Vaccination with mRNA-encoded nanoparticles drives early maturation of HIV bnAb precursors in humans
Jordan R. Willis(Scripps Research Institute), Madhu Prabhakaran(National Institutes of Health), Michelle K. Muthui(Kenya Medical Research Institute), Ansuya Naidoo(International AIDS Vaccine Initiative), Troy Sincomb(Scripps Research Institute), Weiwei Wu(National Institutes of Health), Christopher A. Cottrell(Scripps Research Institute), Elise Landais(Scripps Research Institute), Allan C. deCamp(Fred Hutch Cancer Center), Nahid Keshavarzi(International AIDS Vaccine Initiative), Oleksandr Kalyuzhniy(Scripps Research Institute), Jeong Hyun Lee(Scripps Research Institute), Linda Murungi(Kenya AIDS Vaccine Initiative), Wilfrida A Ogonda(Kenya Medical Research Institute), Nicole L. Yates(Duke University), Martin Corcoran(Karolinska Institutet), Swastik Phulera(Scripps Research Institute), Joel Musando(University of Nairobi), Amanda Tsai(Fred Hutch Cancer Center), Gabrielle Lemire(Fred Hutch Cancer Center), Yiakon Sein(Kenya Medical Research Institute), Michael Muteti(Kenya Medical Research Institute), Praveen Alamuri(International AIDS Vaccine Initiative), Jennifer A. Bohl(National Institutes of Health), Drienna Holman(Fred Hutch Cancer Center), Sunny Himansu(Moderna Therapeutics (United States)), Brett Leav(Moderna Therapeutics (United States)), Caroline Reuter(Moderna Therapeutics (United States)), Li‐An Lin(Moderna Therapeutics (United States)), Baoyu Ding(Moderna Therapeutics (United States)), Chunla He(Moderna Therapeutics (United States)), Walter L. Straus(Moderna Therapeutics (United States)), Kellie J. MacPhee(Fred Hutch Cancer Center), Isabel Regadas(Karolinska Institutet), Diana Nyabundi(Kenya Medical Research Institute), Ruth Chirchir(University of Nairobi), Omu Anzala(University of Nairobi), John Kimotho(Kenya Medical Research Institute), Caleb K. Kibet(Duke University), Kelli Greene(Duke Medical Center), Hongmei Gao(Duke Medical Center), Erica L. Beatman(Fred Hutch Cancer Center), K Benson(International AIDS Vaccine Initiative), Dominick J. Laddy(International AIDS Vaccine Initiative), David M. Brown(Foundation for the National Institutes of Health), Rhianna Bronson(National Institutes of Health), Jalen Baptiste(National Institutes of Health), Suprabhath Gajjala(National Institutes of Health), Zahra Rikhtegaran Tehrani(National Institutes of Health), Alison Benner(National Institutes of Health), Mukundhan Ramaswami(National Institutes of Health), Danny Lu(Scripps Research Institute), Nushin Alavi(Scripps Research Institute), Sonya Amirzehni(Scripps Research Institute), Michael Kubitz(Scripps Research Institute), Ryan Tingle(Scripps Research Institute), Erik Georgeson(Scripps Research Institute), Nicole Phelps(Scripps Research Institute), Yumiko Adachi(Scripps Research Institute), Alessia Liguori(Scripps Research Institute), Claudia Flynn(Scripps Research Institute), Katherine McKenney(Scripps Research Institute), Xiaoya Zhou(Scripps Research Institute), D. Collins Owuor(National Institutes of Health), Sharon Owuor(National Institutes of Health), S Kim(Fred Hutch Cancer Center), Michael Duff(Fred Hutch Cancer Center), Ju Yeong Kim(Fred Hutch Cancer Center), Grace Gibson(Scripps Research Institute), Sabyasachi Baboo(Scripps Research Institute), Jolene K. Diedrich(Scripps Research Institute), Torben Schiffner(Scripps Research Institute), Marisa Shields(International AIDS Vaccine Initiative), Mabela Matsoso(International AIDS Vaccine Initiative), Jairo Ivo dos Santos(International AIDS Vaccine Initiative), Kristen Syvertsen(International AIDS Vaccine Initiative), Allison Kennedy(International AIDS Vaccine Initiative), Melissa Schroeter(International AIDS Vaccine Initiative), Johan Vekemans(International AIDS Vaccine Initiative), John R. Yates(Scripps Research Institute), James C. Paulson(Scripps Research Institute), Ollivier Hyrien(Fred Hutch Cancer Center), Adrian B. McDermott(Swift Engineering (United States)), Pholo Maenetje(Aurum Institute), Julien Nyombayire(Rwanda Biomedical Center), Etienne Karita(Rwanda Biomedical Center), Rosine Ingabire(Rwanda Biomedical Center), Vinodh Edward(Vanderbilt University), Vincent Muturi‐Kioi(Kenya AIDS Vaccine Initiative), Janine Maenza(University of Washington), Adrienne E. Shapiro(University of Washington), M. Juliana McElrath(University of Washington), Srilatha Edupuganti(Emory University), Barbara S. Taylor(The University of Texas at San Antonio Health Science Center), David Diemert(George Washington University), Gabriel Ozorowski(Scripps Research Institute), Richard A. Koup(National Institutes of Health), David C. Montefiori(Duke Medical Center), Andrew B. Ward(Scripps Research Institute), Gunilla B. Karlsson Hedestam(Karolinska Institutet), Georgia D. Tomaras(Duke University), Devin J Hunt(International AIDS Vaccine Initiative), Daniel Muema(University of Nairobi), Devin Sok(International AIDS Vaccine Initiative), Dagna Laufer(International AIDS Vaccine Initiative), Sarah F. Andrews(National Institutes of Health), Eunice Nduati(Kenya Medical Research Institute), William R. Schief(Scripps Research Institute)
Cited by 51Open Access
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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