Stabilized Coronavirus Spike Stem Elicits a Broadly Protective Antibody

Hsieh, Ching-Lin; Werner, Anne P.; Leist, Sarah R.; Stevens, Laura J.; Falconer, Ester; Goldsmith, Jory A.; Chou, Chia-Wei; Abiona, Olubukola M.; West, Ande; Westendorf, Kathryn; Muthuraman, Krithika; Fritch, Ethan J.; Dinnon, Kenneth H.; Schäfer, Alexandra; Denison, Mark R.; Chappell, James D.; Baric, Ralph S.; Graham, Barney S.; Corbett, Kizzmekia S.; McLellan, Jason S.

Current coronavirus vaccines primarily target immunodominant epitopes in the S1 subunit, which are poorly conserved and susceptible to escape mutations, thus threatening vaccine efficacy. Here, we use structure-guided protein engineering to remove the S1 subunit from the MERS-CoV spike (S) glycoprotein and develop stabilized stem (SS) antigens. Vaccination with MERS SS elicits cross-reactive β-coronavirus antibody responses and protects mice against lethal MERS-CoV challenge. High-throughput screening of antibody secreting cells from MERS SS-immunized mice leads to discovery of a panel of cross-reactive monoclonal antibodies. Among them, antibody IgG22 binds with high affinity to both MERS-CoV and SARS-CoV-2 S proteins, and a combination of electron microscopy and crystal structures localizes the epitope to a conserved coiled-coil region in the S2 subunit. Passive transfer of IgG22 protects mice against both MERS-CoV and SARS-CoV-2 challenge. Collectively, these results provide proof-of-principle for cross-reactive coronavirus antibodies and inform the development of pan-coronavirus vaccines and therapeutic antibodies.