2. Academic Validation
  3. Monovalent SARS-COV-2 mRNA vaccine using optimal UTRs and LNPs is highly immunogenic and broadly protective against Omicron variants

Monovalent SARS-COV-2 mRNA vaccine using optimal UTRs and LNPs is highly immunogenic and broadly protective against Omicron variants

  • Proc Natl Acad Sci U S A. 2023 Dec 26;120(52):e2311752120. doi: 10.1073/pnas.2311752120.
Zhongfeng Ye # 1,  Srinivasa Reddy Bonam # 2,  Lindsay G A McKay 3,  Jessica A Plante 2 4,  Jordyn Walker 2 4,  Yu Zhao 1,  Changfeng Huang 1,  Jinjin Chen 1,  Chutian Xu 1,  Yamin Li 5,  Lihan Liu 1,  Joseph Harmon 1,  Shuliang Gao 1,  Donghui Song 1,  Zhibo Zhang 1,  Kenneth S Plante 2 4,  Anthony Griffiths 3,  Jianzhu Chen 6,  Haitao Hu 2,  Qiaobing Xu 1
Affiliations

Affiliations

  • 1 Department of Biomedical Engineering, Tufts University, Medford, MA 02155.
  • 2 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555.
  • 3 National Emerging Infectious Diseases Laboratories and Department of Virology, Immunology, and Microbiology, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA 02215.
  • 4 World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX 77555.
  • 5 Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, NY 13210.
  • 6 Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
  • # Contributed equally.
PMID: 38134199 DOI: 10.1073/pnas.2311752120
Abstract

The emergence of highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that are resistant to the current COVID-19 vaccines highlights the need for continued development of broadly protective vaccines for the future. Here, we developed two messenger RNA (mRNA)-lipid nanoparticle (LNP) vaccines, TU88mCSA and ALCmCSA, using the ancestral SARS-CoV-2 spike sequence, optimized 5' and 3' untranslated regions (UTRs), and LNP combinations. Our data showed that these nanocomplexes effectively activate CD4+ and CD8+ T cell responses and humoral immune response and provide complete protection against WA1/2020, Omicron BA.1 and BQ.1 Infection in hamsters. Critically, in Omicron BQ.1 challenge hamster models, TU88mCSA and ALCmCSA not only induced robust control of virus load in the lungs but also enhanced protective efficacy in the upper respiratory airways. Antigen-specific immune analysis in mice revealed that the observed cross-protection is associated with superior UTRs [Carboxylesterase 1d (Ces1d)/adaptor protein-3β (AP3B1)] and LNP formulations that elicit robust lung tissue-resident memory T cells. Strong protective effects of TU88mCSA or ALCmCSA against both WA1/2020 and VOCs suggest that this mRNA-LNP combination can be a broadly protective vaccine platform in which mRNA cargo uses the ancestral antigen sequence regardless of the antigenic drift. This approach could be rapidly adapted for clinical use and timely deployment of vaccines against emerging and reemerging VOCs.

Keywords

lipid nanoparticle; lung tissue-resident memory T cells; mRNA vaccine; untranslated region.

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