Methods: We tested the vaccine for safety and efficacy in mice using skin scarification and/or vaginal challenge models and passive transfer and analyzed the immune response.
Results: Vaccine doses of 10^5 or 10^6 pfu/ml protected 100% of female mice (n= 180) from lethal challenge using a panel of genetically diverse clinical isolates of HSV-1 and HSV-2 and protected 94 out of 95 mice from latency as measured in dorsal root ganglia by quantitative PCR for viral DNA or ex vivo viral reactivation. Male mice were also protected and no disease was observed following inoculation of SCID mice. HSV-specific Abs (1:800,000), predominantly of the IgG2 subtype, as well as CD4 and CD8 T cell responses were elicited following subcutaneous prime and boost. Passive transfer of immune serum completely protected wild-type, but not FcRγ or Fc neonatal receptor knockout mice, from subsequent lethal challenge. Immunization was associated with rapid recruitment of HSV-specific murine FcγRIV-activating IgG2 Abs into the skin or vaginal mucosa within 48 h of challenge and virus was cleared by day 5 post-challenge. In contrast, a recombinant gD protein vaccine elicited higher neutralizing Abs (1:640) compared to ΔgD (1:5), but little or no FcR activation and failed to protect against latency. To determine if a similar Ab phenotype correlated with protection against clinical disease, we assessed functionality of Abs isolated from plasma or cervicovaginal lavage (CVL) from 5 asymptomatic (≤1 outbreak/year) and 4 symptomatic (≥10 outbreaks/year) HSV-2+ women. The relative ratio of human FcγRIIIA activation to neutralization was greater for asymptomatic vs symptomatic women (7.9±9.7 vs 1.0±0.5, p=0.06) in the plasma; similar results were obtained with CVL.
Conclusion: These findings challenge the dogma that neutralizing Abs are key correlates of protection and suggest that vaccines that elicit ADCC may provide the greatest protection against HSV.
B. C. Herold,
C. Burn, None
K. Weiss, None
N. Ramsey, None
B. Weinrick, None
W. Jacobs, None