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

• 成果类型: Article
• 署名作者: Willis, Jordan R.; Prabhakaran, Madhu; Muthui, Michelle; Naidoo, Ansuya; Sincomb, Troy; Wu, Weiwei; Cottrell, Christopher A.; Landais, Elise; deCamp, Allan C.; Keshavarzi, Nahid R.; Kalyuzhniy, Oleksandr; Lee, Jeong Hyun; Murungi, Linda M.; Ogonda, Wilfrida A.; Yates, Nicole L.; Corcoran, Martin M.; Phulera, Swastik; Musando, Joel; Tsai, Amanda; Lemire, Gabrielle; Sein, Yiakon; Muteti, Michael; Alamuri, Praveen; Bohl, Jennifer A.; Holman, Drienna; Himansu, Sunny; Leav, Brett; Reuter, Caroline; Lin, Li-An; Ding, Baoyu; He, Chunla; Straus, Walter L.; MacPhee, Kellie J.; Regadas, Isabel; Nyabundi, Diana V.; Chirchir, Ruth; Anzala, Omu; Kimotho, John N.; Kibet, Caleb; Greene, Kelli; Gao, Hongmei; Beatman, Erica; Benson, Kiara; Laddy, Dominick; Brown, David M.; Bronson, Rhianna; Jean-Baptiste, Jalen; Gajjala, Suprabhath; Rikhtegaran-Tehrani, Zahra; Benner, Alison; Ramaswami, Mukundhan; Lu, Danny; Alavi, Nushin; Amirzehni, Sonya; Kubitz, Michael; Tingle, Ryan; Georgeson, Erik; Phelps, Nicole; Adachi, Yumiko; Liguori, Alessia; Flynn, Claudia; McKenney, Katherine; Zhou, Xiaoya; Owuor, D. Collins; Owuor, Sharon A.; Kim, Soo-Young; Duff, Michael; Kim, Ju Yeong; Gibson, Grace; Baboo, Sabyasachi; Diedrich, Jolene; Schiffner, Torben; Shields, Marisa; Matsoso, Mabela; Santos, Jennifer; Syvertsen, Kristen; Kennedy, Allison; Schroeter, Melissa; Vekemans, Johan; Yates III, John R.; Paulson, James C.; Hyrien, Ollivier; Mcdermott, Adrian B.; Maenetje, Pholo; Nyombayire, Julien; Karita, Etienne; Ingabire, Rosine; Edward, Vinodh; Muturi-Kioi, Vincent; Maenza, Janine; Shapiro, Adrienne E.; Mcelrath, M. Juliana; Edupuganti, Srilatha; Taylor, Barbara S.; Diemert, David; Ozorowski, Gabriel; Koup, Richard A.; Montefiori, David; Ward, Andrew B.; Karlsson Hedestam, Gunilla B.; Tomaras, Georgia; Hunt, Devin J.; Muema, Daniel; Sok, Devin; Laufer, Dagna S.; Andrews, Sarah F.; Nduati, Eunice W.; Schief, William R.
• 署名单位: Scripps Research Institute; International AIDS Vaccine Initiative; Scripps Research Institute; Scripps Research Institute; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); Kenya Medical Research Institute; International AIDS Vaccine Initiative; Fred Hutchinson Cancer Center; International AIDS Vaccine Initiative; Duke University; Duke University; Duke University; Karolinska Institutet; Scripps Research Institute; University of Nairobi; Duke University; Sanofi-Aventis; Sanofi USA; Vanderbilt University; University of Kwazulu Natal; University of Texas System; University of Texas at San Antonio; George Washington University; George Washington University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9312
• DOI: 10.1126/science.adr8382
• 发表日期: 2025-07-31
• 关键词: neutralizing antibodies; immune activation; b-cells; immunization; infections; diversity; responses; DESIGN; memory; site

摘要

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.