Humoral immunity prevents clinical malaria during Plasmodium relapses without eliminating gametocytes

Abstract

Plasmodium relapses are attributed to the activation of dormant liver-stage parasites and are responsible for a significant number of recurring malaria blood-stage infections. While characteristic of human infections caused by P. vivax and P. ovale, their relative contribution to malaria disease burden and transmission remains poorly understood. This is largely because it is difficult to identify ‘bona fide’ relapse infections due to ongoing transmission in most endemic areas. Here, we use the P. cynomolgi–rhesus macaque model of relapsing malaria to demonstrate that clinical immunity can form after a single sporozoite-initiated blood-stage infection and prevent illness during relapses and homologous reinfections. By integrating data from whole blood RNA-sequencing, flow cytometry, P. cynomolgi-specific ELISAs, and opsonic phagocytosis assays, we demonstrate that this immunity is associated with a rapid recall response by memory B cells that expand and produce anti-parasite IgG1 that can mediate parasite clearance of relapsing parasites. The reduction in parasitemia during relapses was mirrored by a reduction in the total number of circulating gametocytes, but importantly, the cumulative proportion of gametocytes increased during relapses. Overall, this study reveals that P. cynomolgi relapse infections can be clinically silent in macaques due to rapid memory B cell responses that help to clear asexual-stage parasites but still carry gametocytes. Plasmodium vivax contributes significantly to global malaria morbidity and remains a major obstacle for malaria elimination due to its ability to form dormant stages in the liver. These forms can become activated to cause relapsing blood-stage infections. Relapses remain poorly understood because it is difficult to verify whether P. vivax blood-stage infections in patients are due to new infections or relapses in most cases. Here, we use a nonhuman primate model of Plasmodium vivax malaria in concert with state-of-the-art immunological and molecular techniques to assess pathogenesis, host responses, and circulating gametocyte levels during relapses. We found that relapses were clinically silent compared to initial infections, and they were associated with a robust memory B cell response. This response resulted in the production of antibodies that were able to mediate clearance of asexual parasites. Despite this rapid immune protection, the sexual-stage gametocytes continued to circulate. Our study provides mechanistic insights into the host-parasite interface during Plasmodium relapse infections and demonstrates that clinically silent relapses can harbor gametocytes that may be infectious to mosquitoes.