A new study offers insight about why a malaria vaccine is less effective against naturally occurring variants of the parasite that causes the disease. Published in Science Immunology, the work sheds light on how Tfh cells and the malaria parasite’s early life stage interact. Conducted by researchers from the German Cancer Research Centre in Heidelberg, Germany, the study aimed to provide a foundation for developing improved malaria vaccines.
Malaria is a serious life-threatening parasitic infection transmitted by mosquito bites. In 2020, there were an estimated 241 million cases worldwide, with the African region carrying a disproportionately high burden of malaria. Children under 5 are particularly vulnerable.
As of 2021, there is only one approved vaccine, RTS,S (known by the brand name Mosquirix). However, multiple doses are required and it has been shown to be less effective in infants. Insights into factors influencing vaccine efficacy can help develop improved malaria vaccines and reduce malaria cases and mortality rates.
The malaria-causing parasite Plasmodium falciparum (Pf) first enters the human body via mosquito bite in sporozoite form. A sporozoite is a cellular spore-like stage in the life cycle of parasites. The RTS,S malaria vaccine targets the Pf circumsporozoite protein (PfCSP). This induces immune responses that block sporozoite infection.
However, many naturally occurring Pf variants exist in the field and their PfCSPs vary. This enables some variants to escape recognition by the immune system – even following vaccination.
The new study explores human follicular helper T (Tfh) cells to understand how they react to the malaria parasite’s sporozoite form.
TfH cells are a specialised subset of CD4+ T cells. They play an important role in protective immunity by helping B cells produce antibodies against foreign pathogens. The production of long-lasting specific antibodies forms the basics of successful vaccination, therefore a better understanding of Tfh cells could help improve vaccine design.
Discrepancy in Tfh cell response
The team of researchers examined the mechanisms by which Tfh responses change against PfCSP variants. They evaluated cell phenotypes, clonal dynamics and T cell receptor interactions in human Tfh cells after immunisation.
They also performed T cell receptor repertoire studies, which showed that repeated vaccination caused Tfh cells to respond to a small subset of PfCSP sequences but did not facilitate the generation of cross-reactive Tfh cells. The Tfh cell response was limited to the vaccine strain only.
The findings suggest that the high parasite diversity in endemic areas will limit the boosting of the vaccine-induced Tfh cell response by natural infections.
Tfh cells are important for training memory B cells to respond to sporozoite proteins when re-encountered, so this discrepancy may lead to lower vaccine efficacy.
“The data […] identify factors that constrain vaccine responses, findings that have direct relevance for the development of improved PfCSP-based malaria vaccines able to induce potent T helper cell responses,” the authors write.
However, the authors acknowledge that the cell samples came from a cohort of Europeans. Future work could benefit by drawing samples from a more diverse group.
Written by Poppy Jayne Morgan, Front Line Genomics
Image Credit: Canva