Michael S. Simberkoff, MD; Robert D. Arbeit, MD; Gary R. Johnson, MS; Michael N. Oxman, MD; Kathy D. Boardman, RPh; Heather M. Williams, RN; Myron J. Levin, MD; Kenneth E. Schmader, MD; Lawrence D. Gelb, MD; Susan Keay, MD, PhD; Kathleen Neuzil, MD; Richard N. Greenberg, MD; Marie R. Griffin, MD; Larry E. Davis, MD; Vicki A. Morrison, MD; Paula W. Annunziato, MD; Shingles Prevention Study Group
Simberkoff MS, Arbeit RD, Johnson GR, Oxman MN, Boardman KD, Williams HM, et al. Safety of Herpes Zoster Vaccine in the Shingles Prevention Study: A Randomized Trial. Ann Intern Med. 2010;152:545-554. doi: 10.7326/0003-4819-152-9-201005040-00004
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Published: Ann Intern Med. 2010;152(9):545-554.
The herpes zoster vaccine is effective in preventing herpes zoster and postherpetic neuralgia in immunocompetent older adults. However, its safety has not been described in depth.
To describe local adverse effects and short- and long-term safety profiles of herpes zoster vaccine in immunocompetent older adults.
Randomized, placebo-controlled trial with enrollment from November 1998 to September 2001 and follow-up through April 2004 (mean, 3.4 years). A Veterans Affairs Coordinating Center generated the permutated block randomization scheme, which was stratified by site and age. Participants and follow-up study personnel were blinded to treatment assignments. (ClinicalTrials.gov registration number: NCT00007501)
22 U.S. academic centers.
38 546 immunocompetent adults 60 years or older, including 6616 who participated in an adverse events substudy.
Single dose of herpes zoster vaccine or placebo.
Serious adverse events and rashes in all participants and inoculation-site events in substudy participants during the first 42 days after inoculation. Thereafter, vaccination-related serious adverse events and deaths were monitored in all participants, and hospitalizations were monitored in substudy participants.
After inoculation, 255 (1.4%) vaccine recipients and 254 (1.4%) placebo recipients reported serious adverse events. Local inoculation-site side effects were reported by 1604 (48%) vaccine recipients and 539 (16%) placebo recipients in the substudy. A total of 977 (56.6%) of the vaccine recipients reporting local side effects were aged 60 to 69 years, and 627 (39.2%) were older than 70 years. After inoculation, herpes zoster occurred in 7 vaccine recipients versus 24 placebo recipients. Long-term follow-up (mean, 3.39 years) showed that rates of hospitalization or death did not differ between vaccine and placebo recipients.
Participants in the substudy were not randomly selected. Confirmation of reported serious adverse events with medical record data was not always obtained.
Herpes zoster vaccine is well tolerated in older, immunocompetent adults.
Cooperative Studies Program, Department of Veterans Affairs, Office of Research and Development; grants from Merck to the Veterans Affairs Cooperative Studies Program; and the James R. and Jesse V. Scott Fund for Shingles Research.
The herpes zoster vaccine helps prevent herpes zoster and postherpetic neuralgia in older adults, but is it safe?
This secondary report from a very large trial showed that few vaccine and placebo recipients, and equal numbers in both groups, reported serious adverse events (1.4%). More vaccine recipients than placebo recipients (48% vs. 16%) reported inoculation-site side effects, such as redness and tenderness. Inoculation-site side effects were more common in persons aged 60 to 69 years than in persons older than 70 years.
Herpes zoster vaccine causes minor local inoculation-site adverse effects but no more serious adverse events than does placebo.
Appendix Table 1.
* Enrollment into the adverse event substudy was independent of blinded random assignment to receive vaccine or placebo. During the first year of the study, we completed a convenience sample of 300 participants per site, with a target of 50% in each age group.
Appendix Table 2.
The cumulative rates of SAEs are shown for the time to the first SAE from days 0 to 42 after inoculation in all study participants. There is no significant treatment difference within age strata: For persons aged 60 to 69 years, log-rank P = 0.41; for persons 70 years or older, log-rank P = 0.56. Overall treatment comparison: log-rank P = 0.94. Comparison of age strata 60 to 69 years versus 70 years or older: log-rank P < 0.001. SAE = serious adverse event.
Cumulative mortality rate is shown for the time to death in all study participants. There is no significant treatment difference within age strata: For persons aged 60 to 69 years, log-rank P = 0.20; for persons 70 years or older, log-rank P = 0.37. Overall treatment comparison: log-rank P = 0.95. Comparison of age strata 60 to 69 years versus 70 years or older: log-rank P < 0.001.
Cumulative hospitalization rate is shown for the first hospital admission occurring for participants in the adverse events substudy. There is no significant treatment difference within age strata: For persons aged 60 to 69 years, log-rank P = 0.77; for persons 70 years or older, log-rank P = 0.55. Overall treatment comparison: log-rank P = 0.80. Comparison of age strata 60 to 69 years versus 70 years or older: log-rank P < 0.001.
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David A. Nace
University of Pittsburgh Institute on Aging
May 14, 2010
Zoster Vaccine in Nursing Facility Residents: Safety Questions Remain
1. Simberkoff MS, Arbeit RD, Johnson GR, Oxman MN, Boardman KD, Williams HM, et al. Safety of the herpes zoster vaccine in the Shingles prevention Study. Ann Intern Med. 2010;152:545-54.
2. Centers for Disease Control and Prevention. Prevention of herpes zoster: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Early Release. 2008;57,RR5 [June 6]:1-30.
3. Merck. Highlights of prescribing information for Zostravax. Whitehouse Station NJ: 2009 Dec. Available from: http://www.merck.com/product/usa/pi_circulars/z/zostavax/zostavax_pi2.pdf.
4. Merck. Zoster vaccine line (Oka/Merck) Zostavax. FDA clinical briefing document for Merck and Co., 2005. Available from: http://www.fda.gov/ohrms/dockets/ac/05/briefing/5-4198B2_1.pdf.
5. Nace DA, Drinka P, Mann J, Poland GA. LTC Information Series: Immunization in the Long-Term Care Setting. 2nd ed. Columbia, MD: AMDA; 2010.
Dr. Nace currently receives grant support from Merck for a study of the epidemiology of gastroenteritis in nursing facilities. Drs. Drinka and Crnich do not have any conflicts of interest.
Michael S Simberkoff
VA New York Harbor Healthcare System
June 16, 2010
Re:Zoster Vaccine in Nursing Facility Residents: Safety Questions Remain
IN RESPONSE: The letter by RR Nace, et al concerning safety of the live attenuated Oka/Merck herpes zoster (HZ) vaccine (zoster vaccine) in nursing facility (NF) residents, raises questions that were not specifically addressed in the Shingles Prevention Study (1, 2). We agree that most NF populations are heterogeneous and may include individuals with recognized or unrecognized immunosuppression. Though safe for the vast majority of NF residents, decisions to administer zoster vaccine should be individualized, in accordance with the recommendations of the Advisory Committee on Immunization Practices (3). However, we believe that there are several reasons why zoster vaccine can be safely administered to most NF residents; First, zoster vaccine is remarkably safe. As we reported, local side- effects following administration of zoster vaccine to a large population of older adults were mild and transient; serious adverse events, including hospitalizations and death, occurred with equal frequency in vaccine and placebo recipients (1). A few volunteers received zoster vaccine before their protocol-disqualifying conditions were recognized. These included 3 subjects who had recently received immunosuppressive therapy and 2 with active neoplastic disease. None reported any serious adverse events related to vaccination. Furthermore, Weinberg, et al, reported that the less potent Oka/Merck varicella vaccine was well tolerated and immunogenic in HIV-1-infected adults with low or undetected HIV-viral loads and 400 CD4 cells/mm3. Second, the risk of transmitting the attenuated vaccine virus from zoster vaccine recipients to unvaccinated contacts is very small. Despite a theoretical risk of transmission from the transient rash that can occur at the injection site, such spread is very rare, if it occurs at all. No transmissions of the attenuated vaccine virus to household or other contacts were reported by zoster vaccine recipients in the Shingles Prevention Study, and no cases of vaccine virus transmission following administration of zoster vaccine have been documented in the literature. Finally, use of the attenuated zoster vaccine in the majority of NF residents should reduce the occurrence of HZ and thus exposures to wild- type varicella-zoster virus in this closed community. Some NF residents (and staff) may not have had varicella and thus lack acquired immunity to varicella-zoster virus (particularly those born and raised in tropical climates outside of the United States where acquisition of varicella is delayed). Exposure of such individuals to wild-type varicella-zoster virus, especially if they are immunosuppressed, could result in a life- threatening, disseminated infection. Administration of zoster vaccine to the majority of the NF residents will reduce their risk of developing HZ (2) and thus provide a measure of herd immunity to those who have an absolute contraindication to vaccination.
1. Simberkoff MS, Arbeit RD, Johnson GR, et al. Safety of the herpes zoster vaccine in the shingles prevention study. Ann Intern Med 2010; 152:545-54.
2. 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; 352:2271-84.
3. Centers for Disease Control and Prevention. Prevention of herpes zoster: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2008; 57(RR-5):1-30.
4. Weinberg A. Levin MJ, Macgregor RR. Safety and immunogenicity of a live attenuated varicella vaccine in VZV-seropositive HIV-infected adults. Hum Vaccine 2010; 6:318-21.
Michael S. Simberkoff, M.D. Robert D. Arbeit, M.D. Gary Johnson, MS Michael N. Oxman, M.D. For the Shingles Prevention Study Group
Infectious Disease, Vaccines/Immunization, Prevention/Screening.
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