Plasmablast Ig repertoire dynamics through repeat Plasmodium falciparum challenges

Abstract

Abstract The development of natural immunity against malaria requires multiple exposures and even after protection develops against clinical disease individuals continue to be susceptible to infections. To study the dynamics of the immune response to repetitive P. falciparum (PF) infected mosquito exposures, we used controlled human malaria challenges with the same strain of PF. The homologous strain was used to eliminate differences in immune responses due to strain polymorphisms and focus on the maturation of the human immune response to repeat exposures. Consistent with the gradual immune response observed in the field, after 4 sequential exposures over the course of 2 years, symptoms decreased and the time to parasite detection on a blood smear increased significantly, but all the volunteers continued to be susceptible to infections. Anti-PF antibody levels increased over time and were able to inhibit liver cell invasion in an in vitro assay. The Ig repertoire of plasmablasts collected 7 days after peak parasitemia demonstrated large clonal expansions in one or two sequential infections that decreased after subsequent exposures. This pattern suggests a marked difference in the lineage of plasmablast and memory cells populations. Naïve B cells stimulated by PF to proliferate and differentiate into plasmablasts may fail to differentiate into memory cells that can produce both plasmablasts and memory cells following subsequent exposures. This differentiation pattern would lead to new sets of expanded clones at each PF exposure, instead of further maturation of the same antibodies generated during the first response. Such a response could enhance the diversity of the Ig pool, but would delay the generation of a strong, durable memory response U0110852