Investigating the CSP-specific B cell response to Plasmodium sporozoites

Abstract

An effective vaccine is necessary to combat malaria. The most advanced malaria vaccines - the subunit-based RTS,S and live attenuated PfSPZ - target the pre-erythrocytic sporozoite stage of the Plasmodium falciparum lifecycle and induce production of protective antibodies against the parasite antigen CSP (circumsporozoite protein). However, unlike other effective antibody based vaccines, current malaria vaccines fail to induce sustained production of anti-CSP antibodies at protective levels. Given the limited capacity to protect, it was critical to determine the mechanisms that underlie the B cell response to Plasmodium sporozoites. In this thesis, the CSP-specific B cell response to Plasmodium sporozoites was assessed within a murine model.

The generation of a novel Ig heavy chain knockin mouse with a BCR specific for P. falciparum CSP (PfCSP) enabled easy tracking of the PfCSP-specific B cell response to immunisation with PfCSP-expressing transgenic P. berghei sporozoites. It was revealed that a bulk of the early PfCSP-specific B cell response was a short-lived plasmablast response, independent of T cell help, but also that long-lasting plasma cells and memory populations were generated. Notably, attempts to enhance the titres of protective anti-PfCSP IgG by multiple vaccinations revealed a plateauing of titres after two doses. This was determined to be due to antibody-mediated feedback preventing the recall response of PfCSP-specific memory B cells. It was discovered that the amount of antibody required to protect against infection with Plasmodium sporozoites was ~3 fold higher than the amount required to inhibit recall responses by memory. This large disparity between titres capable of protection and titres capable of dampening memory responses may help to explain some of the difficulty in maintaining protective titres in individuals in malaria vaccine trials. It also suggests that simple prime-boost vaccine strategies utilised in other vaccine regimens will not work in this system - instead, targeted approaches to generate potently protective antibody lineages may be required.

Alternative strategies to improve the B cell response were subsequently explored, with a strong focus upon enhancing CD4+ T cell help. Intriguingly, from prime-boost experiments with heterologous P. berghei strains it was determined that CSP-specific B cells were able to receive help from T cells specific for epitopes outside of the CSP region. This indicates that CSP-specific B cells must be able to internalise other parasite antigens alongside CSP. Identification of these novel T cell epitopes may help in the development of more effective malaria vaccine constructs. Show more