Innate and Adaptive Immune Parameters following mRNA Vaccination in Mice

Srinivasa Reddy Bonam, Nicholas C. Hazell, Mano Joseph Mathew, Yuejin Liang, Xuxiang Zhang, Zhi Wei, Mohamad Gabriel Alameh, Drew Weissman, Haitao Hu

Research output: Contribution to journalArticlepeer-review


The COVID-19 pandemic has raised the standard regarding the current vaccine development pace, as several messenger RNA (mRNA)-lipid nanoparticle (LNP) vaccines have proved their ability to induce strong immunogenicity and protective efficacy. We developed 1-methylpseudouridine-containing mRNA-LNP vaccines, expressing either the more conserved SARS-CoV-2 nucleoprotein (mRNA-N) or spike protein (mRNA-S), both based on the prototypic viral sequences. When combining both mRNA-S and mRNA-N together (mRNA-S+N), the vaccine showed high immunogenicity and broad protection against different SARS-CoV-2 variants, including wildtype, Delta, BA.1, BA.5, and BQ.1. To better understand the mechanisms behind this broad protection obtained by mRNA-S+N, we analyzed innate and adaptive immune parameters following vaccination in mice. Compared to either mRNA-S or mRNA-N alone, mice vaccinated with mRNA-S+N exhibited an increase in the innate immune response, as depicted by the higher cytokine (IL-6 and chemokine (MCP-1) levels. In addition, lymph node immunophenotyping showed the maturation and activation of dendritic cells and natural killer cells, respectively. To understand the adaptive immune response, RNA-Seq analyses of the lung and spleen samples of the vaccinated mice were performed in parallel and revealed a stronger immune gene-expression profile in the lung than that in the spleen. Compared to mRNA-S alone, mRNA-S+N vaccination elicited higher levels of expression for genes involved in multiple immune pathways, including T cells, cytokine signaling, antigen presentation, B cells, and innate immunity. Together, our studies provide immunological insights into the mechanisms of broad protection conferred by dual mRNA vaccination against SARS-CoV-2 variants.

Original languageEnglish (US)
Article number543
Issue number5
StatePublished - May 2024


  • adaptive immunity
  • innate immunity
  • lipid nanoparticles
  • mRNA vaccine

ASJC Scopus subject areas

  • Immunology
  • Pharmacology
  • Drug Discovery
  • Infectious Diseases
  • Pharmacology (medical)


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