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.

开发保护性疫苗仍然是控制艾滋病毒/艾滋病大流行的首要任务。在这里，我们展示了一种信使 RNA (mRNA) 疫苗共表达膜锚定的 HIV-1 包膜 (Env) 和猿猴免疫缺陷病毒 (SIV) Gag 蛋白以产生病毒样颗粒 (VLP) 诱导抗体能够广泛中和和降低恒河猴感染的风险。在小鼠中，联合配制的env和gag mRNA 免疫在诱导中和抗体方面优于单独使用env mRNA。猕猴用缺乏 N276 聚糖的传递创始人进化枝-B env mRNA 引发，然后用聚糖修复的自体和随后的二价异源进行多次加强免疫envs（进化枝 A 和 C）。该方案具有高度免疫原性，可引发针对最普遍（第 2 层）HIV-1 病毒株的中和抗体，并伴有强烈的抗 Env CD4 ⁺ T 细胞反应。接种疫苗的动物在用异种 2 级猿猴人类免疫缺陷病毒 (SHIV AD8) 反复进行低剂量粘膜攻击后，每次暴露的风险降低了 79%。因此，多进化枝env-gag VLP mRNA 平台代表了一种开发 HIV-1 疫苗的有前途的方法。