ABSTRACT
Immunity to Plasmodium falciparum (Pf) malaria is only acquired after years of repeated infections and wanes rapidly without ongoing parasite exposure. Antibodies are central to malaria immunity, yet little is known about the B-cell biology that underlies the inefficient acquisition of Pf-specific humoral immunity. This year-long prospective study in Mali of 185 individuals aged 2 to 25 years shows that Pf-specific memory B-cells and antibodies are acquired gradually in a stepwise fashion over years of repeated Pf exposure. Both Pf-specific memory B cells and antibody titers increased after acute malaria and then, after six months of decreased Pf exposure, contracted to a point slightly higher than pre-infection levels. This inefficient, stepwise expansion of both the Pf-specific memory B-cell and long-lived antibody compartments depends on Pf exposure rather than age, based on the comparator response to tetanus vaccination that was efficient and stable. These observations lend new insights into the cellular basis of the delayed acquisition of malaria immunity.
Subject(s)
B-Lymphocytes/immunology , B-Lymphocytes/parasitology , Immunologic Memory/immunology , Malaria, Falciparum/immunology , Plasmodium falciparum/immunology , Acute Disease , Adolescent , Adult , Antibodies, Protozoan/blood , Child , Child, Preschool , Female , Humans , Immunoglobulin G/blood , Immunophenotyping , Longitudinal Studies , Malaria, Falciparum/transmission , Male , Mali , Prospective Studies , Recurrence , Seasons , Young AdultABSTRACT
Despite the central role of memory B cells (MBC) in protective immune responses, little is understood about how they are acquired in naive individuals in response to Ag exposure, and how this process is influenced by concurrent activation of the innate immune system's TLR. In this longitudinal study of malaria-naive individuals, we examined the MBC response to two candidate malaria vaccines administered with or without CpG, a TLR9 ligand. We show that the acquisition of MBC is a dynamic process in which the vaccine-specific MBC pool rapidly expands and then contracts, and that CpG enhances the kinetics, magnitude, and longevity of this response. We observed that the percentage of vaccine-specific MBC present at the time of reimmunization predicts vaccine-specific Ab levels 14 days later; and that at steady-state, there is a positive correlation between vaccine-specific MBC and Ab levels. An examination of the total circulating MBC and plasma cell pools also suggests that MBC differentiate into plasma cells through polyclonal activation, independent of Ag specificity. These results provide important insights into the human MBC response, which can inform the development of vaccines against malaria and other pathogens that disrupt immunological memory.
Subject(s)
B-Lymphocyte Subsets/immunology , Immunologic Memory , Malaria/immunology , Oligodeoxyribonucleotides/administration & dosage , Plasmodium falciparum/immunology , Toll-Like Receptor 9/administration & dosage , Adjuvants, Immunologic/administration & dosage , Adult , Aluminum Hydroxide/administration & dosage , Aluminum Hydroxide/immunology , Animals , B-Lymphocyte Subsets/metabolism , Cells, Cultured , Clinical Trials, Phase I as Topic , CpG Islands/immunology , Epitopes, B-Lymphocyte/immunology , Humans , Immunization, Secondary , Ligands , Malaria Vaccines/administration & dosage , Malaria Vaccines/immunology , Oligodeoxyribonucleotides/metabolism , Toll-Like Receptor 9/metabolismABSTRACT
Antibodies play a key role in controlling blood stage malaria infections, and an effective blood stage malaria vaccine will likely require that it induce vaccine-specific memory B cells (MBCs). Our previous studies showed that the addition of the TLR9 agonist CpG to Plasmodium falciparum protein subunit vaccines greatly increased their efficacy in inducing MBCs in nonimmune U.S. volunteers. Here we show that in contrast the same CpG-containing malaria vaccine did not enhance the acquisition of MBCs in semi-immune adults living in Mali. Understanding the molecular basis of this apparent refractoriness to TLR9 agonist will be of significant interest in vaccine design.