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Peer-reviewedCC BY-NC-ND 4.0NPJ Vaccines

Muscle macrophage regenerative response after squalene-adjuvanted influenza vaccination is associated with type II-skewed response and is reduced with age

  • Moataz Noureddine1,2,3
  • Lauren A. Chang1,2,3
  • Farah El Ayache1,2
  • Gabriel Laghlali1,2,4
  • Eleanor Burgess1,2,3
  • Leonie Gruneberg1,2
  • Prajakta Warang1,2
  • Kaijun Jiang1,2,3
  • Johanna Vandekerckhove1,2,5
  • Vivian Yan1,2,3
  • Haye Nijhuis5
  • Lynda Coughlan6,7
5 more authors
  • Bruno G. De Geest4
  • Juan Garcia-Bernalt Diego1,2
  • Seok-chan Park1,2
  • Jorge Levican1,2
  • Michael Schotsaert1,2,8,9
9 affiliations
  1. 1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY USA
  2. 2Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA
  3. 3Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY USA
  4. 4Department of Pharmaceutics, Ghent University, Ghent, Belgium
  5. 5Department of Medicine, Ghent University, Ghent, Belgium
  6. 6Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD USA
  7. 7Center for Vaccine Development and Global Health (CVD), University of Maryland School of Medicine, Baltimore, MD USA
  8. 8Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA
  9. 9Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY USA
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Abstract

Squalene-based adjuvants like MF59 and AddaVax induce transient muscle injury, but their downstream mechanisms remain unclear. We show that intramuscular injection of a quadrivalent inactivated influenza vaccine (QIV) with AddaVax triggers a muscle regenerative-like immune response, increasing CX3CR1⁺Ly6C⁺ macrophages in muscle and draining lymph nodes within four days. This promotes a type II-skewed immune response, with elevated IgG1 titers and Th2 cytokines in the lungs after influenza challenge. In aged mice, the macrophage response and type II skewing are diminished. Adoptive transfer of young mice bone marrow-derived macrophages into aged mice at vaccination leads to macrophage antigen uptake, lymph node migration, and type II immune bias. However, this restoration does not improve protection against mismatched viral challenge, suggesting additional age-related immune impairments. These findings highlight the role of macrophage-driven muscle regeneration in adjuvant activity and underscore the need to better understand how muscle damage and repair influence intramuscular vaccine efficacy.

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Cite

BibTeXRIS
BibTeX
@article{noureddine2026muscle,
  title = {{Muscle macrophage regenerative response after squalene-adjuvanted influenza vaccination is associated with type II-skewed response and is reduced with age}},
  author = {Moataz Noureddine and Lauren A. Chang and Farah El Ayache and Gabriel Laghlali and Eleanor Burgess and Leonie Gruneberg and Prajakta Warang and Kaijun Jiang and Johanna Vandekerckhove and Vivian Yan and Haye Nijhuis and Lynda Coughlan and Bruno G. De Geest and Juan Garcia-Bernalt Diego and Seok-chan Park and Jorge Levican and Michael Schotsaert},
  journal = {NPJ Vaccines},
  year = {2026},
  month = jul,
  doi = {10.1038/s41541-026-01436-6},
  url = {https://doi.org/10.1038/s41541-026-01436-6},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Muscle macrophage regenerative response after squalene-adjuvanted influenza vaccination is associated with type II-skewed response and is reduced with age
AU  - Moataz Noureddine
AU  - Lauren A. Chang
AU  - Farah El Ayache
AU  - Gabriel Laghlali
AU  - Eleanor Burgess
AU  - Leonie Gruneberg
AU  - Prajakta Warang
AU  - Kaijun Jiang
AU  - Johanna Vandekerckhove
AU  - Vivian Yan
AU  - Haye Nijhuis
AU  - Lynda Coughlan
AU  - Bruno G. De Geest
AU  - Juan Garcia-Bernalt Diego
AU  - Seok-chan Park
AU  - Jorge Levican
AU  - Michael Schotsaert
PY  - 2026
DA  - 2026/07/04
JO  - NPJ Vaccines
DO  - 10.1038/s41541-026-01436-6
UR  - https://doi.org/10.1038/s41541-026-01436-6
AB  - Squalene-based adjuvants like MF59 and AddaVax induce transient muscle injury, but their downstream mechanisms remain unclear. We show that intramuscular injection of a quadrivalent inactivated influenza vaccine (QIV) with AddaVax triggers a muscle regenerative-like immune response, increasing CX3CR1⁺Ly6C⁺ macrophages in muscle and draining lymph nodes within four days. This promotes a type II-skewed immune response, with elevated IgG1 titers and Th2 cytokines in the lungs after influenza challenge. In aged mice, the macrophage response and type II skewing are diminished. Adoptive transfer of young mice bone marrow-derived macrophages into aged mice at vaccination leads to macrophage antigen uptake, lymph node migration, and type II immune bias. However, this restoration does not improve protection against mismatched viral challenge, suggesting additional age-related immune impairments. These findings highlight the role of macrophage-driven muscle regeneration in adjuvant activity and underscore the need to better understand how muscle damage and repair influence intramuscular vaccine efficacy.
SN  - 2059-0105
ER  -