Malaria vaccine add-ons activate three antibody targets, study finds

Malaria remains a major global health concern, claiming over half a million lives annually, predominantly young children in Africa. Two vaccines, RTS,S and R21, are currently recommended by the World Health Organization, yet neither achieves the desired efficacy or longevity. The Batista Lab at the Ragon Institute of Mass General Brigham, MIT, and Harvard, published findings in the Journal of Experimental Medicine that shed light on the reasons behind their shortcomings and propose potential solutions.

Malaria parasites are adorned with a protein called PfCSP, and antibodies targeting this protein can prevent infections before they progress. However, PfCSP is not a uniform structure; it possesses distinct regions, and antibodies against some of these regions exhibit superior efficacy. Both existing vaccines expose the immune system to the same lengthy region, known as the major repeat, which elicits an easily provable response.

Two other regions, the minor repeat and the junction, are harder to access but are targeted by the most potent antimalarial antibodies discovered so far. These regions are absent from the current vaccines. The research team aimed to ascertain whether the vaccines could inadvertently stimulate antibodies against these regions. To explore this, they engineered mouse models with human antibody genes, utilizing the immune cells as a basis for human protective antibodies, segmenting them based on their target on PfCSP.

The results were disheartening. When the mice received a portion of PfCSP similar to that used in R21, only cells producing antibodies against the major repeat responded. The cells that would have generated stronger antibodies showed minimal activity. Even when the full PfCSP protein, containing all the regions, was administered, the major repeat overshadowed the other regions.

Consequently, the researchers adopted a different strategy. Instead of presenting the entire protein, they employed a short peptide displaying solely the minor repeat, allowing the appropriate immune cells to respond without competition. These cells proliferated, persisted for weeks, and acquired the characteristics of mature protective antibodies.

The ultimate test involved combining the R21-style protein with two short peptides, one for the minor repeat and one for the junction. This approach simultaneously activated all three cell types and yielded antibodies against all three PfCSP regions. Upon later exposing the mice to parasites, this combination proved to be the most effective tested method, substantially reducing the number of parasites reaching the liver.

Collaborating with experts at the National Institutes of Health, Johns Hopkins University, and Columbia University, the team also investigated the factors contributing to the efficacy of these antibodies. They created versions that bound the parasite up to ten times more strongly, but even this heightened affinity did not result in improved protection.

The mechanism of antibody binding, rather than the strength of the binding, appeared to be the critical factor. Instead of substituting the existing vaccines entirely, adding these peptide elements could potentially enhance them, encouraging the immune system to focus on the regions of the parasite that would otherwise be overlooked.

While these findings offer a viable pathway to augmenting malaria vaccines and potentially saving lives, human trials are necessary before any treatment can be implemented.