Arthropod-borne viruses (arboviruses) present a substantial threat to human and animal health worldwide. They are transmitted by hematophagous arthropods, in which mosquitoes are one of the main transmitters. The mosquito specie, Aedes aegypti, is the primary mosquito vector of several widely spread arboviruses as zika, dengue or West Nile viruses. Mosquitoes transmit these pathogens by inoculating virus-infected saliva into host skin during probing and feeding. This saliva contains over one hundred unique proteins and these proteins have diverse functions, including facilitating blood feed. Some of these proteins are known to enhance infectivity and pathogenesis in Zika and other arboviruses by modulating immune responses, and the development of blocking therapies against them could be a good approach to reduce infectivity and pathogenesis in the host. In addition, focusing on mosquito proteins as vaccine targets can overcome the problems associated with the use of viral antigens as a vaccine targets, due to their high variability. In this proposal, we will develop a novel transmission-blocking vaccine against Zika virus (ZIKV) by targeting A. aegypti bacteria responsive protein 1 (AgBR1) and A. aegypti neutrophil stimulating factor 1 (NeSt1) salivary gland protein. Using a yeast surface display screen, we identified a set of A. aegypti salivary proteins that react with sera from mice repeatedly bitten by A. aegypti mosquitoes. Passive immunization with antiserum against two of these proteins, AgBR1 and NeSt1, resulted in significantly more survival in mice infected with ZIKV by mosquito bite. Simultaneous passive immunization with both antisera demonstrated a synergy resulting in higher survival than expected from the individual treatments. Based on these results, in this proposal we intend to carefully examine the protective effects of blocking the mosquito AgBR1 and NeSt1 proteins in preventing severe mosquito-borne ZIKV infection in mice. We will develop a strategy for actively immunizing mice against both proteins towards the development of a vaccine for use in humans. The success of this approach also offers a functional paradigm for developing vaccines against other flaviviruses and other arthropod- borne pathogens of medical importance.
Public Health Relevance Statement: Mosquito-borne viruses present a substantial threat to human and animal health worldwide. Some mosquito saliva proteins are known to enhance infectivity and pathogenesis of Zika and other arboviruses by modulating immune responses. Here, we propose to develop a vaccine candidate against the mosquito salivary proteins NeSt1 and AgBR1 to prevent Zika virus transmission in a mouse model.
Project Terms: Active Immunization; Adjuvant; Aedes; Aluminum Hydroxide; Animal Model; Animals; Antibodies; Antibody Response; Arboviruses; arthropod-borne; Arthropods; Bacteria; base; Bite; Blood; Cells; Culicidae; Dengue; Dengue Virus; Development; Dose; Drosophila genus; experimental study; feeding; Flavivirus; glycosylation; Goals; Health; Human; Immune response; Immune Sera; Immunity; Immunization; Immunize; Individual; Infection; Insecta; Mediating; Medical; Methods; mortality; mosquito-borne; mouse model; Mus; neutrophil; novel; Passive Immunization; pathogen; Pathogenesis; Phase; phase 2 study; Physiological; Post-Translational Protein Processing; prevent; protective effect; Proteins; Recombinant Proteins; Recombinants; Regimen; Saliva; Salivary Proteins; Schedule; Serum; Skin; Structure; Subcutaneous Injections; success; Surface; synergism; System; Time; transmission-blocking vaccine; Vaccination; vaccine candidate; vaccine development; Vaccines; vector mosquito; Viral Antigens; viral transmission; Viremia; Virus; Virus Diseases; West Nile virus; Yeasts; ZIKA; Zika Virus; ZIKV disease; ZIKV infection
