) 20.0–49.0
    -  Fever: 1 (2.2) 0.1–11.8
  • Headache:
    -  Any: 24 (53.3) 37.9–68.3
    -  Grade 3: 3 (6.7) 1.4–18.3
  • Myalgia:
    -  Any: 30 (66.7) 51.0–80.0
    -  Grade 3: 3 (6.7) 1.4–18.3

Local reactions:

  • Pain:
    -  Any: 42 (93.3) 81.7–98.6
    -  Grade 3: 5 (11.1) 3.7–24.1
  • Redness:
    -  Any: 25 (55.6) 40.0–70.4
    -  Grade 3: 5 (11.1) 3.7–24.1
  • Swelling:
    -  Any: 21 (46.7) 31.7–62.1
    -  Grade 3: 2 (4.4) 0.5–15.1

Adults aged 18-30 years (n = 20)

RZV only group (n=10):

General reactions:

  • Fatigue:
    - Any: 9 (90.0) 55.5–99.7
    - Grade 3: 0 (0.0) 0.0–30.8
  • Fever:
    -  Any: 3 (30) 6.7–65.2
    -  Grade 3: 0 (0.0) 0.0–30.8
  • Gastrointestinal:
    -  Any: 2 (20) 2.5–55.6
    -  Fever: 0 (0.0) 0.0–30.8
  • Headache:
    -  Any: 7 (70) 34.8–93.3
    -  Grade 3: 1 (10) 0.3–44.5
  • Myalgia:
    -  Any: 7 (70) 34.8–93.3
    -  Grade 3: 0 (0.0) 0.0–30.8

Local reactions:

  • Pain:
    -  Any: 10 (100) 69.2–100.0
    -  Grade 3: 1 (10.0) 0.3–44.5
  • Redness:
    -  Any: 4 (40.0) 12.2–73.8
    -  Grade 3: 1 (10.0) 0.3–44.5
  • Swelling:
    -  Any: 2 (20.0) 2.5–55.6
    -  Grade 3: 1 (10.0) 0.3–44.5

RZV + LZV group (n=10):

General reactions:

  • Fatigue:
    -  Any: 10 (100) 69.2–100.0
    -  Grade 3: 1 (10.0) 0.3–44.5
  • Fever:
    -  Any: 5 (50) 18.7–81.3
    -  Grade 3: 0 (0) 0.0–30.8
  • Gastrointestinal:
    -  Any: 5 (50) 18.7–81.3
    -  Grade 3: 1 (10) 0.3–44.5
  • Headache:
    -  Any: 9 (90) 55.5–99.7
    -  Grade 3: 1 (10) 0.3–44.5
  • Myalgia:
    -  Any: 9 (90) 55.5–99.7
    -  Grade 3: 1 (10) 0.3–44.5

Local reactions:

  • Pain:
    -  Any: 10 (100) 69.2–100.0
    -  Grade 3: 0 (0) 0.0–30.8
  • Redness:
    -  Any: 7 (70.0) 34.8–93.3
    -  Grade 3: 1 (10.0) 0.3–44.5
  • Swelling:
    -  Any: 5 (50.0) 18.7–81.3
    -  Grade 3: 0 (0) 0.0–30.8
I Fair

Vink et al, 2017

Shingrix®

Randomized  open-label controlled trial

Vaccine administered SC or IM

Age
50 years or older

Number
N= 60

Intervention details:

Results 7-day post-vaccination, (%):

SC Group (n= 30):

  • At least one AE: 100%
  • Solicited injection site reaction: 98.3%
  • Pain: 88.3%
  • Redness: 76.7%
  • Swelling: 70%
  • Solicited systemic symptoms: 60%
  • Fatigue: 50%
  • Grade 3 Myalgia: 1.7%
  • Unsolicited AEs: 9 (30%)
  • *Non-fatal SAE: 2 (6.6%)

IM Group (n= 28):

  • At least one AE: 91.5%
  • Solicited injection site reaction: 84.7%
  • Pain: 79.7%
  • Redness: 39%
  • Swelling: 30.5%
  • Solicited systemic symptoms: 50.8%
  • Fatigue: 35.6%
  • Grade 3 headache: 3.4%
  • Unsolicited AEs: 7 (25%)
  • *Non-fatal SAE: 1 (3.6%)

These SAEs were not considered to be causally related to the study vaccine by the investigator.  No HZ cases or potential immune medicated diseases were reported during the study period.

I Fair

References

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