Vaccination with mRNA-encoded nanoparticles drives early maturation of HIV bnAb precursors in humans

Jordan R Willis^#^{1

2

3}, Madhu Prabhakaran^#⁴, Michelle Muthui^#⁵, Ansuya Naidoo^#⁶, Troy Sincomb^#^{1

2

3}, Weiwei Wu^#⁴, Christopher A Cottrell^#^{1

2

3}, Elise Landais^#^{1

2

3}, Allan C deCamp^#⁷, Nahid R Keshavarzi⁶, Oleksandr Kalyuzhniy^{1

2

3}, Jeong Hyun Lee^{1

2

3}, Linda M Murungi⁸, Wilfrida A Ogonda⁵, Nicole L Yates⁹, Martin M Corcoran¹⁰, Swastik Phulera^{3

11}, Joel Musando¹², Amanda Tsai⁷, Gabrielle Lemire⁷, Yiakon Sein⁵, Michael Muteti⁵, Praveen Alamuri⁶, Jennifer A Bohl⁴, Drienna Holman⁷, Sunny Himansu¹³, Brett Leav¹³, Caroline Reuter¹³, Li-An Lin¹³, Baoyu Ding¹³, Chunla He¹³, Walter L Straus¹³, Kellie J MacPhee⁷, Isabel Regadas¹⁰, Diana V Nyabundi⁵, Ruth Chirchir¹², Omu Anzala¹², John N Kimotho⁵, Caleb Kibet⁹, Kelli Greene¹⁴, Hongmei Gao¹⁴, Erica Beatman⁷, Kiara Benson⁶, Dominick Laddy⁶, David M Brown¹⁵, Rhianna Bronson⁴, Jalen Jean-Baptiste⁴, Suprabhath Gajjala⁴, Zahra Rikhtegaran-Tehrani⁴, Alison Benner⁴, Mukundhan Ramaswami⁴, Danny Lu^{1

2

3}, Nushin Alavi^{1

2

3}, Sonya Amirzehni^{1

2

3}, Michael Kubitz^{1

2

3}, Ryan Tingle^{1

2

3}, Erik Georgeson^{1

2

3}, Nicole Phelps^{1

2

3}, Yumiko Adachi^{1

2

3}, Alessia Liguori^{1

2

3}, Claudia Flynn^{1

2

3}, Katherine McKenney^{1

2

3}, Xiaoya Zhou^{1

2

3}, D Collins Owuor⁴, Sharon A Owuor⁴, Soo-Young Kim⁷, Michael Duff⁷, Ju Yeong Kim⁷, Grace Gibson¹¹, Sabyasachi Baboo¹¹, Jolene Diedrich¹¹, Torben Schiffner^{1

2

3}, Marisa Shields⁶, Mabela Matsoso⁶, Jennifer Santos⁶, Kristen Syvertsen⁶, Allison Kennedy⁶, Melissa Schroeter⁶, Johan Vekemans⁶, John R Yates 3rd¹¹, James C Paulson^{1

3}, Ollivier Hyrien⁷, Adrian B McDermott¹⁶, Pholo Maenetje¹⁷, Julien Nyombayire¹⁸, Etienne Karita¹⁸, Rosine Ingabire¹⁸, Vinodh Edward^{17

19

20}, Vincent Muturi-Kioi⁸, Janine Maenza^{7

21}, Adrienne E Shapiro^{7

21}, M Juliana McElrath^{7

21}, Srilatha Edupuganti²², Barbara S Taylor²³, David Diemert^{24

25}, Gabriel Ozorowski^{2

3

11}, Richard A Koup⁴, David Montefiori¹⁴, Andrew B Ward^{2

3

11}, Gunilla B Karlsson Hedestam¹⁰, Georgia Tomaras⁹, Devin J Hunt⁶, Daniel Muema¹², Devin Sok⁶, Dagna S Laufer⁶, Sarah F Andrews⁴, Eunice W Nduati⁵, William R Schief^{1

2

3

13}

Affiliations

¹ Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
² IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, USA.
³ Center for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA, USA.
⁴ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁵ Kenya Medical Research Institute - Wellcome Trust Research Programme, Kilifi, Kenya.
⁶ IAVI, New York, NY, USA.
⁷ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
⁸ IAVI, Nairobi, Kenya.
⁹ Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.
¹⁰ Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
¹¹ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.
¹² KAVI - Institute of Clinical Research, University of Nairobi, Nairobi, Kenya.
¹³ Moderna, Cambridge, MA, USA.
¹⁴ Duke University Medical Center, Durham, NC, USA.
¹⁵ The Foundation for the National Institutes of Health, North Bethesda, MD, USA.
¹⁶ Vaccines Research and Development, Sanofi, Swiftwater, PA, USA.
¹⁷ The Aurum Institute, Rustenburg Research Centre, Rustenburg, South Africa.
¹⁸ Center For Family Health Research, Kicukiro, Kigali, Rwanda.
¹⁹ Department of Medicine, Vanderbilt University, Nashville, TN, USA.
²⁰ School of Health Sciences, College of Health Sciences, Westville Campus, University of KwaZulu-Natal, Durban, South Africa.
²¹ Department of Medicine, University of Washington, Seattle, WA, USA.
²² Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
²³ Division of Infectious Diseases, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
²⁴ Department of Microbiology, Immunology and Tropical Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.
²⁵ Department of Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.

^# Contributed equally.

PMID: 40373112
DOI: 10.1126/science.adr8382

Clinical Trial

Vaccination with mRNA-encoded nanoparticles drives early maturation of HIV bnAb precursors in humans

Jordan R Willis et al. Science. 2025.

. 2025 Jul 31;389(6759):eadr8382.

doi: 10.1126/science.adr8382. Epub 2025 Jul 31.

Authors

Affiliations

¹ Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.
² IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, USA.
³ Center for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA, USA.
⁴ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁵ Kenya Medical Research Institute - Wellcome Trust Research Programme, Kilifi, Kenya.
⁶ IAVI, New York, NY, USA.
⁷ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
⁸ IAVI, Nairobi, Kenya.
⁹ Center for Human Systems Immunology, Departments of Surgery, Immunology, Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.
¹⁰ Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
¹¹ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.
¹² KAVI - Institute of Clinical Research, University of Nairobi, Nairobi, Kenya.
¹³ Moderna, Cambridge, MA, USA.
¹⁴ Duke University Medical Center, Durham, NC, USA.
¹⁵ The Foundation for the National Institutes of Health, North Bethesda, MD, USA.
¹⁶ Vaccines Research and Development, Sanofi, Swiftwater, PA, USA.
¹⁷ The Aurum Institute, Rustenburg Research Centre, Rustenburg, South Africa.
¹⁸ Center For Family Health Research, Kicukiro, Kigali, Rwanda.
¹⁹ Department of Medicine, Vanderbilt University, Nashville, TN, USA.
²⁰ School of Health Sciences, College of Health Sciences, Westville Campus, University of KwaZulu-Natal, Durban, South Africa.
²¹ Department of Medicine, University of Washington, Seattle, WA, USA.
²² Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
²³ Division of Infectious Diseases, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
²⁴ Department of Microbiology, Immunology and Tropical Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.
²⁵ Department of Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.

^# Contributed equally.

PMID: 40373112
DOI: 10.1126/science.adr8382

Abstract

A leading HIV vaccine strategy requires a priming immunogen to induce broadly neutralizing antibody (bnAb) precursors, followed by a series of heterologous boosters to elicit somatic hypermutation (SHM) and produce bnAbs. In two randomized, open-label phase 1 human clinical trials, IAVI G002 in the United States and IAVI G003 in Rwanda and South Africa (IAVI, International Aids Vaccine Initiative), we evaluated the safety and immunogenicity of mRNA-encoded nanoparticles as priming immunogens (both trials) and first-boosting immunogens (IAVI G002). The vaccines were generally safe and well tolerated, except that 18% of IAVI G002 participants experienced skin reactions. Priming induced bnAb precursors with substantial frequencies and SHM; heterologous boosting elicited increased SHM, affinity, and neutralization activity toward bnAb development; and elicited antibodies exhibited precise bnAb structural mimicry. The results establish clinical proof of concept that heterologous boosting can advance bnAb precursor maturation and demonstrate bnAb priming in Africa, where the HIV burden is highest.

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Evolving rare B cell lineages for an effective HIV vaccine.
Permar SR, Wilson PC. Permar SR, et al. Science. 2025 Jul 31;389(6759):455-457. doi: 10.1126/science.adz6436. Epub 2025 Jul 31. Science. 2025. PMID: 40743359

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Vaccination with mRNA-encoded nanoparticles drives early maturation of HIV bnAb precursors in humans

Affiliations

Vaccination with mRNA-encoded nanoparticles drives early maturation of HIV bnAb precursors in humans

Authors

Affiliations

Abstract

Comment in

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical