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

Researchers at the Ragon Institute of Mass General Brigham, MIT, and Harvard have identified why current malaria vaccines elicit a narrow antibody response and tested a strategy to broaden it. The study, published in the Journal of Experimental Medicine, used mouse models carrying human antibody genes to examine immune responses to the circumsporozoite protein (PfCSP) on the malaria parasite.

The two World Health Organization-recommended vaccines, RTS,S and R21, present only the major repeat region of PfCSP. While this region readily stimulates antibody production, the minor repeat and junction regions are targets of the most potent protective antibodies identified to date, yet they are absent from both vaccines.

In the mouse models, immunization with the R21 antigen activated only B cells specific to the major repeat. B cells capable of producing antibodies against the minor repeat and junction regions remained largely inactive, even when the full-length PfCSP protein was used, because the dominant major repeat response suppressed them.

To overcome this immunodominance, the team designed short peptides containing only the minor repeat or the junction region. Without competition from the major repeat, these peptides successfully activated the corresponding B cells, which proliferated, persisted for weeks, and acquired mutations characteristic of mature protective antibodies.

A combination vaccine comprising the R21 antigen plus the two short peptides engaged all three B-cell populations simultaneously and generated antibodies against all three PfCSP regions. In challenge experiments, this combination was the only regimen that significantly reduced the number of parasites reaching the liver.

Collaborating with researchers at the National Institutes of Health, Johns Hopkins University, and Columbia University, the team also found that engineering antibodies to bind PfCSP up to 10 times more tightly did not improve protection, suggesting that binding mode matters more than binding strength.

The authors propose that adding these peptides to existing vaccines could broaden the immune response without replacing current formulations. Human trials would be required before any clinical implementation.