Chemical vaccines for malaria, long-acting causal prophylactic drugs given by injection, are recognized as a promising new approach for longterm protection against infection. Such therapy would benefit populations at risk, not just those living in endemic areas but also the tens of millions of nonimmune travellers who visit these areas every year. International malaria control efforts, though highly successful appear to have slowed, and the availability of a chemical vaccine would provide a new tool to reduce seasonal transmission and sustain already-accomplished malaria control. Broad-spectrum antiprotozoal atovaquone is used at high dose to prophylax and treat immunocompromised patients for Pneumocystis jirovecii pneumonia or toxoplasmosis; atovaquone, at substantially lower dose and in fixed combination with proguanil is also used for causal prophylaxis and treatment of malaria. In some 20 years of use, atovaquone alone and atovaquone+proguanil have track records of safety and efficacy in humans. We previously established that nanoparticulate atovaquone given intramuscularly could protect mice for up to 4 weeks against a lethal sporozoite challenge. In more recent preliminary studies an alternative formulation of atovaquone protects for at least 8 weeks, the longest interval tested, with no behavioral evidence of muscle toxicity. The proposed work is designed to extend these preliminary findings, by establishing the longest interval of protection, obtaining atovaquone levels at the time of challenge so as to complete pharmacokinetic-pharmacodynamic analyses, and conducting a preliminary histopathological examination of muscle at the injection site. Alone among the malaria prophylaxis drugs, atovaquone is administered in combination with a second drug, proguanil. Unequivocally required for treatment of established erythrocytic infection, the necessity of proguanil for causal prophylaxis of malaria has not been well- examined. Proposed experiments in mice will evaluate the contribution of proguanil to causal protection against challenge by atovaquone-sensitive and atovaquone-resistant sporozoites. This information will provide a sound basis for deciding whether an atovaquone chemical vaccine must also include proguanil. Experiments in this project will lay the foundation for a Phase 1/2a clinical trial of atovaquone with or without proguanil, and they furnish a template for preclinical evaluation of chemical vaccine candidates in the future.

Atovaquone and proguanil, taken orally in a combination pill, are commonly prescribed to prevent malaria. This project will evaluate the ability of atovaquone injections to protect against malaria transmitted from mosquitoes, and will assess the advantage, if any, of adding orally dosed proguanil. Treatments will be tested against drug sensitive and drug resistant malaria parasites.