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

PLoS Pathog. 2022 Jul 6;18(7):e1010671. doi: 10.1371/journal.ppat.1010671. eCollection 2022 Jul.

Abstract

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, PyCSP-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 PyCSP-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 PyCSP 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Protozoan
  • Antibody Formation
  • Germinal Center
  • Malaria Vaccines*
  • Malaria*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Protozoan Proteins / genetics

Substances

  • Antibodies, Protozoan
  • Malaria Vaccines
  • Protozoan Proteins

Grants and funding

The project is funded by W.M.Keck Foundation (award number: PT-18-726). DNS and AK are recipients of this funding. http://www.wmkeck.org/grant-programs/research/medical-research-grant-abstracts/medical-research-2018/1850-medical-research-grant-abstracts-center-for-infectious-disease-research The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.