Advancing Understanding of Viral Interference: Insights From Rhinovirus–SARS-CoV-2 Cross-protection and Immunologic Perspectives

To the Editor—We read with great interest the recent publication entitled “The Common Cold Is Associated With Protection From SARS-CoV-2 Infections” by Moore et al [1]. The study shows that recent rhinovirus infections are associated with reduced risk of SARS-CoV-2 infection through an antiviral gene expression mechanism. Despite the innovative and methodologically sound aspects of the work, several limitations remain unaddressed that could affect the validity and translation of findings. The first limitation of this study is the presence of mucosal transcriptomics without systemic immune or serologic (blood or plasma) correlates. Immune protection against SARS-CoV-2 is known to involve humoral and cellular responses, and antibody titers, especially anti-spike IgG and ACE2-neutralizing activity, strongly correlate with infection risk and vaccine effectiveness [2, 3]. Further studies should combine airway transcriptomics with antibody and T-cell profiling in a multi-omic approach to see the complete immune architecture of human rhinovirus (HRV)–mediated cross-protection. Another limitation of the study is that the dynamics of SARS-CoV-2 depend on variants. The efficacy of antiviral gene activity induced by HRV may vary according to the interferon evasion strategies of different viral variants. Research should evaluate whether the protective effect of HRV persists across variants, given that variant-specific immune escape has been well established during the waves of Delta [4] and Omicron. With the integration of sequencing viral genomes in future plans, analyses stratified by variants will refine the understanding of HRV-mediated cross-protection mechanisms.