Herpes zoster (shingles) vaccine: Canadian Immunization Guide

For health professionals

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• Key Information
• Epidemiology
• Preparations Authorized for Use in Canada
• Immunogenicity, Efficacy and Effectiveness
• Recommendations for Use
  • Table 1: Summary of factors to consider and management options for HZ immunization
• Vaccine Administration
  • Table 2: Comparison of herpes zoster vaccines authorized for use in Canada
• Serologic Testing
• Storage Requirements
• Simultaneous Administration with Other Vaccines
• Safety and Adverse Events
• Selected References

Key Information (refer to text and tables for details)

What

• Primary varicella-zoster virus infection causes varicella (chickenpox) and reactivated infection results in herpes zoster (shingles).
• Herpes zoster (HZ) occurs most frequently among older adults and immunocompromised persons.
• HZ is characterized by neuropathic pain and dermatomal vesicular rash.
• Post-herpetic neuralgia (PHN), which can be debilitating, is the most frequent complication of HZ.
• HZ vaccines reduce the incidence of HZ and PHN.
• Two different HZ vaccines are currently authorized for use in Canada: Zostavax II^® (Live Zoster Vaccine, LZV), and Shingrix^® (Recombinant Zoster Vaccine, RZV).

Who

• RZV is recommended for individuals ≥50 years of age without contraindications.
• Individuals ≥50 years of age without contraindications who received LZV, or who have had a previous episode of HZ, should be vaccinated with RZV after at least one year.
• If RZV is contraindicated, unavailable or inaccessible, then LZV may be considered for immunocompetent individuals ≥50 years of age without contraindications.
• 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.

How

• RZV is administered intramuscularly in a two dose schedule with the second dose administered between 2 and 6 months after the first dose.
• LZV is administered subcutaneously in a one dose schedule.

Why

• • Nearly 1 in 3 Canadians develops HZ in their lifetime. The incidence and severity of both HZ and PHN increases sharply after 50 years.
  • Treatment options for HZ and PHN have limited effectiveness.
  • HZ vaccines are safe and effective in reducing the incidence of HZ and PHN

Refer to Table 1 for a summary of factors to consider and management options for HZ immunization and to Table 2 for a comparison of herpes zoster vaccines authorized for use in Canada. For more information on publicly funded vaccine schedules, refer to provincial and territorial immunization information.

Epidemiology

Disease description

Infectious agent

Herpes zoster (shingles) is a manifestation of reactivation of the varicella-zoster virus (VZV), a DNA virus of the Herpesvirus family, which, as a primary infection, causes varicella (chickenpox).

Reservoir

Humans

Transmission

VZV can be spread from a person with HZ to an individual that has never had varicella by direct contact with localized skin lesions. Less commonly, VZV can be spread by the airborne route if the affected person has disseminated HZ. Less frequently, transmission can occur from fomites, such as articles freshly soiled by discharges from vesicles or, in the case of disseminated HZ, mucous membrane secretions. The person who acquires VZV through these routes will develop varicella (chickenpox). The incubation period is from 10 to 21 days, usually in the range of 14 to 16 days. HZ is less likely to result in transmission of VZV than varicella. Persons with HZ are infectious until all lesions are crusted over.

Risk factors

Any person who has had varicella is at risk of developing HZ. However, HZ occurs most frequently among older adults and immunocompromised persons. Age is the most important risk factor for development of HZ. Over two-thirds of the cases occur in individuals over 50 years of age. This age-related risk may be explained by both waning immunity over time following the initial varicella infection, and the loss of components of VZV-specific cell mediated immunity as a result of natural aging processes. The severity of illness associated with HZ and its complications also increases markedly with age. Up to 10% of persons over 65 years of age will be admitted to hospital with an episode of HZ.

Spectrum of clinical illness

VZV causes two distinct clinical syndromes: primary infection (varicella, also called chickenpox) and reactivation of latent infection (HZ, also called shingles). Following varicella, VZV establishes latency in the sensory nerve ganglia, and may reactivate later as HZ. HZ infection is characterized by pain and a unilateral vesicular eruption, usually in a single dermatome. Complications of acute HZ are potentially severe.

The most frequent complication of acute HZ is PHN which is characterized by prolonged and often debilitating neurogenic pain that lasts for more than 90 days from the onset of rash. Because treatment options for PHN are of limited effectiveness, PHN often has major adverse impacts on quality of life. Older adults, people living with chronic conditions such as diabetes or autoimmune diseases, and persons who are immunocompromised may be at greater risk of developing PHN. They are also at risk of experiencing longer lasting HZ rash than the general population. Other potential complications of HZ include ophthalmic sequelae (herpes zoster ophthalmicus), central nervous system infection, nerve palsies including the Ramsay-Hunt Syndrome, neuromuscular disease including Guillain-Barré Syndrome, pneumonia, hepatitis and secondary bacterial infections.

The risk of mortality from VZV-associated disease is low.

Disease distribution

Incidence/prevalence

In recent studies, the lifetime risk of HZ has been estimated to be as high as 30% in the general population. In Canada, it is estimated that each year there are 130,000 new cases of HZ, 17,000 cases of PHN and 20 deaths.

Preparations Authorized for Use in Canada

Herpes zoster vaccines

• SHINGRIX (non-live recombinant vaccine, AS01B adjuvanted), GlaxoSmithKline Inc. (RZV)
• ZOSTAVAX^® II (varicella zoster vaccine live, attenuated [Oka/Merck]), Merck Canada Inc. (LZV)

For complete prescribing information, consult the product leaflet or information contained within the product monograph available through Health Canada's Drug product database. Also refer to Contents of Immunizing Agents Authorized for Use in Canada in Part 1.

Immunogenicity, Efficacy and Effectiveness

Immunogenicity

There are currently no established humoral and/or cellular correlates of protection following immunization against HZ. In studies that assessed vaccine immunogenicity antibody, the response to RZV was found to be more robust (independent of age and with more stable antibody concentrations over time) than the response to LZV.

Efficacy and effectiveness

HZ vaccines significantly reduce the incidence of HZ and PHN as well as the duration and severity of HZ. While protection against HZ remains statistically significant up to 3 years following immunization with LZV, significant waning of protection has been observed one-year post immunization, particularly in older age groups.

In contrast, RZV efficacy in the four years post immunization remains consistent and above 90% in all age groups.

Recommendations for Use

Refer to Table 1 for a summary of herpes zoster vaccine management options.

Adults

Adults (50 years of age and older)

Immunization with a 2 dose series of RZV is recommended for the prevention of HZ and PHN for adults 50 years of age or older without contraindications.

For adults ≥ 50 years of age without contraindications who have previously been immunized with LZV, immunization with a 2 dose series of RZV should be offered. Re-immunization with RZV may be considered at least one year after LZV.

For adults ≥50 years of age without contraindications who have had a previous episode of HZ, immunization with a 2 dose series of RZV should be offered. Immunization with RZV may be considered at least one year after the episode of HZ. Persons with active HZ should not be immunized with HZ vaccine.

If RZV is contraindicated, unavailable or inaccessible, LZV may be considered for immunocompetent individuals 50 years of age and over without contraindications.

Adults with or without a history of varicella

RZV should be administered to individuals for whom vaccine is indicated regardless of whether the person has a history of varicella infection. Nearly all Canadians eligible for HZ immunization will have had prior varicella exposure, even if a diagnosis of varicella cannot be recalled. There is no known safety risk associated with immunization of healthy individuals who are susceptible to VZV.

Special populations

Pregnancy and breastfeeding

LZV is contraindicated during pregnancy. Pregnancy should be avoided for 3 months after LZV administration. Precautions should be also be used in breastfeeding because it is not known whether LZV virus is secreted in human milk. Because no data is available on RZV administration during pregnancy or breastfeeding, precautions should be used in these situations.

For more information, refer to Immunization in Pregnancy and Breastfeeding in Part 3.

Residents in health care institutions

Residents of long-term care facilities should receive all routine immunizations appropriate for their age and risk factors, including RZV.

For more information, refer to Immunization of Patients in Health Care Institutions in Part 3.

Immunocompromised persons

Individuals who are immunocompromised, either due to underlying conditions or immunosuppressive agents, have an increased risk of developing HZ. They may be more likely to experience HZ recurrence, atypical and/or more severe disease and complications.

RZV should be considered based on a case-by-case assessment of benefits vs risks. When indicated, it should be administered before initiating immunosuppressive treatment that might lead to immunodeficiency. It is recommended that RZV be administered at least 14 days before the treatment.

For more information, refer to Contraindications, Precautions and to Immunization of Immunocompromised persons in Part 3.

Persons with chronic diseases

Autoimmune disease

Although definitive data are lacking, individuals with autoimmune disease not being treated with immunosuppressive drugs are not considered significantly immunocompromised. Individuals ≥ 50 years of age without contraindications should receive RZV.

For more information, refer to Immunization of Immunocompromised Persons, and Immunization of Persons with Chronic Diseases in Part 3.

Workers

Workers are not at increased risk of developing HZ because HZ is due to reactivation of a latent VZV infection. However, it is important to promote varicella (chickenpox) immunization to those who are at occupational risk of exposure or transmission to high risk individuals.

For more information, refer to Varicella (Chickenpox) Vaccine and to Immunization of Workers in Part 3.

Post-exposure immunization

HZ vaccine is not indicated for post-exposure management of individuals who are susceptible to varicella after exposition to HZ. Refer to Varicella (Chickenpox) Vaccine, Post-exposure immunization for appropriate management options.

Close contact to a person with HZ includes:

• Touching the rash, exposed lesion or vesicle fluid.
• Contact with an individual who has disseminated HZ.
• Contact with articles freshly soiled by discharges from vesicles.
• Contact with articles freshly soiled by mucous membrane secretions of an infected person with disseminated HZ.
• Exposure to an immunosuppressed person with localized HZ anywhere on the body (viral shedding in these individuals may be greater).

Table 1: Summary of factors to consider and management options for HZ immunization
For more information, refer to text

	Live zoster virus (LZV)	Recombinant zoster virus (RZV)
Recommendations	May be considered for immunocompetent individuals ≥ 50 years of age without contraindications when RZV is contraindicated, unavailable, or inaccessible.	Should be offered to individuals ≥ 50 years of age without contraindications
Vaccine efficacy	Estimates of efficacy against HZ and PHN for RZV are higher than for LZV across all age groups studied.
Duration of protection	Protection wanes rapidly after 1 year post-immunization. Protection against HZ remains statistically significant up to 3 years following immunization, but is uncertain by 5 years post-immunization. It may not provide optimal ongoing protection at older ages. Waning of vaccine efficacy against PHN over time is unknown.	Waning of protection against HZ appears to occur at a slower rate for RZV compared to LZV, and is minimal for at least 4 years following immunization with RZV.
Immunogenicity	Both LZV and RZV are immunogenic. No established correlates of protection following immunization
	Immune response is more robust for those 50-59 years of age and decreases with age. Has been demonstrated up to 3 years post-immunization.	Immunogenicity response is the same across all age groups ˃ 50 years. Has been demonstrated up to 9 years post-immunization.
Safety	Both HZ vaccines are safe with serious adverse events reported very rarely in immunocompetent individuals.
	LZV is a live attenuated vaccine which can cause HZ in rare circumstances. It has been reported to cause vaccine-related VZV in a small number of cases Most common adverse events: mild to moderate injection site reactions.	Most common adverse events: moderate to severe injection site reactions, fatigue, myalgia. The adjuvant in RZV is new, so long term data are not yet available.
Additional considerations	-	Interval for RZV following LZV immunization: at least 1 year. Also consider age at receipt of LZV and time since LZV immunization. Interval for RZV following HZ episode: at least 1 year. Adjuvant is more reactogenic than LZV, leading to more reactions that were severe enough to prevent normal activities. However, these reactions are transient, lasting <3 days. Education and recall/reminders will be important to improve adherence to 2nd dose.

Vaccine Administration

Dose, route of administration, and schedule

Live attenuated zoster vaccine (Zostavax^® II)

Dose

Each dose is 0.65 mL (the entire contents of the reconstituted vial).

Route of administration

Subcutaneous

Schedule

1 dose

Recombinant zoster vaccine (Shingrix ^®)

Dose

Each dose is 0.5 mL (the entire contents of the reconstituted vial).

Route of administration

Intramuscular, into the deltoid region of the upper arm.

Administration of the RZV as a subcutaneous injection is a vaccine administration error and should be avoided. However, if Shingrix is inadvertently administered subcutaneously, that dose will be considered as valid in the vaccine series. The second dose will be given as per vaccine schedule.

For more information, refer to Vaccine Administration Practices in Part 1.

Schedule

2 doses, 2 to 6 months apart. A 0,12 months schedule may be considered for improved adherence to the 2nd dose (which could be administered at the next annual visit, or at the time of the next annual influenza immunization).

Providers should consider different strategies (e.g. education, recalls/reminders) to promote adherence to the two dose schedule for RZV (as vaccine efficacy and duration of protection is unclear after only one dose).

Booster doses and re-immunization

There is no current recommendation for booster doses of either HZ vaccine. It is not known whether booster doses of HZ vaccines are beneficial. This is an area of ongoing research.

Table 2: Comparison of herpes zoster vaccines authorized for use in Canada

	Zostavax® II (LZV)	Shingrix® (RZV)
Date of authorization in Canada	2011 (Zostavax®II)	2017: Shingrix®
Type of Vaccine	Live attenuated	Recombinant subunit (adjuvanted)
Schedule	1 dose	2 doses, 2-6 months apart.Table 2 Footnote 1
Route of administration	Subcutaneous	lntramuscular
Dose	0.65 mL (entire contents of the reconstituted vial)	0.5 mL (entire contents of the reconstituted vial)
Contraindications	Known anaphylactic hypersensitivity to a previous dose of the vaccine, any of its components or vaccine container. Immunosuppression or immunodeficiency Pregnancy	Known anaphylactic hypersensitivity to a previous dose of the vaccine, any of its components or vaccine container.
Precautions	Breastfeeding	Pregnancy (no data in humans) Breastfeeding (no data) Immunocompromised individuals (limited data)
Storage Requirements	Refrigerator - stable	Refrigerator – stable
Table 2 Footnote 1 A 0,12 month schedule may be considered for improved adherence to the 2nd dose (which could be administered at the next annual visit, or at the time of the next annual influenza immunization). Table 2 Return to footnote 1 referrer

For more information on publicly funded vaccine schedules, refer to provincial and territorial immunization information.

Serologic Testing

Serologic testing is not recommended before or after receiving HZ vaccine. There is no known safety risk associated with HZ immunization of healthy individuals who are VZV susceptible. In the rare circumstance that an adult aged 50 years and older is known to be susceptible to VZV, based on previous serological testing for another reason, the individual should be vaccinated with two doses of univalent varicella vaccine rather than HZ vaccine.

Storage Requirements

HZ vaccines should be stored refrigerated at +2°C to +8°C or according to product monographs. Diluent should be stored at room temperature (+20°C to +25°C) or in the refrigerator (+2°C to +8°C) and should not be frozen. Before reconstitution, vaccines should be protected from light.

For more information, refer to Storage and Handling of Immunizing Agents in Part 1.

Simultaneous Administration with Other Vaccines

RZV and LZV may be administered concomitantly with other live vaccines given by the parenteral, oral, or intranasal routes. For concomitant parenteral injections, different injection sites and separate needles and syringes should be used.

In general, inactivated vaccines including RZV may be administered concomitantly with, or at any time before or after, other inactivated vaccines or live vaccines protecting against a different disease.

LZV may be given at any time before or after live oral or intranasal vaccines. If two live parenteral vaccines are not administered concomitantly, there should be a period of at least 4 weeks before the second live parenteral vaccine is given.

Concomitant administration of pneumococcal 23-valent polysaccharide vaccine (Pneu-P-23) and LZV has not resulted in decreased efficacy and so the two vaccines can be given concomitantly.

For more information, refer to Timing of Vaccine Administration in Part 1.

Safety and Adverse Events

Very common and common adverse events

Very common adverse events occur in 10% or more of vaccinees. Common adverse events occur in 1% to less than 10% of vaccinees.

Injection site reactions are very commonly reported for both LZV and RZV. For LZV recipients the frequency is slightly higher in adults aged <60 years. For all ages, the majority (>95%) of these events were rated mild or moderate in intensity and lasted less than 2 days.

Due to the adjuvant in RZV, which induces a high cellular immune response and helps address the natural age-related decline in immunity, RZV is more reactogenic than LZV.

Injection site AEs are very commonly reported by recipients of RZV. Approximately 80% report injection-site pain and approximately 30% report redness at the site of injection.

Systemic adverse events, primarily fatigue and myalgia are common in LZV recipients (less than 8%) and very common in RZV recipients (reported by up to half of clinical trial vaccine recipients). For RZV, they include headache (reported by up to 40% of clinical trial vaccine recipients).

Local and systemic reactions that were severe enough to interfere with normal activities have been more frequently reported following the receipt of RZV than LZV. However, these reactions have been temporary (lasting 2-3 days). Patient education on the short-term reactogenicity of the RZV is recommended prior to vaccine administration to promote adherence to the second dose.

Uncommon, rare and very rare adverse events

Uncommon adverse events occur in 0.1% to less than 1% of vaccinees. Rare and very rare adverse events occur, respectively, in 0.01% to less than 0.1% and less than 0.01% of vaccinees.

Both HZ vaccines are safe with serious adverse events reported very rarely in immunocompetent individuals.

Recurrence or exacerbation of herpes zoster ophthalmicus (HZO) following LZV vaccination has been reported very rarely, involving several cases world-wide following LZV immunization. Following a causality assessment of seven cases of HZO which were temporally associated with the administration of LZV, NACI concluded that there was insufficient evidence to recommend for or against the administration of LZV in individuals with a history of HZO. More evidence is required for further assessment of risk related to HZO recurrence in LZV recipients. At this time, there is insufficient evidence to assess the risk related to HZO recurrence following RZV recipients.

See Contraindications and Precautions if considering vaccinating a person with previous HZO.

For more information, refer to Adverse Events Following Immunization in Part 2 and the product monograph in Health Canada's Drug Product Database.

Guidance on reporting adverse events following immunization (AEFI)

Vaccine providers are asked to report AEFIs through local public health officials and to follow AEFI reporting requirements that are specific to their province or territory. In general, any serious or unexpected adverse event felt to be temporally related to vaccination should be reported.

For LZV the following AEFIs are also of particular interest and should be reported:

• Suspected transmission of vaccine-strain virus to a close household or occupational contact. This phenomenon has been documented following varicella vaccine but it is rare, and transmission has not been documented with LZV.
• Recurrent HZ following immunization of individuals with a history of HZ prior to immunization, noting the area of recurrence.
• Recurrent HZO following immunization of a person who has had a previous episode of HZO. If available, a vitreous fluid specimen should be sent to a laboratory with a request to determine whether the virus is the vaccine strain or wild type virus.

For definitions of serious and unexpected adverse events, refer to Adverse Events Following Immunization in Part 2.

For more information refer to Reporting Adverse Events Following Immunization (AEFI) in Canada.

Contraindications

Both LZV and RZV are contraindicated in persons with a history of anaphylaxis after previous administration of the vaccine. They are also contraindicated in persons with proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its container. Refer to Contents of Immunizing Agents Authorized for Use in Canada in Part 1.

• ZOSTAVAX^®II, known allergens include neomycin and porcine gelatin
• SHINGRIX, no known allergen

Since LZV is a live attenuated vaccine it is contraindicated in:

• individuals with primary and acquired immunocompromised states,
• individuals who have recently used or are currently using immune suppressive medications,
• active untreated tuberculosis,
• pregnancy. Also pregnancy should be avoided for three months after the administration of the vaccine.

LZV is not contraindicated for use in individuals who are receiving: topical, inhaled or low-dose corticosteroids nor in those receiving corticosteroids as replacement therapy (e.g. for adrenal insufficiency).

Refer to Immunization of Immunocompromised Persons in Part 3 for more detailed information.

Precautions

In situations of suspected hypersensitivity or non-anaphylactic allergy to LZV or RZV components, investigation is indicated which may lead to immunization in a controlled setting. Consultation with an allergist is advised.

RZV (not LZV) may be considered for immunocompromised adults ≥ 50 years of age based on a case-by-case assessment of benefits vs risks. RZV should be administered at least 14 days prior to the initiation of immunosuppressive drugs.

Clinical trials are ongoing in the use of RZV in immunocompromised populations.

Precaution should be used if considering use of RZV in pregnancy or breastfeeding given the absence of data on its safety for these groups. 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.

Administration of LZV or RZV should be postponed in persons suffering from severe acute illness with or without fever.

There is a theoretical risk of transmission of LZV virus from vaccinated to susceptible individuals. Varicella vaccines have documented transmission of vaccine virus between vaccinees that develop a varicella-like rash and susceptible contacts. However, no case of transmission of LZV virus from a vaccinated individual who develops a rash to another person has been documented to date.

Refer to Immunization of Immunocompromised Persons in Part 3 and to Contraindications and Precautions in part 2 for additional information.

Drug interactions

There are no known drug interactions with RZV.

LZV may have reduced effectiveness if given concurrently with antivirals active against varicella zoster virus (such as acyclovir, valacyclovir, famciclovir). People taking long-term antiviral therapy should discontinue these drugs, if possible, from at least 24 hours before administration of LZV and should not restart antiviral therapy until 14 days after vaccination.

No safety or efficacy data are available for the administration of LZV to individuals who have recently received immunoglobulins (Ig) or other blood products. However, the LZV is known to be immunogenic in adults with pre-existing antibody to VZV. In theory, administration of Ig should not interfere with the vaccine response; therefore, some experts do not consider recent administration of Ig or blood products as a reason to delay the administration of herpes zoster vaccine.

Refer to Blood Products, Human Immunoglobulin and Timing of Immunization in Part 1 for more information about the administration of live attenuated vaccines and blood products of human origin.

Selected References

• Kimberlin DW, Brady MT, Jackson MA, Long SS, ed, 'Summaries of infectious diseases: varicella zoster virus infections' in Red Book: 2015 Report of the Committee on Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015.
• Centers for Disease Control and Prevention. The Pink Book: Epidemiology and Prevention of Vaccine Preventable Diseases. Updated 13th ed.; August 2015. Accessed May 2018 at: http://www.cdc.gov/vaccines/pubs/pinkbook/default.htm
• GlaxoSmithKlein Inc. Product Monograph - SHINGRIX^®. October 2017.
• Law BJ, Chateau D, Walld R, et al. 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.
• Merck Frosst Canada Ltd. Product Monograph - ZOSTAVAX^®. June 2010.
• National Advisory Committee on Immunization. NACI statement on the recommended use of herpes zoster vaccine. Can Commun Dis Rep 2010; 36 (ACS-1): 1-19
• National Advisory Committee on Immunization. Update on the use of herpes zoster vaccine. Public Health Agency of Canada, February 2014. Retrieved from: https://www.canada.ca/en/public-health/services/publications/healthy-living/update-use-herpes-zoster-vaccine.html.
• National Advisory Committee on Immunization. Update on the use of herpes zoster vaccine. Public Health Agency of Canada, June 2018. https://www.canada.ca/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci.html
• Tseng HF, Chi M, Smith N et al. Herpes zoster vaccine and the incidence of recurrent herpes zoster in an immunocompetent elderly population. J Infect Dis 2012; 206(2): 190-96.
• Yawn BP, Wollan PC, Kurland MJ et al. Herpes zoster recurrences more frequent than previously reported. Mayo Clin Proc 2011; 86(2): 88-93.
• Zhang J, Xie F, Delzell E, Chen L, Winthrop KL, Lewis JD, et al. Association between vaccination for herpes zoster and risk of herpes zoster infection among older patients with selected immune-mediated diseases. JAMA. 2012; Jul 4; 308(1): 43-9.

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