Inclusion of a retroviral protease enhances the immunogenicity of VLP-forming mRNA vaccines against HIV-1 or SARS-CoV-2 in mice

• Published in: Science translational medicine Vol. 17; no. 796; p. eadt9576
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States 30.04.2025
• Subjects: AIDS Vaccines - immunology; Animals; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; COVID-19 - immunology; COVID-19 - prevention & control; COVID-19 Vaccines - immunology; Female; HIV Infections - immunology; HIV Infections - prevention & control; HIV-1 - immunology; Humans; Immunogenicity, Vaccine; Mice; Mice, Inbred BALB C; mRNA Vaccines - immunology; Peptide Hydrolases - metabolism; Retroviridae - enzymology; RNA, Messenger - genetics; RNA, Messenger - immunology; SARS-CoV-2 - immunology; Vaccines, Virus-Like Particle - genetics; Vaccines, Virus-Like Particle - immunology
• ISSN: 1946-6242
• 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.