Ragon Institute 
Malaria kills more than half a million people a year, most of them young children in Africa. Two vaccines are now recommended by the World Health Organization, RTS,S and R21. Both are helpful interventions, but neither work as well or as long as public health officials would like.
A paper from the Batista Lab at the Ragon Institute of Mass General Brigham, MIT, and Harvard, “Overcoming Immunogenic Gaps in Malaria Subunit Vaccines by Broadening CSP-Regions Targeted,” was published in the Journal of Experimental Medicine and explains part of the reason along with testing for a fix.
Malaria parasites are covered in a protein called PfCSP. Antibodies that grab onto this protein can stop an infection before it takes hold. But PfCSP is not one uniform surface. It has several distinct regions, and antibodies against some of them work much better than others.
Both current vaccines show the immune system the same region, a long stretch of repeated amino acids called the major repeat. The immune system responds to it easily, producing a response to target the parasite. Two other regions however, called the minor repeat and the junction, are harder to reach but are the targets of the strongest anti-malarial antibodies found so far. Neither region is in either of the current vaccines, but as both share key binding features with the major repeat region, the investigative team sought to determine whether current vaccines could trigger anti-minor repeat and anti-junction antibodies.
To find out, first authors Ja-Hyun Koo (Batista Lab, Ragon Institute) and Prabhanshu Tripathi (Vaccine Research Center, NIAID) and their colleagues built mouse models carrying human antibody genes. The immune cells in these mice start out with the same genetic blueprints that give rise to protective human antibodies, and each mouse line represents one target on PfCSP.
The findings indicated current vaccines are unlikely to trigger anti-minor repeat and anti-junction antibodies. When the mice received the same piece of PfCSP that R21 uses, only the major repeat cells responded. The cells that would have made the stronger antibodies to other regions did essentially nothing. Even giving mice the full PfCSP protein, which contains all the regions, did not help much. The major repeat drowned out everything else.
As a result, the researchers attempted a different approach. Instead of the whole protein, they used a short peptide, a fragment just long enough to display the minor repeat and nothing else. With no competition, the correct immune cells responded. They multiplied, stuck around for weeks, and accumulated the same changes seen in mature protective antibodies.
The final test combined the R21-style protein with two short peptides, one for the minor repeat and one for the junction. This engaged all three cell types at once and produced antibodies against all three regions. When the mice were later exposed to parasites, this combination was the only approach tested that significantly cut the number of parasites reaching the liver.
Working with colleagues at the National Institutes of Health, Johns Hopkins University, and Columbia University, the team also examined what makes the anti-minor repeat antibodies effective. They engineered versions that bound the parasite up to 10 times more tightly, but the tighter grip did not translate into better protection. How an antibody binds appears to matter more than the strength of the binding.
Rather than replacing the vaccines that already exist, it may be possible to add to them, giving the immune system a reason to notice the parts of the parasite it would otherwise skip. Human trials would have to occur before any treatment can be implemented, however, this study points to a practical path forward to improving malaria vaccines and potentially saving lives.