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Cell Rep Med
. 2025 Sep 25:102369.
doi: 10.1016/j.xcrm.2025.102369. Online ahead of print. Chimeric hemagglutinin-based universal influenza mRNA vaccine induces protective immunity and bone marrow plasma cells in rhesus macaques
Tiffany M Styles 1 , Akil Akhtar 1 , Chunyang Gu 2 , Gabriele Neumann 2 , Hiromi Muramatsu 3 , Justine S McPartlan 4 , Poulami Talukder 4 , Derrik Gratz 5 , Kasey Stokdyk 5 , Hannah L Turner 6 , James A Ferguson 6 , Alesandra J Rodriguez 6 , Madhumathi Loganathan 7 , Benjamin Francis 7 , Anass Abbad 7 , Ghania Chikh 8 , Ying K Tam 8 , Zhaohui S Qin 9 , Julianna Han 6 , Juan Manuel Carreño 7 , Andrew B Ward 6 , Jasdave S Chahal 4 , Christian W Mandl 4 , Norbert Pardi 3 , Yoshihiro Kawaoka 10 , Florian Krammer 11 , Rafi Ahmed 1 , Rama R Amara 12
Affiliations
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.
. 2025 Sep 25:102369.
doi: 10.1016/j.xcrm.2025.102369. Online ahead of print. Chimeric hemagglutinin-based universal influenza mRNA vaccine induces protective immunity and bone marrow plasma cells in rhesus macaques
Tiffany M Styles 1 , Akil Akhtar 1 , Chunyang Gu 2 , Gabriele Neumann 2 , Hiromi Muramatsu 3 , Justine S McPartlan 4 , Poulami Talukder 4 , Derrik Gratz 5 , Kasey Stokdyk 5 , Hannah L Turner 6 , James A Ferguson 6 , Alesandra J Rodriguez 6 , Madhumathi Loganathan 7 , Benjamin Francis 7 , Anass Abbad 7 , Ghania Chikh 8 , Ying K Tam 8 , Zhaohui S Qin 9 , Julianna Han 6 , Juan Manuel Carreño 7 , Andrew B Ward 6 , Jasdave S Chahal 4 , Christian W Mandl 4 , Norbert Pardi 3 , Yoshihiro Kawaoka 10 , Florian Krammer 11 , Rafi Ahmed 1 , Rama R Amara 12
Affiliations
- PMID: 41005301
- DOI: 10.1016/j.xcrm.2025.102369
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.