A multiclade env–gag VLP mRNA vaccine elicits tier-2 HIV-1-neutralizing antibodies and reduces the risk of heterologous SHIV infection in macaques

• Published in: Nature medicine Vol. 27; no. 12; pp. 2234 - 2245
• Main Authors: Zhang, Peng, Narayanan, Elisabeth, Liu, Qingbo, Tsybovsky, Yaroslav, Boswell, Kristin, Ding, Shilei, Hu, Zonghui, Follmann, Dean, Lin, Yin, Miao, Huiyi, Schmeisser, Hana, Rogers, Denise, Falcone, Samantha, Elbashir, Sayda M., Presnyak, Vladimir, Bahl, Kapil, Prabhakaran, Madhu, Chen, Xuejun, Sarfo, Edward K., Ambrozak, David R., Gautam, Rajeev, Martin, Malcom A., Swerczek, Joanna, Herbert, Richard, Weiss, Deborah, Misamore, Johnathan, Ciaramella, Giuseppe, Himansu, Sunny, Stewart-Jones, Guillaume, McDermott, Adrian, Koup, Richard A., Mascola, John R., Finzi, Andrés, Carfi, Andrea, Fauci, Anthony S., Lusso, Paolo
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2021; Nature Publishing Group
• Subjects: 631/326/596/1787; 692/699/255/1901; Acquired immune deficiency syndrome; AIDS; Analysis; Animals; Antibodies; Antibodies, Neutralizing - immunology; Biomedical and Life Sciences; Biomedicine; Cancer Research; Care and treatment; CD4 antigen; Diagnosis; Diseases; Dosage; Gag protein; Genes, env; Genes, gag; Genetic aspects; Glycan; Health aspects; Health risks; HIV; HIV antibodies; HIV Antibodies - biosynthesis; HIV Antibodies - immunology; HIV-1 - immunology; Human immunodeficiency virus; Immune system; Immunization; Immunization, Secondary; Immunogenicity; Infections; Infectious Diseases; Lymphocytes; Lymphocytes T; Macaca mulatta; Macaques; Messenger RNA; Metabolic Diseases; Molecular Medicine; mRNA; mRNA vaccines; mRNA Vaccines - administration & dosage; mRNA Vaccines - immunology; Mucosa; Neurosciences; Neutralization; Neutralizing; Optimization; Pandemics; Primates; Public health; Risk Factors; Risk management; Simian Acquired Immunodeficiency Syndrome - immunology; Simian Acquired Immunodeficiency Syndrome - prevention & control; Simian immunodeficiency virus; Testing; Vaccines; Vaccines, Synthetic - administration & dosage; Vaccines, Synthetic - immunology; Virus-like particles; Viruses; United States
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-021-01574-5

The development of a protective vaccine remains a top priority for the control of the HIV/AIDS pandemic. Here, we show that a messenger RNA (mRNA) vaccine co-expressing membrane-anchored HIV-1 envelope (Env) and simian immunodeficiency virus (SIV) Gag proteins to generate virus-like particles (VLPs) induces antibodies capable of broad neutralization and reduces the risk of infection in rhesus macaques. In mice, immunization with co-formulated env and gag mRNAs was superior to env mRNA alone in inducing neutralizing antibodies. Macaques were primed with a transmitted-founder clade-B env mRNA lacking the N276 glycan, followed by multiple booster immunizations with glycan-repaired autologous and subsequently bivalent heterologous envs (clades A and C). This regimen was highly immunogenic and elicited neutralizing antibodies against the most prevalent (tier-2) HIV-1 strains accompanied by robust anti-Env CD4 + T cell responses. Vaccinated animals had a 79% per-exposure risk reduction upon repeated low-dose mucosal challenges with heterologous tier-2 simian–human immunodeficiency virus (SHIV AD8). Thus, the multiclade env–gag VLP mRNA platform represents a promising approach for the development of an HIV-1 vaccine. An mRNA vaccine platform to prevent HIV-1 infection generated broadly neutralizing antibodies in non-human primates and protected some animals from infection, raising hope that optimization of this approach might lead to an effective HIV vaccine.