Germinal center activity and B cell maturation are associated with protective antibody responses against Plasmodium pre-erythrocytic infection

• Published in: PLoS pathogens 2022-07, Vol.18 (7), p.e1010671-e1010671
• Main Authors: Visweswaran, Ganesh Ram R, Vijayan, Kamalakannan, Chandrasekaran, Ramyavardhanee, Trakhimets, Olesya, Brown, Samantha L, Vigdorovich, Vladimir, Yang, Ashton, Raappana, Andrew, Watson, Alex, Selman, William, Zuck, Meghan, Dambrauskas, Nicholas, Kaushansky, Alexis, Sather, D. Noah
• Format: Article
• Language: English
• Subjects: Antibodies; Antigens; Avidity; B cells; Biology and Life Sciences; Circumsporozoite protein; Disease transmission; Fibroblasts; Flow cytometry; Genetic aspects; Germinal centers; Health aspects; Humoral immunity; Immunization; Immunoglobulin G; Immunological memory; Immunology; Infections; Lymphocytes B; Malaria; Maturation; Medicine and Health Sciences; Memory cells; Mosquitoes; Mutation; Next-generation sequencing; Parasites; Patient outcomes; Plasmodium; Polyclonal antibodies; Proteins; Regulatory approval; Research and Analysis Methods; Somatic hypermutation; Vaccines; Vector-borne diseases; Viral antibodies
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1010671

Blocking Plasmodium , the causative agent of malaria, at the asymptomatic pre-erythrocytic stage would abrogate disease pathology and prevent transmission. However, the lack of well-defined features within vaccine-elicited antibody responses that correlate with protection represents a major roadblock to improving on current generation vaccines. We vaccinated mice (BALB/cJ and C57BL/6J) with Py circumsporozoite protein (CSP), the major surface antigen on the sporozoite, and evaluated vaccine-elicited humoral immunity and identified immunological factors associated with protection after mosquito bite challenge. Vaccination achieved 60% sterile protection and otherwise delayed blood stage patency in BALB/cJ mice. In contrast, all C57BL/6J mice were infected similar to controls. Protection was mediated by antibodies and could be passively transferred from immunized BALB/cJ mice into naïve C57BL/6J. Dissection of the underlying immunological features of protection revealed early deficits in antibody titers and polyclonal avidity in C57BL/6J mice. Additionally, Py CSP-vaccination in BALB/cJ induced a significantly higher proportion of antigen-specific B-cells and class-switched memory B-cell (MBCs) populations than in C57BL/6J mice. Strikingly, C57BL/6J mice also had markedly fewer CSP-specific germinal center experienced B cells and class-switched MBCs compared to BALB/cJ mice. Analysis of the IgG γ chain repertoires by next generation sequencing in Py CSP-specific memory B-cell repertoires also revealed higher somatic hypermutation rates in BALB/cJ mice than in C57BL/6J mice. These findings indicate that the development of protective antibody responses in BALB/cJ mice in response to vaccination with Py CSP was associated with increased germinal center activity and somatic mutation compared to C57BL/6J mice, highlighting the key role B cell maturation may have in the development of vaccine-elicited protective antibodies against CSP.