Clinical Considerations for Use of Recombinant Zoster Vaccine (RZV, Shingrix) in Immunocompromised Adults Aged ≥19 Years

Dosing schedule

Two doses of RZV are necessary regardless of previous history of shingles or previous receipt of zoster vaccine live (ZVL, Zostavax).^†

• The second dose of RZV should typically be given 2–6 months after the first.
• However, for persons who are or will be immunodeficient or immunosuppressed and who would benefit from completing the series in a shorter period, the second dose can be administered 1–2 months after the first (2). For example, a shorter interval between doses may facilitate avoiding vaccination during periods of more intense immunosuppression.
• If the second dose of RZV is given sooner than 4 weeks after the first, a second valid dose should be repeated at least 4 weeks after the dose that was given too early.
• The vaccine series does not need to be restarted if more than 6 months have elapsed since the first dose.

Timing of vaccination

When possible, patients should be vaccinated before becoming immunosuppressed. If vaccination before immunosuppression is not possible, providers should consider timing vaccination when the immune response is likely to be most robust.

Factors to consider in assessing the general level of immune competence in a patient include:

• Disease severity and duration
• Clinical stability
• Complications and comorbidities
• Any potentially immunosuppressing treatment

Vaccine providers should consider consulting with the provider most responsible for managing the patient’s immunocompromising condition or therapy, as needed.

For vaccination of persons with altered immunocompetence, various references, including ACIP’s general best practices (4), Chapter 5 of the CDC Yellow Book (5), and the Infectious Diseases Society of America’s 2013 IDSA Clinical Practice Guideline for Vaccination of the Immunocompromised Host (6), can be consulted for additional information about the degree of immune suppression associated with different medical conditions and treatments.

The risk of deferring vaccination, and thus not mitigating the increased risk for shingles and related complications in immunocompromised patients, should be weighed against a possible diminished response to RZV if given during periods of more intense immunosuppression.

Guidance for persons with selected immunocompromising conditions

Hematopoietic cell transplant (HCT) recipients

• Autologous HCT: Administer RZV at least 3–12 months after transplantation, depending on timing of discontinuation of prophylactic antiviral therapy; vaccination prior to discontinuation of antiviral therapy is preferred (see Antiviral medications section below).
• Allogeneic HCT: Administer RZV at least 6–12 months after transplantation, depending on timing of discontinuation of prophylactic antiviral therapy; vaccination prior to discontinuation of antiviral therapy is preferred (see Antiviral medications section below).

Solid organ transplant recipients

• When possible, administer RZV prior to transplantation.
• If vaccination prior to transplantation is not possible, administer RZV at least 6–12 months after transplantation, preferably at a time of stable graft function (no recent rejection), and on maintenance immunosuppression.

Patients with cancer

• When possible, administer RZV prior to chemotherapy, treatment with immunosuppressive medications, radiation therapy, or splenectomy.
• If vaccination prior to chemotherapy, treatment with immunosuppressive medications, radiation therapy, or splenectomy is not possible, administer RZV:
  • When the immune system is no longer acutely suppressed, or
  • For patients receiving continuous immunosuppressive therapies when the immune response is likely to be most robust.
• For patients receiving anti-B cell therapies (e.g., rituximab), administer a dose of RZV approximately 4 weeks prior to the next scheduled therapy.

Persons living with human immunodeficiency virus (HIV)

• Antiretroviral treatment for HIV may improve immune response to vaccination.
• While greater immunogenicity has been seen in the setting of viral suppression or higher CD4 cell counts with some vaccines, administration of inactivated or recombinant vaccines does not have to be delayed if these criteria have not been met, especially if that would lead to a significant delay of vaccine administration.
• Patients with advanced HIV should receive RZV, because the risk of shingles is further increased in the setting of such immune compromise.

Patients with autoimmune and inflammatory conditions

• Vaccination should optimally occur in the setting of well-controlled autoimmune and inflammatory diseases (i.e., not during acute disease or flares).
• When possible, administer RZV prior to initiation of immunosuppressive medications.
• If vaccination prior to initiation of immunosuppressive medications is not possible, administer RZV when immunosuppression is anticipated to be low.
• For patients receiving anti-B cell therapies (e.g., rituximab), administer a dose of RZV approximately 4 weeks prior to the next scheduled therapy.

Prior varicella or herpes zoster vaccination

RZV may be administered to people who previously received varicella (chickenpox) vaccine (Varivax, ProQuad).

People who previously received ZVL should receive RZV. Studies have shown that ZVL effectiveness wanes substantially over time, leaving recipients with reduced protection against shingles.

• If a patient recently received varicella vaccine or ZVL, wait a minimum of 8 weeks to give RZV.

Currently, patients are recommended to receive a two-dose series of RZV, regardless of age at receipt. Studies on duration of immunity are ongoing and there is no recommendation for booster doses of RZV at this time.

Antiviral medications

Shingles is caused by varicella-zoster virus (VZV), the same virus that causes varicella, or chickenpox. After a person recovers from varicella, the virus stays dormant (inactive) in their body. The virus can reactivate years or decades later, causing shingles.

• Acyclovir, famciclovir, and valacyclovir are antiviral medications that are active against herpesviruses, including VZV.
• Shingles risk is reduced during antiviral treatment. Since RZV is not a live virus vaccine, RZV may be administered while patients are taking antiviral medications if indicated.
• For patients taking prophylactic antiviral medications (e.g., HCT recipients), vaccination with RZV should ideally be initiated approximately 2 months prior to discontinuation of antiviral therapy.

Coadministration with other vaccines

Recombinant and adjuvanted vaccines, such as RZV, can be administered concomitantly at different anatomic sites with other adult vaccines, including COVID-19 vaccines (3).

• Concomitant administration of RZV with Fluarix Quadrivalent (influenza vaccine), 23-valent pneumococcal polysaccharide vaccine (PPSV23, Pneumovax23), tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap, Boostrix), and 13-valent pneumococcal conjugate vaccine (PCV13) has been studied, and there was no evidence for interference in the immune response to either vaccine or safety concerns (7–10).
• Coadministration of RZV with adjuvanted influenza vaccine (Fluad) and COVID-19 vaccines is being studied.

Counseling for reactogenicity

Before vaccination with RZV, providers should counsel patients about expected local and systemic reactogenicity.

• If a patient experiences side effects, any local (e.g., redness, pain, swelling at the injection site) or systemic (e.g., fever, chills, headache, body aches) reactions typically resolve within 72 hours after vaccination.
• It is generally not recommended to take antipyretic or analgesic medications prophylactically before vaccination; however, antipyretic or analgesic medications may be taken for the treatment of postvaccination local or systemic symptoms if needed.
• Patients should be encouraged to complete the series even if they experienced a (nonanaphylactic) grade 1–3 reaction after receipt of the first dose of RZV.

Persons with a history of herpes zoster

Shingles can recur. Persons with a history of shingles should receive RZV.

Persons with no documented history of varicella, varicella vaccination, or herpes zoster

Shingles is caused by VZV (the same virus that causes varicella, or chickenpox). After a person recovers from varicella, the virus stays dormant (inactive) in their body. The virus can reactivate years or decades later, causing shingles.

• Persons who have neither experienced varicella nor received varicella vaccine are not at risk for shingles.
• More than 99% of Americans born before 1980 have had varicella, even if they don’t remember it (11).
• Children and adolescents who have received live-attenuated varicella vaccines are at lower risk for shingles than are those who experienced varicella (12,13).

RZV is not indicated and has not been studied for the prevention of varicella.

• Receipt of RZV is not considered proof of prior varicella disease or varicella immunity.
• RZV cannot be considered as either of the two doses of the varicella vaccine series.

For immunocompromised persons, evidence of immunity to varicella (confirming need for RZV) includes:

• Documentation of two doses of varicella vaccine, or
• Laboratory evidence of immunity or laboratory confirmation of disease, or
• Diagnosis or verification of a history of varicella or herpes zoster by a healthcare provider.

It is important to note that:

• Persons born in the United States prior to 1980 are considered immune to varicella; however, this criterion does not apply to immunocompromised persons who must meet one of the above criteria.
• Commercial assays can be used to assess VZV seroconversion after wild type infection, but sensitivity and specificity can vary.
• Commercial assays are not sensitive and specific enough to reliably detect varicella vaccine seroconversion.
• Varicella vaccines contain live virus and are contraindicated for most immunocompromised persons.

For immunocompromised adults with no documented history of varicella, varicella vaccination, or shingles:

• Providers should refer to the ACIP varicella vaccine recommendations for further guidance, including post-exposure prophylaxis guidance for immunocompromised adults (14).
• Providers may need to consider a variety of factors, including a patient’s age (e.g., birth prior to 1980), recall (e.g., of prior varicella, varicella vaccination, or herpes zoster), documentation, and serology to determine whether to vaccinate with RZV.
• There are limited data on the use of RZV in persons without a history of varicella (15), with or without a history of varicella vaccination.

Pregnancy

There is currently no ACIP recommendation for RZV use in pregnancy. Providers should consider delaying RZV until after pregnancy. There is no recommendation for pregnancy testing prior to vaccination.

Breastfeeding

Recombinant vaccines such as RZV pose no known risk for mothers who are breastfeeding or their infants (4). Clinicians may consider vaccination without regard to breastfeeding status if RZV is otherwise indicated.

Contraindications

Allergy

RZV should not be administered to persons with a history of severe allergic reaction, such as anaphylaxis, to any component of this vaccine.

Precautions

Moderate or severe acute illness with or without fever

In general, vaccination should be delayed for patients experiencing moderate or severe acute illness (4).

Current episode of herpes zoster  

RZV is not a treatment for shingles or postherpetic neuralgia and should not be administered during an acute episode of shingles. If an individual is experiencing an episode of shingles, vaccination should be delayed until the acute stage of the illness is over and symptoms abate (4).

Adverse events that occur in a patient following vaccination can be reported to the Vaccine Adverse Events Reporting System (VAERS). Reporting is encouraged for any clinically significant adverse event even if it is uncertain whether the vaccine caused the event. Information on how to submit a report to VAERS is available at https://vaers.hhs.gov/index.html or by telephone at 1-800-822-7967.

* This recommendation became official CDC policy in January 2018.

^†  Zoster vaccine live (ZVL, Zostavax) is no longer available for use in the United States, as of November 18, 2020.

^§ Grade 3 reactions are defined as reactions related to vaccination severe enough to prevent normal activities.

References

1. Dooling KL, Guo A, Patel M, et al. Recommendations of the Advisory Committee on Immunization Practices for Use of Herpes Zoster Vaccines. MMWR 2018;67:103–108.
2. Food and Drug Administration. Shingrix [package insert], revised: 07/2021. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration; 2021. https://www.fda.gov/media/108597/download
3. Anderson TC, Masters NB, Guo A, et al. Use of Recombinant Zoster Vaccine in Immunocompromised Adults Aged ≥19 Years: Recommendations of the Advisory Committee on Immunization Practices — United States, 2022. MMWR. 2022;71(3):80–84.
4. Kroger A, Bahta L, Hunter P. General Best Practice Guidelines for Immunization. Best Practices Guidance of the Advisory Committee on Immunization Practices (ACIP). Atlanta, GA: US Department of Health and Human Services, CDC. Available at: https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-recs.pdf. Accessed: January 18, 2022.
5. CDC Yellow Book. 2020. Chapter 5, Travelers with Additional Considerations. Available at: https://wwwnc.cdc.gov/travel/yellowbook/2020/travelers-with-additional-considerations/immunocompromised-travelers. Accessed: January 14, 2022.
6. Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA Clinical Practice Guideline for Vaccination of the Immunocompromised Host. Clin Infect Dis. 2014;58(3):e44–e100.
7. Schwarz TF, Aggarwal N, Moeckesch B, et al. Immunogenicity and safety of an adjuvanted herpes zoster subunit vaccine co-administered with seasonal influenza vaccine in adults aged 50 years and older. J Infect Dis. 2017;216:1352–1361.
8. Maréchal C, Lal H, Poder A, et al. Immunogenicity and safety of the adjuvanted recombinant zoster vaccine co-administered with the 23-valent pneumococcal polysaccharide vaccine in adults ≥50 years of age: A randomized trial. Vaccine. 2018;36(29):4278-4286.
9. Strezova A, Lal H, Enweonye I, et al. The adjuvanted recombinant zoster vaccine co-administered with a tetanus, diphtheria and pertussis vaccine in adults aged ≥50 years: A randomized trial. Vaccine. 2019;37(39):5877–5885.
10. Min JY, Mwakingwe-Omari A, Riley M, et al. The adjuvanted recombinant zoster vaccine co-administered with the 13-valent pneumococcal conjugate vaccine in adults aged ≥50 years: a randomized trial. J Infect 2021:S0163-4453(21)00651–4.
11. Kilgore PE, Kruszon-Moran D, Seward JF, et al. Varicella in Americans from NHANES III: implications for control through routine immunization. J Med Virol. 2003;70 Suppl 1:S111–8.
12. Weinmann S, Naleway AL, Koppolu P, et al. Incidence of herpes zoster among children: 2003-2014. Pediatrics. 2019;144:e20182917.
13. Hardy I, Gershon AA, Steinberg SP, et al. The incidence of zoster after immunization with live attenuated varicella vaccine. A study in children with leukemia. N Engl J Med. 1991;325:1545–50. https://www.nejm.org/doi/full/10.1056/nejm199111283252204
14. Marin M, Güris D, Chaves SS, et al. Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention (CDC). Prevention of Varicella: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007;56(RR–4):1–40.
15. L’Huillier AG, Hirzel C, Ferreira VH, et al. Evaluation of Recombinant Herpes Zoster Vaccine for Primary Immunization of Varicella-seronegative Transplant Recipients. Transplantation. 2021;105(10):2316–2323.