Targeting Mosquito Carboxypeptidase B Induces Immediate Metabolic Disruption and Sustained Reduction in Vector Competence

This is the authors' abstract. We don't add key points for this paper.

Malaria remains the deadliest mosquito-borne disease. Complementary interventions targeting the vectors are increasingly needed amid insecticide resistance and incomplete intervention coverage. Carboxypeptidase B (CPB), a blood-meal-induced mosquito midgut protease, is a promising transmission-blocking target, but the antibody determinants of protection and the underlying mechanisms remain poorly defined. Here we develop adeno-associated virus vaccines targeting CPB and show that a single immunization induced mosquitocidal and transmission-blocking antibodies in mice. Functional monoclonal antibodies isolated from the immunized mice inhibited CPB enzymatic activity and preferentially recognized the catalytic-pocket region. CPB blockade deprives mosquitoes of essential amino acids, including lysine and arginine, in the midgut. Supplementation of amino-acids substantially rescued the anti-vector and transmission-blocking phenotypes, supporting a causal role for impaired nutrient acquisition. Notably, transmission-blocking activity persisted after vaccine-induced antibodies were no longer detectable in the mosquito, under asynchronous challenge conditions, and was accompanied by persistent depletion of endogenous midgut CPB protein that was not restored by amino-acid supplementation. Together, our findings identified CPB as a functionally vulnerable mosquito antigen and supported a broader principle whereby essential vector physiology can be exploited to simultaneously impair vector fitness and pathogen permissiveness.