A Zika virus vaccine with E protein fusion loop mutations protects via CD8+ T cells

This is the authors' abstract. We don't add key points for this paper.

There are currently no effective vaccines against Zika virus (ZIKV). Candidate vaccines target the ZIKV envelope (E) protein, the major target of anti-ZIKV neutralizing antibodies (nAbs). Here we utilized DNA and RNA platforms to compare virus-like particle vaccines with premembrane (prM) and E expressed either in the wild-type form (Z-prM/E-WT) or with fusion loop (FL) mutations (Z-prM/E-FLM), which limit antibody-dependent enhancement of infection. Both vaccines induced effective protection against infection in C57BL/6 Ifnar1-/- mice but with different mechanisms. The Z-prM/E-WT vaccine elicited nAbs against both immature and mature ZIKV virions, whereas mutations in the Z-prM/E-FLM vaccine impaired prM cleavage, resulting in a suboptimal antibody response failing to neutralize mature virions. Serum transfer and T cell depletion experiments in two mouse models demonstrated that CD8+ T cells were necessary and sufficient for short-term protection by Z-prM/E-FLM, whereas both antibodies and CD8+ T cells contributed to Z-prM/E-WT-induced long-term protection. Our results identify unexpected roles for CD8+ T cells in protection mediated by predominantly nAb-directed prM/E-based ZIKV vaccines. They also reveal that protection conferred by antibody-centric ZIKV vaccines that rely on CD8+ T cells alone is transient, whereas protection afforded by those that elicit both protective antibodies and CD8+ T cells is durable.