Varicella-zoster virus-specific immune responses to herpes zoster in elderly participants in a trial of a clinically effective zoster vaccine

Abstract

Background: The objectives of this study were to evaluate the association between varicella-zoster virus (VZV)-specific humoral and cell-mediated immunity (CMI) to herpes zoster (HZ) and protection against HZ morbidity and to compare immune responses to HZ and zoster vaccine.

Methods: In 981 elderly persons who developed HZ during a zoster vaccine efficacy trial (321 vaccinees and 660 placebo recipients) and 1362 without HZ (682 vaccinees and 680 placebo recipients), CMI was measured by VZV responder cell frequency and interferon-gamma enzyme-linked immunospot, and antibodies were measured by VZV enzyme-linked immunosorbent assay against affinity-purified VZV glycoproteins (gpELISA).

Results: Robust VZV CMI at HZ onset correlated with reduced HZ morbidity, whereas VZV gpELISA titers did not. Three weeks after HZ onset, gpELISA titers were highest in those with more severe HZ and were slightly increased in placebo recipients (compared with zoster vaccine recipients) and in older individuals. VZV CMI responses to HZ were similar in zoster vaccine and placebo recipients and were not affected by demographic characteristics or antiviral therapy, except for responder cell frequency at HZ onset, which decreased with age. When responses to zoster vaccine and HZ could be compared, VZV CMI values were similar, but antibody titers were lower.

Conclusions: Higher VZV CMI at HZ onset was associated with reduced HZ severity and less postherpetic neuralgia. Higher antibody titers were associated with increased HZ severity and occurrence of postherpetic neuralgia. HZ and zoster vaccine generated comparable VZV CMI.

Figures

Figure 1

Diagram of the Shingles Prevention Study, Immunology Substudy, and distribution of herpes zoster (HZ) cases. The Immunology Substudy included a group of subjects at clinical sites where an immunology laboratory (IL) was located. Subjects with HZ enrolled in the Immunology Substudy are also included in the total count of HZ cases at the IL sites. Likewise, subjects with non-HZ rashes at IL or non-IL sites are also included in the total number of subjects without HZ (non-HZ) at their respective sites; non-IL sites are clinical sites at locations distant from the ILs, which shipped samples overnight to the ILs for immune response assays. Of the 32 subjects with non-HZ rash at IL sites, 14 were vaccine (Vac) and 18 were placebo (Pbo) recipients. Of the 251 subjects with non-HZ rash at non-IL sites, 124 were vaccine and 127 were placebo recipients

Figure 2

Varicella-zoster virus (VZV)–specific immune responses over time in subjects with herpes zoster (HZ). A Bars indicate geometric means and 95% confidence intervals (CIs) for absolute responder cell frequency (RCF) values, measured as responder cells per 105 peripheral blood mononuclear cells (PBMCs); enzyme-linked immunospot (ELISPOT) counts, measured as spot-forming cells per 106 PBMCs; and titers for enzyme-linked immunosorbent assay against affinity-purified VZV glycoproteins (gpELISA), measured as gpELISA units per milliliter. Data for ELISPOT responses were not available in subjects from clinical sites at locations distant from immunology laboratories (ILs) (non-IL sites) beyond week 6 after the onset of HZ rash. RCF and ELISPOT values were significantly lower in subjects from non-IL than in those from IL sites (P<.05). B Bars indicate geometric means and 95% CIs of the fold change in value for each assay at the indicated time point relative to the value measured 1 week after HZ rash onset. Numbers indicate the numbers of subjects who contributed samples at each time point at IL or non-IL sites. Fold change comparisons are not provided for ELISPOT responses beyond week 6 after HZ rash onset, because of the lack of data in the subjects from non-IL sites. RCF and ELISPOT fold changes were similar in subjects from IL and non-IL sites

Figure 3

Immune correlates with severity of illness for herpes zoster (HZ) and occurrence of postherpetic neuralgia (PHN). Data were derived from placebo recipients who developed HZ. HZ severity-of-illness scores (area under the curve for pain severity by time) were calculated using a validated HZ-specific assessment tool, the Zoster Brief Pain Inventory [17]. A and B Observed responder cell frequency (RCF) values, measured as responder cells per 105 peripheral blood mononuclear cells (PBMCs) 1 week and 3 weeks, respectively, after the onset of HZ rash, by HZ severity-of-illness scores and corresponding regression lines. Results are shown separately for subjects at clinical sites where an immunology laboratory (IL) was located (IL sites; blue) and subjects at non-IL sites (red) who developed HZ. RCF values 1 week after HZ rash onset were significantly higher in subjects from non-IL sites with less severe disease (P=.002) and also tended to be higher in subjects with less severe disease among the fewer subjects from the IL sites who developed HZ (P=.09). C and D Observed enzyme-linked immunospot (ELISPOT) counts, measured as spot-forming cells per 106 PBMCs at 1 and 3 weeks, respectively, after HZ rash onset, by HZ severity-of-illness scores and corresponding regression lines. Results are shown separately for subjects at IL and non-IL sites who developed HZ. ELISPOT values during the first week after HZ rash onset were significantly higher in subjects from IL (P=.05) or non-IL (P=.009) sites with less severe disease. E and F Titers for enzyme-linked immunosorbent assay (ELISA) against affinity-purified varicella-zoster virus (VZV) glycoproteins (gpELISA), measured as ELISA units per milliliter, by HZ severity-of-illness scores and corresponding regression lines during the first and third weeks, respectively, after HZ rash onset. gpELISA titers are shown for subjects at all sites. G–I Geometric means and 95% confidence intervals for RCF, ELISPOT, and gpELISA values, respectively, during the first and third weeks after HZ onset in subjects who did not develop PHN (solid bars) and in those who did (hatched bars). For ELISPOT assays and RCF, data were derived from 71 subjects with PHN and 516 subjects without PHN from the non-IL sites (there were only 9 subjects with PHN at the IL sites). For gpELISA, data are shown from both IL and non-IL sites combined. gpELISA values during the third week after HZ rash onset were significantly higher in subjects with more severe disease (P<.001)

Figure 4

Effect of the zoster vaccine on varicella-zoster virus (VZV)–specific immune responses to herpes zoster (HZ). VZV cell-mediated immunity results are shown for vaccine and placebo recipients who were enrolled at clinical sites where an immunology laboratory was located and who developed HZ; titers for enzyme-linked immunosorbent assay (ELISA) against affinity-purified VZV glycoproteins (gpELISA) are for subjects with HZ at all sites. Bars indicate geometric means and 95% confidence interval (CI) at each visit of the absolute responder cell frequency (RCF) values, measured as responder cells per 105 peripheral blood mononuclear cells (PBMCs); enzyme-linked immunospot (ELISPOT) counts, measured as spot-forming cells per 106 PBMCs; and gpELISA titers, measured as ELISA units per milliliter. Numbers indicate the numbers of subjects contributing samples at each time point. There were no significant differences in RCF or ELISPOT values between vaccine and placebo recipients. gpELISA titers were significantly lower in vaccine recipients at 3 weeks and at 1 and 3 years after onset of HZ (P=.002, .025, and .012, respectively)

Figure 5

Comparison of varicella-zoster virus (VZV)–specific immune responses of placebo recipients who developed herpes zoster (HZ) with placebo recipients who did not develop HZ. Data were derived from 73 subjects who received placebo at clinical sites where an immunology laboratory (IL) was located, developed HZ, and were followed up at those sites, as well as from 680 placebo recipients without HZ who were enrolled in the Immunology Substudy and were also followed up at the IL sites. Bars indicate geometric means and 95% confidence intervals (CIs) for the absolute responder cell frequency (RCF) values, measured as responder cells per 105 peripheral blood mononuclear cells (PBMCs); enzyme-linked immunospot (ELISPOT) counts, measured as spot-forming cells per 106 PBMCs; and titers for enzyme-linked immunosorbent assay (ELISA) against affinity-purified VZV glycoproteins (gpELISA), measured as ELISA units per milliliter. Levels before rash onset for subjects without HZ were those measured at enrollment. Levels at other time points were measured after onset of HZ rash in the subjects with HZ or after enrollment in the subjects without HZ. Numbers indicate the numbers of subjects contributing samples at each time point. Subjects who developed HZ had significantly lower values for RCF (P=.001) and gpELISA titers (P=.02) but not for ELISPOT counts at the last visit before HZ onset, compared with subjects who did not develop HZ. HZ significantly increased all immune responses

Figure 6

Comparison of the varicella-zoster virus (VZV)–specific immune responses to herpes zoster (HZ) and to zoster vaccine. Data were derived from subjects with HZ at clinical sites where an immunology laboratory (IL) was located and from recipients of zoster vaccine without HZ who were enrolled in the Immunology Substudy and were also followed up at the IL sites. Bars indicate geometric means and 95% confidence intervals for absolute responder cell frequency (RCF) values, measured as responder cells per 105 peripheral blood mononuclear cells (PBMCs); enzyme-linked immunospot (ELISPOT) counts, measured as spot-forming cells per 106 PBMCs; and titers for enzyme-linked immunosorbent assay (ELISA) against affinity-purified VZV glycoproteins (gpELISA), measured as ELISA units per milliliter. Numbers indicate the numbers of subjects contributing samples at each time point. RCF values were similar at all time points after vaccination and HZ onset; the analysis of ELISPOT responses at 6 weeks was complicated by technical problems, but at 1, 2 and 3 years, responses to vaccine and HZ were similar. gpELISA titers were significantly higher after HZ onset at all time points (P<.001)