Antibodies elicited by Plasmodium falciparum circumsporozoite proteins lacking sequentially deleted C-terminal amino acids reveal mouse strain and epitopes specific differences

Clifford T H Hayashi; Yi Cao; Fidel Zavala; Hayk Simonyan; Colin N Young; Nirbhay Kumar

doi:10.1016/j.vaccine.2023.10.009

Antibodies elicited by Plasmodium falciparum circumsporozoite proteins lacking sequentially deleted C-terminal amino acids reveal mouse strain and epitopes specific differences

Vaccine. 2023 Oct 10:S0264-410X(23)01179-9. doi: 10.1016/j.vaccine.2023.10.009. Online ahead of print.

Authors

Clifford T H Hayashi¹, Yi Cao¹, Fidel Zavala², Hayk Simonyan³, Colin N Young³, Nirbhay Kumar⁴

Affiliations

¹ Department of Global Health, Milken Institute School of Public Health, George Washington University, Washington DC 20052, USA.
² Johns Hopkins Malaria Research Institute, Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21215, USA.
³ Department of Pharmacology and Physiology, School of Medicine and Health Sciences, George Washington University, Washington DC 20052, USA.
⁴ Department of Global Health, Milken Institute School of Public Health, George Washington University, Washington DC 20052, USA. Electronic address: nkumar@gwu.edu.

PMID: 37827967
PMCID: PMC11004087 (available on 2025-04-10)
DOI: 10.1016/j.vaccine.2023.10.009

Abstract

Malaria affects ∼ ¼ billion people globally and requires the development of additional tools to aid in elimination efforts. The recently approved RTS,S/AS01 vaccine represents a positive step, however, the moderate efficacy necessitates the development of more efficacious vaccines. PfCSP is a key target antigen for pre-erythrocytic vaccines aimed at preventing Plasmodium falciparum malaria infections. Epitopes within the central repeat region and at the junction of the repeat and N-terminal domain are well documented as major protective B cell epitopes. On the other hand, a majority of antibodies against the epitopes in the C-terminal domain, have been shown to be non-protective against sporozoite challenge. The C-terminal domain, however, contains CD4⁺ and CD8⁺ T cell epitopes previously shown to be important for regulating immune responses. The present study was designed to further explore the immunomodulatory potential of the C-terminal domain using DNA vaccines encoding PfCSP with sequential C-terminal truncations following known T cell epitopes. Five DNA vaccines encoding different truncations of PfCSP within the C-terminal domain were administered via intramuscular route and in vivo electroporation for effective immunogenicity. Protection in mice was evaluated by challenge with transgenic P. berghei expressing PfCSP. In Balb/c mice, antibody responses and protective efficacy were both affected progressively with sequential deletion of C-terminal amino acid residues. Similar studies in C57Bl/6 mice revealed that immunizations with plasmids encoding truncated PfCSP showed partial protection from sporozoite challenge with no significant differences in antibody titers observed compared to full-length PfCSP DNA immunized mice. Further analysis revealed murine strain-specific differences in the recognition of specific epitopes.

Keywords: Circumsporozoite protein; Malaria; Plasmodium falciparum; Vaccine.

Grants and funding

R01 AI127544/AI/NIAID NIH HHS/United States