Why vaccination against malaria quickly loses its protective effect

Scientists from the German Cancer Research Center (DKFZ) studied the human immune response after immunization with the malaria pathogen Plasmodium falciparum. Their aim was to find out against which protein components the helper T cells thus induced are directed. To the researchers’ surprise, the helper T cells reacted exclusively to the protein sequence of the vaccine strain and showed virtually no cross-reactivity with the naturally occurring pathogen variants. This could explain why natural infections, to which inhabitants of endemic areas are constantly exposed, offer little protection against new diseases with other strains, and why the effect of vaccination available to date only lasts a short time. .

Despite impressive successes in the fight against malaria, more than 600,000 people worldwide still die each year from this tropical disease, according to the World Health Organization. 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 unicellular organism, and its effectiveness, already quite low, does not last long.

The vaccine is directed against CSP, the quantitatively dominant protein on the surface of “sporozoites”. Sporozoites are the stage of the malaria pathogen that is transmitted through the mosquito bite and enters human blood. “To improve the vaccine, we need to understand which protective antibodies are induced by immunization. But the production of such antibodies depends to a large extent on the help of so-called follicular helper T cells,” explains Hedda Wardemann from the German Cancer Research Center. “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, the team led by DKFZ immunologist Wardemann examined the blood of volunteers infected with killed P. falciparum sporozoites of the vaccine strain. The volunteers were of European descent and had no previous contact with malaria pathogens. The researchers analyzed induced Plasmodium-specific follicular helper T cells at the single-cell level. In particular, they focused their search on CSP sequences that are recognized by T helper cell receptors.

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

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 T-cell clones prevents constantly recurrent natural infections by the pathogen from acting as a natural ‘booster’. This could perhaps explain why the protective effect of the malaria vaccine wears off so quickly,” Wardemann said. The researcher recommends that further vaccine development test whether induction of a broader spectrum of helper T cells could generate longer-lasting immune protection.

Source of the story:

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

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