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Safety, tolerability, and immunogenicity of zoster vaccine in subjects with a history of herpes zoster
Vaccine 28 (2010) 4204–4209
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Vaccine journal homepage: www.elsevier.com/locate/vaccine
Safety, tolerability, and immunogenicity of zoster vaccine in subjects with a history of herpes zoster Richard Mills a , Stephen K. Tyring b , Myron J. Levin c , Janie Parrino d , Xiaoming Li d , Kathleen E. Coll d , Jon E. Stek d,∗ , Katia Schlienger d , Ivan S.F. Chan d , Jeffrey L. Silber d a
Palmetto Medical Research, Mount Pleasant, SC, United States University of Texas Health Science Center, Houston, TX, United States University of Colorado Denver and Health Sciences Center, Denver, CO, United States d Merck Research Laboratories, P.O. Box 1000, North Wales, PA 19454, United States b c
a r t i c l e
i n f o
Article history: Received 15 May 2009 Received in revised form 29 March 2010 Accepted 5 April 2010 Available online 21 April 2010 Keywords: Zoster vaccine Herpes zoster gpELISA Safety Immunogenicity
a b s t r a c t Background: Prior clinical studies of zoster vaccine enrolled subjects without a history of herpes zoster (HZ), so there are limited data on safety and immunogenicity in vaccinees with a prior history of HZ. This study was conducted to evaluate the safety and immunogenicity of zoster vaccine recipients who had a prior episode of HZ. Methods: A total of 101 subjects ≥50 years of age with a prior history of HZ were enrolled. They were stratified by number of years since their HZ (5 to 9 years and ≥10 years, in an approximate 2:1 ratio), and randomized 1:1 to one of two vaccination groups. On day 1, Group I was administered zoster vaccine and Group II received placebo. At week 4, Group I received placebo and Group II received zoster vaccine. Subjects were followed for adverse experiences (AEs), exposure to varicella or HZ, and development of any varicella/varicella-like or HZ/HZ-like rashes, for 28 days after each injection. Blood samples were obtained prior to study injection on day 1 and week 4, and at week 8. Serum was assessed for varicella-zoster virus (VZV) antibody concentration by glycoprotein enzyme-linked immunosorbent assay. Results: No serious AEs were reported within the 28-day safety follow-up period following any vaccination. Although a higher percentage of subjects reported injection-site AEs after receiving zoster vaccine than did placebo recipients, the proportion of subjects reporting systemic clinical AEs was similar in both groups. Zoster vaccine induced a VZV antibody response at 4 weeks post-vaccination. The estimated geometric mean titer (GMT) ratio (vaccine/placebo) was 2.07 (95% CI: 1.48, 2.88). The geometric mean fold-rise (GMFR) from prevaccination to week 4 post-vaccination was 2.1 in zoster vaccine recipients, versus 1.0 in placebo recipients. Conclusions: In HZ history-positive adults ≥50 years of age, zoster vaccine: (1) was well tolerated; and (2) significantly boosted the level of VZV antibody from baseline to 4 weeks post-vaccination as measured by GMT and GMFR. These data support the Advisory Committee on Immunization Practices’ recommendation for routine zoster vaccination for all immunocompetent persons ≥60 years of age irrespective of HZ history. © 2010 Elsevier Ltd. All rights reserved.
1. Introduction Herpes zoster ([HZ]; shingles) is a neurocutaneous infection caused by the reactivation of the varicella-zoster virus (VZV), which has remained latent in the spinal dorsal root or cranial sensory ganglia since an episode of chickenpox (varicella) earlier in life [1,2]. ZOSTAVAX® (zoster vaccine live) [3], a vaccine for prevention of HZ and its complications in older adults, is licensed in the U.S., European Union, and other countries [4,5], and is recommended
∗ Corresponding author. Tel.: +1 484 344 2837. E-mail address: jon [email protected] (J.E. Stek). 0264-410X/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2010.04.003
for universal vaccination of individuals 60 years of age and older by the Advisory Committee on Immunization Practices (ACIP) of the U.S. Centers for Disease Control and Prevention (CDC) [6,7]. The pivotal efficacy trial (Shingles Prevention Study [SPS]) demonstrated that zoster vaccine reduced the incidence of HZ by 51% and of post-herpetic neuralgia (PHN) by 67% in adults ≥60 years of age, with a 61% relative reduction of burden of illness associated with HZ pain in vaccinees who developed HZ, presumably through boosting VZV-specific immune responses [8,9]. Zoster vaccine boosted VZV-specific cellular and humoral immune responses from baseline to 6 weeks post-vaccination, including antibody responses assessed by glycoprotein enzyme-linked immunosorbent assay (gpELISA) [10].
R. Mills et al. / Vaccine 28 (2010) 4204–4209
The ACIP recommends that zoster vaccine can be administered to adults of the appropriate age without regard to HZ history [7], but there is little data to document the response of vaccinees with prior HZ to the vaccine. One reason for this recommendation is that self-reporting of prior illness or vaccination status in older adults is frequently unreliable. For example, one study of self-reported pneumococcal vaccination status in adults ≥65 years of age found that positive and negative predictive values were only 78% and 61%, respectively [11]. Another study of patient reports of cardiovascular disease compared with patient medical records found positive predictive values of 31% (medical problem or surgery related to arteries to the head, arms, or legs or the aorta) to 78% (high blood pressure) and negative predictive values of 90% (high cholesterol) to 95% (medical problem or surgery related to arteries to the head, arms, or legs or the aorta) [12]. For individuals who may have an unclear history of HZ, especially if the HZ occurred in the distant past, questions are expected to be raised by physicians and patients regarding the use of zoster vaccine. The purpose of this study (NCT00322231) was to determine the safety profile and immunogenicity of zoster vaccine in individuals who experienced a prior episode of HZ. Favorable data in persons with a confirmed history of HZ will support the ACIP recommendation, and will help address questions regarding administration of zoster vaccine to individuals whose HZ history is unclear. 2. Methods 2.1. Study population Healthy subjects ≥50 years of age with a physician-documented history of HZ (≥5 years prior to study entry) were eligible for the study. Subjects were excluded if they had an episode of HZ <5 years before study entry; ≥2 prior episodes of HZ; previous vaccination with any VZV-containing vaccine; immune deficiency associated with illness or medical treatments; received blood products within 5 months prior to the first study dose through 8 weeks after enrollment; had hypersensitivity or anaphylactic reactions to gelatin or neomycin; currently were using any form of non-topical antiviral therapy; received any live vaccine 4 weeks prior to the first study dose or during the study period or received any inactivated vaccine 7 days prior to the first study dose or during the study period; or had a history of alcohol or drug abuse. The protocol was approved by the Ethical Review Committee of each participating site and written informed consent was obtained from each subject prior to entry into the study.
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by number of years since their episode of HZ (5 to 9 years and ≥10 years). On day 1, subjects in Group 1 were administered zoster vaccine and subjects in Group 2 received placebo. At week 4, subjects in Group 1 received placebo and subjects in Group 2 received zoster vaccine. Blood samples were drawn on day 1, week 4, and week 8 postenrollment and tested for VZV antibody titer by gpELISA. Lesion samples were to be collected from all rashes that developed during the study and evaluated by VZV polymerase chain reaction (PCR) assay for the presence of vaccine strain VZV DNA. 2.4. Study objectives This was an estimation study with no hypothesis testing. The primary objective was to determine whether zoster vaccine was generally well tolerated when administered to HZ history-positive adults ≥50 years of age. The secondary objective was to determine whether zoster vaccine was immunogenic when administered to HZ history-positive adults. 2.5. Safety surveillance Subjects were followed for injection-site and systemic adverse experiences (AEs), VZV-like rash, and exposure to varicella/HZ for 28 days after each injection. Safety and tolerability were assessed by using a Vaccination Report Card (VRC). The subject recorded the maximum size (in inches) of erythema and swelling, and the maximum severity of pain or tenderness (based on a scale of none, mild, moderate, and severe) for injection-site reactions. The site investigator evaluated each AE as to seriousness, action taken, maximum intensity (excluding injection-site AEs during days 1 to 5 following each vaccination), duration, and relationship to vaccine. All VRCs were reviewed to ensure that all varicella, varicella-like, HZ, or HZ-like rashes and serious AEs were recorded. 2.6. Immunogenicity measurements Immune response to zoster vaccine was based on VZV gpELISA antibody geometric mean titer (GMT) 4 weeks after administration of zoster vaccine and the geometric mean fold-rise (GMFR) from prevaccination to 4 weeks after administration of zoster vaccine. For immunogenicity evaluation, Group 1 subjects who received placebo at week 4 were excluded from immunogenicity analysis at week 8 in order to avoid a carry-over effect of zoster vaccine that was administered on day 1.
2.2. Vaccine 2.7. Statistical methods The lyophilized zoster vaccine (∼89,000 plaque-forming units [PFU]/dose at release) and placebo were supplied to the study centers in 0.7-mL single-dose vials and stored at −15 ◦ C or colder. Vaccine and placebo were reconstituted with sterile diluent immediately prior to administration, and were indistinguishable from each other. All subjects received a single 0.65-mL subcutaneous injection of either zoster vaccine or placebo. 2.3. Study design This was a randomized, double blind, placebo controlled, crossover, multicenter (9 sites) study conducted in the United States between May 2006 and July 2007 to examine the safety, tolerability, and immunogenicity of zoster vaccine administered to subjects with a history of HZ. A total of 101 subjects, ≥50 years of age with a history of HZ ≥5 years prior to screening, were enrolled and randomized in a 1:1 ratio to one of two vaccination groups. Enrollment in each group was stratified in an approximate 2:1 ratio
2.7.1. Safety Safety and tolerability was assessed by statistical and clinical review of safety data collected for 28 days after each injection. The number and proportion (%) of subjects with specific AEs, risk differences, and the associated 95% confidence intervals (CIs) were provided by vaccination group (vaccine or placebo). These summaries combined clinical safety information from the two vaccine groups according to the clinical material subjects received. In accordance with the crossover design, in which each subject served as his/her own control, the risk differences between the two groups (vaccine versus placebo) and the associated two-sided 95% CIs were calculated based on the method of correlated binomial data [13]. 2.7.2. Immunogenicity The VZV gpELISA GMT at prevaccination and 4 weeks after each injection, and corresponding GMFR, in VZV gpELISA antibody responses were summarized, along with 95% CIs, based on
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R. Mills et al. / Vaccine 28 (2010) 4204–4209
Fig. 1. Subject accounting.
the per-protocol population by vaccination group (vaccine versus placebo). In addition, the GMT ratio (vaccine/placebo) and its 95% CI were provided based on a longitudinal regression model [14] adjusting for prevaccination antibody titers and using natural log-transformed antibody titers. Data for subjects in Group 1, who received placebo at week 4, were excluded from immunogenicity analysis at week 8, in order to avoid the impact of a carry-over effect of zoster vaccine.
groups were generally comparable with respect to baseline characteristics (Table 1), except there were a higher percentage of females in Group 1 (70.6%) than in Group 2 (48.0%). The mean age at enrollment was 68.3 years for Group 1 and 67.4 years for Group 2. The overall study group was mostly Caucasian, with a higher percentage of females (59.4%) than males (40.6%). All subjects in both groups had one or more underlying medical conditions, the most common being hypertension (59.4%) and hypercholesterolemia (46.5%). Over 90% of the subjects in both vaccination groups were receiving one or more medication at baseline and during study treatment. The most frequently reported concomitant medications were lipidreducing agents (∼60%), analgesics (∼57%), and renin-angiotensin inhibitors (∼47%).
3. Results 3.1. Participant accounting and demographics As shown in Fig. 1, 100% (51/51) of the subjects randomized to Group 1 and 98.0% (49/50) of subjects randomized to Group 2 completed all study visits. After randomization, one subject in Group 2 was discontinued from the study after withdrawing consent prior to receipt of zoster vaccine at dose 2. Subjects in both
3.2. Safety All subjects who had safety data were included in the safety summary (Table 2). No subjects reported a serious AE during
Table 1 Demographics. Group 1 a ZOSTAVAX® /Placebo
Group 2 a Placebo/ZOSTAVAX®
(N = 51)
(N = 50)
n
(%)
n
(%)
15 36
(29.4) (70.6)
26 24
(52.0) (48.0)
Age (years) 50–59 ≥60 Mean SD Median Range
10 41 68.3 9.9 68 51–93
(19.6) (80.4)
10 40 67.4 9.8 66 50–89
(20.0) (80.0)
Race White Black Asian Hispanic
47 3 1 0
(92.2) (5.9) (2.0) (0.0)
42 3 3 2
(84.0) (6.0) (6.0) (4.0)
Gender Male Female
N = number of subjects randomized in the vaccination group. n = number of subjects contributing to each category. a Indicates order of receipt.
R. Mills et al. / Vaccine 28 (2010) 4204–4209
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Table 2 Clinical adverse experience (AE) summary – days 1–28 post-vaccinationa . ZOSTAVAX®
Placebo
n
(%)
n
(%)
100 98 51 45 15 2 0 0 0 0
(98.0) (52.0) (45.9) (15.3) (2.0) (0.0) (0.0) (0.0) (0.0)
101 96 17 4 13 0 0 0 0 0
(95.0) (17.7) (4.2) (13.5) (0.0) (0.0) (0.0) (0.0) (0.0)
Subjects with 5–9 years since prior HZ episodes (stratum I) Number of subjects Subjects with follow-up With one or more AE Injection-site AEsb Systemic AEs With vaccine-related systemic AEsc
70 68 37 32 9 1
(97.1) (54.4) (47.1) (13.2) (1.5)
71 66 15 3 12 0
(93.0) (22.7) (4.5) (18.2) (0.0)
Subjects with ≥10 years since prior HZ episodes (stratum II) Number of subjects Subjects with follow-up With one or more AE Injection-site AEsb Systemic AEs With vaccine-related systemic AEsc
30 30 14 13 6 1
(100) (46.7) (43.3) (20.0) (3.3)
30 30 2 1 1 0
(100) (6.7) (3.3) (3.3) (0.0)
Subjects 50–59 years of age Number of subjects Subjects with follow-up With one or more AE Injection-site AEsb Systemic AEs With vaccine-related systemic AEsc
20 19 9 9 1 0
(95.0) (47.4) (47.4) (5.3) (0.0)
20 19 5 1 4 0
(95.0) (26.3) (5.3) (21.1) (0.0)
Subjects ≥60 years of age Number of subjects Subjects with follow-up With one or more AE Injection-site AEsb Systemic AEs With vaccine-related systemic AEsc
80 79 42 36 14 2
(98.8) (53.2) (45.6) (17.7) (2.5)
81 77 12 3 9 0
(95.1) (15.6) (3.9) (11.7) (0.0)
Overall per-protocol summary Number of subjects Subjects with follow-up With one or more AE Injection-site AEsb Systemic AEs With vaccine-related systemic AEsc With serious AEs Serious vaccine-related AEs Who died Discontinued due to a vaccine-related AE
n = number of subjects in each category. The same subject may appear in different categories, but counted only once in each category. a AEs were collected after each dose of the relevant vaccination. b All injection-site AEs were considered vaccine-related. c Determined by the investigator to be possibly, probably, or definitely related to the vaccine.
the 28-day safety follow-up period post-vaccination; no subjects discontinued due to an AE. One serious AE of tachy–brady syndrome was reported beyond the safety follow-up period at day 33 post-vaccination 2, following receipt of placebo. This was determined by the investigator to be definitely not related to the study vaccine. The proportion of subjects reporting systemic AEs was similar and low following receipt of either zoster vaccine (15.3%) or placebo (13.5%). Two vaccine-related systemic AEs were reported, both in Group 2 subjects following administration of zoster vaccine (dose 2): pain and myalgia of moderate intensity; and axillary pain of mild intensity. The rate of reported injection-site AEs was higher in vaccine recipients (45.9%) than in placebo recipients (4.2%). The most frequently reported injection-site AEs in vaccine recipients were erythema (33.7%), pain (36.7%), and swelling (26.5%). All AE rates were generally similar regardless of time (5 to 9 years versus ≥10 years) since prior HZ episode or age (50 to 59 years versus ≥60 years). One varicelliform rash was noted in both the zoster vaccine group and in the placebo group; specimens from these rashes were not obtained for PCR testing. No other varicella, varicella-like, HZ, or HZ-like rashes were reported during the study. No subjects reported exposure to varicella or HZ.
3.3. Immunogenicity Table 3 summarizes the VZV gpELISA antibody response by randomization stratum (time since prior HZ episode: 5 to 9 years and ≥10 years), by age group (50 to 59 years and ≥60 years), and for all subjects combined. Among adults ≥50 years of age, zoster vaccine induced an increase in VZV gpELISA antibody at 4 weeks postvaccination with an estimated GMT ratio (vaccine/placebo) of 2.07 (95% CI: 1.48, 2.88), which was significantly (p < 0.001) higher than that induced by placebo. The GMFR from prevaccination to week 4 post-vaccination was higher in the vaccine recipients when compared with the placebo-only recipients, regardless of stratum or age group (Table 3).
4. Discussion Immunogenicity data from previous zoster vaccine clinical trials, with populations that excluded subjects with a history of HZ, indicate that older adults have readily detectable high baseline VZV gpELISA titers [8,9,15,16]. Immunogenicity data obtained from a substudy of the SPS showed that despite these VZV gpELISA antibody levels (GMT was 278.8) at baseline among
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Table 3 VZV gpELISA antibody titer summary. ZOSTAVAX® (N = 100)
Placeboa (N = 50)
n
Response (95% CI)
n
Response (95% CI)
97 97 95
376 (315, 448) 810 (688, 953) 2.1 (1.8, 2.4)
45 48 45
390 (289, 526) 391 (292, 524) 1.0 (0.9, 1.1)
Subjects with 5–9 years since prior HZ episodes (stratum I) GMT Prevaccination GMT 4 weeks post-vaccination GMFR 4 weeks post-vaccination
67 68 66
414 (331, 518) 888 (719, 1098) 2.1 (1.8, 2.5)
31 33 31
409 (276, 606) 451 (307, 663) 1.1 (1.0,1.2)
Subjects with ≥10 years since prior HZ episodes (stratum II) GMT Prevaccination GMT 4 weeks post-vaccination GMFR 4 weeks post-vaccination
30 29 29
302 (231, 395) 653 (524, 812) 2.2 (1.7, 2.8)
14 15 14
351 (218, 565) 286 (189, 433) 0.8 (0.7, 1.0)
Subjects 50–59 years of age GMT Prevaccination GMT 4 weeks post-vaccination GMFR 4 weeks post-vaccination
19 19 18
304 (182, 508) 884 (622, 1257) 2.8 (1.8, 4.4)
8 9 8
265 (112, 625) 304 (122, 756) 1.0 (0.7, 1.3)
Subjects ≥60 years of age GMT Prevaccination GMT 4 weeks post-vaccination GMFR 4 weeks post-vaccination
78 78 77
395 (329, 475) 793 (658, 956) 2.0 (1.7, 2.3)
37 39 37
424 (306, 588) 415 (303, 568) 1.0 (0.9, 1.1)
Endpoint
All subjects combined GMT GMT GMFR
Time point
Prevaccination 4 weeks post-vaccination 4 weeks post-vaccination
N = number of subjects vaccinated. n = number of subjects contributing to the immunogenicity summary. VZV antibody GMT is in gpELISA units/mL. a Immunogenicity was assessed for placebo recipients only in Group 2.
vaccinees, zoster vaccine was immunogenic with a GMFR of 1.7 at 6 weeks post-vaccination [9]. The SPS also established that the 6 week post-vaccination VZV antibody response measured by gpELISA (individual titer and fold-rise) and measures of cell-mediated immunity, correlated with protection against HZ [9]. The population with prior HZ enrolled in this study had numerically higher baseline VZV gpELISA antibody levels (GMT: 376, zoster vaccine; 390 placebo) on average than the population without prior HZ enrolled in the SPS (GMT: 278 zoster vaccine; 291 placebo). The post-vaccination VZV antibody response was measured at 4 weeks in this study, which was 2 weeks earlier than in the SPS. Zoster vaccine induced a GMFR of 2.1 at 4 weeks post-vaccination in subjects with prior HZ, demonstrating that regardless of a subject’s HZ history zoster vaccine elicited an immunologic antibody boost. The baseline GMTs in subjects with an episode of HZ ≥10 years prior was numerically lower than in subjects with an episode of HZ 5 to 9 years prior, suggesting that the strong boost in VZV-specific immune response provided by an HZ episode continued to wane over time. The VZV gpELISA GMT 4 weeks after zoster vaccine was significantly higher than in placebo recipients. The VZV gpELISA GMFR from prevaccination to 4 weeks post-vaccination was higher in the zoster vaccine group than in placebo recipients regardless of time since prior HZ episode or age group. In addition, consistent with results from previous studies, subjects in the 50 to 59 years old age group had a greater GMFR than subjects in the ≥60 years of age group [15–17]. Zoster vaccine was generally well tolerated with no significant AEs during the 28-day safety follow-up phase. The rates of injection-site AEs in subjects with prior HZ (45.9%) were comparable to that observed in the SPS (48.3%), in which subjects with prior HZ were excluded [8]; the rates of injection-site AEs for placebo recipients were 4.2% and 16.6% in the two studies, respectively. Routine vaccination of all persons aged ≥60 years, including those who report a previous episode of HZ, with one dose of zoster vaccine is recommended by the ACIP [6]; however, the optimal time for vaccination has not been established. Data from this clinical trial confirm that zoster vaccine is safe and immunogenic when administered to persons with a prior history of HZ.
Financial disclosure Other than employees of Merck & Co., Inc. (as indicated on the title page), all authors have been investigators for the sponsor. Employees may hold stock and/or stock options in the company. R. Mills has no additional disclosures. S. Tyring has been a consultant to Merck and has served as a speaker for Merck products. M. Levin has been a consultant to Merck, has served as a speaker for Merck products, and shares in the patent for ZOSTAVAX® . Acknowledgements The authors would like to thank all the study participants and staff at the study sites and the ZOSTAVAX® Protocol 014 investigators who made this study possible. ZOSTAVAX® Protocol 014 Study Group R. Cain, L. Gilderman, J. Lawless, F. Maggiacomo, M. Nunez, and B. Venkateswaralu. Contributions: Mills, Tyring, and Levin: enrollment of subjects and/or data collection, analysis and interpretation of data, and preparation of manuscript. Parrino, Li, Coll, and Stek: analysis and interpretation of data, and preparation of manuscript. Schlienger, Chan, and Silber: study concept and design, analysis and interpretation of data, and preparation of manuscript. Funding: This study was funded by Merck & Co., Inc. The sponsor formally reviewed a penultimate draft. All co-authors approved the final version of the manuscript.
References [1] Hope-Simpson RE. Postherpetic neuralgia. J R Coll Gen Pract 1975;25:571–5. [2] Gnann Jr JW, Whitley RJ. Herpes zoster. N Engl J Med 2002;347:340–6. [3] ZOSTAVAX® (zoster vaccine, live) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2007. Available from: http://www.fda.gov/Cber/ label/zostavaxLB.pdf [accessed 27.03.09]. [4] U.S. Food and Drug Administration, Center for Biologics Evaluation and Research. ZOSTAVAX® Product Approval Information. Available from: http://www.fda.gov/cber/products/zostavax.htm [accessed 07.05.09]. [5] EMEA Committee for Medical Products for Human Use: March 2006 Monthly Report. Available from: http://www.emea.europa.eu/pdfs/ human/press/pr/10293706en.pdf [accessed 12.12.06].
R. Mills et al. / Vaccine 28 (2010) 4204–4209 [6] Recommendations of the Advisory Committee on Immunization Practices. Centers for Disease Control, Prevention of herpes zoster. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5705a1.htm?s cid= rr5705a1 e [accessed 20.08.08]. [7] Centers for Disease Control. National Immunization Program, Adult Immunization Schedule. Available from: http://www.cdc.gov/nip/recs/adultschedule.htm [accessed 27.11.06]. [8] Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271–84. [9] Levin MJ, Oxman MN, Zhang JH, Johnson GR, Stanley H, Hayward AR, et al. Varicella-zoster virus-specific immune responses in elderly recipients of a herpes zoster vaccine. J Infect Dis 2008;197:825–35. [10] Hammond O, Wang Y, Green T, Antonello J, Kuhn R, Motley C, et al. The optimization and validation of the glycoprotein ELISA assay for quantitative varicella-zoster virus (VZV) antibody detection. J Med Virol 2006;78:1679–87. [11] Long CE, Kouides RW, Peer S, LaForce FM, Whitney C, Bennett NM. Accuracy of self-report of pneumococcal vaccine status in older adults. Abstracts of the 127th American Public Health Association Meeting, November 7-11, 1999. Chicago, Illinois: American Public Health Association, 1999. p. 124.
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Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Safety, tolerability, and immunogenicity of zoster vaccine in subjects with a history of herpes zoster Richard Mills a , Stephen K. Tyring b , Myron J. Levin c , Janie Parrino d , Xiaoming Li d , Kathleen E. Coll d , Jon E. Stek d,∗ , Katia Schlienger d , Ivan S.F. Chan d , Jeffrey L. Silber d a
Palmetto Medical Research, Mount Pleasant, SC, United States University of Texas Health Science Center, Houston, TX, United States University of Colorado Denver and Health Sciences Center, Denver, CO, United States d Merck Research Laboratories, P.O. Box 1000, North Wales, PA 19454, United States b c
a r t i c l e
i n f o
Article history: Received 15 May 2009 Received in revised form 29 March 2010 Accepted 5 April 2010 Available online 21 April 2010 Keywords: Zoster vaccine Herpes zoster gpELISA Safety Immunogenicity
a b s t r a c t Background: Prior clinical studies of zoster vaccine enrolled subjects without a history of herpes zoster (HZ), so there are limited data on safety and immunogenicity in vaccinees with a prior history of HZ. This study was conducted to evaluate the safety and immunogenicity of zoster vaccine recipients who had a prior episode of HZ. Methods: A total of 101 subjects ≥50 years of age with a prior history of HZ were enrolled. They were stratified by number of years since their HZ (5 to 9 years and ≥10 years, in an approximate 2:1 ratio), and randomized 1:1 to one of two vaccination groups. On day 1, Group I was administered zoster vaccine and Group II received placebo. At week 4, Group I received placebo and Group II received zoster vaccine. Subjects were followed for adverse experiences (AEs), exposure to varicella or HZ, and development of any varicella/varicella-like or HZ/HZ-like rashes, for 28 days after each injection. Blood samples were obtained prior to study injection on day 1 and week 4, and at week 8. Serum was assessed for varicella-zoster virus (VZV) antibody concentration by glycoprotein enzyme-linked immunosorbent assay. Results: No serious AEs were reported within the 28-day safety follow-up period following any vaccination. Although a higher percentage of subjects reported injection-site AEs after receiving zoster vaccine than did placebo recipients, the proportion of subjects reporting systemic clinical AEs was similar in both groups. Zoster vaccine induced a VZV antibody response at 4 weeks post-vaccination. The estimated geometric mean titer (GMT) ratio (vaccine/placebo) was 2.07 (95% CI: 1.48, 2.88). The geometric mean fold-rise (GMFR) from prevaccination to week 4 post-vaccination was 2.1 in zoster vaccine recipients, versus 1.0 in placebo recipients. Conclusions: In HZ history-positive adults ≥50 years of age, zoster vaccine: (1) was well tolerated; and (2) significantly boosted the level of VZV antibody from baseline to 4 weeks post-vaccination as measured by GMT and GMFR. These data support the Advisory Committee on Immunization Practices’ recommendation for routine zoster vaccination for all immunocompetent persons ≥60 years of age irrespective of HZ history. © 2010 Elsevier Ltd. All rights reserved.
1. Introduction Herpes zoster ([HZ]; shingles) is a neurocutaneous infection caused by the reactivation of the varicella-zoster virus (VZV), which has remained latent in the spinal dorsal root or cranial sensory ganglia since an episode of chickenpox (varicella) earlier in life [1,2]. ZOSTAVAX® (zoster vaccine live) [3], a vaccine for prevention of HZ and its complications in older adults, is licensed in the U.S., European Union, and other countries [4,5], and is recommended
∗ Corresponding author. Tel.: +1 484 344 2837. E-mail address: jon [email protected] (J.E. Stek). 0264-410X/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2010.04.003
for universal vaccination of individuals 60 years of age and older by the Advisory Committee on Immunization Practices (ACIP) of the U.S. Centers for Disease Control and Prevention (CDC) [6,7]. The pivotal efficacy trial (Shingles Prevention Study [SPS]) demonstrated that zoster vaccine reduced the incidence of HZ by 51% and of post-herpetic neuralgia (PHN) by 67% in adults ≥60 years of age, with a 61% relative reduction of burden of illness associated with HZ pain in vaccinees who developed HZ, presumably through boosting VZV-specific immune responses [8,9]. Zoster vaccine boosted VZV-specific cellular and humoral immune responses from baseline to 6 weeks post-vaccination, including antibody responses assessed by glycoprotein enzyme-linked immunosorbent assay (gpELISA) [10].
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The ACIP recommends that zoster vaccine can be administered to adults of the appropriate age without regard to HZ history [7], but there is little data to document the response of vaccinees with prior HZ to the vaccine. One reason for this recommendation is that self-reporting of prior illness or vaccination status in older adults is frequently unreliable. For example, one study of self-reported pneumococcal vaccination status in adults ≥65 years of age found that positive and negative predictive values were only 78% and 61%, respectively [11]. Another study of patient reports of cardiovascular disease compared with patient medical records found positive predictive values of 31% (medical problem or surgery related to arteries to the head, arms, or legs or the aorta) to 78% (high blood pressure) and negative predictive values of 90% (high cholesterol) to 95% (medical problem or surgery related to arteries to the head, arms, or legs or the aorta) [12]. For individuals who may have an unclear history of HZ, especially if the HZ occurred in the distant past, questions are expected to be raised by physicians and patients regarding the use of zoster vaccine. The purpose of this study (NCT00322231) was to determine the safety profile and immunogenicity of zoster vaccine in individuals who experienced a prior episode of HZ. Favorable data in persons with a confirmed history of HZ will support the ACIP recommendation, and will help address questions regarding administration of zoster vaccine to individuals whose HZ history is unclear. 2. Methods 2.1. Study population Healthy subjects ≥50 years of age with a physician-documented history of HZ (≥5 years prior to study entry) were eligible for the study. Subjects were excluded if they had an episode of HZ <5 years before study entry; ≥2 prior episodes of HZ; previous vaccination with any VZV-containing vaccine; immune deficiency associated with illness or medical treatments; received blood products within 5 months prior to the first study dose through 8 weeks after enrollment; had hypersensitivity or anaphylactic reactions to gelatin or neomycin; currently were using any form of non-topical antiviral therapy; received any live vaccine 4 weeks prior to the first study dose or during the study period or received any inactivated vaccine 7 days prior to the first study dose or during the study period; or had a history of alcohol or drug abuse. The protocol was approved by the Ethical Review Committee of each participating site and written informed consent was obtained from each subject prior to entry into the study.
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by number of years since their episode of HZ (5 to 9 years and ≥10 years). On day 1, subjects in Group 1 were administered zoster vaccine and subjects in Group 2 received placebo. At week 4, subjects in Group 1 received placebo and subjects in Group 2 received zoster vaccine. Blood samples were drawn on day 1, week 4, and week 8 postenrollment and tested for VZV antibody titer by gpELISA. Lesion samples were to be collected from all rashes that developed during the study and evaluated by VZV polymerase chain reaction (PCR) assay for the presence of vaccine strain VZV DNA. 2.4. Study objectives This was an estimation study with no hypothesis testing. The primary objective was to determine whether zoster vaccine was generally well tolerated when administered to HZ history-positive adults ≥50 years of age. The secondary objective was to determine whether zoster vaccine was immunogenic when administered to HZ history-positive adults. 2.5. Safety surveillance Subjects were followed for injection-site and systemic adverse experiences (AEs), VZV-like rash, and exposure to varicella/HZ for 28 days after each injection. Safety and tolerability were assessed by using a Vaccination Report Card (VRC). The subject recorded the maximum size (in inches) of erythema and swelling, and the maximum severity of pain or tenderness (based on a scale of none, mild, moderate, and severe) for injection-site reactions. The site investigator evaluated each AE as to seriousness, action taken, maximum intensity (excluding injection-site AEs during days 1 to 5 following each vaccination), duration, and relationship to vaccine. All VRCs were reviewed to ensure that all varicella, varicella-like, HZ, or HZ-like rashes and serious AEs were recorded. 2.6. Immunogenicity measurements Immune response to zoster vaccine was based on VZV gpELISA antibody geometric mean titer (GMT) 4 weeks after administration of zoster vaccine and the geometric mean fold-rise (GMFR) from prevaccination to 4 weeks after administration of zoster vaccine. For immunogenicity evaluation, Group 1 subjects who received placebo at week 4 were excluded from immunogenicity analysis at week 8 in order to avoid a carry-over effect of zoster vaccine that was administered on day 1.
2.2. Vaccine 2.7. Statistical methods The lyophilized zoster vaccine (∼89,000 plaque-forming units [PFU]/dose at release) and placebo were supplied to the study centers in 0.7-mL single-dose vials and stored at −15 ◦ C or colder. Vaccine and placebo were reconstituted with sterile diluent immediately prior to administration, and were indistinguishable from each other. All subjects received a single 0.65-mL subcutaneous injection of either zoster vaccine or placebo. 2.3. Study design This was a randomized, double blind, placebo controlled, crossover, multicenter (9 sites) study conducted in the United States between May 2006 and July 2007 to examine the safety, tolerability, and immunogenicity of zoster vaccine administered to subjects with a history of HZ. A total of 101 subjects, ≥50 years of age with a history of HZ ≥5 years prior to screening, were enrolled and randomized in a 1:1 ratio to one of two vaccination groups. Enrollment in each group was stratified in an approximate 2:1 ratio
2.7.1. Safety Safety and tolerability was assessed by statistical and clinical review of safety data collected for 28 days after each injection. The number and proportion (%) of subjects with specific AEs, risk differences, and the associated 95% confidence intervals (CIs) were provided by vaccination group (vaccine or placebo). These summaries combined clinical safety information from the two vaccine groups according to the clinical material subjects received. In accordance with the crossover design, in which each subject served as his/her own control, the risk differences between the two groups (vaccine versus placebo) and the associated two-sided 95% CIs were calculated based on the method of correlated binomial data [13]. 2.7.2. Immunogenicity The VZV gpELISA GMT at prevaccination and 4 weeks after each injection, and corresponding GMFR, in VZV gpELISA antibody responses were summarized, along with 95% CIs, based on
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Fig. 1. Subject accounting.
the per-protocol population by vaccination group (vaccine versus placebo). In addition, the GMT ratio (vaccine/placebo) and its 95% CI were provided based on a longitudinal regression model [14] adjusting for prevaccination antibody titers and using natural log-transformed antibody titers. Data for subjects in Group 1, who received placebo at week 4, were excluded from immunogenicity analysis at week 8, in order to avoid the impact of a carry-over effect of zoster vaccine.
groups were generally comparable with respect to baseline characteristics (Table 1), except there were a higher percentage of females in Group 1 (70.6%) than in Group 2 (48.0%). The mean age at enrollment was 68.3 years for Group 1 and 67.4 years for Group 2. The overall study group was mostly Caucasian, with a higher percentage of females (59.4%) than males (40.6%). All subjects in both groups had one or more underlying medical conditions, the most common being hypertension (59.4%) and hypercholesterolemia (46.5%). Over 90% of the subjects in both vaccination groups were receiving one or more medication at baseline and during study treatment. The most frequently reported concomitant medications were lipidreducing agents (∼60%), analgesics (∼57%), and renin-angiotensin inhibitors (∼47%).
3. Results 3.1. Participant accounting and demographics As shown in Fig. 1, 100% (51/51) of the subjects randomized to Group 1 and 98.0% (49/50) of subjects randomized to Group 2 completed all study visits. After randomization, one subject in Group 2 was discontinued from the study after withdrawing consent prior to receipt of zoster vaccine at dose 2. Subjects in both
3.2. Safety All subjects who had safety data were included in the safety summary (Table 2). No subjects reported a serious AE during
Table 1 Demographics. Group 1 a ZOSTAVAX® /Placebo
Group 2 a Placebo/ZOSTAVAX®
(N = 51)
(N = 50)
n
(%)
n
(%)
15 36
(29.4) (70.6)
26 24
(52.0) (48.0)
Age (years) 50–59 ≥60 Mean SD Median Range
10 41 68.3 9.9 68 51–93
(19.6) (80.4)
10 40 67.4 9.8 66 50–89
(20.0) (80.0)
Race White Black Asian Hispanic
47 3 1 0
(92.2) (5.9) (2.0) (0.0)
42 3 3 2
(84.0) (6.0) (6.0) (4.0)
Gender Male Female
N = number of subjects randomized in the vaccination group. n = number of subjects contributing to each category. a Indicates order of receipt.
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Table 2 Clinical adverse experience (AE) summary – days 1–28 post-vaccinationa . ZOSTAVAX®
Placebo
n
(%)
n
(%)
100 98 51 45 15 2 0 0 0 0
(98.0) (52.0) (45.9) (15.3) (2.0) (0.0) (0.0) (0.0) (0.0)
101 96 17 4 13 0 0 0 0 0
(95.0) (17.7) (4.2) (13.5) (0.0) (0.0) (0.0) (0.0) (0.0)
Subjects with 5–9 years since prior HZ episodes (stratum I) Number of subjects Subjects with follow-up With one or more AE Injection-site AEsb Systemic AEs With vaccine-related systemic AEsc
70 68 37 32 9 1
(97.1) (54.4) (47.1) (13.2) (1.5)
71 66 15 3 12 0
(93.0) (22.7) (4.5) (18.2) (0.0)
Subjects with ≥10 years since prior HZ episodes (stratum II) Number of subjects Subjects with follow-up With one or more AE Injection-site AEsb Systemic AEs With vaccine-related systemic AEsc
30 30 14 13 6 1
(100) (46.7) (43.3) (20.0) (3.3)
30 30 2 1 1 0
(100) (6.7) (3.3) (3.3) (0.0)
Subjects 50–59 years of age Number of subjects Subjects with follow-up With one or more AE Injection-site AEsb Systemic AEs With vaccine-related systemic AEsc
20 19 9 9 1 0
(95.0) (47.4) (47.4) (5.3) (0.0)
20 19 5 1 4 0
(95.0) (26.3) (5.3) (21.1) (0.0)
Subjects ≥60 years of age Number of subjects Subjects with follow-up With one or more AE Injection-site AEsb Systemic AEs With vaccine-related systemic AEsc
80 79 42 36 14 2
(98.8) (53.2) (45.6) (17.7) (2.5)
81 77 12 3 9 0
(95.1) (15.6) (3.9) (11.7) (0.0)
Overall per-protocol summary Number of subjects Subjects with follow-up With one or more AE Injection-site AEsb Systemic AEs With vaccine-related systemic AEsc With serious AEs Serious vaccine-related AEs Who died Discontinued due to a vaccine-related AE
n = number of subjects in each category. The same subject may appear in different categories, but counted only once in each category. a AEs were collected after each dose of the relevant vaccination. b All injection-site AEs were considered vaccine-related. c Determined by the investigator to be possibly, probably, or definitely related to the vaccine.
the 28-day safety follow-up period post-vaccination; no subjects discontinued due to an AE. One serious AE of tachy–brady syndrome was reported beyond the safety follow-up period at day 33 post-vaccination 2, following receipt of placebo. This was determined by the investigator to be definitely not related to the study vaccine. The proportion of subjects reporting systemic AEs was similar and low following receipt of either zoster vaccine (15.3%) or placebo (13.5%). Two vaccine-related systemic AEs were reported, both in Group 2 subjects following administration of zoster vaccine (dose 2): pain and myalgia of moderate intensity; and axillary pain of mild intensity. The rate of reported injection-site AEs was higher in vaccine recipients (45.9%) than in placebo recipients (4.2%). The most frequently reported injection-site AEs in vaccine recipients were erythema (33.7%), pain (36.7%), and swelling (26.5%). All AE rates were generally similar regardless of time (5 to 9 years versus ≥10 years) since prior HZ episode or age (50 to 59 years versus ≥60 years). One varicelliform rash was noted in both the zoster vaccine group and in the placebo group; specimens from these rashes were not obtained for PCR testing. No other varicella, varicella-like, HZ, or HZ-like rashes were reported during the study. No subjects reported exposure to varicella or HZ.
3.3. Immunogenicity Table 3 summarizes the VZV gpELISA antibody response by randomization stratum (time since prior HZ episode: 5 to 9 years and ≥10 years), by age group (50 to 59 years and ≥60 years), and for all subjects combined. Among adults ≥50 years of age, zoster vaccine induced an increase in VZV gpELISA antibody at 4 weeks postvaccination with an estimated GMT ratio (vaccine/placebo) of 2.07 (95% CI: 1.48, 2.88), which was significantly (p < 0.001) higher than that induced by placebo. The GMFR from prevaccination to week 4 post-vaccination was higher in the vaccine recipients when compared with the placebo-only recipients, regardless of stratum or age group (Table 3).
4. Discussion Immunogenicity data from previous zoster vaccine clinical trials, with populations that excluded subjects with a history of HZ, indicate that older adults have readily detectable high baseline VZV gpELISA titers [8,9,15,16]. Immunogenicity data obtained from a substudy of the SPS showed that despite these VZV gpELISA antibody levels (GMT was 278.8) at baseline among
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Table 3 VZV gpELISA antibody titer summary. ZOSTAVAX® (N = 100)
Placeboa (N = 50)
n
Response (95% CI)
n
Response (95% CI)
97 97 95
376 (315, 448) 810 (688, 953) 2.1 (1.8, 2.4)
45 48 45
390 (289, 526) 391 (292, 524) 1.0 (0.9, 1.1)
Subjects with 5–9 years since prior HZ episodes (stratum I) GMT Prevaccination GMT 4 weeks post-vaccination GMFR 4 weeks post-vaccination
67 68 66
414 (331, 518) 888 (719, 1098) 2.1 (1.8, 2.5)
31 33 31
409 (276, 606) 451 (307, 663) 1.1 (1.0,1.2)
Subjects with ≥10 years since prior HZ episodes (stratum II) GMT Prevaccination GMT 4 weeks post-vaccination GMFR 4 weeks post-vaccination
30 29 29
302 (231, 395) 653 (524, 812) 2.2 (1.7, 2.8)
14 15 14
351 (218, 565) 286 (189, 433) 0.8 (0.7, 1.0)
Subjects 50–59 years of age GMT Prevaccination GMT 4 weeks post-vaccination GMFR 4 weeks post-vaccination
19 19 18
304 (182, 508) 884 (622, 1257) 2.8 (1.8, 4.4)
8 9 8
265 (112, 625) 304 (122, 756) 1.0 (0.7, 1.3)
Subjects ≥60 years of age GMT Prevaccination GMT 4 weeks post-vaccination GMFR 4 weeks post-vaccination
78 78 77
395 (329, 475) 793 (658, 956) 2.0 (1.7, 2.3)
37 39 37
424 (306, 588) 415 (303, 568) 1.0 (0.9, 1.1)
Endpoint
All subjects combined GMT GMT GMFR
Time point
Prevaccination 4 weeks post-vaccination 4 weeks post-vaccination
N = number of subjects vaccinated. n = number of subjects contributing to the immunogenicity summary. VZV antibody GMT is in gpELISA units/mL. a Immunogenicity was assessed for placebo recipients only in Group 2.
vaccinees, zoster vaccine was immunogenic with a GMFR of 1.7 at 6 weeks post-vaccination [9]. The SPS also established that the 6 week post-vaccination VZV antibody response measured by gpELISA (individual titer and fold-rise) and measures of cell-mediated immunity, correlated with protection against HZ [9]. The population with prior HZ enrolled in this study had numerically higher baseline VZV gpELISA antibody levels (GMT: 376, zoster vaccine; 390 placebo) on average than the population without prior HZ enrolled in the SPS (GMT: 278 zoster vaccine; 291 placebo). The post-vaccination VZV antibody response was measured at 4 weeks in this study, which was 2 weeks earlier than in the SPS. Zoster vaccine induced a GMFR of 2.1 at 4 weeks post-vaccination in subjects with prior HZ, demonstrating that regardless of a subject’s HZ history zoster vaccine elicited an immunologic antibody boost. The baseline GMTs in subjects with an episode of HZ ≥10 years prior was numerically lower than in subjects with an episode of HZ 5 to 9 years prior, suggesting that the strong boost in VZV-specific immune response provided by an HZ episode continued to wane over time. The VZV gpELISA GMT 4 weeks after zoster vaccine was significantly higher than in placebo recipients. The VZV gpELISA GMFR from prevaccination to 4 weeks post-vaccination was higher in the zoster vaccine group than in placebo recipients regardless of time since prior HZ episode or age group. In addition, consistent with results from previous studies, subjects in the 50 to 59 years old age group had a greater GMFR than subjects in the ≥60 years of age group [15–17]. Zoster vaccine was generally well tolerated with no significant AEs during the 28-day safety follow-up phase. The rates of injection-site AEs in subjects with prior HZ (45.9%) were comparable to that observed in the SPS (48.3%), in which subjects with prior HZ were excluded [8]; the rates of injection-site AEs for placebo recipients were 4.2% and 16.6% in the two studies, respectively. Routine vaccination of all persons aged ≥60 years, including those who report a previous episode of HZ, with one dose of zoster vaccine is recommended by the ACIP [6]; however, the optimal time for vaccination has not been established. Data from this clinical trial confirm that zoster vaccine is safe and immunogenic when administered to persons with a prior history of HZ.
Financial disclosure Other than employees of Merck & Co., Inc. (as indicated on the title page), all authors have been investigators for the sponsor. Employees may hold stock and/or stock options in the company. R. Mills has no additional disclosures. S. Tyring has been a consultant to Merck and has served as a speaker for Merck products. M. Levin has been a consultant to Merck, has served as a speaker for Merck products, and shares in the patent for ZOSTAVAX® . Acknowledgements The authors would like to thank all the study participants and staff at the study sites and the ZOSTAVAX® Protocol 014 investigators who made this study possible. ZOSTAVAX® Protocol 014 Study Group R. Cain, L. Gilderman, J. Lawless, F. Maggiacomo, M. Nunez, and B. Venkateswaralu. Contributions: Mills, Tyring, and Levin: enrollment of subjects and/or data collection, analysis and interpretation of data, and preparation of manuscript. Parrino, Li, Coll, and Stek: analysis and interpretation of data, and preparation of manuscript. Schlienger, Chan, and Silber: study concept and design, analysis and interpretation of data, and preparation of manuscript. Funding: This study was funded by Merck & Co., Inc. The sponsor formally reviewed a penultimate draft. All co-authors approved the final version of the manuscript.
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R. Mills et al. / Vaccine 28 (2010) 4204–4209 [6] Recommendations of the Advisory Committee on Immunization Practices. Centers for Disease Control, Prevention of herpes zoster. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5705a1.htm?s cid= rr5705a1 e [accessed 20.08.08]. [7] Centers for Disease Control. National Immunization Program, Adult Immunization Schedule. Available from: http://www.cdc.gov/nip/recs/adultschedule.htm [accessed 27.11.06]. [8] Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005;352:2271–84. [9] Levin MJ, Oxman MN, Zhang JH, Johnson GR, Stanley H, Hayward AR, et al. Varicella-zoster virus-specific immune responses in elderly recipients of a herpes zoster vaccine. J Infect Dis 2008;197:825–35. [10] Hammond O, Wang Y, Green T, Antonello J, Kuhn R, Motley C, et al. The optimization and validation of the glycoprotein ELISA assay for quantitative varicella-zoster virus (VZV) antibody detection. J Med Virol 2006;78:1679–87. [11] Long CE, Kouides RW, Peer S, LaForce FM, Whitney C, Bennett NM. Accuracy of self-report of pneumococcal vaccine status in older adults. Abstracts of the 127th American Public Health Association Meeting, November 7-11, 1999. Chicago, Illinois: American Public Health Association, 1999. p. 124.
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