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

Abstract

BACKGROUND T cells control viral infection and promote vaccine durability and in COVID-19 associate with mild disease. We investigated whether prior Measles-Mumps-Rubella (MMR) or Tetanus-Diptheria-Pertussis (Tdap) vaccination elicit cross-reactive T cells that mitigate COVID-19. METHODS Antigen presenting cells (APC) loaded ex vivo with SARS-CoV-2, MMR or Tdap antigens and autologous T cells from COVID-19 convalescent and uninfected individuals, and COVID-19 mRNA vaccinated donors were co-cultured and T cell activation and phenotype were detected by IFN-γ ELISpot assays and flow cytometry. ELISA assays and validation studies identified the APC-derived cytokine(s) driving T cell activation. TCR clonotyping and 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 (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 disease. FUNDING National Institutes of Health (R01HL065095, R01AI152522, R01NS097719), donation from Barbara and Amos Hostetter and the Chleck Foundation.

Breathing more breadth into COVID-19 T cell responses

“…Here, the authors combined physiological processing of SARS-CoV-2 with a single-cell resolution characterization of TCR specificity and diversity, generating a detailed helpful resource to understand the transcriptional basis of heterologous T cell responses and to utilize such knowledge designing more efficient vaccines. 1 Convalescent and COVID-19 mRNA vaccinated individuals exhibited a significant increase of MMR-and Tdapspecific T EMRA cells corroborating the efficacy of vaccines in triggering a heterologous adaptive response to SARS-CoV-2. 1 CD8 + T EMRA cells have been shown to be essential for viral control and as a central cornerstone for the control of reinfection.…”

“…10 Here the effect of MMR and Tdap vaccination was retrospectively evaluated and a reduction of severe COVID-19 was found and attributed to the induction of heterologous adaptive immune response. 1 However, effects of the innate immune system cannot be ruled out in this retrospective analysis as MMR and Tdap have been shown before to induce trained immunity in humans.…”

“…In this issue of Med, Mysore et al show that T cell responses elicited by SARS-CoV-2 infection or vaccination correlate with those induced by MMR and Tdap immunization, revealing the transcriptomic basis of these correlations and find that heterologous adaptive immunity contributes to a better prognosis of COVID-19 disease. 1…”

“…Cross-reactive memory CD4 + and CD8 + T EMRA cells are persistent and can react to different antigens creating a broader barrier, as shown by a recent publication exploring the effect of MMR and Tdap vaccines on the adaptive immune responses to SARS-CoV-2. 1 Other vaccines, such as BCG are also capable of inducing similar heterologous responses by priming myeloid cells, which undergo metabolic and epigenetic changes that trigger broad and persistent protection. Both mechanisms of heterologous immunity should be considered to improve vaccine efficacy and prolong protection.…”

“…Origin and mechanisms of innate and adaptive heterologous immunityVaccination and infection events along a person's lifetime generate immune memory to confer long-lasting protection. Cross-reactive memory CD4 + and CD8 + T EMRA cells are persistent and can react to different antigens creating a broader barrier, as shown by a recent publication exploring the effect of MMR and Tdap vaccines on the adaptive immune responses to SARS-CoV-2 1. Other vaccines, such as BCG are also capable of inducing similar heterologous responses by priming myeloid cells, which undergo metabolic and epigenetic changes that trigger broad and persistent protection.…”