Abstract
In response to the 2016 Zika virus (ZIKV) outbreak, we developed a purified, formalin-inactivated, Alum-adjuvanted ZIKV vaccine (ZPIV) candidate that was protective in animal models and advanced to human testing in four phase 1 clinical trials. We have previously reported the interim analysis of three trials. Here we present the final analysis of a phase 1, placebo controlled, double-blind trial of ZPIV. Seventy-five flavivirus-naïve adults—divided into three groups of 25—were randomly assigned to receive three 5μg doses of ZPIV or placebo at days 1, 29 and 196. Group 1 only received ZPIV, while Groups 2 and 3 first received either licensed Japanese encephalitis (IXIARO®) or yellow fever (YF-VAX®) vaccine two-months prior to receiving ZPIV. Immune responses were assessed by a live-virus microneutralization assay. ZPIV was well tolerated across groups. Group 1 exhibited neutralizing antibody (nAb) geometric mean titers (GMT) of 101 and 511 after the 2nd and 3rd doses. GMTs in Groups 2 and 3 were significantly lower at 11.8 and 6.6 after two doses, and 174 and 79 after the 3rd dose. There were no differences in binding antibody titers or in antibody affinity maturation across groups. These data suggest that flavivirus vaccine priming of B cells directed antibodies toward non-neutralizing epitopes and that decline in ZIKV nAb titers did not reflect overall decrements in B cell responses. Other studies have shown prior dengue virus infection boosts subsequent ZIKV responses. These results indicate the interplay of flavivirus immunity is contextual and likely specific to the mode and timing of antigen presentation. More studies are needed to investigate these factors, so as to optimize the rational use of vaccines against co-endemic flaviviruses.