Research from the Batista Lab at the Ragon Institute of Mass General Brigham, MIT, and Harvard, published in the Journal of Experimental Medicine, outlines a new approach to malaria vaccination that targets previously overlooked regions of the malaria parasite. The findings were announced on Aug. 7.
Malaria continues to kill more than half a million people each year, with most victims being young children in Africa. Two vaccines currently recommended by the World Health Organization—RTS,S and R21—have been helpful but do not provide lasting or comprehensive protection as desired by public health officials.
The research explains that malaria parasites are coated with a protein called PfCSP. While antibodies targeting this protein can prevent infection, PfCSP has several distinct regions, and only some are effectively targeted by existing vaccines. Both RTS,S and R21 focus on the major repeat region of PfCSP—a long stretch of repeated amino acids—which elicits an immune response but does not target other critical areas known as the minor repeat and junction. These two regions have been identified as targets for some of the strongest anti-malarial antibodies discovered so far; however, neither is included in current vaccines.
To investigate whether current vaccines might still trigger protective antibodies against these neglected regions, researchers created mouse models carrying human antibody genes specific to different parts of PfCSP. Results showed that when mice received vaccine components similar to those used in R21, only immune cells targeting the major repeat responded; cells that could produce stronger antibodies remained inactive even when exposed to full-length PfCSP protein.
In response, researchers tested an alternative strategy using short peptides representing just the minor repeat or junction region without competition from other segments. This approach successfully activated protective immune cells and led to antibody development similar to those found in mature human responses. Combining these peptides with existing vaccine proteins engaged all three cell types simultaneously and produced broader immunity; this combination was also effective at reducing parasite levels in mice following exposure.
Further collaboration with colleagues at institutions including Johns Hopkins University and Columbia University revealed that how an antibody binds is more important than binding strength alone for effective protection against malaria parasites. The study suggests enhancing current vaccines rather than replacing them may be possible by incorporating elements that prompt immune recognition of previously ignored parts of PfCSP.
