Varicella-zoster virus-specific immune responses in elderly recipients of a herpes zoster vaccine

M J Levin, M N Oxman, J H Zhang, G R Johnson, H Stanley, A R Hayward, M J Caulfield, M R Irwin, J G Smith, J Clair, I S F Chan, H Williams, R Harbecke, R Marchese, S E Straus, A Gershon, A Weinberg, Veterans Affairs Cooperative Studies Program Shingles Prevention Study Investigators, Michael N Oxman, Robert Arbeit, Patricia Barry, Chris Beisel, Kathy D Boardman, Cindy L Colling, Larry Davis, Lawrence Gelb, Anne A Gershon, Anthony R Hayward, Michael R Irwin, Gary R Johnson, Myron J Levin, Peter N Peduzzi, Kenneth Schmader, Michael S Simberkoff, Stephen E Straus, Adriana Weinberg, Heather M Williams, Jeffrey L Silber, Paula Annunziato, Christina Y Chan, Ivan S F Chan, L E Davis, C A Kauffman, S K Keay, A R Marques, N E Soto, P Brunell, J W Gnann, R Serrao, D J Cotton, R P Goodman, R D Arbeit, C T Pachucki, M J Levin, K E Schmader, W A Keitel, R N Greenberg, V A Morrison, P F Wright, M R Griffin, M S Simberkoff, S S Yeh, Z Lobo, M Holodniy, J Loutit, R F Betts, L D Gelb, G E Crawford, J Guatelli, P A Brooks, K M Neuzil, J F Toney, M J Levin, M N Oxman, J H Zhang, G R Johnson, H Stanley, A R Hayward, M J Caulfield, M R Irwin, J G Smith, J Clair, I S F Chan, H Williams, R Harbecke, R Marchese, S E Straus, A Gershon, A Weinberg, Veterans Affairs Cooperative Studies Program Shingles Prevention Study Investigators, Michael N Oxman, Robert Arbeit, Patricia Barry, Chris Beisel, Kathy D Boardman, Cindy L Colling, Larry Davis, Lawrence Gelb, Anne A Gershon, Anthony R Hayward, Michael R Irwin, Gary R Johnson, Myron J Levin, Peter N Peduzzi, Kenneth Schmader, Michael S Simberkoff, Stephen E Straus, Adriana Weinberg, Heather M Williams, Jeffrey L Silber, Paula Annunziato, Christina Y Chan, Ivan S F Chan, L E Davis, C A Kauffman, S K Keay, A R Marques, N E Soto, P Brunell, J W Gnann, R Serrao, D J Cotton, R P Goodman, R D Arbeit, C T Pachucki, M J Levin, K E Schmader, W A Keitel, R N Greenberg, V A Morrison, P F Wright, M R Griffin, M S Simberkoff, S S Yeh, Z Lobo, M Holodniy, J Loutit, R F Betts, L D Gelb, G E Crawford, J Guatelli, P A Brooks, K M Neuzil, J F Toney

Abstract

Background: A double-blind, placebo-controlled trial that involved 38,546 subjects > or =60 years old demonstrated efficacy of a high-potency live-attenuated Oka/Merck varicella-zoster virus (VZV) vaccine. The trial included an immunology substudy to determine the relationship of VZV-specific immune responses to vaccination and clinical outcome.

Methods: The immunology substudy enrolled 1395 subjects at 2 sites where blood samples obtained prior to vaccination, at 6 weeks after vaccination, and at 1, 2, and 3 years thereafter were tested for VZV-specific cell-mediated immunity (VZV-CMI) by gamma-interferon ELISPOT and responder cell frequency assays and for VZV antibody by glycoprotein ELISA.

Results: VZV-CMI and VZV antibodies were significantly increased in vaccine recipients at 6 weeks after vaccination. The vaccine-induced increases in VZV-CMI persisted during the 3 years of follow-up, although their magnitude decreased over time. The magnitude of these VZV-specific immune responses was greater in subjects 60-69 years old than in subjects > or =70 years old.

Conclusions: The zoster vaccine induced a significant increase in VZV-CMI and VZV antibody. The magnitude and duration of the boost in VZV-CMI in vaccine recipients and the relationship of this boost to age paralleled the clinical effects of the vaccine observed during the efficacy trial. These findings support the hypothesis that boosting VZV-CMI protects older adults against herpes zoster and postherpetic neuralgia.

Figures

Figure 1
Figure 1
Varicella-zoster virus–specific immune responses at baseline (i.e., prior to vaccination), according to age group. Responder cell frequency (RCF) value, no. of responding cells per 105 peripheral blood mononuclear cells (PBMCs); ELISPOT counts, no. of spot-forming cells per 106 PBMCs; glycoprotein ELISA (gpELISA) titer, gpELISA units/mL. Error bars 95% confidence intervals for the geometric mean. N no. of subjects who had blood samples collected in the age group. P values for differences between age groups are shown below the graphs
Figure 2
Figure 2
Varicella-zoster virus–specific immune responses, according to time since randomization. Responder cell frequency (RCF) value, no. of responding cells per 105 peripheral blood mononuclear cells (PBMCs); ELISPOT count, no. of spot-forming cells per million PBMCs; glycoprotein ELISA (gpELISA) titer, gpELISA units/mL. Error bars 95% confidence intervals for the geometric mean. N no. of subjects who had blood samples obtained within the time interval; V no. of subjects in the vaccine group for each time interval; P no. of subjects in the placebo group for each time interval. Data from subjects who developed herpes zoster were censored from subsequent time point analyses. The immune response at each time is the observed geometric mean of the responses to each assay for each treatment group. A total of 409 ELISPOT assays were excluded (6.1%); 154 were from baseline; 133, 52, 30, and 40 are from week 6, year 1, year 2, and year 3, respectively
Figure 3
Figure 3
Estimated percentage increase in varicella-zoster virus–specific immune responses in vaccine recipients and placebo recipients, according to time after vaccination. The percentage increase in immune response in vaccine recipients, relative to placebo recipients, at each time is the estimated geometric mean percentage increase from the placebo recipients for each assay. The estimated increase is adjusted for age, sex, and study site. Error bars 95% confidence intervals for geometric mean. N no. of subjects who had blood samples obtained within the time interval; V no. of subjects in the vaccine group for each time interval; P no. of subjects in the placebo group for each time interval. Data from subjects who developed herpes zoster were censored from subsequent time points. None of the immune responses at baseline differed by treatment. At baseline, the responses of vaccine and placebo recipients did not differ significantly (P=.489 to .854). After baseline, all responses of the vaccine recipients differed significantly from those of the placebo recipients (P⩽.001 to .001)
Figure 4
Figure 4
Varicella-zoster virus–specific immune responses at 6 weeks after vaccination, according to age group. Responder cell frequency (RCF) value, no. of responding cells per 105 peripheral blood mononuclear cells (PBMCs); ELISPOT counts, no. of spot-forming cells per million PBMCs; glycoprotein ELISA (gpELISA) titer, gpELISA units/mL. Error bars 95% confidence intervals for geometric mean. N no. of subjects who had blood samples obtained within the time interval; V no. of subjects in the vaccine group for each age range; P no. of subjects in the placebo group for each age range. Among vaccinees there was a significant linear age effect (age slope) for the week 6 responses as measured by RCF and ELISPOT (P<.001). There was a lesser association between age and gpELISA response (slope was 1% per year of age; P=.034). When the >79 age group was excluded (n=62; no boost in gpELISA titer in vaccine recipients), the slope was not significant (P=.11)
Table 1
Table 1
Demographic and clinical characteristics of subjects at baseline
Table 2
Table 2
Varicella-zoster virus–specific immune responses at 6 weeks after vaccination in relation to baseline response
Table 3
Table 3
Comparison of varicella-zoster virus (VZV)-specific immune responses in immunology substudy subjects who developed herpes zoster (HZ) and those who did not

Source: PubMed

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