Understanding transmission-blocking immunity compared to clinical immunity in malaria

What is it about?

TITLE - Low Levels of Human Antibodies to Gametocyte-Infected Erythrocytes Contrasts the PfEMP1-Dominant Response to Asexual Stages in P. falciparum Malaria Vaccines that target Plasmodium falciparum gametocytes have the potential to reduce malaria transmission and are thus attractive targets for malaria control. However, very little is known about human immune responses to gametocytes present in human hosts. We evaluated naturally-acquired antibodies to gametocyte-infected erythrocytes (gametocyte-IEs) of different developmental stages compared to other asexual parasite stages among naturally-exposed Kenyan residents. We found that acquired antibodies strongly recognized the surface of mature asexual-IEs, but there was limited reactivity to the surface of gametocyte-IEs of different stages. We used genetically-modified P. falciparum with suppressed expression of PfEMP1, the major surface antigen of asexual-stage IEs, to demonstrate that PfEMP1 is a dominant target of antibodies to asexual-IEs, in contrast to gametocyte-IEs. Antibody reactivity to gametocyte-IEs was similar to asexual-IEs lacking PfEMP1. Significant antibody reactivity to the surface of gametocytes was observed when outside of the host erythrocyte, including recognition of the major gametocyte antigen, Pfs230. This indicates that there is a deficiency of acquired antibodies to gametocyte-IEs despite the acquisition of antibodies to gametocyte antigens and asexual IEs. Our findings suggest that the acquisition of substantial immunity to the surface of gametocyte-IEs is limited, which may facilitate immune evasion to enable malaria transmission even in the face of substantial host immunity to malaria. Further studies are needed to understand the basis for the limited acquisition of antibodies to gametocytes and whether vaccine strategies can generate substantial immunity.

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Why is it important?

Strategies to develop highly effective vaccines against malaria remain a high priority. In particular, the development of vaccines that interrupt malaria transmission, known as transmission-blocking vaccines, is currently recognized as a key goal to sustain long-term malaria elimination (1).As such, there is a renewed interest in gametocytes, the sexual, transmissible stages of Plasmodium falciparum, which involves distinct parasite forms that establish infection in the mosquito vector. Currently, the advancement of transmission-blocking vaccines is hampered because very little is known about immune responses to sexual-stage antigens. We found that the limited acquisition of antibodies targeting gametocyte-IEs contrasts with the PfEMP1-dominant antibody response toward asexual trophozoite-IEs. Reactivity to gametocyte-IEs was comparable to the low antibody reactivity observed against trophozoite-IEs lacking PfEMP1. However, human antibodies were acquired against the surface of intact gametocytes and to Pfs230. The deficiency in acquired antibodies to gametocyte-IEs could be an important mechanism to avoid clearance by host immunity. Our findings provide new insights to address the major knowledge gaps in understanding immunity and malaria transmission, which will help inform the development of transmission-blocking vaccines.