Dynamic regulation-based stabilizing mutations are highly effective for designing RSV pre-fusion F mRNA vaccines

Shuai Shao1, Ze Yuan Dong2, Zi Yao Kang3

  • 1The Sixth Laboratory, National Vaccine and Serum Institute (NVSI), Beijing, 101111, China; National Engineering Center for New Vaccine Research, Beijing, 101111, China.

Insights

A novel messenger RNA (mRNA) vaccine candidate targeting respiratory syncytial virus (RSV) demonstrated superior immunogenicity and protection in mice. This RSV mRNA vaccine, based on a stabilized F protein, shows promise for future vaccine development.

Area of Science:

  • Vaccinology
  • Virology
  • Molecular Biology

Background:

  • Respiratory syncytial virus (RSV) causes severe respiratory infections, particularly in vulnerable populations.
  • Existing protein-based RSV vaccines may have limitations for mRNA vaccine development.
  • Stabilized pre-fusion F protein (pre-F) strategies are crucial for effective RSV vaccine design.

Purpose of the Study:

  • To develop and evaluate an mRNA vaccine candidate based on the pre-fusion stabilized F protein, TriM-5.
  • To assess the efficacy of dynamic regulation-based stabilizing mutations in an mRNA vaccine format.
  • To optimize the mRNA coding sequence (CDS) for enhanced immunogenicity.

Main Methods:

  • Designed a TriM-5 mRNA vaccine candidate with codon optimization using NVSI_GAmRNAopt software.
  • Encapsulated the mRNA using lipid nanoparticles (LNPs).
  • Performed mouse immunization studies, including antibody titer measurements, cytokine analysis, and virus challenge experiments.

Main Results:

  • Codon optimization of the mRNA CDS increased IgG antibody titers approximately threefold.
  • The TriM-5 mRNA-LNP induced 3.03-fold higher neutralizing antibody titers compared to a Moderna RSV mRNA sequence.
  • Both TriM-5 mRNA-LNP and Moderna mRNA-LNP effectively reduced lung viral loads with no significant lung pathology.

Conclusions:

  • The TriM-5 mRNA-LNP vaccine candidate demonstrates superior immunogenicity and protective efficacy against RSV in a mouse model.
  • The codon optimization algorithm and stabilizing mutations are effective in the mRNA vaccine format.
  • This TriM-5 mRNA-LNP holds significant potential for future RSV vaccine development.

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