Zhang Peng, Singh Mamta, Becker Vada A, Croft Jacob, Tsybovsky Yaroslav, Gopan Vinay, Seo Yuna, Liu Qingbo, Rogers Denise, Miao Huiyi, Lin Yin, Rogan Daniel, Shields Courtney, Elbashir Sayda M, Calabrese Samantha, Renzi Isabella, Preznyak Vladimir, Narayanan Elizabeth, Stewart-Jones Guillaume, Himansu Sunny, Connors Mark, Lee Kelly, Carfi Andrea, Lusso Paolo
Laboratory of Immunoregulation and Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195, USA.
Sci Transl Med. 2025 Apr 30;17(796):eadt9576. doi: 10.1126/scitranslmed.adt9576.
Messenger RNA (mRNA) has emerged as a highly effective and versatile platform for vaccine delivery. We previously designed a virus-like particle (VLP)-forming mRNA vaccine against human immunodeficiency virus-1 (HIV-1) that elicited envelope-specific neutralizing antibodies and protection from heterologous simian-human immunodeficiency virus (SHIV) infection in rhesus macaques. Here, we introduce a key technological advance to this platform by inclusion of mRNA encoding a retroviral protease to process Gag and produce mature VLPs. Appropriately dosed and timed expression of the protease was achieved using a full-length mRNA transcript. Addition of mRNA to an HIV-1 mRNA vaccine resulted in enhanced titers of envelope trimer-binding and neutralizing antibodies in a mouse model. Analogous results were obtained with a hybrid Gag-based, VLP-forming severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine expressing an engineered spike protein. Thus, inclusion of a retroviral protease can increase the immunogenicity of Gag-based, VLP-forming mRNA vaccines against human pathogens.
信使核糖核酸（mRNA）已成为一种高效且通用的疫苗递送平台。我们之前设计了一种针对人类免疫缺陷病毒1型（HIV-1）的形成病毒样颗粒（VLP）的mRNA疫苗，该疫苗能在恒河猴体内引发包膜特异性中和抗体，并提供针对异源猴-人免疫缺陷病毒（SHIV）感染的保护。在此，我们通过纳入编码逆转录病毒蛋白酶以加工Gag并产生成熟VLP，为该平台引入了一项关键技术进展。使用全长mRNA转录本实现了蛋白酶的适当剂量和适时表达。在小鼠模型中，向HIV-1 mRNA疫苗中添加mRNA导致包膜三聚体结合抗体和中和抗体滴度升高。对于表达工程化刺突蛋白的基于Gag的形成VLP的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）杂交mRNA疫苗，也获得了类似结果。因此，纳入逆转录病毒蛋白酶可增强针对人类病原体的基于Gag的形成VLP的mRNA疫苗的免疫原性。
