Researchers at the La Jolla Institute for Immunology have shown that an experimental Zika virus vaccine can protect mice through CD8+ T cells alone, without reliance on virus-neutralising antibodies, a finding with significant implications for the development of vaccines against Zika and related orthoflaviviruses. The study is published in Nature Microbiology.
The absence of approved Zika vaccines is partly attributable to a phenomenon called antibody-dependent enhancement (ADE). Zika virus is closely related to dengue virus, and antibodies raised against one can cross-react with the other. When such antibodies bind a virus without neutralising it, they can facilitate viral entry into immune cells, potentially worsening infection. This risk has made antibody-based vaccine strategies for orthoflaviviruses particularly challenging.
To investigate an alternative approach, the research team compared two experimental vaccines in mice susceptible to Zika infection. Both were built around the virus’s outer coat proteins. One retained the natural protein structure, while the other incorporated mutations in the fusion loop, the region responsible for generating most of the cross-reactive antibodies associated with ADE.
The unmodified vaccine generated both antibody and T cell responses, with transferred CD8+ T cells from vaccinated animals providing measurable protection when introduced into unvaccinated mice. The fusion-loop mutant vaccine produced a more unexpected result: its antibodies failed to protect unvaccinated recipients, but its CD8+ T cell response alone conferred protection, confirming a T cell-mediated mechanism.
However, this protection was not durable. By twelve weeks after the final dose, mice vaccinated with the fusion-loop mutant showed no advantage over unvaccinated animals, while those given the unmodified vaccine remained protected. The findings indicate that modifications intended to reduce ADE risk inadvertently compromised long-term immune memory.
The researchers are now investigating strategies to generate durable T cell responses, with the broader goal of developing a pan-orthoflavivirus vaccine effective against multiple related viruses simultaneously.
Source: La Jolla Institute for Immunology. A Zika virus vaccine with E protein fusion loop mutations protects via CD8+ T cells. Nature Microbiology (2026). DOI: 10.1038/s41564-026-02465-6
