Characterization of Immunogenicity of HIV mRNA vaccine in Humanized mice

Human Immunodeficiency Virus (HIV) remains a leading global cause of mortality. Despite decades of research, a definitive cure or an effective vaccine for HIV infection has yet to be discovered. The major target for HIV vaccine development is the envelope (Env) trimeric protein that is responsible for host cell attachment and fusion. This comprises gp120 and the transmembrane gp41. Gp140, a truncated form of gp160(full envelope trimer) lacks the transmembrane and cytoplasmic domains of gp41, closely mimics the native HIV envelope has been shown to enhance the induction of broadly neutralizing antibodies (BnAbs) when used as protein vaccine in previous studies. We thus hypothesize that an HIV mRNA vaccine carrying the gp140 mRNA sequence can induce robust antibody response in humanized mice. To test this, we generated HIV mRNA vaccine, characterized the uptake and expression in cell culture, and evaluated its immunogenicity and protective efficacy in vaccinated humanized mice challenged with HIV. The results show that the HIV GP140 mRNA-LNP vaccine was efficiently delivered and expressed in 293 T cells and human monocytes-derived dendritic cells. However, the vaccination could not elicit significant GP140- specific IgG and IgM antibodies or any neutralizing antibodies, and did not reduce viral load post-challenge. Nevertheless, the HIV GP140 mRNA-LNP seems to be able to provide partial protection by maintaining the normal level of CD4+ T cells. Our newly developed humanized mouse model offers a versatile platform for HIV vaccines candidates, while the HIV gp140 mRNA introduces an innovative strategy for HIV vaccine development.