The COVID-19 pandemic is a worldwide public health crisis with over 100 million confirmed cases and 2.4 million deaths as of February 2021. COVID-19 is caused by a novel coronavirus called SARS-CoV-2. Almost all the neutralizing antibodies targeting SARS-CoV-2 that are in development recognize the receptor binding domain (RBD) on the spike (S) protein. Blocking the interaction of RBD and the ACE2 receptor on human cells is the first of the two critical steps for neutralization of the virus. However, the S2 subunit of the spike is also critical for viral infection and entry into human cells. It is highly conserved across many coronaviruses, including other SARS-CoV-2 like viruses. To date there are no antibodies targeting the S2 subunit.