As the SARS-CoV-2 pandemic continues to spread around the world, a vaccine is urgently needed and clinical trials are ongoing. However, successful vaccine design is contingent on understanding which immune responses efficiently prevent and control infection. Previous research revealed that like the 2003 SARS-CoV, SARS-CoV-2 surface spike protein (S) is necessary for viral entry via the cell receptor angiotensin-converting enzyme 2 (ACE2), and that neutralizing antibodies target S. However, the specifics of a successful antibody response are unknown.
To understand what constitutes an effective SARS-Cov-2-neutralizing antibody, researchers from the McGuire, Pancera, and Stamatatos labs in the Vaccine and Infectious Disease Division isolated antibody-producing B cells from a COVID-19 patient and interrogated antibody structure and binding properties. This work, led by Dr. Emilie Seydoux, was recently published in Immunity and “describes the isolation and characterization of monoclonal antibodies from a patient who suffered from COVID-19,” she explained.
The authors isolated serum containing antibodies from a Seattle SARS-CoV-2 patient with severe COVID-19 disease, at three weeks post-diagnosis. Upon an initial screen, the patient’s antibodies neutralized S protein expressed on a pseudovirus, suggesting that the donor had developed a potent binding and neutralizing antibody response in a relatively short time period. To further assess this response, the authors also isolated the patient’s B cells, whose B cell receptor (BCR) sequences encode antibodies, and screened them against a SARS-CoV-2 receptor binding domain (RBD) or a variant of SARS-CoV-2 S protein (S2P) “bait.” The BCRs from B cells that successfully bound the bait were sequenced and made into antibodies and directly tested for binding against S2P. While all BCRs bound S2P, only 3 were able to bind the RBD, suggesting that early SARS-CoV-2 antibodies target epitopes outside the RBD.
Antibody binding, however, does not guarantee neutralization, where the virus is prevented from entering a cell. The authors tested the ability of the S2P-binding antibodies to block SARS-CoV-2 infection in cell culture, and Dr. Seydoux explained that they “found two antibodies that could neutralize the virus and prevent it from entering human cells.” She added that these two antibodies “bind to different sites (so-called epitopes) on the virus, but both are neutralizing, indicating different modes of action.” This suggests that a combination of antibody binding strategies could be more effective for vaccine-elicited responses.
Although only two neutralizing antibodies were recovered, the “information gathered from these antibodies is very valuable, as they could be laboratory-produced and used to either prevent or treat the disease as an emergency treatment,” Dr. Seydoux said. “In order to develop a potent vaccine candidate against SARS-CoV-2, we also need to understand the immune responses elicited during a natural infection and which will need to be replicated by the vaccine to prevent a future infection. It is postulated that neutralizing antibodies are of central importance. This work therefore provides an important insight that neutralizing antibodies elicited by a vaccine will need to target different virus epitopes to be fully effective.”
Going forward, the authors are working to enhance the neutralizing ability of these two promising antibodies, and are testing “whether a combination of several antibodies could improve virus neutralization,” Dr. Seydoux explained. Additionally, the authors are interested in “understanding the differences in antibody production and ‘quality’ between adults and younger patients,” Dr. Seydoux said.
This work was supported by donations to Fred Hutch COVID-19 Research Fund .
Fred Hutch/UW Cancer Consortium members Julie McElrath, Janet Englund, Steven Pergam, and Michael Boeckh contributed to this work.
Seydoux E, Homan LJ, MacCamy AJ, Parks KR, Hurlburt NK, Jennewein MF, Akins NR, Stuart AB, Wan Y, Feng J, Whaley RE, Singh S, Boeckh M, Cohen KW, McElrath JM, Englund JA, Chu HY, Pancera M, McGuire AT, Stamatatos L. Analysis of a SARS-CoV-2-Infected Individual Reveals Development of Potent Neutralizing Antibodies with Limited Somatic Mutation. Immunity. doi: 10.1016/j.immuni.2020.06.001