Antibodies targeting the intracellular liver stage malaria parasite after infection can be a potent means of reducing parasite liver burden

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Abstract Malaria is one of the oldest and deadliest diseases known to humans, and in 2017 an estimated 216 million people were infected with 445,000 succumbing to disease. Antibodies which block the skin-to-liver stages of malaria infection continue to be pursued due to their potential to stop infection prior to the progression to the disease and transmission-causing blood stages. Phase III clinical trials with a vaccine targeting the major sporozoite surface protein (circumsporozoite protein) have provided suboptimal efficacy in the field which must be improved before large scale use for malaria prevention and eradication. New antibody targets will likely be needed in order to provide complete, sterilizing protection. Thus far, the search has largely been limited to targeting surface and secreted proteins of the sporozoite, merozoite or gametocyte stages. Here, we present data demonstrating that antibodies which instead target the intracellular liver stage parasite after hepatocyte infection can be a potent means of limiting parasite liver infection in vivo. This was done in a rodent malaria model by targeting two different proteins found on the parasitophorous vacuole membrane that forms the border between parasite and host cytoplasm—indicating antibodies are entering the hepatocyte to mediate their effect. This phenomenon was also demonstrated using the most common human malaria species Plasmodium falciparum in humanized liver chimeric mice where human antibodies targeting the parasite periphery were able to potently reduce liver burden and parasite liver growth between days 5–6. These data present a new class of antibody targets for malaria and strongly argue for the inclusion of intracellular antigens in novel vaccine formulations.

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