More than 600 000 people worldwide still die from malaria every year, according to the WHO. The vast majority of fatal cases of malaria are caused by the single-celled pathogen Plasmodium falciparum, which so far has only one approved vaccine against it, and its efficacy, which is already rather low, is also short-lived. A new study in Science Immunology may have the explanation: a lack of cross-reactivity in T helper cells.
The vaccine targets CSP, the quantitatively dominant protein on the surface of the “sporozoites”. Sporozoites are the stage of the malaria pathogen which is transmitted with the bite of the mosquito and enters human blood. “To improve the vaccine, we need to understand which protective antibodies are induced by the immunisation. But the production of such antibodies depends to a large extent on help from the so-called follicular T helper cells,” explained Dr Hedda Wardemann, immunologist and senior author of the study. “They ensure that B cells transform into antibody-producing plasma cells and memory B cells.”
To study the T helper cell response against CSP in detail, Dr Wardemann’s team examined the blood of volunteers infected with killed P. falciparum sporozoites from the vaccine strain. The volunteers were of European descent and had no prior contact with malaria pathogens. The researchers analysed the induced Plasmodium-specific follicular T helper cells at the single cell level. They focused on which sequences of CSP are recognised by the T helper cells’ receptors.
The analyses revealed that the T-cell receptors mainly targeted amino acids 311 to 333 of the CSP. But the researchers were stunned by another finding: there was virtually no cross-reactivity between the individual T-cell clones. “The receptors highly specifically bind only the CSP epitopes of the vaccine strain used. Even deviations of only a single amino acid component were not tolerated in some cases,” Dr Wardemann explained.
The immunologist points out that in the natural population of P. falciparum, sequence polymorphisms occur to a high degree in this region of the CSP. “The specificity of the T-cell clones prevents the constantly recurring natural infections with the pathogen from acting as a natural ‘booster.’ This could possibly explain why the protective effect of the malaria vaccine wears off so quickly,” Dr Wardemann said. The researcher recommends that further development of the vaccine should test whether inducing a broader spectrum of T helper cells could generate longer-lasting immune protection.
Source: German Cancer Research Centre
