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<p><i>P. falciparum</i> (<i>Pf</i>) 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 (<i>Pf</i>CSP). 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 <i>P. berghei</i> sporozoites have been engineered to contain <i>Pf</i>CSP instead of the native <i>Pb</i>CSP 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.</p>

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Epitope-selective vaccine designs to elicit protective antibodies against the Plasmodium falciparum circumsporozoite protein

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月3日

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  • Mohammad Naghizadeh,
  • Yevel Flores-Garcia,
  • Reem Moskovitz,
  • Sayit Mahmut Erdogan,
  • Gregory M. Martin,
  • Ebenezer Addo Ofori,
  • Jordan Plieskatt,
  • Fabien Cannac,
  • Randall S. MacGill,
  • Morten Agertoug Nielsen,
  • Emily Locke,
  • C. Richter King,
  • Kazutoyo Miura,
  • Ashley Birkett,
  • Lorraine A. Soisson,
  • Adam F. Sander,
  • Kristin Skogstrand,
  • Lea Barfod,
  • Berenice Salgado-Jimenez,
  • Nis Borbye-Lorenzen,
  • Ian A. Wilson,
  • Andrew B. Ward,
  • Fidel Zavala,
  • Michael Theisen

摘要

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.