Comparative Antibody Responses to the Live-Attenuated and Recombinant Herpes Zoster Vaccines

Abstract

Two herpes zoster (HZ) vaccines licensed in the United States are recommended by the Advisory Committee on Immunization Practices (ACIP): (i) live-attenuated vaccine (ZVL) using vOka strain varicella-zoster virus (VZV) and (ii) recombinant adjuvanted vaccine (RZV) containing recombinant varicella-zoster virus (VZV) glycoprotein E (gE). Two phase 3 clinical trials of RZV led the Advisory Committee on Immunization Practices (ACIP) to recommend it with preferred status. VZV T cell-mediated immunity (CMI), but not humoral immunity, is considered essential for protection against HZ. Published studies of humoral immunity focused on VZV-specific IgG concentration. To complement reports comparing the CMI responses to these vaccines, we compared humoral responses in ZVL and RZV recipients, emphasizing functional qualities (avidity and neutralization). Baseline avidities to a VZV glycoprotein mixture (gp) were near the upper limit of detection, but avidity to gE was much lower. Small increases in gp avidity were observed for both RZV and ZVL vaccination (19 and 12 avidity index units [AIU], respectively). RZV boosted both gE avidity and VZV neutralizing antibody significantly more than ZVL (mean gE avidity boost, 47 AIU versus 22 AIU; mean neutralizing antibody boost, 22-fold versus 8-fold). Increases in neutralizing antibodies strongly correlated with gE avidity increases (r = 0.5) and moderately with gp avidity increases (r = 0.23). After 1 year, 81% of RZV recipients and only 18% of ZVL recipients retained >50% of their peak avidity boosts. These results are consistent with the CMI responses to these vaccines: RZV responses are skewed to long-term memory, whereas ZVL preferentially induces transient effector responses.IMPORTANCE These observations further distinguish the immunogenicity and duration of the immune response of the two vaccines. In addition, measurements of functional humoral immunity (IgG avidity and neutralizing antibody) in response to zoster immunization, alone or combined with other immune markers, might contribute to practical in vitro correlates of protection. Combined with previous observations of the cell-mediated response to these vaccines, this study suggests that vaccine development will benefit from more expansive and granular assessments of acquired immunity during early phase 1 immunogenicity trials.

Keywords: avidity; herpes zoster; humoral immunity; neutralizing antibodies; vaccine.

FIG 1

Baseline and peak postimmunization VZV IgG levels measured by gpELISA and gE ELISA. (A) Participants with no previous shingles vaccination history, subdivided into two age groups. (B) Participants who received one dose of ZVL at least 5 years prior to study entry. Blue figures represent gpELISA, and green figures represent gE ELISA. Box-and-whisker plots subdivide the respondents into quartiles, with the colored boxes representing the middle 50% of respondents and the whiskers representing the extreme 50% of respondents. Baseline horizontal lines represent titers across all 6 groups and are indicated for gpELISA (blue) and gE ELISA (green).

FIG 2

Comparison of preimmunization (day 0) avidity to gp antigens and purified gE antigen. Blue sector, >60 AIU; pink sector, ≤60 AIU.

FIG 3

Comparison of day 0 gp and gE avidities with peak postimmunization avidities. Results are displayed in quartiles as per Fig. 1. (A) Day 0 avidities among participants with no previous shingles immunization. (B) Peak boosts in avidity among previously unimmunized persons. (C) Day 0 avidities among participants previously immunized with ZVL. (D) Peak boosts in avidity among participants previously immunized with RZV.

FIG 4

Residual gE avidity boost, 1 year postimmunization. Purple plots represent the percentage of peak avidity retained for ZVL recipients; pink plots represent the percentage of peak avidity retained for RZL recipients.

FIG 5

Relative level of boosting of VZV neutralizing antibody. Red bars indicate the number of participants who failed to develop at least a 4-fold increase in NA. Green bars indicate the total number of participants who developed boosts in NA greater than or equal to the indicated fold boost. As such, the magnitude of boosting declines with each successive boost level.

FIG 6

Comparison of boosting in gp avidity, gE avidity, and neutralizing antibody titer among study participants. Ordinates for avidity boosting and NA antibody boosting were scaled to roughly reflect the maximum observed responses in the two categories of measurements.