The mRNA vaccine BNT162b2 demonstrates impaired TH1 immunogenicity in human elders in vitro and aged mice in vivo

Byron Brook; Benoit Fatou; Abhinav Kumar Checkervarty; Soumik Barman; Cali Sweitzer; Anna-Nicole Bosco; Amy C Sherman; Lindsey R Baden; Elena Morrocchi; Guzman Sanchez-Schmitz; Paolo Palma; Etsuro Nanishi; Timothy R O'Meara; Marisa E McGrath; Matthew B Frieman; Dheeraj Soni; Simon D van Haren; Al Ozonoff; Joann Diray-Arce; Hanno Steen; David J Dowling; Ofer Levy

doi:10.21203/rs.3.rs-2395118/v1

The mRNA vaccine BNT162b2 demonstrates impaired T_H1 immunogenicity in human elders in vitro and aged mice in vivo

Res Sq [Preprint]. 2022 Dec 21:rs.3.rs-2395118. doi: 10.21203/rs.3.rs-2395118/v1.

Authors

Byron Brook^{1

2}, Benoit Fatou³, Abhinav Kumar Checkervarty^{1

4

5}, Soumik Barman^{1

2}, Cali Sweitzer¹, Anna-Nicole Bosco¹, Amy C Sherman^{1

6}, Lindsey R Baden⁶, Elena Morrocchi^{1

7}, Guzman Sanchez-Schmitz^{1

2}, Paolo Palma^{8

9}, Etsuro Nanishi^{1

2}, Timothy R O'Meara¹, Marisa E McGrath¹⁰, Matthew B Frieman¹⁰, Dheeraj Soni^{1

2}, Simon D van Haren^{1

2}, Al Ozonoff^{1

2}, Joann Diray-Arce^{1

2}, Hanno Steen^{1

3}, David J Dowling^{1

2}, Ofer Levy^{1

2

11}

Affiliations

¹ Precision Vaccines Program, Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA.
² Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
³ Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Prevention of Organ Failure (PROOF) Centre of Excellence, St Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.
⁵ UBC Centre for Heart Lung Innovation, Providence Research, St Paul's Hospital, Vancouver, BC, Canada.
⁶ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁷ Academic Department of Pediatrics (DPUO), Research Unit of Clinical Immunology and Vaccinology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁸ Bambino Gesù Children's Hospital, Rome, Italy.
⁹ Chair of Pediatrics, University of Rome, Tor Vergata, Italy.
¹⁰ Center for Pathogen Research, Department of Microbiology and Immunology, The University of Maryland School of Medicine, Baltimore, MD, USA.
¹¹ Broad Institute of MIT & Harvard, Cambridge, MA, USA.

Abstract

mRNA vaccines have been key to addressing the SARS-CoV-2 pandemic but have impaired immunogenicity and durability in vulnerable older populations. We evaluated the mRNA vaccine BNT162b2 in human in vitro whole blood assays with supernatants from adult (18-50 years) and elder (≥60 years) participants measured by mass spectrometry and proximity extension assay proteomics. BNT162b2 induced increased expression of soluble proteins in adult blood (e.g., C1S, PSMC6, CPN1), but demonstrated reduced proteins in elder blood (e.g., TPM4, APOF, APOC2, CPN1, and PI16), including 30-85% lower induction of T_H1-polarizing cytokines and chemokines (e.g., IFNγ, and CXCL10). Elder T_H1 impairment was validated in mice in vivo and associated with impaired humoral and cellular immunogenicity. Our study demonstrates the utility of a human in vitro platform to model age-specific mRNA vaccine activity, highlights impaired T_H1 immunogenicity in older adults, and provides rationale for developing enhanced mRNA vaccines with greater immunogenicity in vulnerable populations.

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