In a study published in the international journal Science Immunology titled “Clonal evolution and TCR specificity of the human TFH cell response to Plasmodium falciparum CSP”, scientists from the German Cancer Research Center and other institutions analyzed the human immune response after immunization with malaria pathogen Plasmodium falciparum in order to clarify which protein components of T helper cells were induced in this way. Surprisingly, T helper cells only react to the protein sequence of vaccine strains, with very minimal cross-reaction to naturally occurring pathogen mutants. It might explain why the natural infections that people often come into contact with in epidemic areas do not protect against new diseases caused by other strains, and why the effect of the malaria vaccine can only last for a short time so far.
Despite recent scientific advances in controlling malaria, according to the data from WHO, more than 600,000 people worldwide die from this tropical disease every year, and the vast majority of fatal malaria cases are caused by Plasmodium falciparum. Only one vaccine against this single-celled organism has been approved so far, and its efficacy is relatively low and does not provide continuous protection.
The vaccine can target the quantitative dominant protein CSP on the surface of the sporophyte of Plasmodium, a special stage of the malaria pathogen that enters the host via mosquito bites. To improve the efficacy of the vaccine, researchers need to know which protective antibodies can be induced by immune reception, but the production of such antibodies is heavily dependent on the assistance of so-called follicular T helper cells. The researchers ensure that B cells can be converted into plasma cells that produce antibodies as well as memory B cells. The researchers examined the blood of volunteers who had been infected with the killed sporophyte of Plasmodium falciparum in the vaccine strain, all of whom were of European descent and had not previously been exposed to malaria pathogens, in order to study in detail the response of T helper cells to CSP. Then, specifically at the single cell level, the researchers examined the follicular T helper cells that were specific to the malaria parasite and especially focused on which sequences of CSP can be recognized by T helper cell receptors.
The results showed that T cell receptors mainly target amino acids at site 311-333 on CSP, but another observational study surprised the researchers by demonstrating that there is almost no cross-reactivity between single T cell clones, and these receptors can only bind to the CSP epitopes of the vaccine strains used. In some cases, even a single amino acid component deviation cannot be accepted.
The researchers point out that sequence polymorphism is more prevalent in this area of the CSP in the Plasmodium falciparum wild population, and the specificity of T cell clones prevents repeated natural infection of pathogens from acting as a natural booster, which might explain why the protective effect of malaria vaccine will disappear rapidly. The researchers suggest that further vaccine development will examine if a wider range of T helper cells would result in long-lasting immune protection.