NACI Statement: Herpes zoster vaccine


Volume 36 ACS-1, January 2010

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

Statement on the Recommended Use of Herpes Zoster Vaccine


*Members: Dr. J. Langley (Chairperson), Dr. B. Warshawsky (Vice-Chairperson), Dr. S. Ismail (Executive Secretary), Ms. A. Hanrahan, Dr. K. Laupland, Dr. A. McGeer, Dr. S. McNeil, Dr. B. Seifert, Dr. D. Skowronski, Dr. B. Tan.

Liaison Representatives: Dr. B. Bell (CDC), Dr. P. Orr (AMMI Canada), Ms. S. Pelletier (CHICA), Ms. K. Pielak (CNCI), Dr. P. Plourde (CATMAT), Dr. S. Rechner (CFPC), Dr. M. Salvadori (CPS), Dr. D. Scheifele (CAIRE), Dr. N. Sicard (CPHA), Dr. V. Senikas (SOGC).

Ex-Officio Representatives: Dr. S. Desai (CIRID – Vaccine Preventable Diseases), Mrs. M. FarhangMehr (CIRID - National Advisory Committee on Immunization), Dr. P. Varughese (CIRID), Major P. Laforce (DND), Dr. B. Law (CIRID-Vaccine Safety), Dr. R. Ramsingh (FNIHB), Dr. F. Hindieh (BGTD).

† This statement was prepared by Dr. Kevin Laupland and approved by NACI and the Public Health Agency of Canada.



The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada with ongoing and timely medical, scientific, and public health advice relating to immunization. The Public Health Agency of Canada 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 the Public Health Agency of Canada's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.


In August 2008, a live, injectable, attenuated herpes zoster vaccine (Zostavax™, Merck Frosst Canada, Inc.) was authorized for use in Canada for the prevention of herpes zoster (shingles) infection in adults aged 60 years and older. It was licensed in the United States (US) by the Food and Drug Administration (FDA) in May 2006 and recommended for use in adults by the Advisory Committee on Immunization Practices (ACIP) in October 2006Footnote 1Footnote 2. This statement provides recommendations for use of Zostavax™ in Canadian adults. As new information regarding Zostavax™ and/or the burden of illness becomes available, the recommendations will be reviewed. Issues including cost-effectiveness, acceptability of vaccine programs, and feasibility will be addressed by other provincial or federal groups.

In order to facilitate preparation of the National Advisory Committee on Immunization (NACI) recommendations for use of this vaccine, a systematic review of the literature was undertaken focusing on the burden of herpes zoster in Canadian adults and the safety and efficacy of the vaccine in clinical trials. Relevant published articles were identified by a PubMed search from 1995 to August 31, 2008, using the search terms "zoster" and "Canada" or "zoster" and "vaccine." A total of 768 studies were initially identified. These were screened by one member, and potentially relevant full-length articles were selected for further review. Two other authors reviewed the selected studies for appropriateness for inclusion and for accuracy of data abstraction. Recommendations and levels of evidence evaluations were agreed to by consensus of NACI members and were based on a recently published guidelineFootnote 3.

Clinical Features and Epidemiology of Herpes Zoster–Associated Disease in Adults

The varicella-zoster virus (VZV) is an enveloped double-stranded DNA virus of the Herpesviridae family. This virus causes two distinct clinical syndromes: varicella (chickenpox) and zoster (shingles). Chickenpox is usually a primary systemic infection characterized by a generalized exanthematous vesicular rash. Mainly a childhood disease, chickenpox is highly contagious and occurs ubiquitously in non-vaccinated children. In the pre-vaccine era, 90% or more of Canadian children were infected by 12 years of ageFootnote 4.

Herpes zoster infection is characterized by pain and a unilateral vesicular eruption, usually in a single dermatome. It arises from the reactivation of latent VZV from sensory ganglia present from previous chickenpox infection. Complications of acute zoster are potentially severe and may include sight-threatening eye infections (zoster ophthalmicus), central nervous system infection, nerve palsies including the Ramsay-Hunt Syndrome, neuromuscular disease including Guillain-Barre Syndrome, and secondary bacterial infectionsFootnote 5. The most frequent complication is post-herpetic neuralgia (PHN), which is characterized by prolonged (usually defined by presence of 90+ days) and often debilitating neurogenic pain that either persists from or follows the acute zoster infection. This complication occurs in approximately 20% of adults overall but in one-third or more of octogenariansFootnote 6. Treatment options are of limited effectivenessFootnote 7Footnote 8. Post-herpetic neuralgia frequently has a major adverse impact on quality of life, especially in elderly personsFootnote 9-Footnote 11.

Although implementation of childhood VZV vaccination has been hypothesized to contribute to increasing zoster ratesFootnote 12-Footnote 17, different jurisdictions have reported varying trends in the incidence of zoster over time. Studies in ManitobaFootnote 18 AlbertaFootnote 19, and in the United KingdomFootnote 20 demonstrated increases in incidence of herpes zoster prior to the implementation of varicella vaccination programs. It has been proposed that decreased natural immune boosting of older persons from circulating wild-type VZV virus could increase the risk of VZV reactivation. In the US childhood varicella program have been in place since 1996; two studies reported no change in the incidence of zoster and one found the age standardized rate of 2.77 cases/1000 person-years in 1999 increased to 5.25 in 2003 using a telephone survey methodFootnote 21. Multiple other factors could contribute to changes in the incidence of zoster over time including changes in reporting or in diagnostic coding of zoster cases, or changes in risk factors for herpes zoster over time (e.g. use of steroids or immunosuppressive therapy). Further studies on the factors influencing the epidemiology of herpes zoster will be useful.

A number of studies using administrative data have assessed the burden of zoster infection in Canadian adultsFootnote 19Footnote 20Footnote 22Footnote 23. Brisson et al. investigated the burden of herpes zoster by examining annual physician billing claims and hospital separations in Manitoba between 1979 and 1997Footnote 20. They found that among the age groups 15–44, 45–64, and ≥65 years that the annual incidence was 1.9, 4.2, and 8.1 per 1,000 population, and that the rate of hospitalization per case was 1%, 2.8%, and 10.6%, respectively.

Russell et al. investigated the epidemiology of zoster in Alberta between 1986 and 2002Footnote 19. They observed an overall progressive increase in the incidence of zoster during the study duration with an incidence of 2.7 per 1,000 in 1986, increasing to 4.3 per 1,000 in 2002. The incidence of zoster increased with advancing age, showing a steep increase after age 50 and an incidence of >10 per 1,000 in those ≥75 years of age.

Edgar et al. studied varicella-associated illness in British Columbia between 1994 and 2003Footnote 22. They observed an increasing incidence of zoster in adults throughout the duration of the study. The incidence in those aged 20–64 was 2.6 per 1,000 and 7.0 per 1,000 among those ≥ 65 years of age. The overall hospitalization rate was approximately 0.5 per 1,000 annually in all adults 20 years and older. The mortality rate was 0.04 per million in 20- to 64-year-olds and 5 per million among those ≥ 65 years of age.

Manuel et al. reported on the occurrence of zoster in lung transplant recipients at a Canadian centreFootnote 23. They found that in the cohort of 239 patients, 55.1 cases per 1,000 person-years of follow-up occurred and the cumulative incidence was 5.8% at 1 year, 18.1% at 3 years, and 20.2% at 5 years post-transplantFootnote 23.

Live, Attenuated, Injectable Herpes Zoster Vaccine: Zostavax™ (Merck Frosst Canada, Ltd.)

Vaccine composition

Zostavax™ is a live, attenuated vaccine based on the Oka/Merck strain developed through serial passages in tissue culture. The vaccine contains the same components as the varicella vaccine Varivax™ (Merck) but with an approximately 14-fold or higher virus concentration (not less than 19,400 plaque forming units per 0.65 mL single dose vial). Each dose contains sucrose, hydrolyzed porcine gelatin, sodium chloride, monosodium L-glutamate, sodium phosphate dibasic, potassium phosphate monobasic, and potassium chloride. Residual DNA and protein from MRC-5 cell culture are also present, as are trace amounts of neomycin and bovine calf serum.


The cellular and humoral immune correlates of protection from zoster among patients previously infected with chickenpox are not well established, and none have been accepted as markers of protectionFootnote 24Footnote 25. In addition, commercially available laboratory tests developed for assessing immunity to wild-type VZV are not accurate for the diagnosis of vaccine-induced chickenpox immunityFootnote 4. Studies evaluating the immunogenicity of zoster vaccination should therefore be interpreted with caution.

Immune responses to vaccination were assessed in a sub-study of the Shingles Prevention Study, involving 1,395 patientsFootnote 26. Antibody titers to VZV were measured by glycoprotein enzyme linked immunosorbent assay (ELISA), and cell-mediated immunity was assessed by interferon-γ (IFN-γ) ELISPOT and responder cell frequency (RCF) assaysFootnote 27. At baseline, all patients with sufficient samples had VZV antibody but the ELISPOT and RCF assays were negative in 18.5% and 5.9% of subjects, respectively. Six weeks post vaccination geometric mean (95% confidence interval) VZV antibody titres were increased at 471.3 (438.2–506.8) versus 292.3 (269.9–316.5) units/mL in recipients of the Oka/Merck zoster vaccine as compared to placebo, as were ELISPOT [70.1 (61.6–79.8) versus 31.7 (28.0–35.8) spot-forming cells per 106 peripheral blood mononuclear cells (PBMCs)], and RCF [9.8 (9.2–10.5) versus 5.3 (4.9–5.7) responder cells per 105 PBMCs] assays. Vaccine-related cell-mediated and antibody boost declined significantly over the subsequent year, then remained relatively stable for the following two years.

Kerzner et al. conducted a randomized, double-blinded, placebo-controlled trial comparing the immunogenicity of Zostavax™ and inactivated trivalent influenza vaccine in adults aged 50 and older administered either concomitantly (both on day 1) or sequentially (influenza day 1 and Zostavax™ at week 4)Footnote 28. Geometric mean (95% confidence interval) glycoprotein ELISA titres to VZV 4 weeks post-vaccination were 554 (499.0–613.9) units/mL in the concomitant and 589 (531.9–651.5) units/mL for the sequential groups, for a ratio of 0.9 (95% confidence interval 0.8–1.0) that fulfilled criteria for non-inferiority (i.e., greater than 0.67).

MacIntyre et al. reported on a randomized, double-blinded, multi-centre, placebo-controlled study comparing the immunogenicty of concomitant and sequential (1 month later) Pneumovax™23 and Zostavax™ in 471 patients[29]. Varicella history-positive subjects ≥60 years of age with no history of invasive pneumococcal disease or zoster were immunized with open-label Pneumovax™23 and then randomized to either Zostavax™ or placebo at a separate injection site concomitantly or sequentially (4 weeks later). Baseline VZV GMT were higher in the concomitant group (192.2; 95% CI, 169.2–218.4) than the non-concomitant group (150.5; 95% CI, 133.6–169.6). At 4 weeks post-immunization, VZV GMT were significantly lower among the concomitant (371.6; 95% CI, 328.7–420.0) as compared to non-concomitant (448.5; 95% CI, 400.3–502.4) groups, fulfilling a pre-specified criterion for inferiority for concomitant administration. However, the VZV GMT mean fold rise for the concomitant (1.9; 95% CI, 1.7–2.1) and non-concomitant (3.1; 95% CI, 2.8–3.5) groups fulfilled a second criterion of >1.4 for non-inferiority. Pneumococcal GMT for the four serotypes tested (3, 14, 19A, and 22F) were not significantly different among the two groups at 4 weeks post-immunization.

Macaladad et al. evaluated the immunogenicity of live attenuated Oka/Merck vaccine (50,000 plaque forming units/0.5 mL dose) in VZV seronegative or low (≤5 glycoprotein ELISA units/mL) sero-titre subjects aged ≥30 years of ageFootnote 30. Subjects were randomized 4:1 to receive a single dose of zoster vaccine or placebo. Of the four initially seronegative subjects, all seroconverted (day 42 geometric mean titre 12.0 units/mL) with vaccination. Of the 13 low seropositive patients who were vaccinated, the geometric mean titre increased from a baseline of 6.7 to 25.7 units/mL at 6 weeks post-vaccination.

Gilderman et al. assessed the immunogenicity of a refrigerator-stable as compared to a frozen formulation of Zostavax™ in a double-blinded, placebo-controlled multi-centred randomized trial in adults ≥50 years of age who did not have a history of zoster infection [31]. Day 28 VZV geometric mean titres as measured by glycoprotein ELISA were similar among the refrigerated (n = 182; 727.4 units/mL) and frozen (n = 185; 834.4 units/mL) formulations. The estimated refrigerated/frozen ratio was 0.87 (95% confidence interval, 0.71 to 1.07), fulfilling criteria for non-inferiority.


The efficacy of live attenuated injectable Oka/Merck herpes zoster vaccine has been evaluated in one large phase III randomized clinical trial conducted in the United States: the Shingles Prevention Study [32]. In this trial, 38,546 healthy adults aged ≥ 60 years who had a previous history of chickenpox infection or had resided in the continental United States for 30 years or longer were randomized to either a single subcutaneous injection of 0.5 mL of live attenuated Oka/Merck zoster vaccine (minimum 18,700 plaque forming units per dose) or to a placebo[32]. Patients who were immune compromised, had previous chickenpox vaccination, or had a history of herpes zoster were excluded. The primary endpoint was herpes zoster burden of illness as determined using a previously validated health-related quality of life measurement tool[10]. Follow-up was a median of 3.1 years. The herpes-zoster burden-of-illness score was significantly reduced in the zoster vaccine group as compared to placebo (2.21 vs. 5.68; p<0.001), as was the incidence of herpes zoster (5.42 vs. 11.12 per 1,000 person-years; p<0.001), and post-herpetic neuralgia (0.46 vs 1.38 cases per 1,000 person-years; p<0.001). Both the duration and severity of zoster were reduced in the vaccine recipients. Overall vaccine efficacy was 61.1% (95% CI, 51.1-69.1%) for burden-of-illness score, 51.3% (95% CI, 44.2–57.6%) for confirmed zoster incidence, and 66.5% (95% CI, 47.5–79.2%) for post-herpetic neuralgia.

Vaccine safety and adverse events

In the Shingles Prevention Study[32], all adverse events occurring within 42 days after injection and all serious events thereafter were reported on all subjects. A sub-study of 6,616 patients was also performed in order to closely monitor for adverse events. Vaccine recipients were significantly (p<0.05) more likely to experience one or more adverse event overall (58.1% vs. 34.4%) and one or more serious adverse events (1.9% vs. 1.3%) as compared to subjects who received placebo. The significantly higher rates of adverse events seen among vaccine recipients as compared to placebo subjects was principally related to an increase in injection site reactions with erythema (35.8% vs. 7.0%), pain or tenderness (34.5 vs. 8.5%), swelling (26.2% vs. 4.5%), pruritis (7.1 vs. 1.0%), and warmth (1.7 vs. 0.3%). During the first 42 days, the rate of a varicella-like rash at the injection site was significantly (p<0.05) more common in vaccine recipients than in placebo recipients (20 cases; 0.1% vs. 7 cases; 0.04%), although rates of herpes zoster were lower (7; <0.1% vs. 24; 0.1%) in vaccine recipients. A case-by-case review suggested that there were no clinically significant differences in serious adverse events between the treatment and placebo groups. Among serious adverse events that were deemed potentially vaccine related, two occurred in vaccine recipients and three in patients randomized to placebo. Overall (34.0% vs. 34.1%) and herpes zoster–related (0.2% for each) rates of hospitalization were similar between the vaccine and placebo groups. There was no overall difference in mortality observed [14 (4.1%) deaths for zoster vaccinated group as compared to 16 (4.1%) deaths for placebo group].

A number of smaller studies have assessed the safety and tolerability of live attenuated herpes zoster vaccine. No significant increase in reactogenicity or adverse events was observed in either the trial by Kerzner et al. comparing concomitant and sequential influenza and zoster vaccineFootnote 28 or the Gilderman and colleagues comparison of refrigerator-stable and frozen formulations of Zostavax™Footnote 31. In the study by MacIntyre et al. comparing concomitant and sequential (1 month later) Pneumovax™23 and Zostavax™, injection-site reactions of erythema and swelling at the Pneumovax™23 site occurred at higher rates (7% and 8%, respectively) in the concomitant group as compared to the reaction rates in the sequential groupFootnote 29. Systemic and serious adverse events were uncommon and not different between the groups. In the small study by Macaladad et al. where seronegative or low seropositive adults aged ≥30 years were vaccinated with zoster vaccine, no serious vaccine-related events or clinical varicella lesions were observedFootnote 30. Minor local reactions occurred in 2 of 18 vaccine recipients. Tyring and colleagues conducted a randomized, double-blinded comparison of two different dosages of live attenuated injectable Oka/Merck herpes zoster vaccine (58,000 vs. 207,000 pfu/0.65mL dose) in 698 adults aged 50 + who had a history of varicella infection but not zosterFootnote 33. At 42 days of follow-up, 5 serious adverse events had been registered, of which none were deemed vaccine related. Rates of minor injection site reactions occurred in 63% and 60%, and systemic reactions in 11% and 13% of patients receiving higher and lower doses, respectively. According to the Zostavax™ monograph, a double-blinded clinical trial assessing the safety and tolerability of a second dose of Zostavax™ versus placebo 42 days after all patients received Zostavax™ has been conducted in 98 adults older than 60 years. The frequency of adverse events after the second dose was reportedly similar to that seen with the first dose.

Dosage and schedule

Zostavax™ is given as a single dose by subcutaneous injection in the deltoid region of the upper arm. Each 0.65-mL single dose vial contains a minimum of 19,400 plaque-forming units.

Shedding and transmission of vaccine virus

As with all live vaccines, there is a theoretical risk of transmission from vaccinated to susceptible individuals. No case of transmission of Zostavax™ from a vaccinated individual to another person has been documented to date.

Prevention of shingles and not chickenpox

Zostavax™ is indicated for the prevention of herpes zoster in patients with prior chickenpox infection. It is not recommended for prevention of primary VZV infection. Individuals who do not have immunity and no contraindications should be immunized with a chickenpox vaccineFootnote 4.


It is not known whether Zostavax™ is secreted in human milk. Zostavax™ is not recommended for use in women of child-bearing potential. Given the age indication for Zostavax™, breastfeeding is unlikely among the target population.


Zostavax™ is contraindicated during pregnancy, and NACI recommends that women should avoid pregnancy for at least one month after the receipt of any varicella vaccine. Given the age indication for Zostavax™, pregnancy is unlikely among the target population.

Storage and handling

Zostavax™ is stored frozen at an average temperature of -15°C until it is prepared for injection by reconstitution of the lyophilized vaccine with the supplied diluent. The reconstitution should occur no more than 30 minutes before administration to the patient/client, in order to avoid loss of potency. Reconstitution should occur immediately upon removal from the freezer. The diluent should be stored separately at room temperature (20-25 °C) or in a refrigerator between 2°C and 8°C and should never be frozen.

Simultaneous administration with other vaccines

Concomitant administration of Zostavax™ and trivalent influenza has been demonstrated to have comparable safety, tolerability, and immunogenicity as when given sequentiallyFootnote 28. One clinical trial of co-administration of Zostavax™ with Pneumovax™23 has demonstrated the safety of co-administration of these vaccines but inferior VZV GMT at 4 weeks post-vaccinationFootnote 29. Co-administration of Zostavax™ with other vaccines has not been evaluated.

Simultaneous administration with other therapies

Use of anti-viral medications active against VZV (i.e., acyclovir, famciclovir, valacyclovir) within weeks of Zostavax™ may be expected to reduce the vaccine efficacy. There is no evidence to evaluate the timing of and any potential interaction with immunization with Zostavax™ in relation to administration of immune globulins or other blood products. However, it is prudent to delay Zostavax™ administration for 3 months after a dose of intravenous immunoglobulin if practical, as efficacy may be reducedFootnote 4.


Zostavax™ should not be given to patients with anaphylactic hypersensitivity to any of its components. It is a live attenuated vaccine and should not be given to individuals with congenital or acquired immune deficiency, to those who have recently used or are currently using immune suppressive medications, or to women who are pregnant. The vaccine is not recommended for use in women of childbearing potential or those less than 50 years of age. Vaccination should be deferred in patients with active untreated tuberculosis. Deferral should be considered in acute illness, for example, in the presence of fever.

Duration of protection

The efficacy of Zostavax™ in preventing herpes zoster infection has been demonstrated to 4 years of follow-up. In the one large phase III study (Shingles Prevention Study) all patients randomized to placebo were offered Zostavax ® at the end of the study; hence no further long-term prospectively controlled data will be available and estimates will need to be based on historical controls[32, 34] prior to vaccine availability. In a recent abstract, investigators showed that persistence of the effect of Zostavax on burden of illness and incidence of herpes zoster in 14, 275 consenting participants in the (Short-Term Persistence Sub-study) was seen up to year 7 post-vaccination [35].

Zostavax™ Recommended Usage

Zoster is a potentially serious condition that is common and results in significant burden of illness principally related to acute disease and chronic PHN. In those aged 60 and older, vaccination with Zostavax™ reduces the occurrence of zoster and its complications by approximately 60%. Zostavax™ is not intended for the prevention of chickenpox or for the treatment of shingles or post-herpetic neuralgia and is intended for individuals aged 60 and older who are not immunocompromised. The duration of protection beyond 4 years and the need for repeat booster dosing is not known. The decision to include Zostavax™ in universal, publicly funded provincial and territorial programs will depend upon a number of other factors, such as detailed cost-benefit evaluation and assessment of other elements of the Erikson and DeWals analytic framework for immunization programs in CanadaFootnote 36-Footnote 39. Specific recommendations for the use of Zostavax™ are presented below. For each group, the level of evidence given is based on research design rating and recommendation grades for specific clinical preventive action as previously describedFootnote 3.

  • Zostavax™ is recommended for the prevention of herpes zoster and its complications in persons 60 years and older without contraindications (NACI recommendation A, good).

NACI makes no recommendation for Zostavax™ immunization of individuals with a past episode of zoster (NACI recommendation I, insufficient). Patients who have had a previous episode of zoster are at risk for further episodes. Individuals with a prior history of zoster were excluded from the pivotal efficacy trial (SPS) and therefore the efficacy of Zostavax™ in this population was not demonstrated. In a small study of 101 subjects ≥ 50 years of age with a previous history of herpes zoster, no safety concerns were identifiedFootnote 40.

  • Zostavax™ should be administered to patients indicated for vaccine irrespective of a prior history of chickenpox or documented prior varicella infection (NACI recommendation A, good). Given that nearly all Canadians indicated for immunization will have had prior chickenpox exposure even if a prior diagnosis of VZV cannot be recalled, routine testing for varicella antibody is not recommended. There is no known safety risk associated with vaccination of healthy individuals who are susceptible. In the rare circumstance that patients are known to be serologically varicella susceptible based on previous testing for another reason, they should be vaccinated with 2 doses of varicella vaccineFootnote 4.
  • Booster (repeat) doses of Zostavax™ are not recommended for healthy individuals (NACI recommendation I, insufficient). The efficacy of protection has not been assessed beyond 4 years and it is not known whether booster doses of vaccine are beneficial. This recommendation may need to be revisited as further information becomes available.
  • Individuals who inadvertently receive systemic anti-viral therapy active against VZV within 2 days before and 14 days after Zostavax™ injection may benefit from a second dose of vaccine 42 days or later and after discontinuing antiviral therapy (NACI recommendation B, fair). While systemic anti-viral therapy active against VZV should ideally be avoided in the peri-immunization period, if it is used, then vaccine efficacy may be affected.
  • Zostavax™ may be used in patients aged 50 and older (NACI recommendation B, fair). Although Zostavax™ has been demonstrated to be safe and immunogenic in patients 50 years of age and older, effectiveness has been studied only in those aged ≥60 years. The incidence and severity of herpes zoster begins to increase with age after 50 to 60 years. While all patients aged ≥50 years may be expected to receive some benefit, the greatest benefit will be seen in those 60 years and older. As the duration of protection is unknown beyond 4 years, it is uncertain whether vaccination at younger ages (such as between 50 and 60) will provide ongoing protection at older ages when the incidence of zoster is higher.
  • Trivalent influenza vaccine may be administered concomitantly with Zostavax™ at a different body injection site (NACI recommendation A, good). Pneumovax™23 and Zostavax™ should be administered at least 4 weeks apart (NACI recommendation B, fair). No data are currently available for concomitant administration of Zostavax™ with other vaccines.
Table 1. Summary of evidence for live attenuated injectable herpes zoster vaccine
Evidence for efficacy
Study Vaccine Study Design Participants Outcome measure Level of Evidence Quality
Oxman et al. 2005 (32) Live attenuated Oka/Merck VZV vaccine (minimum potency 18,700 PFU/dose) DB (Double-blind) RCT (Randomized controlled trial) Shingles Prevention Study (SPS) 38,546 subjects ≥60 years of age with either a past history of VZV or residence in the continental US for >30 years Primary endpoint VZV-associated burden of illness; secondary endpoint incidence of post-herpetic neuralgia up to 4 years post-vaccination I Good
(tested vaccine slightly lower minimum PFU than Zostavax)
Schmader et al. 2008 (35) Live attenuated Oka/Merck VZV vaccine (minimum potency 18,700 PFU/dose) Short-term Persistence Sub-study (STPS) of Oxman et al., above (40) 14 270 subjects =60 years of age, with past history of VZV or US residence >30 years but no history of zoster Incidence of herpes zoster, incidence of post-herpetic neuralgia and herpes zoster burden of illness; 3.5 to 7 years post vaccination I Good
(tested vaccine slightly lower minimum PFU than Zostavax)
Evidence for safety
Study Vaccine Study Design Participants Outcome measure Level of Evidence Quality
Oxman et al. 2005 (32) As above As above As above including detailed sub-study of 6,616 subjects All AE within 42 days of immunization, and serious AE I Good
(tested vaccine slightly lower minimum PFU than Zostavax)
Kerzner et al. 2007 (28) Zostavax ™ DB RCT Influenza vaccine and concurrent or sequential Zostavax 762 subjects ≥50 years of age with past history of VZV but no history of zoster AE within 28 days I Fair
MacIntyre et al. 2008 (29) Zostavax™ DB RCT Pneumovax and concomitant or sequential Zostavax 471 subjects ≥60 years of age with past history of VZV but not zoster Injection site AE and systemic AE within 28 days I Fair
Macaladad et al. 2007 (30) Live attenuated Oka/Merck VZV vaccine (~50,000 PFU/dose) DB RCT 21 subjects ≥30 years, VZV seronegative or low sero-titre Day 1–42 vaccine-related AE and laboratory-confirmed varicella-like rashes I Poor (small sample size; tested vaccine may have different PFU than Zostavax)
Gilderman et al. 2008 (31) Zostavax™ refrigerator stable versus Zostavax™ frozen DB RCT 367 subjects ≥50 years of age Day 1–28 vaccine-related AE I Fair
(tested vaccines have higher PFU than authorized Zostavax vaccine)
Tyring et al. 2007 (33) ~207,000 PFU or ~58,000 PFU Oka/Merck VZV vaccine DB RCT 698 subjects ≥50 years of age (459 in higher potency group) Day 1–42 vaccine-related AE I Fair
(tested vaccines have higher PFU than Zostavax)
Mills et al. 2008 (40) Zostavax™ RCT cross-over 101 adults ≥50 years of age with history of herpes zoster ≥5 years prior to screening Day 1–28 vaccine-related AE I Fair
(Small sample size, no validated correlates of VZV immunity)
Evidence for immunogenicity
Study Vaccine Study Design Participants Outcome measure Level of Evidence Quality
Levin et al. 2008 (26) Substudy of Oxman et al., above (40) Substudy of Oxman et al., above (40) 1,395 subjects Responder cell frequency assay, ELISPOT , glycoprotein ELISA Ab to VZV I Fair (no validated correlates of VZV immunity; tested vaccine slightly lower minimum PFU than Zostavax)
Kerzner et al. 2007 (28) Zostavax™ DB RCT Influenza vaccine and concurrent or sequential Zostavax 762 subjects ≥50 years of age with past history of VZV but no history of zoster GMT of VZV Ab at 4 weeks by gp ELISA, GMFR of VZV Ab from baseline to 4 weeks and GMT influenza Ab at 4 weeks for 3 strains I Fair
(no validated correlates of VZV immunity)
MacIntyre et al. 2008 (29) Zostavax™ DB RCT Pneumovax and concomitant or sequential Zostavax 471 subjects ≥60 years of age with past history of VZV but no history of zoster GMT VZV Ab 4 weeks post-immunization, GMFR >1.4 I Fair
(no validated correlates of VZV immunity)
Macaladad et al. 2007 (30) Live attenuated Oka/Merck VZV vaccine (~50,000 PFU/dose) DB RCT 21 in VZV seronegative or low sero-titre subjects aged ≥30 years ≥4-fold rise in VZV-specific antibody titre at 6 weeks I Fair (no validated correlates of VZV immunity; tested vaccine may have different PFU than Zostavax)
Gilderman et al. 2008 (31) Zostavax™ refrigerator stable versus Zostavax™ frozen DB RCT 367 subjects ≥50 years of age Gp ELISA GMR and post-vaccination GMT I Fair
(no validated correlates of VZV immunity)
Mills et al. 2008 (40) Zostavax™ RCT (cross-over design) 101 adults ≥50 years of age with history of herpes zoster ≥5 years prior to screening GMT VZV Ab 4 weeks post-vaccination

GMFR VZV AB from pre-vaccination to 4 weeks post-vaccination
I Fair
(Small sample size, no validated correlates of VZV immunity)


plaque-forming units
double blinded randomized controlled trial
adverse event
geometric mean titre
geometric mean rise
Varicella Zoster Virus
plaque forming units
geometric mean fold rise
flagellar antigen enzyme-linked immunosorbent assay

Table 2. Levels of Evidence Based on Research Design

Evidence from randomized controlled trial(s).
Evidence from controlled trial(s) without randomization.
Evidence from cohort or case–control analytic studies, preferably from more than one centre or research group using clinical outcome measures of vaccine efficacy.
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.
Opinions of respected authorities, based on clinical experience, descriptive studies and case reports, or reports of expert committees.

Table 3. Quality (internal validity) Rating of Evidence

A study (including meta-analyses or systematic reviews) that meets all design- specific criteria* well.
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 criterion* but has no known "fatal flaw".
A study (including meta-analyses or systematic reviews) that has at least one design-specific* "fatal flaw", or an accumulation of lesser flaws to the extent that the results of the study are not deemed able to inform recommendations.

* General design specific criteria are outlined in Harris et al., 2001. 

Table 4. NACI Recommendation for Immunization - Grades

NACI concludes that there is good evidence to recommend immunization.
NACI concludes that there is fair evidence to recommend immunization.
NACI concludes that the existing evidence is conflicting and does not allow making a recommendation for or against immunization, however other factors may influence decision-making.
NACI concludes that there is fair evidence to recommend against immunization.
NACI concludes that there is good evidence to recommend against immunization.
NACI concludes that there is insufficient evidence (in either quantity and/or quality) to make a recommendation, however other factors may influence decision-making.



Footnote 1

Mitka M. FDA approves shingles vaccine: herpes zoster vaccine targets older adults. JAMA 2006, 296(2):157-158.

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Footnote 2

Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2008, 57(RR-5):1-30; quiz CE32-34.

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Footnote 3

National Advisory Committee on Immunization (NACI). Evidence-based recommendations for immunization—methods of the National Advisory Committee on Immunization. An Advisory Committee Statement (ACS). Can Commun Dis Rep 2009, 35(ACS-1):1-10.

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Footnote 4

National Advisory Committee on Immunization (NACI). Update on varicella. Can Commun Dis Rep 2004, 30:1-26.

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Footnote 5

Liesegang TJ. Herpes zoster ophthalmicus natural history, risk factors, clinical presentation, and morbidity. Ophthalmology 2008, 115(2 Suppl):S3-12.

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Footnote 6

Yawn BP, Saddier P, Wollan PC et al. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc 2007, 82(11):1341-1349.

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Footnote 7

Pavan-Langston D. Herpes zoster antivirals and pain management. Ophthalmology 2008, 115(2 Suppl):S13-20.

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Footnote 8

Dworkin RH, Gnann JW, Jr., Oaklander AL et al. Diagnosis and assessment of pain associated with herpes zoster and postherpetic neuralgia. J Pain 2008, 9(1 Suppl 1):S37-44.

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Footnote 9

Lieu TA, Ortega-Sanchez I, Ray GT et al. Community and patient values for preventing herpes zoster. Pharmacoeconomics 2008, 26(3):235-249.

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Footnote 10

Coplan PM, Schmader K, Nikas A et al. Development of a measure of the burden of pain due to herpes zoster and postherpetic neuralgia for prevention trials: adaptation of the brief pain inventory. J Pain 2004, 5(6):344-356.

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Footnote 11

Lydick E, Epstein RS, Himmelberger D et al. Herpes zoster and quality of life: a self-limited disease with severe impact. Neurology 1995, 45(12 Suppl 8):S52-53.

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Footnote 12

Yih WK, Brooks DR, Lett SM et al. The incidence of varicella and herpes zoster in Massachusetts as measured by the Behavioral Risk Factor Surveillance System (BRFSS) during a period of increasing varicella vaccine coverage, 1998-2003. BMC Public Health 2005, 5(1):68.

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Footnote 13

Jumaan AO, Yu O, Jackson LA et al. Incidence of herpes zoster, before and after varicella-vaccination-associated decreases in the incidence of varicella, 1992-2002. J Infect Dis 2005, 191(12):2002-2007.

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Footnote 14

Chaves SS, Santibanez TA, Gargiullo P et al. Chickenpox exposure and herpes zoster disease incidence in older adults in the U.S. Public Health Rep 2007, 122(2):155-159.

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Footnote 15

Goldman GS. Universal varicella vaccination: efficacy trends and effect on herpes zoster. Int J Toxicol 2005, 24(4):205-213.

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Footnote 16

Brisson M, Gay NJ, Edmunds WJ et al, Exposure to varicella boosts immunity to herpes-zoster: implications for mass vaccination against chickenpox. Vaccine 2002, 20(19-20):2500-2507.

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Footnote 17

Takahashi M, Kamiya H, Asano Y et al. Immunization of the elderly to boost immunity against varicella-zoster virus (VZV) as assessed by VZV skin test reaction. Arch Virol Suppl 2001(17):161-172.

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Footnote 18

Law BJ, Chateau D, Walld R, Roos L. Temporal trends in the annual population-based incidence of herpes zoster by age and gender: Manitoba,1979–1998. Can J Infect Dis Med Microbiol 2004; 15:357–8.],

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Footnote 19

Russell ML, Schopflocher DP, Svenson L et al. Secular trends in the epidemiology of shingles in Alberta. Epidemiol Infect 2007, 135(6):908-913.

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Footnote 20

Brisson M, Edmunds WJ, Law B et al. Epidemiology of varicella zoster virus infection in Canada and the United Kingdom. Epidemiol Infect 2001, 127(2):305-314.

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Footnote 21

Reynolds MA, Chaves SS, Harpaz R, Lopez AS, Seward JF. The impact of the varicella vaccination program on herpes zoster epidemiology in the United States: a review. J Infect Dis 2008 Mar 1;197 Suppl 2:S224-S227.

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Footnote 22

Edgar BL, Galanis E, Kay C et al. The burden of varicella and zoster in British Columbia 1994-2003: baseline assessment prior to universal vaccination. Can Commun Dis Rep 2007, 33(11):1-15.

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Footnote 23

Manuel O, Kumar D, Singer LG et al. Incidence and clinical characteristics of herpes zoster after lung transplantation. J Heart Lung Transplant 2008, 27(1):11-16.

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Footnote 24

Klein NP, Holmes TH, Sharp MA et al. Variability and gender differences in memory T cell immunity to varicella-zoster virus in healthy adults. Vaccine 2006, 24(33-34):5913-5918.

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Footnote 25

Katial RK, Ratto-Kim S, Sitz KV et al. Varicella immunity: persistent serologic non-response to immunization. Ann Allergy Asthma Immunol 1999, 82(5):431-434.

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Footnote 26

Levin MJ, Oxman MN, Zhang JH et al. Varicella-zoster virus-specific immune responses in elderly recipients of a herpes zoster vaccine. J Infect Dis 2008, 197(6):825-835.

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Footnote 27

Smith JG, Levin M, Vessey R et al. Measurement of cell-mediated immunity with a Varicella-Zoster Virus-specific interferon-gamma ELISPOT assay: responses in an elderly population receiving a booster immunization. J Med Virol 2003, 70 Suppl 1:S38-41.

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Footnote 28

Kerzner B, Murray AV, Cheng E et al. Safety and immunogenicity profile of the concomitant administration of ZOSTAVAX and inactivated influenza vaccine in adults aged 50 and older. J Am Geriatr Soc 2007, 55(10):1499-1507.

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Footnote 29

MacIntyre CR, Egerton T, McCaughey M et al. Concomitant administration of zoster and pneumococcal vaccines in adults ≥ 60 years old. Abstract presented at the ICAAC/IDSA 2008 Joint Meeting, October 25-28, 2008, Washington, D.C.

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Footnote 30

Macaladad N, Marcano T, Guzman M et al. Safety and immunogenicity of a zoster vaccine in varicella-zoster virus seronegative and low-seropositive healthy adults. Vaccine 2007, 25(11):2139-2144.

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Footnote 31

Gilderman LI, Lawless JF, Nolen TM et al. A double-blind, randomized, controlled, multicenter safety and immunogenicity study of a refrigerator-stable formulation of Zostavax. Clin Vaccine Immunol 2008, 15(2):314-319.

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Footnote 32

Oxman MN, Levin MJ, Johnson GR et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005, 352(22):2271-2284.

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Footnote 33

Tyring SK, Diaz-Mitoma F, Padget LG et al. Safety and tolerability of a high-potency zoster vaccine in adults ≥ 50 or years of age. Vaccine 2007, 25(10):1877-1883.

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Footnote 34

Levin MJ, Barber D, Goldblatt E et al. Use of a live attenuated varicella vaccine to boost varicella-specific immune responses in seropositive people 55 years of age and older: duration of booster effect. J Infect Dis 1998, 178 Suppl 1:S109-112.

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Footnote 35

Schmader K, Oxman MN, Levin M, Betts R, Morrison VA, Gelb L, et al. Persistence of Zoster Vaccine Efficacy. Abstract presented at the ICAAC/IDSA 2008 Joint Meeting, October 25-28, 2008, Washington, D.C.

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Footnote 36

Brisson M, Pellissier JM, Camden S et al. The potential cost-effectiveness of vaccination against herpes zoster and post-herpetic neuralgia. Hum Vaccin 2008, 4(3).

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Footnote 37

Rothberg MB, Virapongse A, Smith KJ. Cost-effectiveness of a vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. Clin Infect Dis 2007, 44(10):1280-1288.

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Footnote 38

Pellissier JM, Brisson M, Levin MJ. Evaluation of the cost-effectiveness in the United States of a vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. Vaccine 2007, 25(49):8326-8337.

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Footnote 39

Hornberger J, Robertus K. Cost-effectiveness of a vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. Ann Intern Med 2006, 145(5):317-325.

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Footnote 40

Mills R, Tyring SK, Lawless JF, Levin MJ, Parrino J, Li X, et al. Safety, Tolerability and Immunogenicity of Zoster Vaccine in Subjects with a History of Herpes Zoster. Abstract presented at the ICAAC/IDSA 2008 Joint Meeting, October 25-28, 2008, Washington, D.C.

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