Chimeric hemagglutinin-based universal influenza mRNA vaccine induces protective immunity and bone marrow plasma cells in rhesus macaques
A universal influenza vaccine that elicits a strong and lasting stalk-specific antibody response is advantageous. We utilize nucleoside-modified mRNA in lipid nanoparticles (mRNA-LNP) and unmodified self-amplifying mRNA in modified dendritic nanoparticles (sam-MDNP), expressing chimeric hemagglutinin (cHA) antigens to induce stalk-specific humoral immunity in non-human primates with pre-existing influenza virus immunity. mRNA-LNP immunization induces strong stalk-specific binding antibodies capable of protecting mice from lethal heterologous influenza virus challenges and bone marrow plasma cells (BMPCs) that persist for up to 8 months. sam-MDNP vaccine induces lower humoral immunity, despite showing strong innate activation. Transcriptomic and cytokine analyses reveal a more persistent induction of interferon responses, interleukin (IL)-1β signaling, and IL-6 production in the mRNA-LNP group, correlating with the induction of serum antibody responses and BMPCs. These results identify a transcriptional signature associated with induction of BMPCs following mRNA vaccination and highlight the utility of cHA-based mRNA-LNP vaccines in inducing persistent stalk-directed protective antibody responses.
Authors
- Yoshihiro Kawaoka
- Juan Manuel Carreño (ORCID: https://orcid.org/0000-0002-9039-9275)
- Rafi Ahmed (ORCID: https://orcid.org/0000-0002-9591-2621)
- Poulami Talukder (ORCID: https://orcid.org/0000-0002-3322-1235)
- Justine S. McPartlan
- Christian W. Mandl (ORCID: https://orcid.org/0000-0001-6782-2218)
- Rama Rao Amara (ORCID: https://orcid.org/0000-0002-6309-6797)
- Madhumathi Loganathan (ORCID: https://orcid.org/0000-0002-3751-8036)
- James A. Ferguson (ORCID: https://orcid.org/0000-0003-2891-0850)
- Zhaohui Qin (ORCID: https://orcid.org/0000-0002-1583-146X)
- Akil Akhtar (ORCID: https://orcid.org/0000-0002-9069-6827)
- Julianna Han (ORCID: https://orcid.org/0000-0002-3402-2609)
- Ghania Chikh
- Hannah L. Turner (ORCID: https://orcid.org/0000-0002-4745-8057)
- Jasdave S. Chahal (ORCID: https://orcid.org/0000-0003-3052-0501)
- Ben Francis (ORCID: https://orcid.org/0000-0002-2130-5976)
- Ying K. Tam (ORCID: https://orcid.org/0000-0002-4083-5251)
- Gabriele Neumann (ORCID: https://orcid.org/0000-0001-7054-1775)
- Anass Abbad (ORCID: https://orcid.org/0000-0002-4617-0473)
- Norbert Pardi (ORCID: https://orcid.org/0000-0003-1008-6242)
- Florian Krammer (ORCID: https://orcid.org/0000-0003-4121-776X)
- Chunyang Gu (ORCID: https://orcid.org/0000-0003-1283-1701)
- Tiffany M. Styles (ORCID: https://orcid.org/0000-0002-0102-6566)
- Derrik Gratz
- Alesandra J. Rodriguez (ORCID: https://orcid.org/0009-0009-6510-7558)
- Hiromi Muramatsu
- Kasey Stokdyk
Institutions
- Scripps Research Institute (US)
- University of Wisconsin–Madison (US)
- Emory University (US)
- Emory and Henry College (US)
- 490 BioTech (United States) (US)
- National Center for Global Health and Medicine (JP)
- Acuitas Therapeutics (Canada) (CA)
- University of Pennsylvania (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-09-25
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102369
- Citations
- 2
- Primary Topic
- Immune Response and Inflammation
- Type
- article
- Field-Weighted Citation Impact
- 1.59