Correlate of immune protection against HSV-1 genital disease in vaccinated women

Abstract

Background: Previously we conducted a double-blind controlled, randomized efficacy field trial of gD-2 HSV vaccine adjuvanted with ASO4 in 8323 women. Subjects had been previously selected to be seronegative for HSV-1 and HSV-2. We found that vaccine was 82% protective against HSV-1 genital disease, but offered no significant protection against HSV-2 genital disease.

Methods: To better understand the results of the efficacy study, post-vaccination anti-gD-2 antibody concentrations from all HSV infected subjects and matched uninfected controls were measured. Three models were used to determine whether thes responses correlated with protection against HSV infection or disease. Similarly, cellular immune responses from a subset of subjects and matched controls were evaluated for a correlation with HSV protection.

Results: Antibodies to gD-2 correlated with protection against HSV-1 infection with higher antibody concentration associated with higher efficacy. Cellular immune responses to gD-2 did not correlate with protection.

Conclusions: The protection against HSV-1 infection observed in the Herpevac Trial for Women was associated with antibodies directed against the vaccine. Clinical Trials Registration NCT00057330.

Keywords: HSV vaccine; protective antibodies; vaccine efficacy.

Figure 1.

A and B, Subjects in the Case-Cohort study were classified into seven groups based on ELISA titers at month 7. The sample size of each group is displayed below the x-axis. The observed probability of HSV infection was calculated within each group and is plotted along with a 95% confidence interval band. The probability of infection was estimated using the weighted log-poisson regression model (Table 1), and is plotted as a dashed line. The proportion (and 95% CI) of subjects in the HAV arm of the RCT with infection is displayed as reference. Figure 1 panel A displays results for HSV-1 infection; panel B for HSV-2 infection.

Figure 2.

Vaccine efficacy (VE) displayed as a function of post vaccine antibody titer. The observed VE to prevent HSV-1 infection (with or without disease) was calculated within each group and is plotted along with a 95% confidence interval band. VE was also estimated from the weighted log-bin model from case-cohort study (Table 1), and is plotted as a solid line. The shaded area represents the 95% bootstrap CI.

Figures 3.

A–D, Display Cell Mediated Immune Response (per million CD4 T-cells) for four cytokines (A) CD40L (B) inf-γ (C) TNF-α (D) IL-2. Within each figure three cells on the top row display results for HSV Vaccine recipients who were HSV-1 infected, HSV-2 infected, or never infected; similarly three cells on the bottom row display results for control vaccine recipients by HSV infection status. Within each cell the CMI response at month 2 and at month 7 are displayed as box plots.

Figure 3.

Figure 4.

Displays the correlation between ELISA and CD4 cells with response to at least 2 cytokines. Although a weak correlation of antibody response and CD4 All was found, higher CD4 responses did not correlate with protection from infection.