An ENV-GAG MRNA vaccine protects macaques from heterologous TIER-2 SHIV infection

ABSTRACT

Background: The development of a preventive vaccine remains a critical priority for ending the HIV/AIDS pandemic. Critical improvements in mRNA technology, as attested by recent successes in preventing COVID-19 disease, led us to develop an mRNA platform for HIV vaccines. Methods: In this regard, we designed an mRNA vaccine with different HIV-1 envelope mRNAs from 3 different clades co-formulated with SIV gag mRNA, which can assemble virus like particles (VLPs) in vivo. Rhesus macaques were primed with a transmitted-founder clade-B Env lacking the 276 N-glycan followed by multiple glycan-repaired autologous and bivalent heterologous (clades A and C) booster immunizations. Results: Immunized animals rapidly developed autologous neutralizing antibodies and eventually, after the second heterologous boost, cross-reactive tier-2 neutralizing antibodies, albeit at low titers. Vaccinated animals were protected from repeated low-dose rectal challenges with a heterologous tier-2 simian-human immunodeficiency virus (AD8). Protection was correlated with the presence of antibodies to the CD4-binding site. Conclusion: Thus, the Gag-Env VLP mRNA platform offers a promising strategy for the development of an HIV-1 vaccine.