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

  1. Author:
    Zhang, Peng [ORCID]
    Singh, Mamta
    Becker, Vada A [ORCID]
    Croft, Jacob [ORCID]
    Tsybovsky,Yaroslav [ORCID]
    Gopan, Vinay [ORCID]
    Seo, Yuna [ORCID]
    Liu, Qingbo [ORCID]
    Rogers, Denise
    Miao, Huiyi [ORCID]
    Lin, Yin
    Rogan, Daniel [ORCID]
    Shields, Courtney
    Elbashir, Sayda M [ORCID]
    Calabrese, Samantha
    Renzi, Isabella [ORCID]
    Preznyak, Vladimir
    Narayanan, Elizabeth [ORCID]
    Stewart-Jones, Guillaume [ORCID]
    Himansu, Sunny [ORCID]
    Connors, Mark
    Lee, Kelly [ORCID]
    Carfi, Andrea
    Lusso, Paolo [ORCID]

  2. Author Address

    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., Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA., Moderna Inc., Cambridge, MA 02139, USA.,
    1. Year: 2025
    2. Date: Apr 30
    3. Epub Date: 2025 04 30
  2. Journal: Science Translational Medicine
    1. 17
    2. 796
    3. Pages: eadt9576
  4. Type of Article: Article
  5. Article Number: eadt9576
  1. Abstract:

    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.

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External Sources

  1. View Full Text
  2. DOI: 10.1126/scitranslmed.adt9576
  3. PMID: 40305570

Library Notes

  1. Fiscal Year: FY2024-2025
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