R42AI142846

SUMMARY Arboviruses present a constant threat to human and animal health worldwide. They are transmitted by hematophagous arthropods, primarily mosquitoes. One of them, Aedes aegypti, is the primary vector of several widely spread arboviruses such as Zika, dengue and West Nile viruses, and for most of them, human-licensed vaccines do not exist or are suboptimal. These pathogens are transmitted into the host skin together with saliva during feeding. This saliva contains over one hundred unique proteins which can modulate many physiological functions, facilitating blood feeding. It has been shown that many salivary proteins enhance infectivity and pathogenesis of arboviruses by modulating immune responses at the bite site. The development of blocking therapies against them could be a good approach to reduce viral spread in the infected host. This approach may also overcome issues associated with the use of viral antigens as a vaccine targets, due to their high variability or the possibility of induction of antibody- dependent enhancement episodes. In Phase I, a proof-of-principle has been established for a novel strategy of prophylaxis, targeting one salivary protein secreted in A. aegypti saliva, AgBR1, in which passively and actively immunized immunocompromised murine models were partially protected against Zika virus transmitted via mosquito bites. The degree of protection correlated with the antibody titer reached in the immunized animals. However, the use of immunocompromised models has some limitations, such as the weakness of the antibody response, a fact that limits the maximum protection that can be achieved. In this Phase II application, we will define, optimize, and validate a vaccination regimen. We will circumvent the limitations of the immunocompromised animal model by conducting immunizations in immunocompetent murine hosts. We will test the degree of protection achieved by transferring antibodies and/or immune cells to immunocompromised mice, also studying the role of the cellular branch of the immune response against ZIKV infection, as the cellular immune response against mosquito salivary antigens is poorly understood. In addition, we will perform these vaccination studies in guinea pigs and hamsters, to demonstrate that a strong immune response against AgBR1 can be elicited in species other than mice. We will develop a guinea pig and a hamster model of Zika infection transmitted by A. aegypti mosquito bites, and we will test the immunization efficacy of our vaccine candidates. Lastly, we will analyze the potential efficacy of our vaccine against other Zika- related flaviviruses, such as DENV and WNV, with the aim to generate a pan-flaviviral vaccine candidate which could be used alone or in conjunction with pathogen-specific vaccines.NARRATIVE Zika and other related flaviviruses are responsible for human and animal infections in which the mosquito Aedes aegypti is the main vector. Some mosquito salivary components facilitate viral spread in the host. We will develop a vaccine candidate based on the A. aegypti salivary protein AgBR1 to control Zika virus infection and other related flaviviruses in the mouse model and in other rodent models such as guinea pigs and hamsters, which better resemble the human disease.