Protective heterologous T cell immunity in COVID-19 induced by the trivalent MMR and Tdap vaccine antigens

Med. 2021 Sep 10;2(9):1050-1071.e7. doi: 10.1016/j.medj.2021.08.004. Epub 2021 Aug 14.


Background: T cells control viral infection, promote vaccine durability, and in coronavirus disease 2019 (COVID-19) associate with mild disease. We investigated whether prior measles-mumps-rubella (MMR) or tetanus-diphtheria-pertussis (Tdap) vaccination elicits cross-reactive T cells that mitigate COVID-19.

Methods: Antigen-presenting cells (APC) loaded ex vivo with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), MMR, or Tdap antigens and autologous T cells from COVID-19-convalescent participants, uninfected individuals, and COVID-19 mRNA-vaccinated donors were co-cultured. T cell activation and phenotype were detected by interferon-γ (IFN-γ) enzyme-linked immunospot (ELISpot) assays and flow cytometry. ELISAs (enzyme-linked immunosorbant assays) and validation studies identified the APC-derived cytokine(s) driving T cell activation. TCR clonotyping and single-cell RNA sequencing (scRNA-seq) identified cross-reactive T cells and their transcriptional profile. A propensity-weighted analysis of COVID-19 patients estimated the effects of MMR and Tdap vaccination on COVID-19 outcomes.

Findings: High correlation was observed between T cell responses to SARS-CoV-2 (spike-S1 and nucleocapsid) and MMR and Tdap proteins in COVID-19-convalescent and -vaccinated individuals. The overlapping T cell population contained an effector memory T cell subset (effector memory re-expressing CD45RA on T cells [TEMRA]) implicated in protective, anti-viral immunity, and their detection required APC-derived IL-15, known to sensitize T cells to activation. Cross-reactive TCR repertoires detected in antigen-experienced T cells recognizing SARS-CoV-2, MMR, and Tdap epitopes had TEMRA features. Indices of disease severity were reduced in MMR- or Tdap-vaccinated individuals by 32%-38% and 20%-23%, respectively, among COVID-19 patients.

Conclusions: Tdap and MMR memory T cells reactivated by SARS-CoV-2 may provide protection against severe COVID-19.

Funding: This study was supported by a National Institutes of Health (R01HL065095, R01AI152522, R01NS097719) donation from Barbara and Amos Hostetter and the Chleck Foundation.

Keywords: SARS-CoV-2; TCR repertoire; antibody titers; antigen presenting cells; antigens; heterologous immunity; memory T cells; risk prediction; transcriptome; vaccines.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19* / prevention & control
  • Humans
  • Measles*
  • Mumps Vaccine
  • Receptors, Antigen, T-Cell
  • Rubella Vaccine
  • SARS-CoV-2
  • Spike Glycoprotein, Coronavirus
  • T-Lymphocytes
  • Whooping Cough*


  • Mumps Vaccine
  • Receptors, Antigen, T-Cell
  • Rubella Vaccine
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2