Analysing 83 vaccine-induced human monoclonal antibodies (mAbs) against the RIPR malaria protein (which is essential for the parasite to invade red blood cells), the lab study, published in Immunity, showed that single mAbs did not block parasite growth on their own. However, combinations of mAbs were over 90% effective at limiting parasite growth, through ‘team’ attacks on different parts of the RIPR protein’s ‘tail’ – thus deciphering how the proven polyclonal antibodies induced by the vaccine are working.
Dr Barnabas Williams, Senior Postdoctoral Research Associate in the Draper Lab and senior author of the study, said: "Most vaccine research has focused on identifying individual antibodies that can strongly neutralise a pathogen. What we found here is different: the strongest protection comes from antibodies working together in a coordinated way."
RIPR stands for RH5-Interacting Protein. It is a protein expressed by Plasmodium falciparum, the parasite responsible for the most severe form of malaria, and plays a critical role in the parasite’s invasion of human red blood cells.
Using high-resolution cryo-electron microscopy and molecular simulations, the researchers discovered that the antibodies target two distinct regions of the RIPR protein. One region, which the team termed a “neutralisation zone”, contains antibody targets that can partially inhibit parasite growth. A second “synergy zone” has little effect when targeted alone but substantially enhances protection when antibodies bind alongside those targeting the neutralisation zone.
The study showed that these antibodies work together by restricting the movement of a flexible region of RIPR known as the “tail”. This structural change appears to interfere with the interactions required for successful parasite invasion, effectively disrupting the machinery that enables infection of red blood cells.
Malaria remains one of the world's most significant infectious diseases, causing an estimated 282 million cases and more than 600,000 deaths each year, the majority among young children in sub-Saharan Africa. Symptoms occur when parasites invade and multiply inside red blood cells, making blood-stage vaccines an important area of research.
Current World Health Organization-recommended malaria vaccines target earlier stages of infection before parasites enter the bloodstream. Researchers are now developing blood-stage vaccines that aim to stop the parasite once it reaches red blood cells.
One such candidate, the R78C vaccine, which contains part of the RIPR protein, is currently undergoing Phase 1 clinical testing. The Oxford team found that antibodies targeting additional regions of RIPR significantly improved the effectiveness of vaccine-induced responses, suggesting that future vaccine designs could benefit from targeting multiple regions of the protein simultaneously.
The findings provide the first detailed structural explanation for why vaccine-induced antibody responses against RIPR can be highly effective, even when individual antibodies appear only modestly protective.
Dr Williams added: "Our work shows that effective protection against malaria can emerge from cooperation between antibodies. By understanding these interactions, we can begin designing vaccines that deliberately generate the most effective combinations of immune responses."
The researchers hope the findings will help guide the development of next-generation blood-stage malaria vaccines capable of delivering stronger and more durable protection against one of the world's deadliest infectious diseases.