Epitope-selective vaccine designs to elicit protective antibodies against the Plasmodium falciparum circumsporozoite protein
9 affiliations
- 1Statens Serum Institut (SSI), Copenhagen, Denmark
- 2Centre for translational Medicine and Parasitology at Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- 3Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD USA
- 4Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA USA
- 5Present Address: Deptartment of Biomedical Sciences, College of Veterinary Medicine, Iowa State University of Science and Technology, Ames, IA USA
- 6Present Address: Research Institute for Development (IRD), Faculty of Pharmacy, University of Paris Cité, Paris, France
- 7Center for Vaccine Innovation and Access, PATH, Washington, DC USA
- 8Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD USA
- 9USAID, 1300 Pennsylvania Ave. NW, Washington, DC USA
Abstract
P. falciparum (Pf) malaria is a major cause of morbidity and mortality in sub-Saharan Africa. Recently introduced malaria vaccines, RTS,S/AS01 and R21/Matrix-M, are effective in preventing infection, but their efficacy declines over time. To address this challenge, next-generation vaccine candidates have been designed to improve the functional immunogenicity to the circumsporozoite protein (PfCSP). In this study, we tested multiple hypotheses for improved vaccine design. Immunogens were constructed to target regions containing functional epitopes, and these were displayed on a well-characterized clinically relevant particle display platform. These candidate vaccines were tested in the established infection mouse model in which P. berghei sporozoites have been engineered to contain PfCSP instead of the native PbCSP protein. Our results show that induction of antibodies to the junctional region and the minor and major repeats are all effective at reducing parasite infection of the liver, while antibodies to the C-terminal domain did not contribute to protective immunity. None of the domains showed evidence of antigenic competition when co-administered on separate particles or when expressed on the surface of a single particle. Immunogens expected to allow bivalent antibody binding were potently immunogenic while those with shorter structures permitting only 1-2 Fab binding interactions exhibited poor immunogenicity. No construct was found to be superior to the clinical benchmark RTS,S/AS01 in the mouse model. These results can inform approaches to malaria vaccine design and direct future research.
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BibTeX
@article{naghizadeh2026epitopeselective,
title = {{Epitope-selective vaccine designs to elicit protective antibodies against the Plasmodium falciparum circumsporozoite protein}},
author = {Mohammad Naghizadeh and Yevel Flores-Garcia and Reem Moskovitz and Sayit Mahmut Erdogan and Gregory M. Martin and Ebenezer Addo Ofori and Jordan Plieskatt and Fabien Cannac and Randall S. MacGill and Morten Agertoug Nielsen and Emily Locke and C. Richter King and Kazutoyo Miura and Ashley Birkett and Lorraine A. Soisson and Adam F. Sander and Kristin Skogstrand and Lea Barfod and Berenice Salgado-Jimenez and Nis Borbye-Lorenzen and Ian A. Wilson and Andrew B. Ward and Fidel Zavala and Michael Theisen},
journal = {NPJ Vaccines},
year = {2026},
month = jul,
doi = {10.1038/s41541-026-01518-5},
url = {https://doi.org/10.1038/s41541-026-01518-5},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Epitope-selective vaccine designs to elicit protective antibodies against the Plasmodium falciparum circumsporozoite protein
AU - Mohammad Naghizadeh
AU - Yevel Flores-Garcia
AU - Reem Moskovitz
AU - Sayit Mahmut Erdogan
AU - Gregory M. Martin
AU - Ebenezer Addo Ofori
AU - Jordan Plieskatt
AU - Fabien Cannac
AU - Randall S. MacGill
AU - Morten Agertoug Nielsen
AU - Emily Locke
AU - C. Richter King
AU - Kazutoyo Miura
AU - Ashley Birkett
AU - Lorraine A. Soisson
AU - Adam F. Sander
AU - Kristin Skogstrand
AU - Lea Barfod
AU - Berenice Salgado-Jimenez
AU - Nis Borbye-Lorenzen
AU - Ian A. Wilson
AU - Andrew B. Ward
AU - Fidel Zavala
AU - Michael Theisen
PY - 2026
DA - 2026/07/03
JO - NPJ Vaccines
DO - 10.1038/s41541-026-01518-5
UR - https://doi.org/10.1038/s41541-026-01518-5
AB - P. falciparum (Pf) malaria is a major cause of morbidity and mortality in sub-Saharan Africa. Recently introduced malaria vaccines, RTS,S/AS01 and R21/Matrix-M, are effective in preventing infection, but their efficacy declines over time. To address this challenge, next-generation vaccine candidates have been designed to improve the functional immunogenicity to the circumsporozoite protein (PfCSP). In this study, we tested multiple hypotheses for improved vaccine design. Immunogens were constructed to target regions containing functional epitopes, and these were displayed on a well-characterized clinically relevant particle display platform. These candidate vaccines were tested in the established infection mouse model in which P. berghei sporozoites have been engineered to contain PfCSP instead of the native PbCSP protein. Our results show that induction of antibodies to the junctional region and the minor and major repeats are all effective at reducing parasite infection of the liver, while antibodies to the C-terminal domain did not contribute to protective immunity. None of the domains showed evidence of antigenic competition when co-administered on separate particles or when expressed on the surface of a single particle. Immunogens expected to allow bivalent antibody binding were potently immunogenic while those with shorter structures permitting only 1-2 Fab binding interactions exhibited poor immunogenicity. No construct was found to be superior to the clinical benchmark RTS,S/AS01 in the mouse model. These results can inform approaches to malaria vaccine design and direct future research.
SN - 2059-0105
ER -