Weaver, Scott (sweaver@utmb.edu)2024-07-152024-07-152024-082024-08August 202https://hdl.handle.net/2152.3/12414During the recent yellow fever (YF) epidemics in Brazil, human cases were attributed only to spillover infections via sylvatic mosquito transmission. Despite YF virus (YFV) transmission in major urban centers with insufficient vaccination coverage and abundant populations of the domestic vector, Aedes aegypti, there was no evidence of human-amplified transmission. Furthermore, the complete historic absence of YF in Asia, despite abundant Ae. aegypti and a completely immunologically naive human population represents a longstanding epidemiological enigma. We tested the hypothesis that pre-existing, heterologous flavivirus immunity, specifically from dengue (DENV) and Zika (ZIKV) viruses, limits YFV viremia and transmission by Ae. aegypti. We infected cynomolgus macaques with DENV or ZIKV, then challenged them 6-9 months later with YFV. We then measured viremia and disease, and allowed Ae. aegypti mosquitoes to feed during peak macaque viremia. Although prior heterologous immunity had variable effects on disease, DENV and ZIKV immunity consistently suppressed YFV viremia, leading to a significant reduction in Ae. aegypti infection and a lack of transmission potential. Next, we utilized an interferon α/β receptor knock-out mouse model to determine the role of pre-existing DENV-2 and ZIKV immunity in YF virus infection, and to determine mechanisms of cross-protection. We utilized African and Brazilian YF strains and found that DENV-2 and ZIKV immunity significantly suppresses YFV viremia in mice but did not consistently protect against disease outcome. Cross-protection appears to be mediated mainly by humoral immune responses. These studies underscore the importance to re-assess the risk of YF outbreak accounting for prior immunity from flaviviruses that are endemic.application/pdfEnglishYellow FeverDengueZikaCross-protectionFlavivirus ImmunityThesis2024-07-15