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
Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD, USA.
Moderna Inc., Cambridge, MA, USA.
Nat Med. 2021 Dec;27(12):2234-2245. doi: 10.1038/s41591-021-01574-5. Epub 2021 Dec 9.
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.
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