mRNA-encoded HIV-1 Env trimer ferritin nanoparticles induce monoclonal antibodies that neutralize heterologous HIV-1 isolates in mice

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 VH + VL 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. [Display omitted] •mRNA-expressed HIV-1 Envs are well folded with optimal stabilizing mutations•mRNA-expressed stabilized Envs show preferential bnAb binding•mRNA-LNP elicit autologous tier 2 neutralizing antibodies with key bnAb mutations•Induced monoclonal antibodies with key mutations neutralize heterologous viruses mRNA vaccines are highly effective against COVID-19. Mu et al. demonstrate the use of mRNA to express HIV-1 Env trimers scaffolded on ferritin nanoparticles. mRNA vaccination in mice induced autologous tier 2 neutralizing antibodies and key functional mutations. Isolated monoclonal antibodies neutralized heterologous HIV-1 isolates.