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Abstract During the recent yellow fever (YF) epidemics in Brazil, human cases were attributed 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 historic absence of YF in Asia, despite abundant Ae. aegypti and an immunologically naive human population, is unexplained. 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. Despite no statistical difference due to a small sample size, the suppression in viremia led to a significant reduction in Ae. aegypti infection and a lack of transmission potential. These results support the hypothesis that, in DENV- and ZIKV-endemic regions such as South America and Asia, human flavivirus immunity suppresses YFV human amplification potential, reducing the risk of urban outbreaks.

Ilhéus virus (ILHV)(Flaviviridae:Orthoflavivirus) is an arthropod-borne virus (arbovirus) endemic to Central and South America and the Caribbean. First isolated in 1944, most of our knowledge derives from surveillance and seroprevalence studies. These efforts have detected ILHV in a broad range of mosquito and vertebrate species, including humans, but laboratory investigations of pathogenesis and vector competence have been lacking. Here, we develop an immune intact murine model with several ages and routes of administration. Our model closely recapitulates human neuroinvasive disease with ILHV strain- and mouse age-specific virulence, as well as a uniformly lethal Ifnar−/− A129 immunocompromised model. Replication kinetics in several vertebrate and invertebrate cell lines demonstrate that ILHV is capable of replicating to high titers in a wide variety of potential host and vector species. Lastly, vector competence studies provide strong evidence for efficient infection of and potential transmission by Aedes species mosquitoes, despite ILHV's phylogenetically clustering with Culex vectored flaviviruses, suggesting ILHV is poised for emergence in the neotropics.

The complete lack of yellow fever virus (YFV) in Asia, and the lack of urban YFV transmission in South America, despite the abundance of the peridomestic mosquito vector Aedes (Stegomyia.) aegypti is an enigma. An immunologically naïve population of over 2 billion resides in Asia, with most regions infested with the urban YF vector. One hypothesis for the lack of Asian YF, and absence of urban YF in the Americas for over 80 years, is that prior immunity to related flaviviruses like dengue (DENV) or Zika virus (ZIKV) modulates YFV infection and transmission dynamics. Here we utilized an interferon α/β receptor knock-out mouse model to determine the role of pre-existing dengue-2 (DENV-2) and Zika virus (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 may or may not protect relative to disease outcomes. Cross-protection appears to be mediated mainly by humoral immune responses. These studies underscore the importance of re-assessing the risks associated with YF outbreak while accounting for prior immunity from flaviviruses that are endemic.

Anosmia, a total or partial loss of the ability to smell, is one of the most frequently documented sequelae of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Persistent anosmia is associated with a decrease in quality of life. Here, we assess the impact of virus lineage and vaccination status on anosmia development in the golden Syrian hamster model. To characterize anosmia driven by current variants, we assessed olfactory function in hamsters infected with SARS-CoV-2 lineages A, BA.2, BA.5, BQ.1, and BQ.1.1 using a buried food detection test. We found that significant anosmia occurs upon infection with all variants with a significant correlation between disease severity and degree of anosmia. Moreover, we found that vaccination with either the Pfizer (BNT16b2) or Moderna (mRNA-1273) mRNA vaccines does not protect against anosmia, despite protection against severe disease.

Ilheus virus (ILHV) is a mosquito-borne flavivirus circulating throughout Central and South America and the Caribbean. It has been detected in several mosquito genera including Aedes and Culex, and birds are thought to be its primary amplifying and reservoir host. Here, we describe the genomic and morphologic characterization of ten ILHV strains. Our analyses revealed a high conservation of both the 5′- and 3′-untranslated regions but considerable divergence within the open reading frame. We also showed that ILHV displays a typical flavivirus structural and genomic organization. Our work lays the foundation for subsequent ILHV studies to better understand its transmission cycles, pathogenicity, and emergence potential.

The Delta variant of SARS-CoV-2 has caused many breakthrough infections in fully vaccinated individuals. While vaccine status did not generally impact the number of viral RNA genome copies in nasopharyngeal swabs of breakthrough patients, as measured by Ct values, it has been previously found to decrease the infectious viral load in symptomatic patients. We quantified the viral RNA, infectious virus, and anti-spike IgA in nasopharyngeal swabs collected from individuals asymptomatically infected with the Delta variant of SARS-CoV-2. Vaccination decreased the infectious viral load, but not the amount of viral RNA. Furthermore, vaccinees with asymptomatic infections had significantly higher levels of anti-spike IgA in their nasal secretions compared to unvaccinated individuals with asymptomatic infections. Thus, vaccination may decrease the transmission risk of Delta, and perhaps other variants, despite not affecting the amount of viral RNA measured in nasopharyngeal swabs.

Yellow fever virus (YFV) is a mosquito-borne flavivirus circulating throughout the tropical and sub-tropical regions of Africa and South America. It is responsible for an estimated 30,000 deaths annually, and while there is a highly successful vaccine, coverage is incomplete, and there is no approved treatment for YFV infection. Despite advancements in the field, animal models for YFV infection remain scarce, and care must be taken to select an appropriate model for a given hypothesis. Small animal models require either adapted YFV strains or immunocompromised hosts. Non-human primates (NHPs) recapitulate human disease, but they require specialized facilities and training, are often in short supply and cost-prohibitive, and can present ethical concerns. The limitations in studying the mosquito vectors for YFV infection include inconsistency in the laboratory environment, the requirement for a high containment insectary, and difficulty in maintaining sylvatic mosquitoes. In this review, we discuss the roles of animal models and arthropod vector studies in understanding epidemic emergence.