Why vaccination against malaria quickly loses its protective effect

Scientists at the German Cancer Research Center (DKFZ) have examined the human immune response after immunization with the malaria pathogen Plasmodium falciparum. Their goal was to find out against which protein building blocks the helper T cells induced in this way are directed. To the surprise of the researchers, the helper T cells only reacted to the protein sequence of the vaccine strain and showed practically no cross-reactivity with the naturally occurring pathogen variants. This could explain why natural infections to which residents of endemic areas are constantly exposed offer little protection against new diseases with other strains and why the effect of previously available vaccines is short-lived.

Despite impressive successes in the fight against malaria, according to the World Health Organization, more than 600,000 people worldwide still die from this tropical disease every year. The vast majority of fatal cases of malaria are caused by the pathogen Plasmodium falciparum. To date, there is only one approved vaccine against this protozoa, and its effectiveness, which is already quite low, will not last long.

The vaccine targets CSP, the quantitatively dominant protein on the surface of ‘sporozoites’. Sporozoites are the stage of the malaria pathogen that is transmitted through the bite of a mosquito and enters human blood. “In order to improve the vaccine, we need to understand which protective antibodies are induced by the immunization. But the production of such antibodies depends largely on the help of so-called follicular T helper cells,” explains Hedda Wardemann from the German Cancer Research Center. “They ensure that B cells turn into antibody-producing plasma cells and memory B cells. »

In order to examine the T helper cell response against CSP in detail, the team led by DKFZ immunologist Wardemann examined the blood of test persons infected with killed P. falciparum sporozoites of the vaccine strain. The volunteers were of European descent and had not previously been in contact with malaria pathogens. Researchers analyzed induced Plasmodium-specific follicular helper T cells at the single cell level. In particular, they focused their search on CSP sequences recognized by T helper cell receptors.

Analyzes revealed that T-cell receptors mainly target amino acids 311-333 of CSP. But another observation amazed the researchers: There was practically no cross-reactivity between the individual T-cell clones: “The receptors only bind very specifically to the CSP epitopes of the vaccine strain used. Even deviations in a single amino acid component were sometimes not tolerated,” says Wardemann.

The immunologist points out that in the natural population of P. falciparum, sequence polymorphisms are high in this region of the CSP. “The specificity of T-cell clones prevents recurring natural infections caused by the pathogen from acting as a natural ‘booster’. That could perhaps explain why the protective effect of the malaria vaccination wears off so quickly,” said Wardemann. The researcher recommends testing whether the induction of a broader range of helper T cells could produce longer-lasting immune protection during further vaccine development.

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Materials provided by German Cancer Research Center (DKFZ). Note: Content can be edited for style and length.

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