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Insect-specific flaviviruses (ISFVs) are incapable of replication in humans and have emerged as a novel and promising tool for flavivirus vaccine development. ISFV-based flavivirus vaccines have shown exceptional safety, immunogenicity, and efficacy, however, a detailed assessment of the correlates of protection and immune responses induced by these vaccines are still needed for vaccine optimization. Here, we explore the mechanisms of protective immunity induced by a previously created pre-clinical Zika virus (ZIKV) vaccine candidate, called Aripo\/Zika (ARPV\/ZIKV). In brief, immunocompromised IFN-\u03b1\u03b2R<jats:sup>-\/-<\/jats:sup> mice passively immunized with ARPV\/ZIKV immune sera experienced protection after lethal ZIKV challenge, although this protection was incomplete. ARPV\/ZIKV-vaccinated IFN-\u03b1\u03b2R<jats:sup>-\/-<\/jats:sup> mice depleted of CD4<jats:sup>+<\/jats:sup> or CD8<jats:sup>+<\/jats:sup> T-cells at the time of ZIKV challenge showed no morbidity or mortality. However, the adoptive transfer of ARPV\/ZIKV-primed T-cells into recipient IFN-\u03b1\u03b2R<jats:sup>-\/-<\/jats:sup> mice resulted in a two-day median increase in survival time compared to controls. Altogether, these results suggest that ARPV\/ZIKV-induced protection is primarily mediated by neutralizing antibodies at the time of challenge and that T-cells may play a comparatively minor but cumulative role in the protection observed. Lastly, ARPV\/ZIKV-vaccinated Tcra KO mice, which are deficient in T-cell responses, experienced significant mortality post-challenge. These results suggest that ARPV\/ZIKV-induced cell-mediated responses are critical for development of protective immune responses at vaccination. Despite the strong focus on neutralizing antibody responses to novel flavivirus vaccine candidates, these results suggest that cell-mediated responses induced by ISFV-based vaccines remain important to overall protective responses.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012566","type":"journal-article","created":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T17:39:00Z","timestamp":1728581940000},"page":"e1012566","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Humoral and T-cell-mediated responses to an insect-specific flavivirus-based Zika virus vaccine candidate"],"prefix":"10.1371","volume":"20","author":[{"given":"Danielle 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Liao","year":"2011","journal-title":"Curr Opin Immunol"},{"issue":"7","key":"ppat.1012566.ref031","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.00038-18","article-title":"Cellular and Humoral Immunity Protect against Vaginal Zika Virus Infection in Mice","volume":"92","author":"JM Scott","year":"2018","journal-title":"J Virol"},{"issue":"304","key":"ppat.1012566.ref032","doi-asserted-by":"crossref","first-page":"304ra141","DOI":"10.1126\/scitranslmed.aaa3787","article-title":"Dengue virus NS1 triggers endothelial permeability and vascular leak that is prevented by NS1 vaccination.","volume":"7","author":"PR Beatty","year":"2015","journal-title":"Sci Transl Med."},{"issue":"3","key":"ppat.1012566.ref033","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1128\/JVI.80.3.1340-1351.2006","article-title":"Antibodies against West Nile Virus Nonstructural Protein NS1 Prevent Lethal Infection through Fc \u03b3 Receptor-Dependent and -Independent 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