Naturally acquired IgG responses to Plasmodium falciparum do not target the conserved termini of the malaria vaccine candidate Merozoite Surface Protein 2

Front Immunol. 2024 Dec 9:15:1501700. doi: 10.3389/fimmu.2024.1501700. eCollection 2024.

Abstract

Introduction: Malaria remains a significant burden, and a fully protective vaccine against Plasmodium falciparum is critical for reducing morbidity and mortality. Antibody responses against the blood-stage antigen Merozoite Surface Protein 2 (MSP2) are associated with protection from P. falciparum malaria, but its extensive polymorphism is a barrier to its development as a vaccine candidate. New tools, such as long-read sequencing and accurate protein structure modelling allow us to study the genetic diversity and immune responses towards antigens from clinical isolates with unprecedented detail. This study sought to better understand naturally acquired MSP2-specific antibody responses.

Methods: IgG responses against recombinantly expressed full-length, central polymorphic regions, and peptides derived from the conserved termini of MSP2 variants sequenced from patient isolates, were tested in plasma from travelers with recent, acute malaria and from individuals living in an endemic area of Tanzania.

Results: IgG responses towards full MSP2 and truncated MSP2 antigens were variant specific. IgG antibodies in the plasma of first-time infected or previously exposed travelers did not recognize the conserved termini of expressed MSP2 variants by ELISA, but they bound 13-amino acid long linear epitopes from the termini in a custom-made peptide array. Alphafold3 modelling suggests extensive structural heterogeneity in the conserved termini upon antigen oligomerization. IgG from individuals living in an endemic region, many who were asymptomatically infected, did not recognize the conserved termini by ELISA.

Discussion: Our results suggest that responses to the variable regions are critical for the development of naturally acquired immunity towards MSP2.

Keywords: antibody response; immune evasion; malaria vaccine; merozoite; natural immunity; polymorphic antigens; structural heterogeneity.

MeSH terms

  • Adolescent
  • Adult
  • Antibodies, Protozoan* / blood
  • Antibodies, Protozoan* / immunology
  • Antigens, Protozoan* / immunology
  • Epitopes / immunology
  • Female
  • Humans
  • Immunoglobulin G* / blood
  • Immunoglobulin G* / immunology
  • Malaria Vaccines* / immunology
  • Malaria, Falciparum* / immunology
  • Malaria, Falciparum* / parasitology
  • Malaria, Falciparum* / prevention & control
  • Male
  • Middle Aged
  • Plasmodium falciparum* / immunology
  • Protozoan Proteins* / genetics
  • Protozoan Proteins* / immunology
  • Tanzania
  • Young Adult

Substances

  • Immunoglobulin G
  • merozoite surface protein 2, Plasmodium
  • Antigens, Protozoan
  • Protozoan Proteins
  • Antibodies, Protozoan
  • Malaria Vaccines
  • Epitopes

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Swedish Research Council grants 2018-02688, 2018-04468, 2021-04072, and 2021-03105. In addition, grants 2020-02084 and 2021-00315 from Karolinska Institutet and grants 960104 and 986923 from Region Stockholm ALF funded part of this research. The work conducted at NGI/Uppsala Genome Center was funded by RFI/VR and the Science for Life Laboratory, Sweden. Data processing and storage were made possible through resources supplied by the Swedish National Infrastructure for Computing (SNIC) at the Uppsala Multidisciplinary Center for Advanced Computational Science, with partial funding from the Swedish Research Council (VR 2018-05973). Additionally, bioinformatics analysis for longread sequencing data and protein structure predictions in Alphafold2 were carried out using the Galaxy server, which is partially funded by the Collaborative Research Center 992 Medical Epigenetics (DFG grant SFB 992/1 2012) and the German Federal Ministry of Education and Research (BMBF grants 031 A538A/A538C RBC, 031L0101B/031L0101C de.NBIepi, and 031L0106 de.STAIR (de.NBI)).