Mosquito Saliva: The Hope for a Universal Arbovirus Vaccine?

Abstract

Arthropod-borne viruses (arboviruses) are taxonomically diverse causes of significant morbidity and mortality. In recent decades, important mosquito-borne viruses such as West Nile, chikungunya, dengue, and Zika have re-emerged and spread widely, in some cases pandemically, to cause serious public health emergencies. There are no licensed vaccines against most of these viruses, and vaccine development and use has been complicated by the number of different viruses to protect against, by subtype and strain variation, and by the inability to predict when and where outbreaks will occur. A new approach to preventing arboviral diseases is suggested by the observation that arthropod saliva facilitates transmission of pathogens, including leishmania parasites, Borrelia burgdorferi, and some arboviruses. Viruses carried within mosquito saliva may more easily initiate host infection by taking advantage of the host's innate and adaptive immune responses to saliva. This provides a rationale for creating vaccines against mosquito salivary proteins, rather than against only the virus proteins contained within the saliva. As proof of principle, immunization with sand fly salivary antigens to prevent leishmania infection has shown promising results in animal models. A similar approach using salivary proteins of important vector mosquitoes, such as Aedes aegypti, might protect against multiple mosquito-borne viral infections.

Figure 1.

Mosquito saliva-based vaccine: proposed mechanism of action. (A) A virus-infected mosquito seeks a blood meal while injecting salivary proteins and viral particles from its salivary glands. The bite trauma coupled with the salivary effects cause vascular leakage, edema, mast cell degranulation, and release of host Th2-predominant cytokines. As the virus infects stromal cells in the dermis, neutrophils are recruited to the dermis, which in turn release chemokines that attract myeloid cells that become infected, and which traffic virus to the lymph nodes, leading to systemic infection. (Note: This scenario is based on evidence primarily derived from dengue virus-infected mice using natural transmission models, as cited within text.) (B) Upon inoculation with immunodominant synthetic salivary peptides, antigen-presenting cells such as dendritic cells can take them up and interact with CD4⁺ T cells to prime an immune response upon re-exposure to mosquito saliva. It is not clear what role CD8⁺ T cells play in this milieu. (C) Upon challenge with a virus-infected mosquito, the host may mount a rapid response to the saliva via skin-resident memory CD4 T cells. The saliva is then unable to immunomodulate the host immune response towards a Th2 response, but the host can mount a Th1-type antiviral response with interferon release by CD4⁺ T cells and macrophage activation. Given that the virus is a “bystander” because the response is primed to salivary antigens, systemic infection may not succeed because of one of the following scenarios: (1) the virus is unable to infect myeloid cells and replicate; (2) the virus is unable to infect cellular targets such as macrophages or monocyte-derived dendritic cells that will traffic virus to draining lymph nodes; or (3) the virus is phagocytosed by the activated macrophage. Further research is needed to determine the exact mechanism of action. Abbreviations: APC, antigen presenting cell; IFN, interferon; IL, interleukin.