Developing a multi-component vaccine harnessing potent antibody and cellular responses against the blood-stage of Plasmodium falciparum

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PROJECT SUMMARY The malaria parasite P. falciparum continues to cause significant morbidity and mortality, with 228 million clinical cases and 405,000 deaths in 2019. With progress towards controlling malaria stalling in many high burden countries and the continuing spread of drug resistant parasites, an effective malaria vaccine is urgently needed. RTS,S, a vaccine currently under implementation, has modest efficacy (~30%) and immunity waning rapidly. Importantly, this vaccine does not target the disease-causing forms of the parasite. An efficacious vaccine targeting Plasmodium blood-forms is required to reduce parasite burden, clinical disease and sequelae to severe disease. Our proposal aims to address this gap by developing a multi-modal P. falciparum vaccine targeting the blood-stage parasite and evaluating its efficacy using a relevant primate model of human malaria. We will build this multi-modal vaccine by incorporating two vaccine candidates with distinct effector mechanisms. The individual components have been tested rigorously and reproducibly in pre-clinical efficacy models. The first is a sub-unit vaccine candidate (AMA1-RON2L complex), designed to enhance antibody quality by increasing the proportion of neutralizing antibodies targeting AMA1. Using a structure-based approach we have now designed this subunit vaccine to cover AMA1 polymorphisms and generate strain-transcending, neutralizing antibodies. The second is a whole blood-stage parasite vaccine that induces a strain-transcending, anti-parasite response through direct cell-mediated killing. This multi-modal vaccine will be formulated with a novel cationic liposomal adjuvant that potently activates both the humoral and cell-mediated arms of the immune system, thereby providing a human-compatible adjuvant platform. We will perform dosing studies to optimize the P. falciparum multi-component vaccine in mice and evaluate impact of biological sex on the vaccine-induced immune response. We will also assess memory B cell and T cell responses induced by the multi-modal P. falciparum vaccine (Aim 1). Next, we will assess immunogenicity and protective efficacy of this multi-modal vaccine against homologous and heterologous P. falciparum in Aotus nancymaae and evaluate the persistence of the immune responses using a delayed re-challenge model (Aim2). Lastly, we will use validated immunological assays and apply cutting-edge technology (single-cell RNASeq) to help inform our understanding of immune correlates of protection. The major deliverable of this project will be a novel, pre-clinically validated, multi-modal P. falciparum blood-stage vaccine in a human-compatible liposomal adjuvant that can be progressed towards clinical trials.