mRNA delivery of circumsporozoite protein epitope-based malaria vaccines induces protection in a mouse model

Nelson R Wu; Nathan Beutler; Xiaozhen Hu; Patrick D Skog; Alessia Liguori; Yevel Flores-Garcia; Laura Maiorino; Sierra Terada; Danny Lu; Yen-Chung Lai; Justin Ndihokubwayo; Torben Schiffner; Christopher A Cottrell; Saman Eskandarzadeh; Nushin Alavi; Michael Kubitz; Nicole Phelps; Ryan Tingle; Sam Hodges; John E Youhanna; Sonya Amirzehni; Darrell J Irvine; Sunny Himansu; Fidel Zavala; Thomas F Rogers; Dennis R Burton; William R Schief

doi:10.1038/s41541-025-01296-6

mRNA delivery of circumsporozoite protein epitope-based malaria vaccines induces protection in a mouse model

NPJ Vaccines. 2025 Nov 18;10(1):238. doi: 10.1038/s41541-025-01296-6.

Authors

Nelson R Wu^#¹, Nathan Beutler^#¹, Xiaozhen Hu^{1

2}, Patrick D Skog^{1

3}, Alessia Liguori^{1

3}, Yevel Flores-Garcia⁴, Laura Maiorino^{5

6}, Sierra Terada^{1

3}, Danny Lu^{1

3}, Yen-Chung Lai^{1

7}, Justin Ndihokubwayo^{1

7}, Torben Schiffner^{1

3}, Christopher A Cottrell^{1

3}, Saman Eskandarzadeh^{1

3}, Nushin Alavi^{1

3}, Michael Kubitz^{1

3}, Nicole Phelps^{1

3}, Ryan Tingle^{1

3}, Sam Hodges^{1

3}, John E Youhanna^{1

3}, Sonya Amirzehni^{1

3}, Darrell J Irvine^{5

6

8}, Sunny Himansu², Fidel Zavala⁴, Thomas F Rogers^{9

10}, Dennis R Burton^{11

12

13}, William R Schief^{14

15

16}

Affiliations

¹ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
² Moderna Inc., Cambridge, MA, USA.
³ IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, USA.
⁴ Johns Hopkins Malaria Research Institute, Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
⁵ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁶ Howard Hughes Medical Institute, Chevy Chase, MD, USA.
⁷ Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
⁸ The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
⁹ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA. trogers@scripps.edu.
¹⁰ Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA, USA. trogers@scripps.edu.
¹¹ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA. burton@scripps.edu.
¹² IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, USA. burton@scripps.edu.
¹³ The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. burton@scripps.edu.
¹⁴ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA. schief@scripps.edu.
¹⁵ Moderna Inc., Cambridge, MA, USA. schief@scripps.edu.
¹⁶ IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, USA. schief@scripps.edu.

^# Contributed equally.

Abstract

Malaria is a leading cause of disease in developing countries. The licensed malaria vaccines (RTS,S/AS01 and R21/Matrix-M) have shown significant efficacy in human phase 3 trials. Vaccination with radiation-attenuated sporozoites has achieved high levels of protection against malaria in controlled infection studies, although protection was more moderate in clinical trials conducted in malaria-endemic areas. RTS,S/AS01, and R21/Matrix-M contain the repeating NANP motif and the C-terminal domain of the dominant surface circumsporozoite protein (CSP) of Plasmodium falciparum (Pf) sporozoites, but do not include the CSP N-terminal domain or epitopes in the junctional region between the N-terminal domain and the NANP repeats. In pursuit of a second-generation malaria PfCSP vaccine that surpasses the protection elicited by attenuated sporozoites and current subunit vaccines, we developed self-assembling nanoparticle immunogens each displaying one or more of four different classes of PfCSP epitope regions: NANP-repeat epitopes, junctional region-repeat epitopes, and epitopes from the N-terminal and C-terminal domains. In a mouse model of malaria infection, immunization with protein nanoparticles displaying different CSP epitope regions showed a reduction in liver burden ranging from minimal to 90%, with N- and C-terminal domains providing little reduction, but a combination of junctional and NANP repeat epitopes providing a strong reduction. mRNA-delivered nanoparticle and membrane-anchored immunogens displaying both the junctional and NANP repeat epitopes were most effective, exhibiting 99% reduction in liver burden and sterilizing immunity from parasitemia in some mice. The mRNA immunogens represent promising candidates for rapid translation to human challenge studies and could be combined with T cell vaccines to comprise a potential next-generation malaria vaccine.

Abstract

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