Elicitation of liver-stage immunity by nanoparticle immunogens displaying P. falciparum CSP-derived antigens

Mark D Langowski; Joseph R Francica; Alex L Roederer; Nicholas K Hurlburt; Justas V Rodarte; Lais Da Silva Pereira; Barbara J Flynn; Brian Bonilla; Marlon Dillon; Patience Kiyuka; Rashmi Ravichandran; Connor Weidle; Lauren Carter; Mangala Rao; Gary R Matyas; Marion Pepper; Azza H Idris; Robert A Seder; Marie Pancera; Neil P King

doi:10.1038/s41541-025-01140-x

Elicitation of liver-stage immunity by nanoparticle immunogens displaying P. falciparum CSP-derived antigens

NPJ Vaccines. 2025 May 5;10(1):87. doi: 10.1038/s41541-025-01140-x.

Authors

Mark D Langowski^{1

2

3}, Joseph R Francica⁴, Alex L Roederer¹, Nicholas K Hurlburt⁵, Justas V Rodarte⁵, Lais Da Silva Pereira⁴, Barbara J Flynn⁴, Brian Bonilla⁴, Marlon Dillon⁴, Patience Kiyuka⁴, Rashmi Ravichandran^{1

2}, Connor Weidle⁵, Lauren Carter^{1

2}, Mangala Rao^{6

7}, Gary R Matyas^{6

7}, Marion Pepper⁸, Azza H Idris⁴, Robert A Seder⁴, Marie Pancera⁹, Neil P King^{10

11}

Affiliations

¹ Institute for Protein Design, University of Washington, Seattle, WA, USA.
² Department of Biochemistry, University of Washington, Seattle, WA, USA.
³ Graduate Program in Molecular and Cellular Biology, University of Washington, Seattle, WA, USA.
⁴ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁵ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
⁶ Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
⁷ U.S. Military HIV Research Program, Center for Infectious Diseases Research, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
⁸ Department of Immunology, University of Washington, Seattle, WA, USA.
⁹ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. mpancera@fredhutch.org.
¹⁰ Institute for Protein Design, University of Washington, Seattle, WA, USA. neilking@uw.edu.
¹¹ Department of Biochemistry, University of Washington, Seattle, WA, USA. neilking@uw.edu.

Abstract

A vaccine that provides robust, durable protection against malaria remains a global health priority. Although a breakthrough in the fight against malaria has recently been achieved by the licensure of two vaccines based on the circumsporozoite protein (CSP), the effectiveness and durability of protection can still be improved. Both vaccines contain a portion of CSP that does not include epitopes targeted by recently identified, potently protective monoclonal antibodies, suggesting that newer immunogens can expand the breadth of immunity and potentially increase protection. Here we explored >100 alternative CSP-based immunogens and evaluated the immunogenicity and protection of a large number of candidates, comparing several to the licensed R21 vaccine. The data highlight several general features that improve the stability and immunogenicity of CSP-based vaccines, such as inclusion of the C-terminal domain and high-density display on protein nanoparticle scaffolds. We also identify antigen design strategies that do not warrant further exploration, such as synthetic repeat regions that include non-native repeat cadences. The benchmark R21 vaccine outperformed our best immunogen for immunogenicity and protection. Overall, our data provide valuable insights on the inclusion of junctional region epitopes that will guide the development of potent and durable vaccines against malaria.

Abstract

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