Malaria kills about half a million people each year, and the majority of them are young children in Africa. The World Health Organization now recommends two vaccines: RTS, S, and R21. Both treatments are beneficial, but neither performs as well or for as long as public health experts would prefer.
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The Batista Lab at the Ragon Institute of Mass General Brigham, MIT, and Harvard published a study in the Journal of Experimental Medicine titled "Overcoming Immunogenic Gaps in Malaria Subunit Vaccines by Broadening CSP-Regions Targeted," which explains part of the reason and testing for a solution.
Malaria parasites are wrapped in a protein known as PfCSP. Antibodies that bind to this protein can halt an infection before it takes hold. But PfCSP is not a single homogeneous surface. It has multiple unique areas, and antibodies to some of them are far more effective than others.
Both existing vaccines show the immune system the same region: a large stretch of repeated amino acids known as the major repeat. It elicits an immediate reaction from the immune system, which targets the parasite.
Two additional locations, known as the minor repeat and the junction, are more difficult to reach yet are the targets of the most potent anti-malarial antibodies discovered thus far. Neither area is included in either of the existing vaccinations, but because they share important binding properties with the major repeat region, the research team wanted to see if the current vaccines may elicit anti-minor repeat and anti-junction antibodies.
To find out, first authors Ja-Hyun Koo (Batista Lab, Ragon Institute), Prabhanshu Tripathi (Vaccine Research Center, NIAID), and colleagues created mouse models containing human antibody genes. The immune cells in these mice begin with the identical genetic blueprints that give birth to protective human antibodies, and each mouse line represents a single target on PfCSP.
The findings revealed that current vaccinations are unlikely to elicit anti-minor repeat and anti-junction antibodies. When the mice were given the identical PfCSP that R21 utilizes, only the main repeat cells responded. The cells that would have produced stronger antibodies for other places did almost nothing. Even feeding mice the entire PfCSP protein, which includes all of the areas, did not assist much. The main repeat overshadowed everything else.
As a result, the researchers used a different method. Instead of the entire protein, they employed a short peptide, a segment only long enough to show the minor repetition and nothing more. Without competition, the appropriate immune cells responded. They multiplied, remained for weeks, and exhibited the same characteristics as mature protective antibodies.
The last test involved combining the R21-style protein with two short peptides, one for the minor repeat and one for the junction. This activated all three cell types at once, resulting in antibodies against all three regions. When the mice were later exposed to parasites, this combination was the only one shown to significantly reduce the number of parasites reaching the liver.
Working with partners at the National Institutes of Health, Johns Hopkins University, and Columbia University, the team also investigated what makes anti-minor repeat antibodies successful. They developed versions that tied the parasite up to 10 times tighter, but a tighter grasp did not result in improved protection. How an antibody binds appears to be more important than the strength of the binding.
Rather than replacing existing vaccinations, it may be able to supplement them, providing the immune system with a reason to recognize parasite sections that it would otherwise ignore. Human trials are required before any treatment can be adopted; nonetheless, this study suggests a viable road ahead for strengthening malaria vaccinations and perhaps saving lives.
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