Systems vaccinology of the BNT162b2 mRNA vaccine in humans

The emergency use authorization of two mRNA vaccines in less than a year from the emergence of SARS-CoV-2 represents a landmark in vaccinology 1 , 2 . Yet, how mRNA vaccines stimulate the immune system to elicit protective immune responses is unknown. Here we used a systems vaccinology approach to c...

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Published in:	Nature (London) Vol. 596; no. 7872; pp. 410 - 416
Main Authors:	Arunachalam, Prabhu S., Scott, Madeleine K. D., Hagan, Thomas, Li, Chunfeng, Feng, Yupeng, Wimmers, Florian, Grigoryan, Lilit, Trisal, Meera, Edara, Venkata Viswanadh, Lai, Lilin, Chang, Sarah Esther, Feng, Allan, Dhingra, Shaurya, Shah, Mihir, Lee, Alexandra S., Chinthrajah, Sharon, Sindher, Sayantani B., Mallajosyula, Vamsee, Gao, Fei, Sigal, Natalia, Kowli, Sangeeta, Gupta, Sheena, Pellegrini, Kathryn, Tharp, Gregory, Maysel-Auslender, Sofia, Hamilton, Sydney, Aoued, Hadj, Hrusovsky, Kevin, Roskey, Mark, Bosinger, Steven E., Maecker, Holden T., Boyd, Scott D., Davis, Mark M., Utz, Paul J., Suthar, Mehul S., Khatri, Purvesh, Nadeau, Kari C., Pulendran, Bali
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 19-08-2021 Nature Publishing Group
Subjects:	38 38/91 631/250/590 631/250/590/2293 631/326/596/4130 Activator protein 1 Adaptive Immunity Adult Aged Antibodies Antibodies, Neutralizing - immunology Antibodies, Viral - immunology Antibody response Antigens Autoantibodies - immunology BNT162 Vaccine CD14 antigen CD16 antigen CD4 antigen CD8 antigen Coronaviruses COVID-19 COVID-19 - immunology COVID-19 Vaccines - administration & dosage COVID-19 Vaccines - immunology Cytokines Female Health aspects Humanities and Social Sciences Humans Immune response Immune system Immunity, Innate Immunization Immunization, Secondary Inflammation Innate immunity Interferon Lymphocytes Lymphocytes T Male Middle Aged Monocytes mRNA vaccines multidisciplinary Neutralizing Plasma Science Science (multidisciplinary) Severe acute respiratory syndrome coronavirus 2 Single-Cell Analysis Spike Glycoprotein, Coronavirus - immunology T-Lymphocytes - immunology Transcription factors Transcription, Genetic Transcriptome - genetics Vaccines Vaccinology Young Adult United States
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Summary:	The emergency use authorization of two mRNA vaccines in less than a year from the emergence of SARS-CoV-2 represents a landmark in vaccinology 1 , 2 . Yet, how mRNA vaccines stimulate the immune system to elicit protective immune responses is unknown. Here we used a systems vaccinology approach to comprehensively profile the innate and adaptive immune responses of 56 healthy volunteers who were vaccinated with the Pfizer–BioNTech mRNA vaccine (BNT162b2). Vaccination resulted in the robust production of neutralizing antibodies against the wild-type SARS-CoV-2 (derived from 2019-nCOV/USA_WA1/2020) and, to a lesser extent, the B.1.351 strain, as well as significant increases in antigen-specific polyfunctional CD4 and CD8 T cells after the second dose. Booster vaccination stimulated a notably enhanced innate immune response as compared to primary vaccination, evidenced by (1) a greater frequency of CD14 + CD16 + inflammatory monocytes; (2) a higher concentration of plasma IFNγ; and (3) a transcriptional signature of innate antiviral immunity. Consistent with these observations, our single-cell transcriptomics analysis demonstrated an approximately 100-fold increase in the frequency of a myeloid cell cluster enriched in interferon-response transcription factors and reduced in AP-1 transcription factors, after secondary immunization. Finally, we identified distinct innate pathways associated with CD8 T cell and neutralizing antibody responses, and show that a monocyte-related signature correlates with the neutralizing antibody response against the B.1.351 variant. Collectively, these data provide insights into the immune responses induced by mRNA vaccination and demonstrate its capacity to prime the innate immune system to mount a more potent response after booster immunization. Profiling the immune responses of 56 volunteers vaccinated with BNT162b2 reveals how this mRNA vaccine primes the innate immune system to mount a potent response to SARS-CoV-2 after booster immunization.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3 Author contributions B.P., K.C.N., M.M.D., S.D.B. and P.S.A. conceptualized and designed the trial; P.S.A. and B.P. designed the study; P.S.A., M.S., A.S.L., S.C. and S.B.S. coordinated and performed blood collections under the supervision of K.C.N.; P.S.A., C.L., Y.F., F.W., L.G., V.M. and F.G. processed blood and prepared all samples; P.S.A., C.L., Y.F. and L.G. performed enzyme-linked immunosorbent assays; V.V.E. and L.L. performed neutralization assays under the guidance of M.S.S.; P.S.A., C.L., M.T., S.G. and S.M.-A. performed T cell assays; P.S.A., N.S. and S.K. performed CyTOF under the guidance of H.T.M.; K.H. and M.R. performed SIMOA; S.E.C., A.F. and S.D. performed autoantibody assays under the guidance of P.J.U.; K.P., G.T., H.A. and S.H. performed bulk transcriptomics under the guidance of S.E.B.; P.S.A., F.W., C.L. and Y.F. performed CITE-seq; P.S.A. performed monocyte stimulation experiments; P.S.A. analysed antibody responses, T cell responses, CyTOF and Olink; M.K.D.S. and T.H. analysed bulk transcriptomics; M.K.D.S. and P.S.A. analysed CITE-seq; T.H. performed vaccine response meta-analysis; P.S.A., M.S. and T.H. performed data visualization. B.P., K.C.N., P.K., M.S.S., P.J.U., M.M.D., S.D.B., H.T.M. and S.E.B. supervised the project. P.S.A., M.S., T.H. and B.P wrote the paper. B.P., K.C.N. and P.K. acquired funding. All the authors read and accepted the manuscript.
ISSN:	0028-0836 1476-4687
DOI:	10.1038/s41586-021-03791-x