Why malaria vaccines do not raise the right antibodies (and infection does!)

Image: malaria-infected red blood cell

Researchers from Sanquin, in collaboration with various other research groups, have found that naturally acquired antibodies towards the malaria parasite Plasmodium falciparum are highly afucosylated and therefore extremely potent in fighting and protecting against malaria. The researchers report in Nature Communications that this sharpened immune response might be a result of the proteins from P. falciparum being incorporated in the membrane of infected red blood cells. This new knowledge could be utilized for improved vaccine design, but also renders clues to why pregnancy-related alloimmunizations can lead to potent antibody responses. 

So far, vaccine efforts to put malaria to a halt have not been successful. PhD student Mads Larsen, in the group of Gestur Vidarsson, and colleagues at Sanquin Research have now found clues as to why immune responses to malaria vaccines do not equal natural immunity to malaria. They discovered that the naturally acquired antibodies are highly afucosylated. This rare sugar compositions results in an extremely potent antibodies, required for protection against malaria.  


Highly afucosylated antibodies can also be acquired during transfusion- and pregnancy-related alloimmunizations towards paternally-derived alloantigens on blood cells of the fetus. However, these are unwanted responses, that turn the immune response into overdrive resulting in more severe disease, as the same research group recently reported to occur in severe COVID-19 cases. As this class of antigens are all presented on blood cells similarly to the proteins of the malaria parasite, this may point to an evolutionary conserved mechanism increasing the potency of antibodies towards foreign proteins on human cells. 

These results may provide tools for improved vaccine design as well as aid our understanding of potent adverse antibody responses in pregnancy-related alloimmunizations. This has been a subject of intense studies for decades at Sanquin. 

A great interdisciplinary and intercontinental collaboration with scientists from various African and European groups, including University of Copenhagen and Leiden University Medical Center, facilitated this research by combining knowledge of techniques, parasitology, and immunology.