Impact of vector-borne infections
Insect-borne diseases are responsible for over 1 million deaths every year. Mosquito-borne infections make up many of these deaths, with malaria accounting for over 500 million cases every year and dengue for over 20 million cases.
Triatomine bugs, Tsetse flies, sand flies and ticks are just a few of the other insect vectors that can transmit parasitic, viral and bacterial infections, such as Chagas disease, sleeping sickness, leishmaniasis and Lyme’s disease.
With the exception of Chagas, these diseases are transmitted from the insect to the host during a blood-meal. Often residing in the mouth parts of the insect, the pathogen is commonly transferred along with the vector’s saliva. Salivary molecules therefore constitute a common link between many different vector-borne diseases. These molecules often play a role in modulating host-immune responses to assist insect feeding e.g anti-haemostatic proteins that dysregulate platelet aggregation and the blood coagulation cascade.
These immune-regulatory properties can in turn be exploited by transmitted pathogens to facilitate infection. Researchers have shown that in mice, co-inoculation of salivary proteins with parasites exacerbates the infection in comparison to inoculation with parasites alone. This has been demonstrated for example in several species of Leishmania in sand flies, Borrelia in Ixodes ticks, and numerous viruses transmitted by Aedes mosquitoes.
Consequently, salivary proteins have been explored as possible vaccine targets to not only protect against infection, but also block transmission from the host to the vector. The protective role of saliva used to immunise dogs against Leishmania is promising, however evidence to demonstrate this in mosquito-borne pathogens is conflicting. Previous exposure to mosquito saliva did not effect the infectivity nor the spread of Plasmodium berghei sporozoites injected from mosquitoes in to mice. Data surrounding mosquito saliva and arboviral transmission are even more confounding, suggesting outcomes could be specific to the pathogen and vector species.
The AGS-v vaccine
Never-the-less, recruitment for the clinical trial of a new anti-mosquito-saliva vaccine is currently underway at the National Institutes of Health, Maryland. The AGS-v vaccine is the product of a joint venture between London-based pharmaceutical company Seek and clinical research organisation hVivo, the collaboration also resulted in the creation of a new company “Imuntex”.
Rather than targeting specific pathogens, the peptide vaccine elicits an immune response to four proteins found in mosquito saliva. Hence, the vaccine could potentially protect against numerous mosquito-borne infections including malaria, dengue, zika, chikungunya and yellow fever. Thus it has been coined a Universal Mosquito-Borne Disease Vaccine.
The randomized, double-blind, Phase I study will evaluate the safety and immunogenicity of the vaccine in healthy volunteers aged 18-50. The study has two arms- the intervention; AGS-v vaccine with or without an adjuvant, and a Placebo comparator (water for injection, WFI) on both on Days 0 and 21.
Primary and other outcomes
Their primary outcomes are to 1. Assess the safety of the vaccine, 2. Measure host immune responses through total AGS-v specific immunoglobulin, as well as more specific Th1/Th2 associated markers.
The study will measure base-line and post-vaccination host immune responses to uninfected Aedes aegypti mosquito feeding, again measuring AGS-v specific total immunoglobulin, primarily IgG1, IgG3, and IgM. It will also look at the vaccine effect on the mosquitoes, their feeding habits and fecundity after feeding on the blood of vaccinated individuals. Time permitting, the researchers aim to investigate interactions between PBMCs/serum from vaccinated participants and mosquito saliva-coated Zika viruses in-vitro.
The trial is expected to finish this part of the study in the next 18 months, with the trial ending in December 2019. Considering the potential impact that such a vaccine could have against numerous infections, we eagerly await the results.