Association Between Immunogenicity and Reactogenicity: A Post Hoc Analysis of 2 Phase 3 Studies With the Adjuvanted Recombinant Zoster Vaccine

Abstract

A recurrent question is whether transient reactions to vaccines translate into better immune responses. Using clinical data from 2 large phase 3 studies of the recombinant zoster vaccine, we observed a small but statistically significant association between the intensity of a frequent side effect (pain) after vaccination and immune responses to vaccination. However, despite the statistical correlation, the impact on the immune response is so small, and the immune response in individuals without pain already sufficient, that pain cannot be a surrogate marker for an appropriate immune response. Reactogenicity cannot be used to predict immunity after vaccination.

Keywords: AS01; T cells; antibodies; reactogenicity; recombinant zoster vaccine.

Figure 1.

Correlation between maximum reactogenicity scores and immunogenicity. A, Principal component (PC) analysis of reactogenicity post–dose 1 (PD1) and post–dose 2 (PD2) of recombinant zoster vaccine. The right-hand graph shows the absolute loading (importance of each variable) on PC1. There is a strong correlation between PD1 and PD2 for individual symptoms; local symptoms of redness and swelling are different from all other symptoms, whereas pain is between redness and swelling and systemic variables. The most important factors on PC1 (ie, those showing the maximum variance from zero on the PC1 axis) are pain post–dose 2 (PA2), fatigue post–dose 2 (FA2), and myalgia post–dose 2 (MY2). B, Univariate analysis showing the correlation between the reactogenicity variables PD1 or PD2, and PD2 immunogenicity (level of anti–glycoprotein E [gE] antibodies and CD4⁺ T cells). Horizontal lines represent Bonferroni-corrected threshold. The figure shows that the humoral immunogenicity profile is correlated with PA2 and MY2. The humoral and cell-mediated estimates refer to the estimated change in antibody concentrations/CD4⁺ counts with reactogenicity score. C, Immune response according to pain level. Upper panel shows anti-gE antibodies and lower panel shows CD4⁺ T cells. The x-axis shows distribution of maximum pain score (no pain, grade 1, grade 2, or grade 3) at each time point. At each time point there is a visible trend, albeit low in magnitude, for CD4⁺ T-cell responses to be higher in participants who experienced more pain PD2. The same trend is much less apparent for humoral responses. D, Multivariate mixed model of the average of all maximum pain scores vs level of anti-gE antibodies and CD4⁺ T cells with adjustment for age and baseline anti-gE antibody level. Model input parameters are presented in terms of the estimate of the effect size, standard error, 95% confidence interval, and P value. The T value is the ratio between the estimate and the standard error. Maximum pain score PD2 is significantly correlated with postvaccination anti-gE antibody levels, whereas the correlation between reactogenicity PD2 and postvaccination cell-mediated immunity is not significant. Abbreviations: 3/14/26/38 months, 3/14/26 or 38 months post–dose 2; CMI, cell-mediated immunity; ELISA, enzyme-linked immunosorbent assay; FA1/2, fatigue post–dose 1 and post–dose 2; gE, glycoprotein E; GI1/2, gastrointestinal symptoms post–dose 1 and post–dose 2; HE1/2, headache post–dose 1 and post–dose 2; MY1/2, myalgia post–dose 1 and post–dose 2; PA1/2, pain post–dose 1 and post–dose 2; PC1/PC2, principal components 1 and 2; Q1/Q3, interquartile range; RE1/2, redness post–dose 1 and post–dose 2; SH1/2, shivering post–dose 1 and post–dose 2; SW1/2, swelling post–dose 1 and post–dose 2; TE1/2, raised body temperature post–dose 1 and post–dose 2.