The WHO and US authorities have declared a public health emergency over the recent outbreak of a new coronavirus (CoV) originating from Wuhan, China (nCoV-2019, recently renamed SARS-CoV-2 and responsible for causing the coronavirus disease termed COVID-2019). The discovery of human monoclonal antibodies to this new CoV and obtaining a molecular understanding of its target epitopes will advance the development of diagnostics, therapeutics and vaccines to limit virus spread. The overall goal of this proposal is to discover and characterize potent broadly neutralizing antibodies to nCoV-2019 that also neutralize closely related strains of CoV such as SARS and other variants currently found in bats but likely to be able to produce human infections in the future. The Nussenzweig laboratory has developed robust methods to isolate, recombinantly produce and characterize human antibodies from the memory B cells of individuals infected by a series of different pathogens including HIV-1, Flaviviruses including Zika, and Hepatitis B virus (1, 2). These methods have also been used by other laboratories to isolate neutralizing antibodies to malaria, Ebola, influenza and other human infections (reviewed in (3)). The Bjorkman laboratory has performed structural studies using these antibodies to obtain information that directs vaccine design and therapies (2, 4-23).
In Aim 1, we obtain samples from nCoV-2019 convalescing individuals (see letter from Dr. Wesley Van Voorhis). Serum samples will be tested for binding to the trimeric nCoV-2019 spike protein (S) and to the isolated receptor binding domain (RBD) of the S protein (see letter of collaboration from Dr. John Pak at Chan- Zuckerberg Biohub). Individuals with high titers against S and RBD will be recruited for large blood donations. Antibodies will be identified from the memory B cells of these individuals.
In Aim 2 we will clone and express the antibodies obtained in Aim 1. The anti-nCoV-2019 antibodies will be tested for binding to the S protein from Severe Acute Respiratory Syndrome (SARS) and other closely related bat-derived CoV to test for cross- reactivity. Any promising antibodies will be evaluated for neutralizing activity (see letter by Dr. Timothy Sheahan at the University of North Carolina).
In Aim 3 Dr. Bjorkman will solve crystal structures of antibody Fabs, and cryo-EM structures of coronavirus spike trimers complexed with Fabs from antibodies identified from Aims 1 and 2. In addition to helping guide vaccine development through the identification of neutralizing targets, the proposed discovery of human monoclonal antibodies to nCoV-2019 and related viruses bears a significant translational potential, such as the treatment and prophylaxis of severe medical conditions associated with nCoV-2019 infection by passive antibody transfer.
No prophylaxis or treatment is available to limit the harm that coronaviruses cause to human health. The development of medical countermeasures that are safe and efficacious could help prevent and curb medical conditions associated with the disease. By combining our discovery of potent nCoV-2019-neutralizing antibodies with knowledge of the structural correlates of virus neutralization, we will set the basis for countermeasures to limit the present and future coronavirus outbreaks.
| Keeffe, Jennifer R; Van Rompay, Koen K A; Olsen, Priscilla C et al. (2018) A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates. Cell Rep 25:1385-1394.e7 |
