Vaccine Preventable Diseases

Varicella / Shingles / Herpes Zoster

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Infants and Children
• All children without contraindications should receive two doses of varicella vaccine (trade name: Varivax®) after 1 year of age and at least 3 months apart. The first dose should be administered between 12 and 15 months of age and the second between 4 and 6 years of age, generally at the same time as measles-mumps-rubella combination vaccine (abbreviation: MMR; trade name: M-M-R II®).
• The CDC recommends that MMR and varicella vaccine be administered separately albeit simultaneously for the first dose in order to reduce the risk of infant fever and febrile seizures, but the measles-mumps-rubella-varicella combination vaccine (abbreviation: MMRV; trade name: ProQuad®) vaccine can be administered for the second dose.

Adolescents and Adults
• The ACIP recommends all persons over 13 years of age without evidence of varicella immunity receive 2 doses of varicella vaccine separated by a minimum of 4 weeks. Immunity to varicella is especially important for health care personnel [1, 2].
• Two doses of recombinant zoster vaccine (abbreviation: RZV; trade name: Shingrix®) are recommended for all persons without contraindications over 50 years of age, including among those who have previously been vaccinated with live attenuated zoster vaccine (abbreviation: ZVL; trade name: Zostavax®).
• One dose of ZVL is still recommended for all persons without contraindications over 60 years of age in the absence of RZV. However, there is now a preferential recommendation for RZV over ZVL [3].

For More Information
ACIP recommendations:
• Varicella: https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/varicella.html
• Zoster (Shingles): https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/shingles.html
Immunization schedules: http://www.cdc.gov/vaccines/schedules/index.html

Varicella is a highly infectious acute disease caused by the DNA herpesvirus varicella zoster virus (VZV). VZV is transmitted via the respiratory route. The incubation period generally lasts about 15 days. Symptoms of primary infection with VZV, also known as chickenpox, include mild fever, malaise and a generalized vesicular rash.

Although varicella disease is usually mild, there are potentially serious complications including bacterial infection of skin lesions, pneumonia, Reye syndrome, cerebellar ataxia, aseptic meningitis or encephalitis. Infants under 1 year of age have an increased risk of complications.

Congenital varicella syndrome, resulting from maternal primary infection with varicella during the first 20 weeks of gestation, is associated with low birth weight, localized muscular atrophy, skin scarring and eye and neurologic abnormalities.

Herpes zoster, also known as shingles, occurs after reactivation of latent VZV and is associated with aging, immunosuppression, and other factors. Between 0.5 and 1 million episodes of herpes zoster occur in the United States every year, and half of all persons living until age 85 will develop zoster [1].

Varicella vaccine is a live attenuated viral vaccine. MMRV is a combination vaccine that includes measles, mumps, rubella and varicella vaccines [1].

There are two herpes zoster vaccines licensed in the United States: live attenuated zoster vaccine (abbreviation: ZVL; trade name: Zostavax®), and inactivated, recombinant, adjuvanted, subunit zoster vaccine (abbreviation: RZV; trade name: Shingrix®). ACIP has given a preferential recommendation for RZV over ZVL [3]. The ZVL vaccine has the same antigen as the aforementioned varicella vaccine but at a much higher titer [1].

Vaccine Effectiveness: Varicella vaccine effectiveness after a single dose is estimated to be 76-94% in preventing clinically diagnosed or laboratory confirmed disease and 78-100% effective for prevention of severe cases of varicella in children [6-8]. Effectiveness decreases with time since vaccination [2]. Effectiveness after two doses is estimated to be 94% against any varicella and 98% against moderate or severe varicella [8].

Efficacy of RZV (Shingrix®) against herpes zoster was estimated to be 96.6% for those aged 50-59, 97.4% for those aged 60-69, 91.3% for those aged 70-79, and 91.4% for those age 80 or above. RZV was shown to have a good duration of protection, maintaining efficacy of at least 85% among those over 70 years of age even after 4 years post-vaccination [3, 9-11]. In comparison, efficacy of ZVL (Zostavax®) against herpes zoster was estimated to be 70% for those aged 50-59, 64% for those aged 60-69, 41% for those aged 70-79, and 18% for those age 80 or above. Efficacy of ZVL was shown to decline each year after vaccination, estimated at less than 35% after 6 years post-vaccination [3, 12-15]. ZVL recipients 60-80 years of age had 51% fewer zoster episodes than a comparison control group [1]. In a community based retrospective cohort study of Medicare participants over 65 years of age, the effectiveness of ZVL was 33% for the first 3 years after vaccination, and 19% after 4 years post-vaccination. Effectiveness against post-herpetic neuralgia was higher; 57% for the first 3 years and 45% after 4 years post-vaccination [13].

Vaccine Safety: Mild injection site reactions such as pain and/or erythema are the most common adverse reactions following varicella vaccination, reported in roughly 21-25% of children within three days of vaccination. Rash is reported in 1-4% of children after varicella vaccination. Fever is reported in 4-7% of children between 7 and 21 days after vaccination [2].

Injection site reactions are also the most common adverse reactions following herpes zoster vaccination. Such reactions were reported in 48.3% of ZVL (Zostavax®) recipients versus 16.6% of placebo recipients in the Shingles Prevention Study [5], and in 81.5% of RZV (Shingrix®) recipients versus 11.9% of placebo recipients in the Zoster Efficacy Study in Adults 50 Years of Age or Older (ZOE-50) [9]. Minor systemic adverse events such as headaches were reported slightly more commonly in ZVL vaccine recipients (6.3%) than placebo recipients (4.9%), but no difference in risk of fever after vaccination was shown. In comparison, systemic adverse events were reported much more commonly in RZV vaccine recipients (66.1%) than placebo recipients (29.5%). Most reactions to ZVL were mild and resolved within 4 days. Most reactions to RZV were of mild or moderate intensity, with a median duration of 1 to 3 days. However, grade 3 reactions (symptoms prevented normal everyday activities) were reported in 17% of RZV vaccinees compared to only 3% of controls. No difference in serious adverse events between vaccinated and control groups was shown for either RZV or ZVL [3, 5, 9, 11].

Mild zoster illness resulting from a latent infection with varicella vaccine virus has been reported [16]. This has been very rarely associated with viral meningitis, although affected patients without immune deficiencies recover fully without any lasting effects. Varicella vaccine can also cause hepatitis if mistakenly administered to severely immune deficient individuals [1]. See the Do Vaccines Cause Hepatitis?, the Do Vaccines Cause Meningitis or Encephalitis?, the Do Vaccines Cause Disseminated Varicella Infection?, and the Do Vaccines Cause Herpes Zoster? summaries for more details.

Vaccines which may induce fever may also rarely induce febrile seizures. Febrile seizures are a common and typically benign childhood condition, occurring in 2-5% of children at some point during their first five years of life. Febrile seizures have an estimated background incidence of 240–480 per 100,000 person-years in children under five years, although this varies considerably by age, genetics, co-morbidities and environmental risk factors. There are no long-term effects of simple febrile seizures, with the possible exception of an increased risk of recurrence [17-20]. The rate of febrile seizures in the 7-10 days after vaccination was approximately 2-3 times higher for children who received MMRV as compared to MMR and varicella vaccines administered separately on the same day, and 4 times higher as compared to MMR alone [21]. There is no increased risk of fever or febrile seizures in children receiving their second dose of measles-containing vaccine at 4 to 6 years of age, whether given MMR or MMRV [1, 22]. See the Do Vaccines Cause Seizures summary for more details.

Although transmission of varicella vaccine virus is rare, it may very occasionally occur if a recently vaccinated person develops a rash. To be safe, close contact with persons without varicella immunity at high risk of complications, especially those who are immunocompromised, should be avoided until such a rash has disappeared [1]. There is no risk of transmission following the inactivated zoster vaccine (RZV).

Post-licensure safety studies are being carried out by the manufacturer and FDA/CDC independently to monitor the safety of RZV (Shingrix®) [190]. A recent self-controlled analysis by the FDA found an association between RZV and Guillain Barré Syndrome (GBS). The rate ratio, comparing cases in risk versus control windows, was 4.30 (95% Confidence Interval: 1.76-10.53); this corresponds to an attributable risk of 6.47 additional cases of GBS per million doses of Shingrix (95%CI: 2.47-10.47). However, these results should be interpreted with caution, as the number of cases in the study was small (13 in risk window versus 8 in control window), and the study is not yet peer reviewed. See the Do Vaccines Cause GBS? summary for more details.

Contraindications and Precautions: Severe allergic reaction (e.g. anaphylaxis) to a previous dose or vaccine component is a contraindication to further vaccination with any varicella-containing product, including herpes zoster vaccine. Other contraindications to vaccination with varicella-containing vaccines or ZVL include pregnancy, altered immunity, and family history of altered immunocompetence [1, 2, 4]. The following is a direct excerpt from the 2007 ACIP recommendations regarding the contraindication of varicella vaccine in persons with altered immunity:

“Single-antigen varicella and combination MMRV vaccines are not licensed for use in persons who have any malignant condition, including blood dyscrasias, leukemia, lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic systems. Combination MMRV vaccine should not be administered to persons with primary or acquired immunodeficiency, including immunosuppression associated with AIDS or other clinical manifestations of HIV infections, cellular immunodeficiencies, hypogammaglobulinemia, and dysgammaglobulinemia. Combination MMRV vaccine should not be administered as a substitute for the component vaccines when vaccinating HIV-infected children.

“Varicella vaccines should not be administered to persons who have a family history of congenital or hereditary immunodeficiency in first-degree relatives (e.g., parents and siblings) unless the immune competence of the potential vaccine recipient has been clinically substantiated or verified by a laboratory.

“Varicella vaccines should not be administered to persons receiving high-dose systemic immunosuppressive therapy, including persons on oral steroids >2 mg/kg of body weight or a total of >20 mg/day of prednisone or equivalent for persons who weigh >10 kg, when administered for >2 weeks. Such persons are more susceptible to infections than healthy persons. Administration of varicella vaccines can result in a more extensive vaccine-associated rash or disseminated disease in persons receiving immunosuppressive doses of corticosteroids. This contraindication does not apply to persons who are receiving inhaled, nasal, or topical corticosteroids or low-dose corticosteroids as are used commonly for asthma prophylaxis or for corticosteroid-replacement therapy.” [2]

The following is a direct excerpt from the 2008 ACIP recommendations regarding the contraindication of ZVL in immunocompromised persons. New guidelines are in preparation.
“Zoster vaccine should not be administered to persons with primary or acquired immunodeficiency including:

“Persons with leukemia, lymphomas, or other malignant neoplasms affecting the bone marrow or lymphatic system. However, patients whose leukemia is in remission and who have not received chemotherapy (e.g., alkylating drugs or antimetabolites) or radiation for at least 3 months can receive zoster vaccine.

“Persons with AIDS or other clinical manifestations of HIV, including persons with CD4+ T-lymphocyte values <200 per mm3 or <15% of total lymphocytes.

“Persons on immunosuppressive therapy, including high-dose corticosteroids (>20 mg/day of prednisone or equivalent) lasting two or more weeks. Zoster vaccination should be deferred for at least 1 month after discontinuation of such therapy. Short-term corticosteroid therapy (< 14 days); low-to-moderate dose (< 20 mg/day of prednisone or equivalent); topical (e.g., nasal, skin, inhaled); intra-articular, bursal, or tendon injections; or long-term alternate-day treatment with low to moderate doses of short-acting systemic corticosteroids are not considered to be sufficiently immunosuppressive to cause concerns for vaccine safety. Persons receiving this dose or schedule can receive zoster vaccine. Therapy with low-doses of methotrexate (< 0.4 mg/Kg/week), azathioprine (< 3.0 mg/Kg/day), or 6-mercaptopurine (< 1.5 mg/Kg/day) for treatment of rheumatoid arthritis, psoriasis, polymyositis, sarcoidosis, inflammatory bowel disease, and other conditions are also not considered sufficiently immunosuppressive to create vaccine safety concerns and are not contraindications for administration of zoster vaccine.

“Persons with clinical or laboratory evidence of other unspecified cellular immunodeficiency. However, persons with impaired humoral immunity (e.g., hypogammaglobulinemia or dysgammaglobulinemia) can receive zoster vaccine.

“Persons undergoing hematopoietic stem cell transplantation (HSCT). The experience of HSCT recipients with VZV-containing vaccines (e.g., zoster vaccine) is limited. Physicians should assess the immune status of the recipient on a case-by-case basis to determine the relevant risks. If a decision is made to vaccinate with zoster vaccine, the vaccine should be administered at least 24 months after transplantation.

“Persons receiving recombinant human immune mediators and immune modulators, especially the antitumor necrosis factor agents adalimumab, infliximab, and etanercept. The safety and efficacy of zoster vaccine administered concurrently with these agents is unknown. If it is not possible to administer zoster vaccine to patients before initiation of therapy, physicians should assess the immune status of the recipient on a case-by-case basis to determine the relevant risks and benefits. Otherwise, vaccination with zoster vaccine should be deferred for at least 1 month after discontinuation of such therapy.” [5]

Current moderate to severe acute illness is a precaution to any vaccination. Recent receipt of antibody-containing blood products is a precaution to both varicella and MMRV vaccination and may require waiting until the antibodies wane before administering the vaccine. Personal or family history of seizures is a precaution to MMRV vaccination [1, 2]. “Receipt of specific antiviral drugs (acyclovir, famiciclovir, or valacyclovir) 24 hours before vaccination (avoid use of these antiviral drugs for 14 days after vaccination)” has also recently been added to the list of precautions in the CDC’s General Best Practice Guidelines for Immunization report [4].

Precautions to vaccination with RZV include current herpes zoster infection, pregnancy and breastfeeding [3].

For more details, please see the most recent ACIP recommendations.

Considerations in Pregnancy: Varicella and ZVL are live attenuated vaccines and are thus contraindicated during pregnancy.

Having a pregnant household member is not a contraindication to vaccination.

Women who are vaccinated for varicella should avoid becoming pregnant for a month after each injection. If a pregnant woman is inadvertently vaccinated or becomes pregnant within 4 weeks after varicella vaccination, she should be counseled as to the potential effects on the fetus, but this should not be considered an indication for termination of the pregnancy.

The theoretical concerns stem from the fact that wild-type varicella poses a low risk of development of congenital varicella syndrome and its associated birth defects; however, since the virulence of the attenuated vaccine virus is substantially less than the wild-type virus, the risk to the fetus from the vaccine, if any, should be even lower. Beginning in 1995, the Merck/CDC Pregnancy Registry for VZV-Containing Vaccines monitored the maternal and fetal outcomes of pregnant women who were inadvertently administered any varicella-containing vaccine up to 3 months before or at any time during pregnancy, and no birth defects consistent with congenital varicella syndrome were documented. Although this does not exclude the possibility of such events, the potential risk, if any, is low. Due to the low rate of exposure of pregnant women to this vaccine and the rarity of congenital varicella syndrome, new patient enrollment in the VARIVAX® Pregnancy Registry was discontinued in 2013 [2, 23].

There is not yet any data to establish whether RZV is safe during pregnancy or breastfeeding, thus there is currently no ACIP recommendation for RZV in pregnant or breastfeeding women. For now, the CDC says to consider delaying vaccination with RZV under such circumstances [3].

References

1. Epidemiology and Prevention of Vaccine-Preventable Diseases, K.A. Hamborsky J, Wolfe S Editor. 2015, Centers for Disease Control and Prevention: Washington D.C.
2. Marin M, et al. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007;56(Rr-4):1-40.
3. Dooling KL, et al. Recommendations of the Advisory Committee on Immunization Practices for Use of Herpes Zoster Vaccines. MMWR Morb Mortal Wkly Rep 2018;67(3):103-8.
4. Kroger AT, Duchin J, Vazquez M. General Best Practice Guidelines for Immunization. Best Practices Guidance of the Advisory Committee on Immunizaition Practices (ACIP). 2017. Last accessed May 2018.
5. 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 CE2-4.
6. Seward JF, Marin M, Vazquez M. Varicella vaccine effectiveness in the US vaccination program: a review. J Infect Dis 2008;197 Suppl 2:;S82-9.
7. Shapiro ED, et al. Effectiveness of 2 doses of varicella vaccine in children. J Infect Dis 2011;203(3):312-5.
8. Perella D, et al. Varicella Vaccine Effectiveness in Preventing Community Transmission in the 2-Dose Era. Pediatrics 2016;137(4).
9. Lal H, et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med, 2015;372(22):2087-96.
10. Cunningham AL, et al. Efficacy of the Herpes Zoster Subunit Vaccine in Adults 70 Years of Age or Older. New England Journal of Medicine 2016;375(11):1019-32.
11. Centers for Disease Control and Prevention. Herpes Zoster Vaccine. in Meeting of the Advisory Committee on Immunization Practices (ACIP). 2017. Atlanta, GA.
12. Schmader KE, 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.
13. Izurieta HS, et al. Effectiveness and Duration of Protection Provided by the Live-attenuated Herpes Zoster Vaccine in the Medicare Population Ages 65 Years and Older. Clin Infect Dis 2017;64(6):785-93.
14. Baxter R, et al. Long-Term Effectiveness of the Live Zoster Vaccine in Preventing Shingles: A Cohort Study. Am J Epidemiol 2018;187(1):161-9.
15. Tseng HF, et al. Declining Effectiveness of Herpes Zoster Vaccine in Adults Aged ≥60 Years. J Infect Dis 2016;213(12):1872-5.
16. Dreyer S, et al. Pediatric vaccine-strain herpes zoster: a case series. Pediatr Dermatol, 2017.
17. AAP. Neurodiagnostic evaluation of the child with a simple febrile seizure. Pediatrics 2011;127(2):389-94.
18. AAP. Febrile seizures: clinical practice guideline for the long-term management of the child with simple febrile seizures. Pediatrics 2008;121(6):1281-6.
19. Bonhoeffer J, et al. Generalized convulsive seizure as an adverse event following immunization: case definition and guidelines for data collection, analysis, and presentation. Vaccine 2004;22(5-6):557-62.
20. Tse A, et al. Signal identification and evaluation for risk of febrile seizures in children following trivalent inactivated influenza vaccine in the Vaccine Safety Datalink Project, 2010-2011. Vaccine 2012;30(11):2024-31.
21. Klein NP, et al. Measles-mumps-rubella-varicella combination vaccine and the risk of febrile seizures. Pediatrics 2010;126(1):e1-8.
22. Centers for Disease Control and Prevention. Vaccine Information Statements (VIS). August 7, 2015. Last accessed May 2018.
23. Marin M, et al. Closure of varicella-zoster virus-containing vaccines pregnancy registry - United States, 2013. MMWR Morb Mortal Wkly Rep 2014;63(33):732-3.