ABSTRACT
Background: SARS-CoV-2 remains a global threat, despite the rapid deployment but limited coverage of multiple vaccines. Alternative vaccine strategies that have favorable manufacturing timelines, greater ease of distribution and improved coverage may offer significant public health benefits, especially in resource-limited settings. Live oral vaccines have the potential to address some of these limitations;however no studies have yet been conducted to assess the immunogenicity and protective efficacy of a live oral vaccine against SARS-CoV-2. Thus far, we assessed whether oral administration of live SARS-CoV-2 in non-human primates might offer prophylactic benefits. Methods: In this study, we assessed the immunogenicity of gastrointestinal (GI) delivery of SARS-CoV-2 and the protective efficacy against intranasal and intratracheal SARS-CoV-2 challenge in rhesus macaques. Esophagogastroduodenoscopy (EGD) administration of 106 50% Tissue Culture Infectious Dose (TCID50) of SARS-CoV-2 elicited low levels of serum neutralizing antibodies (NAb), which correlated with modestly diminished viral loads in nasal swabs (NS) and Bronchoalveolar Lavage (BAL) post-challenge. In addition, mucosal NAb titers from the rectal swabs (RS), NS, and BAL and Spike-specific T-cell responses appear to be below the limit of detection post-vaccination. Replicating virus was only observed in 44% of macaques and on limited number of dates post vaccination, suggesting limited, if any, productive infection in the GI tract. Results: We demonstrate that GI delivery of live 1x106 TCID50 SARS-CoV-2 elicited modest immune responses and provided partial protection against intranasal and intratracheal challenge with SARS-CoV-2. Moreover, serum neutralizing antibody titers correlated with protective efficacy. Conclusion: These data provide proof-of-concept that an orally administered vaccine can protect against respiratory SARS-CoV-2 challenge, but the limited immunogenicity and protective efficacy observed here suggests that the oral vaccine approach will require optimization.
ABSTRACT
SARS-CoV-2 is a zoonotic virus that has caused a pandemic of severe respiratory disease-COVID-19-within several months of its initial identification. Comparable to the first SARS-CoV, this novel coronaviruss surface Spike (S) glycoprotein mediates cell entry via the human ACE-2 receptor, and, thus, is the principal target for the development of vaccines and immunotherapeutics. Molecular information on the SARS-CoV-2 S glycoprotein remains limited. Here we report the crystal structure of the SARS-CoV-2 S receptor-binding-domain (RBD) at a the highest resolution to date, of 1.95 . We identified a set of SARS-reactive monoclonal antibodies with cross-reactivity to SARS-CoV-2 RBD and other betacoronavirus S glycoproteins. One of these antibodies, CR3022, was previously shown to synergize with antibodies that target the ACE-2 binding site on the SARS-CoV RBD and reduce viral escape capacity. We determined the structure of CR3022, in complex with the SARS-CoV-2 RBD, and defined a broadly reactive epitope that is highly conserved across betacoronaviruses. This epitope is inaccessible in the closed prefusion S structure, but is accessible in open conformations. This first-ever resolution of a human antibody in complex with SARS-CoV-2 and the broad reactivity of this set of antibodies to a conserved betacoronavirus epitope will allow antigenic assessment of vaccine candidates, and provide a framework for accelerated vaccine, immunotherapeutic and diagnostic strategies against SARS-CoV-2 and related betacoronaviruses.
ABSTRACT
[Figure: see text].