mRNA-encoded HIV-1 Env trimer ferritin nanoparticles induce monoclonal antibodies that neutralize heterologous HIV-1 isolates in mice
Zekun Mu, Kevin Wiehe, Kevin O. Saunders, Rory Henderson, Derek W. Cain, Robert Parks, Diana Martik, Katayoun Mansouri, Robert J. Edwards, Amanda Newman, Xiaozhi Lu, Shi-Mao Xia, Amanda Eaton, Mattia Bonsignori, David C. Montefiori, Qi Han, Sravani Venkatayogi, Tyler Evangelous, Yunfei Wang, Wes Rountree, Bette Korber, Kshitij Wagh, Ying K. Tam, Christopher Barbosa, S. Munir Alam, Wilton B. Williams, Ming Tian, Frederick W. Alt, Norbert Pardi, Drew Weissman, Barton F. Haynes
Abstract
The success of nucleoside-modified mRNAs in lipid nanoparticles (mRNA-LNP) as COVID-19 vaccines heralded a new era of vaccine development. For HIV-1, multivalent envelope (Env) trimer protein nanoparticles are superior immunogens compared with trimers alone for priming of broadly neutralizing antibody (bnAb) B cell lineages. The successful expression of complex multivalent nanoparticle immunogens with mRNAs has not been demonstrated. Here, we show that mRNAs can encode antigenic Env trimers on ferritin nanoparticles that initiate bnAb precursor B cell expansion and induce serum autologous tier 2 neutralizing activity in bnAb precursor V H + V L knock-in mice. Next-generation sequencing demonstrates acquisition of critical mutations, and monoclonal antibodies that neutralize heterologous HIV-1 isolates are isolated. Thus, mRNA-LNP can encode complex immunogens and may be of use in design of germline-targeting and sequential boosting immunogens for HIV-1 vaccine development.