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

Zhao, Jincun; Zhao, Jingxian; Mangalam, Ashutosh K.; Channappanavar, Rudragouda; Fett, Craig; Meyerholz, David K.; Agnihothram, Sudhakar; Baric, Ralph S.; David, Chella S.; Perlman, Stanley

Two zoonotic coronaviruses (CoV), 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 interferon-γ-dependent 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 may have broad applicability in the context of new CoV and other respiratory virus outbreaks.