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

作者：Jordan R. Willis, Madhu Prabhakaran, Michelle K. Muthui, Ansuya Naidoo, Troy Sincomb, Weiwei Wu, Christopher A. Cottrell, Elise Landais, Allan C. deCamp, Nahid Keshavarzi, Oleksandr Kalyuzhniy, Jeong Hyun Lee, Linda Murungi, Wilfrida A Ogonda, Nicole L. Yates, Martin Corcoran, Swastik Phulera, Joel Musando, Amanda Tsai, Gabrielle Lemire, Yiakon Sein, Michael Muteti, Praveen Alamuri, Jennifer A. Bohl, Drienna Holman, Sunny Himansu, Brett Leav, Caroline Reuter, Li‐An Lin, Baoyu Ding, Chunla He, Walter L. Straus, Kellie J. MacPhee, Isabel Regadas, Diana Nyabundi, Ruth Chirchir, Omu Anzala, John Kimotho, Caleb K. Kibet, Kelli Greene, Hongmei Gao, Erica L. Beatman, K Benson, Dominick J. Laddy, David M. Brown, Rhianna Bronson, Jalen Baptiste, Suprabhath Gajjala, Zahra Rikhtegaran Tehrani, Alison Benner, Mukundhan Ramaswami, Danny Lu, Nushin Alavi, Sonya Amirzehni, Michael Kubitz, Ryan Tingle, Erik Georgeson, Nicole Phelps, Yumiko Adachi, Alessia Liguori, Claudia Flynn, Katherine McKenney, Xiaoya Zhou, D. Collins Owuor, Sharon Owuor, S Kim, Michael Duff, Ju Yeong Kim, Grace Gibson, Sabyasachi Baboo, Jolene K. Diedrich, Torben Schiffner, Marisa Shields, Mabela Matsoso, Jairo Ivo dos Santos, Kristen Syvertsen, Allison Kennedy, Melissa Schroeter, Johan Vekemans, John R. Yates, James C. Paulson, Ollivier Hyrien, Adrian B. McDermott, Pholo Maenetje, Julien Nyombayire, Etienne Karita, Rosine Ingabire, Vinodh Edward, Vincent Muturi‐Kioi, Janine Maenza, Adrienne E. Shapiro, M. Juliana McElrath, Srilatha Edupuganti, Barbara S. Taylor, David Diemert, Gabriel Ozorowski, Richard A. Koup, David C. Montefiori, Andrew B. Ward, Gunilla B. Karlsson Hedestam, Georgia D. Tomaras, Devin J Hunt, Daniel Muema, Devin Sok, Dagna Laufer, Sarah F. Andrews, Eunice Nduati, William R. Schief · 发表于：Science · 年份：2025 · DOI：10.1126/science.adr8382 · 被引用次数：67 · 研究领域：HIV Research and Treatment、HIV/AIDS Research and Interventions、Immunotherapy and Immune Responses

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.