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Mechanisms of innate and adaptive immunity to the Pfizer-BioNTech BNT162b2 vaccine
Open accessAbstract
Despite the success of the BNT162b2 mRNA vaccine, the immunological mechanisms that underlie its efficacy are poorly understood. Here we analyzed the innate and adaptive responses to BNT162b2 in mice, and show that immunization stimulated potent antibody and antigen-specific T cell responses, as well as strikingly enhanced innate responses after secondary immunization, which was concurrent with enhanced serum interferon (IFN)-γ levels 1 d following secondary immunization. Notably, we found that natural killer cells and CD8+ T cells in the draining lymph nodes are the major producers of this circulating IFN-γ. Analysis of knockout mice revealed that induction of antibody and T cell responses to BNT162b2 was not dependent on signaling via Toll-like receptors 2, 3, 4, 5 and 7 nor inflammasome activation, nor the necroptosis or pyroptosis cell death pathways. Rather, the CD8+ T cell response induced by BNT162b2 was dependent on type I interferon-dependent MDA5 signaling. These results provide insights into the molecular mechanisms by which the BNT162b2 vaccine stimulates immune responses.
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Quantification of TRM cells has yielded variable results using different modified mRNA vaccine constructs in a mouse model, ranging from detection in the lungs to absence in the same tissue despite using much higher doses of 2-5 μg.
“Quantification of TRM cells has yielded variable results, as reported by others, using different modified mRNA vaccine constructs in a mouse model, ranging from their detection in the lungs14 to absence in the same tissue15 despite using it at much higher doses of 2–5 µg.”
From Efficacy of an unmodified bivalent mRNA vaccine against SARS-CoV-2 variants in female small animal models (2023) · cites this paper as [15]
Induction of CD8+ T-cell response to BNT162b2 was dependent on type I interferon (IFN-I)-dependent MDA5 signaling in knockout mice.
“Analysis of knockout mice revealed that the induction of CD8+ T-cell response to BNT162b2 was dependent on type I interferon (IFN-I)-dependent melanoma differentiation-associated protein 5 (MDA5) signaling [29].”
From Systemic profiling of immune responses in healthy adults vaccinated with an RBD-targeting COVID-19 mRNA vaccine (2025) · cites this paper as [29]
The divergent dynamics observed in Treg, monocyte, DCs, and Prof T clusters suggest that mRNA modification and antigen design may influence both the magnitude and kinetics of immune activation.
“The divergent dynamics observed in Treg, monocyte, DCs, and Prof T clusters further suggest that mRNA modification and antigen design may influence both the magnitude and kinetics of immune activation [29,46].”
From Systemic profiling of immune responses in healthy adults vaccinated with an RBD-targeting COVID-19 mRNA vaccine (2025) · cites this paper as [29]
The enhanced response may reflect the modified mRNA's increased translational efficiency and reduced toll-like receptor sensing, enabling sustained protein expression without early innate immune suppression.
“This enhanced response may reflect the modified mRNA’s increased translational efficiency and reduced toll-like receptor sensing, enabling sustained protein expression without early innate immune suppression [29,46].”
From Systemic profiling of immune responses in healthy adults vaccinated with an RBD-targeting COVID-19 mRNA vaccine (2025) · cites this paper as [29]
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References 69 · Cited by 505
Research works printed but not linked: 1
- Walsh, E. E. et al. Safety and immunogenicity of two RNA-based COVID-19 vaccine candidates. N. Engl. J. Med. 383, 2439–2450 (2020). · DOI · Paper page
Metadata
- Authors
- Li, C., Lee, A., Grigoryan, L., Arunachalam, P. S., Scott, M. K. D., Trisal, M., Wimmers, F., Sanyal, M., Weidenbacher, P. A., Feng, Y., Adamska, J. Z., Valore, E., Wang, Y., Verma, R., Reis, N., Dunham, D., O’Hara, R., Park, H., Luo, W., Gitlin, A. D., Kim, P., Khatri, P., Nadeau, K. C., & Pulendran, B.
- Affiliations
- Stanford University (US)
- Stanford Medicine (US)
- VA Palo Alto Health Care System (US)
- Indiana University School of Medicine (US)
- Genentech (US)
- Chan Zuckerberg Biohub San Francisco (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Pulendran, Bali
- ORCID
- Venue
- Nature Immunology
- Published
- 2022-03-14
- Volume
- 23
- Issue
- 4
- Pages
- 543-555
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC8989677
- OpenAlex
- W4220978613
- Cited by
- 505
- References
- 69
- Citations by year
- 2026: 90 · 2025: 130 · 2024: 131 · 2023: 110 · 2022: 43
- FWCI
- 50.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (R01 AI048638, U19 AI057266)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- BNT162b2, mRNA vaccines, SARS-CoV-2, innate immunity, adaptive immunity, interferon-gamma, natural killer cells, CD8+ T cells, MDA5, type I interferon signaling, Toll-like receptors, inflammasome, pyroptosis, necroptosis, secondary immunization, antibody response, vaccine immunogenicity
- MeSH terms
- mRNA Vaccines, BNT162 Vaccine, Animals, Humans, Immunity, Innate, Vaccines, Vaccines, Synthetic, CD8-Positive T-Lymphocytes, Mice, Adaptive Immunity
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