Malaria, caused by the Plasmodium falciparum (P. falciparum) parasite, remains a significant global health challenge, particularly in sub-Saharan Africa. Despite advances in malaria control, the disease still claims hundreds of thousands of lives annually. The development of highly effective tools against P. falciparum is a long-sought priority, with recent progress in vaccines and monoclonal antibodies (mAbs) targeting the parasite's sporozoites. However, these interventions do not protect against the blood-stage parasites, necessitating the development of tools that target this stage as a second line of defense.
The Challenge of Blood-Stage Vaccine Development
Decades of efforts to develop blood-stage vaccines have been hindered by the parasite's ability to evade antibodies by mutating its surface antigens and invading erythrocytes via multiple redundant pathways. However, the identification of a well-conserved complex used by P. falciparum merozoites to invade host erythrocytes has bolstered these efforts. This complex includes reticulocyte-binding protein homolog 5 (RH5), cysteine-rich protective antigen (CyRPA), and RH5-interacting protein (RIPR), among others.
RH5 as a Vaccine Candidate
RH5 is the most well-studied member of this complex and is at the most advanced stage of clinical development. It plays an indispensable role in mediating merozoite invasion by binding the erythrocyte surface protein basigin. RH5 vaccination can elicit broadly neutralizing antibodies in animals, and a single RH5-specific mAb has conferred protection against blood-stage P. falciparum challenge in Aotus monkeys.
Clinical Trials and Challenges
Clinical trials in sub-Saharan Africa are underway to test the safety, immunogenicity, and efficacy of RH5 vaccines. However, the biological role and location of RH5 during erythrocyte invasion present unique challenges. RH5 is not constitutively expressed on the merozoite surface but is sequestered within intracellular organelles and is only released to the surface just prior to engagement of basigin, providing a limited time window for antibodies to bind.
B Cell Response to RH5
A recent study investigated the B cell response to RH5 during natural malaria infection and compared it to the response elicited by RH5 vaccination. The study found that natural infection induces low frequencies of RH5-reactive memory B cells and generates short-lived antibody responses. Despite repeated malaria infections, the antibody levels to RH5 often decline rapidly after infection, suggesting that natural infection does not often induce productive germinal center responses.
Neutralizing Antibodies and Epitope Specificity
The study isolated and characterized a panel of 186 RH5-specific mAbs derived from natural infection and vaccination. Neutralization potency was strongly associated with binding to specific regions of RH5 proximal to the receptor-binding site that contacts basigin. While mAbs induced by malaria infection were less potent on average, two infection-derived mAbs (MAD8–151 and MAD8–502) targeted critical RH5 epitopes and were among the most potently neutralizing mAbs.
Implications for Vaccine Development
The findings suggest that natural infection can elicit potent, albeit uncommon, RH5-specific mAbs. However, antibodies from natural infection were more commonly found to target non-neutralizing bottom regions of RH5, which could favor the expansion of these non-neutralizing B cells after vaccination. This highlights the need for a next-generation RH5 vaccine that includes only the top regions of the protein (bins I–III) to maximize neutralizing antibody responses. The RH5 vaccine field is at an exciting point, with ongoing clinical trials in malaria-endemic regions. Understanding the antibody responses to infection and vaccination separately is crucial for evaluating hybrid immunity. The study's findings provide valuable insights for fine-tuning the design of next-generation RH5 vaccines, aiming to develop tools that can effectively target P. falciparum and contribute to the global effort to eliminate malaria.
