Why vaccination against malaria quickly loses its protective effect?

Scientists at the German Cancer Research Center (DKFZ) have investigated which protein components the T cells induced by the malaria vaccination target and found that they have reacted exclusively to the protein sequence of the vaccine strain and barely have shown cross-reactivity with variants of the wild-type strain.

To improve the vaccine, we need to understand which protective antibodies are induced by the immunization. But the production of these antibodies largely depends on the help of so-called follicular helper T cells," says researcher Hedda Wardemann.

To study in detail the response of helper T cells against the CSP protein, the team led by the immunologist Wardemann of the DKFZ has examined the blood of volunteers infected with dead Plasmodium falciparum sporozoites of the vaccine strain.

The volunteers were of European descent and had no previous contact with malaria pathogens. Researchers have analyzed Plasmodium-specific follicular helper T cells induced at the single-cell level. In particular, they have focused their research on which CSP sequences are recognized by T helper cell receptors.

The scientists reported that the vaccine targets the P. falciparum circumambulatory sporozoite protein (CSP), a quantitatively dominant protein on the "sporozoite" surface. Sporozoites are a stage of malaria transmission that is transmitted through mosquito bites and passes into human blood. To improve vaccines, we need to understand which protective antibodies are affected by vaccination.

Heda Wardmann of the German Cancer Research Center says that the production of such antibodies relies heavily on the help of so-called follicular helper T cells. They explain that they ensure that B cells become antibody-producing plasma cells and memory B cells.

Analyzes revealed that T cell receptors primarily targeted amino acids 311 to 333 of CSP. But another observation surprised the researchers: There was virtually no cross-reactivity between the individual T-cell clones. "The receptors bind highly specifically only to the CSP epitopes of the vaccine strain used. In some cases, even single amino acid component deviations were not tolerated," explains Wardemann.

The immunologist points out that in the natural population of P. falciparum there are high-grade sequence polymorphisms in this region of the CSP. "The specificity of the T cell clones prevents 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," Wardemann said. The researcher recommends that further development of the vaccine test whether the induction of a broader spectrum of helper T cells could lead to longer-lasting immune protection.

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