The BNT162b2 mRNA vaccine demonstrates reduced age-associated TH1 support in vitro and in vivo

Byron Brook; 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:10.1016/j.isci.2024.111055

The BNT162b2 mRNA vaccine demonstrates reduced age-associated T_H1 support in vitro and in vivo

iScience. 2024 Sep 26;27(11):111055. doi: 10.1016/j.isci.2024.111055. eCollection 2024 Nov 15.

Authors

Byron Brook^{1

2}, Abhinav Kumar Checkervarty^{1

3

4}, Soumik Barman^{1

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

5}, Lindsey R Baden⁵, Elena Morrocchi^{1

2

6}, Guzman Sanchez-Schmitz^{1

2}, Paolo Palma^{6

7}, Etsuro Nanishi^{1

2}, Timothy R O'Meara¹, Marisa E McGrath⁸, Matthew B Frieman⁸, Dheeraj Soni⁹, Simon D van Haren^{1

2}, Al Ozonoff^{1

2

10}, Joann Diray-Arce^{1

2}, Hanno Steen^{1

11}, David J Dowling^{1

2}, Ofer Levy^{1

2

10}

Affiliations

¹ Precision Vaccines Program, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA.
² Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
³ Prevention of Organ Failure (PROOF) Centre of Excellence, St Paul's Hospital, University of British Columbia, Vancouver, BC V6Z 2K5, Canada.
⁴ UBC Centre for Heart Lung Innovation, Providence Research, St Paul's Hospital, Vancouver, BC V6Z 1Y6, Canada.
⁵ Department of Medicine, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁶ Research Unit of Clinical Immunology and Vaccinology, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.
⁷ Department of Systems Medicine- Chair of Pediatrics, University of Rome, 00133 Tor Vergata, Italy.
⁸ Center for Pathogen Research, Department of Microbiology and Immunology, The University of Maryland School of Medicine, Baltimore, MD 21201, USA.
⁹ Global Investigative Toxicology, Preclinical Safety, Sanofi, Cambridge, MA 02142, USA.
¹⁰ Broad Institute of MIT & Harvard, Cambridge, MA 02142, USA.
¹¹ Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Abstract

mRNA vaccines demonstrate impaired immunogenicity and durability in vulnerable older populations. We hypothesized that human in vitro modeling and proteomics could elucidate age-specific mRNA vaccine actions. BNT162b2-stimulation changed the plasma proteome of blood samples from young (18-50Y) and older adult (≥60Y) participants, assessed by mass spectrometry, proximity extension assay, and multiplex. Young adult up-regulation (e.g., PSMC6, CPN1) contrasted reduced induction in older adults (e.g., TPM4, APOF, APOC2, CPN1, PI16). 30-85% lower T_H1-polarizing cytokines and chemokines were induced in elderly blood (e.g., IFNγ, CXCL10). Analytes lower in older adult samples included human in vivo mRNA immunogenicity biomarkers (e.g., IFNγ, CXCL10, CCL4, IL-1RA). BNT162b2 also demonstrated reduced CD4⁺ T_H1 responses in aged vs. young adult mice. Our study demonstrates the utility of human in vitro platforms modeling age-specific mRNA vaccine immunogenicity, highlights impaired support of T_H1 polarization in older adults, and provides a rationale for precision mRNA vaccine adjuvantation to induce greater immunogenicity.

Keywords: Geriatrics; Health sciences; Immunity; Immunology; Proteomics.