Age-Dependent Variability in Immune Host Responses to SARS-CoV-2: Implications for Inclusive Clinical Trial Design

Abstract

The COVID-19 pandemic, caused by SARS-CoV-2 has disproportionately affected older adults,who account for the majority of COVID-19-related hospitalizations and deaths. Although disease severity has declined, periodic surges continue to pose significant risks to aging populations, exacerbated by age-associated immune dysfunction, or immunosenescence. This dissertation investigates the immune responses that contribute to protection against SARS-CoV-2 and how these responses become dysregulated with increasing age. Given the evidence of impaired antiviral immunity in aged models, we also evaluated the representation of older adults in COVID-19 vaccine clinical trials to assess whether key age-associated immune differences are being adequately captured in clinical research. In Chapter 1, we examined the effects of IFNβ pre-treatment on SARS-CoV-2 infection dynamics in lung epithelial cell models. We identified interferon-stimulated gene signatures associated with antiviral protection, and found that pre-activation of the IFN pathway significantly reduced viral replication and dampened inflammatory responses associated with severe disease. In Chapter 2, leveraging a cohort of young, mature, and aged mice infected with mouse-adapted SARS-CoV-2, we performed temporally resolved transcriptomic analyses of lung tissues. Aged mice exhibited impaired early cytokine and IFN signaling, dysregulated T cell activation during recovery, and elevated baseline inflammatory signatures, all of which contributed to delayed viral clearance and worsened disease outcomes. Moreover, these immune response are crucial for effective vaccine-induced protection against COVID-19. In Chapter 3, we conducted a cross-sectional analysis of COVID-19 vaccine clinical trials, quantifying the underrepresentation of older adults and identifying exclusion criteria disproportionately impacting this group. Our analysis reveals significant underrepresentation of older adults in these trials, key barriers to their enrollment, and provides recommendations for improving inclusivity of this group in clinical trials. Together, these studies provide new insights into the molecular mechanisms underlying age-associated susceptibility to SARS-CoV-2 and offer a framework for improving immune protection and clinical trial participation for older adults.