Chimeric hemagglutinin-based universal influenza mRNA vaccine induces protective immunity and bone marrow plasma cells in rhesus macaques

Tiffany M Styles¹, Akil Akhtar¹, Chunyang Gu², Gabriele Neumann², Hiromi Muramatsu³, Justine S McPartlan⁴, Poulami Talukder⁴, Derrik Gratz⁵, Kasey Stokdyk⁵, Hannah L Turner⁶, James A Ferguson⁶, Alesandra J Rodriguez⁶, Madhumathi Loganathan⁷, Benjamin Francis⁷, Anass Abbad⁷, Ghania Chikh⁸, Ying K Tam⁸, Zhaohui S Qin⁹, Julianna Han⁶, Juan Manuel Carreño⁷, Andrew B Ward⁶, Jasdave S Chahal⁴, Christian W Mandl⁴, Norbert Pardi³, Yoshihiro Kawaoka¹⁰, Florian Krammer¹¹, Rafi Ahmed¹, Rama R Amara¹²

Affiliations

¹ Emory Vaccine Center, Emory National Primate Research Center, Emory University, Atlanta, GA, USA; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30329, USA.
² Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53711, USA.
³ Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Tiba Biotech LLC, Cambridge, MA, 02142 USA.
⁵ Emory Vaccine Center, Emory National Primate Research Center, Emory University, Atlanta, GA, USA.
⁶ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁷ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸ Acuitas Therapeutics, Vancouver BC V6T 1Z3, Canada.
⁹ Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
¹⁰ Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53711, USA; Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; The Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo 162-8655, Japan; Pandemic Preparedness, Infection and Advanced Research Center, The University of Tokyo, Tokyo 162-8655, Japan.
¹¹ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Molecular and Cell-based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Vaccine Research and Pandemic Preparedness (C-VaRPP), Icahn School of Medicine at Mount Sinai, New York, NY, USA; Ignaz Semmelweis Institute, Interuniversity Institute for Infection Research, Medical University of Vienna, Vienna, Austria.
¹² Emory Vaccine Center, Emory National Primate Research Center, Emory University, Atlanta, GA, USA; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30329, USA. Electronic address: ramara@emory.edu.

PMID: 41005301
DOI: 10.1016/j.xcrm.2025.102369

Free article

Chimeric hemagglutinin-based universal influenza mRNA vaccine induces protective immunity and bone marrow plasma cells in rhesus macaques

Tiffany M Styles et al. Cell Rep Med. 2025.

Free article

. 2025 Oct 21;6(10):102369.

doi: 10.1016/j.xcrm.2025.102369. Epub 2025 Sep 25.

Authors

Affiliations

¹ Emory Vaccine Center, Emory National Primate Research Center, Emory University, Atlanta, GA, USA; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30329, USA.
² Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53711, USA.
³ Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Tiba Biotech LLC, Cambridge, MA, 02142 USA.
⁵ Emory Vaccine Center, Emory National Primate Research Center, Emory University, Atlanta, GA, USA.
⁶ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁷ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸ Acuitas Therapeutics, Vancouver BC V6T 1Z3, Canada.
⁹ Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
¹⁰ Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53711, USA; Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; The Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo 162-8655, Japan; Pandemic Preparedness, Infection and Advanced Research Center, The University of Tokyo, Tokyo 162-8655, Japan.
¹¹ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Molecular and Cell-based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Vaccine Research and Pandemic Preparedness (C-VaRPP), Icahn School of Medicine at Mount Sinai, New York, NY, USA; Ignaz Semmelweis Institute, Interuniversity Institute for Infection Research, Medical University of Vienna, Vienna, Austria.
¹² Emory Vaccine Center, Emory National Primate Research Center, Emory University, Atlanta, GA, USA; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30329, USA. Electronic address: ramara@emory.edu.

PMID: 41005301
DOI: 10.1016/j.xcrm.2025.102369

Abstract

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.

Keywords: bone marrow plasma cells; chimeric hemagglutinin; mRNA-LNP; rhesus macaques; self-amplifying mRNA; transcriptional signatures; universal influenza vaccine.

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Conflict of interest statement

Declaration of interests The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-CoV-2 serological assays, Newcastle Disease Virus-based SARS-CoV-2 vaccines, influenza virus vaccines, and influenza virus therapeutics, which list Florian Krammer as a co-inventor. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2, and another company, CastleVax, to develop SARS-CoV-2 vaccines. F.K. is a co-founder and scientific advisory board member of CastleVax. F.K. has consulted for Merck, CureVac, Seqirus, and Pfizer and is currently consulting for Third Rock Ventures, GSK, Gritstone, and Avimex. The Krammer laboratory is also collaborating with Dynavax on influenza vaccine development. N.P. is named on patents describing the use of nucleoside-modified mRNA in lipid nanoparticles as a vaccine platform. He has disclosed those interests fully to the University of Pennsylvania, and he has in place an approved plan for managing any potential conflicts arising from the licensing of these patents. N.P. served on the mRNA strategic advisory board of Sanofi Pasteur in 2022 and the advisory board of Pfizer in 2023 and 2024. N.P. is a member of the Scientific Advisory Board of AldexChem and BioNet Asia. C.W.M. is a co-founder and CSO for Tiba Biotech and Accurius Therapeutics, is an advisor to Adjuvant Capital and the International Vaccine Institute, and works as a consultant for Vaccines and Viral Vectors. J.S.C. is a co-founder of Tiba Biotech and Revela Bio. C.W.M., J.S.C., J.S.M., and P.T. hold equity in Tiba Biotech. The laboratory of A.B.W. received unrelated sponsored research agreements from Third Rock Ventures during the conduct of the study.

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Chimeric hemagglutinin-based universal influenza mRNA vaccine induces protective immunity and bone marrow plasma cells in rhesus macaques

Affiliations

Chimeric hemagglutinin-based universal influenza mRNA vaccine induces protective immunity and bone marrow plasma cells in rhesus macaques

Authors

Affiliations

Abstract

Conflict of interest statement

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Full Text Sources

Medical