Airway Memory CD4⁺ T Cells Mediate Protective Immunity against Emerging Respiratory Coronaviruses

Two zoonotic coronaviruses (CoVs)-SARS-CoV and MERS-CoV-have crossed species to cause severe human respiratory disease. Here, we showed that induction of airway memory CD4⁺ T cells specific for a conserved epitope shared by SARS-CoV and MERS-CoV is a potential strategy for developing pan-coronavirus vaccines. Airway memory CD4⁺ T cells differed phenotypically and functionally from lung-derived cells and were crucial for protection against both CoVs in mice. Protection was dependent on interferon-γ and required early induction of robust innate and virus-specific CD8⁺ T cell responses. The conserved epitope was also recognized in SARS-CoV- and MERS-CoV-infected human leukocyte antigen DR2 and DR3 transgenic mice, indicating potential relevance in human populations. Additionally, this epitope was cross-protective between human and bat CoVs, the progenitors for many human CoVs. Vaccine strategies that induce airway memory CD4⁺ T cells targeting conserved epitopes might have broad applicability in the context of new CoVs and other respiratory virus outbreaks. Zoonotic CoVs have emerged twice in the past 10 years and have caused severe human respiratory disease. Using an alphavirus vaccine vector, Perlman and colleagues show that intranasal vaccination induces airway memory CD4⁺ T cell responses that protect mice from lethal challenge and are cross-reactive to different CoVs.