tetano
Editor, Senior Moderator
Sci Transl Med
. 2025 Apr 30;17(796):eadt9576.
doi: 10.1126/scitranslmed.adt9576. Epub 2025 Apr 30. Inclusion of a retroviral protease enhances the immunogenicity of VLP-forming mRNA vaccines against HIV-1 or SARS-CoV-2 in mice
Peng Zhang[SUP] 1 [/SUP], Mamta Singh[SUP] 1 [/SUP], Vada A Becker[SUP] 2 [/SUP], Jacob Croft[SUP] 2 [/SUP], Yaroslav Tsybovsky[SUP] 3 [/SUP], Vinay Gopan[SUP] 1 [/SUP], Yuna Seo[SUP] 1 [/SUP], Qingbo Liu[SUP] 1 [/SUP], Denise Rogers[SUP] 1 [/SUP], Huiyi Miao[SUP] 1 [/SUP], Yin Lin[SUP] 1 [/SUP], Daniel Rogan[SUP] 1 [/SUP], Courtney Shields[SUP] 1 [/SUP], Sayda M Elbashir[SUP] 4 [/SUP], Samantha Calabrese[SUP] 4 [/SUP], Isabella Renzi[SUP] 4 [/SUP], Vladimir Preznyak[SUP] 4 [/SUP], Elizabeth Narayanan[SUP] 4 [/SUP], Guillaume Stewart-Jones[SUP] 4 [/SUP], Sunny Himansu[SUP] 4 [/SUP], Mark Connors[SUP] 1 [/SUP], Kelly Lee[SUP] 2 [/SUP], Andrea Carfi[SUP] 4 [/SUP], Paolo Lusso[SUP] 1 [/SUP]
Affiliations
Messenger RNA (mRNA) has emerged as a highly effective and versatile platform for vaccine delivery. We previously designed a virus-like particle (VLP)-forming env-gag 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 gag-pol mRNA transcript. Addition of gag-pol mRNA to an HIV-1 env-gag 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.
. 2025 Apr 30;17(796):eadt9576.
doi: 10.1126/scitranslmed.adt9576. Epub 2025 Apr 30. Inclusion of a retroviral protease enhances the immunogenicity of VLP-forming mRNA vaccines against HIV-1 or SARS-CoV-2 in mice
Peng Zhang[SUP] 1 [/SUP], Mamta Singh[SUP] 1 [/SUP], Vada A Becker[SUP] 2 [/SUP], Jacob Croft[SUP] 2 [/SUP], Yaroslav Tsybovsky[SUP] 3 [/SUP], Vinay Gopan[SUP] 1 [/SUP], Yuna Seo[SUP] 1 [/SUP], Qingbo Liu[SUP] 1 [/SUP], Denise Rogers[SUP] 1 [/SUP], Huiyi Miao[SUP] 1 [/SUP], Yin Lin[SUP] 1 [/SUP], Daniel Rogan[SUP] 1 [/SUP], Courtney Shields[SUP] 1 [/SUP], Sayda M Elbashir[SUP] 4 [/SUP], Samantha Calabrese[SUP] 4 [/SUP], Isabella Renzi[SUP] 4 [/SUP], Vladimir Preznyak[SUP] 4 [/SUP], Elizabeth Narayanan[SUP] 4 [/SUP], Guillaume Stewart-Jones[SUP] 4 [/SUP], Sunny Himansu[SUP] 4 [/SUP], Mark Connors[SUP] 1 [/SUP], Kelly Lee[SUP] 2 [/SUP], Andrea Carfi[SUP] 4 [/SUP], Paolo Lusso[SUP] 1 [/SUP]
Affiliations
- PMID: 40305570
- 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 env-gag 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 gag-pol mRNA transcript. Addition of gag-pol mRNA to an HIV-1 env-gag 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.