Vaccination with mRNA-encoded membrane-anchored HIV envelope trimers elicited tier 2 neutralizing antibodies in a phase 1 clinical trial
K. Rachael Parks, Zoe Moodie, Mary Allen, Catherine Yen, Briana D. Furch, Kellie J. MacPhee, Gabriel Ozorowski, Jack Heptinstall, William O. Hahn, Zihan Zheng, Huiyin Lu, Shannon Grant, Elize Domin, Michael O. Duff, Aaron Seese, Constanza Marini-Macouzet, Lamar Ballweber-Fleming, Wen-Hsin Lee, Christopher A. Cottrell, Alessia Liguori, Erik Georgeson, Nushin Alavi, Michael Kubitz, Nicole Phelps, Kelly E. Seaton, Kristen W. Cohen, Maija Anderson, Kajari Mondal, Dagna Laufer, James G. Kublin, Andrew B. Ward, Ollivier Hyrien, Stephen C. De Rosa, Sunny Himansu, Brett Leav, Caroline Reuter, Georgia D. Tomaras, David C. Montefiori, Stephen R. Walsh, Ian Frank, Magdalena E. Sobieszczyk, Paul Goepfert, Kathryn E. Stephenson, Lindsey R. Baden, Hong‐Van Tieu, Michael C. Keefer, Jesse L. Clark, Sharon A. Riddler, William R. Schief, M. Juliana McElrath
Abstract
mRNA technology might accelerate development of an urgently needed preventive human immunodeficiency virus (HIV) vaccine. We evaluated the safety and immunogenicity of three mRNA-encoded envelope trimers, including two doses of soluble and membrane-anchored forms, in a randomized, open-label, phase 1 clinical trial. Vaccines were generally well tolerated, although 6.5% (7 of 108) of participants developed urticaria, a higher proportion than seen with other mRNA vaccines. mRNA-encoded trimers induced strong envelope-specific B and T cell responses. Immunization with membrane-anchored trimers, intended to obscure epitopes at the trimer base targeted by nonneutralizing antibodies, reduced the frequency of base-binding serum antibodies in comparison with soluble trimers. Three immunizations elicited autologous tier 2 serum neutralizing antibodies in 80% of vaccinees receiving the membrane-anchored trimers, in contrast to only 4% receiving the soluble trimer. Thus, with demonstration of more favorable safety, mRNA-encoded membrane-anchored HIV envelope trimers represent a promising platform for HIV vaccine clinical development.