Researchers at Columbia University Irving Medical Centre have isolated antibodies from several COVID-19 patients that, to date, are among the most potent in neutralizing the SARS-CoV-2 virus. These antibodies could be produced in large quantities by pharmaceutical companies to treat patients, especially early in the course of infection, and to prevent infection, particularly in the elderly.
"We now have a collection of antibodies that's more potent and diverse compared to other antibodies that have been found so far, and they are ready to be developed into treatments," says Dr David Ho, scientific director of the Aaron Diamond AIDS Research Centre and professor of medicine at Columbia University Vagelos College of Physicians and Surgeons, who directed the work.
The researchers have confirmed that their purified, strongly neutralising antibodies provide significant protection from SARS-CoV-2 infection in hamsters, and they are planning further studies in other animals and people.
One of the human body's major responses to an infection is to produce antibodies – proteins that bind to the invading pathogen to neutralize it and mark it for destruction by cells of the immune system. Though a number of drugs and vaccines in development for COVID-19 are in clinical trials, they may not be ready for several months. In the interim, SARS-CoV-2 neutralising antibodies produced by COVID-19 patients could be used to treat other patients or even prevent infection in people exposed to the virus. The development and approval of antibodies for use as a treatment usually take less time than conventional drugs.
This approach is similar to the use of convalescent serum from COVID-19 patients but potentially more effective. Convalescent serum contains a variety of antibodies, but because each patient has a different immune response, the antibody-rich plasma used to treat one patient may be vastly different from the plasma given to another, with varying concentrations and strengths of neutralising antibodies.
When SARS-CoV-2 arrived and led to a pandemic at the beginning of the year, Ho rapidly shifted the focus of his HIV/Aids laboratory to work on the new virus. "Most of my team members pretty much have been working nonstop 24/7 since early March," says Ho.
The researchers had easy access to blood samples from patients with moderate and severe disease who were treated at Columbia University Irving Medical Centre in New York City, the epicentre of the pandemic earlier this year. "There was plenty of clinical material, and that allowed us to select the best cases from which to isolate these antibodies," Ho says.
Ho's team found that although many patients infected with SARS-CoV-2 produce significant quantities of antibodies, the quality of those antibodies varies. In the patients they studied, those with severe disease requiring mechanical ventilation produced the most potent neutralising antibodies.
“We think that the sicker patients saw more virus and for a longer period of time, which allowed their immune system to mount a more robust response,” Ho says. “This is similar to what we have learned from the HIV experience.”
The majority of anti-SARS-CoV-2 antibodies bind to the spike glycoprotein – a feature that gives the virus its corona—on the virus's surface. Some of the most potent antibodies were directed to the receptor binding domain (where the virus attaches to human cells), but others were directed to the N-terminal region of the spike protein. The Columbia team found a more diverse variety of antibodies than previous efforts, including new, unique antibodies that were not reported earlier.
“These findings show which sites on the viral spike are most vulnerable,” Ho says. “Using a cocktail of different antibodies that are directed to different sites in spike will help prevent the virus becoming resistant to the treatment.”
“We discovered that these powerful antibodies are not too difficult for the immune system to generate. This bodes well for vaccine development,” Ho says. “Vaccines that elicit strong neutralising antibodies should provide robust protection against the virus.”
Antibodies also may be useful even after a vaccine is available. For example, a vaccine may not work well in the elderly, in which case the antibodies could play a key role in protection.
This research demonstrates that people with severe disease are more likely to have a durable antibody response, however more research needs to be done to answer the critical question about how long immunity to COVID-19 will last.
The researchers are now designing experiments to test the strategy in other animals and eventually in humans.
If the animal results hold true in humans, the pure, highly neutralising antibodies could be given to patients with COVID-19 to help them clear the virus.
Although tremendously informative for researchers developing vaccines and antiviral therapies, the findings are early-stage preclinical results and the antibodies are not yet ready for use in people.
Abstract
The SARS-CoV-2 pandemic rages on with devasting consequences on human lives and the global economy1,2. The discovery and development of virus-neutralizing monoclonal antibodies could be one approach to treat or prevent infection by this novel coronavirus. Here we report the isolation of 61 SARS-CoV-2-neutralizing monoclonal antibodies from 5 infected patients hospitalized with severe disease. Among these are 19 antibodies that potently neutralized the authentic SARS-CoV-2 in vitro, 9 of which exhibited exquisite potency, with 50% virus-inhibitory concentrations of 0.7 to 9 ng/mL. Epitope mapping showed this collection of 19 antibodies to be about equally divided between those directed to the receptor-binding domain (RBD) and those to the N-terminal domain (NTD), indicating that both of these regions at the top of the viral spike are immunogenic. In addition, two other powerful neutralizing antibodies recognized quaternary epitopes that overlap with the domains at the top of the spike. Cryo-electron microscopy reconstructions of one antibody targeting RBD, a second targeting NTD, and a third bridging two separate RBDs revealed recognition of the closed, “all RBD-down” conformation of the spike. Several of these monoclonal antibodies are promising candidates for clinical development as potential therapeutic and/or prophylactic agents against SARS-CoV-2.
Authors
Lihong Liu, Pengfei Wang, Manoj S Nair, Jian Yu, Micah Rapp, Qian Wang, Yang Luo, Jasper FW Chan, Vincent Sahi, Amir Figueroa, Xinzheng Guo, Gabriele Cerutti, Jude Bimela, Jason Gorman, Tongqing Zhou, Zhiwei Chen, Kwok-Yung Yuen, Peter D Kwong, Joseph G Sodroski, Michael T Yin, Zizhang Sheng, Yaoxing Huang, Lawrence Shapiro, David D Ho
[link url="https://www.cuimc.columbia.edu/news/neutralizing-antibodies-isolated-covid-19-patients-may-suppress-virus"]Columbia University material[/link]
[link url="https://www.nature.com/articles/s41586-020-2571-7"]Nature abstract[/link]