As the SARS-CoV-2 vaccine race continues, and effective COVID-19 treatments remain scarce, many researchers are looking to find antibodies that would be an effective way to treat patients infected with SARS-CoV-2, especially early in the course of infection, and to prevent infection, particularly in the elderly. They could also be used to protect those in high-risk situations, such as healthcare workers in COVID-19 wards.

These antibodies can either be designed and engineered, based on similar infections such as SARS and MERS. Or, they can be isolated from people who survived a SARS-CoV-2 infection.

A team from Columbia University Irving Medical Center noted that they have isolated antibodies from several COVID-19 patients that are, to date, among the most potent in neutralizing the SARS-CoV-2 virus.

Their work is published today in Nature in a paper titled, “Potent neutralizing antibodies directed to multiple epitopes on SARS-CoV-2 spike.

The team reported the isolation of 61 SARS-CoV-2-neutralizing monoclonal antibodies from five infected patients hospitalized with severe disease. Among these are 19 antibodies that potently neutralized the authentic SARS-CoV-2 in vitro, nine of which exhibited exquisite potency, with 50% virus-inhibitory concentrations of 0.7 to 9 ng/mL.

“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,” said David Ho, MD, scientific director of the Aaron Diamond AIDS Research Center 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 neutralizing antibodies provide significant protection from SARS-CoV-2 infection in hamsters, and they are planning further studies in other animals and people.

Why look for neutralizing antibodies?

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 neutralizing antibodies.

Earlier in the year, when SARS-CoV-2 first arrived, 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,” said Ho.

The researchers had easy access to blood samples from patients with moderate and severe disease who were treated at Columbia University Irving Medical Center in New York City, the epicenter 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 said.

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 potently neutralizing 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 said.  “This is similar to what we have learned from the HIV experience.”

Antibody cocktails

The majority of anti-SARS-CoV-2 antibodies bind to the spike glycoprotein on the virus’s surface. Epitope mapping, the authors noted, 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.”

Cryo-EM reconstructions show how two different antibodies (blue) bind to the spike protein of the SARS-CoV-2 virus. [David Ho/Columbia University Irving Medical Center]
In addition, two 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.

“These findings show which sites on the viral spike are most vulnerable,” Ho said. “Using a cocktail of different antibodies that are directed to different sites in spike will help prevent the virus becoming resistant to the treatment.”

Implications for vaccines

“We discovered that these powerful antibodies are not too difficult for the immune system to generate. This bodes well for vaccine development,” Ho said. “Vaccines that elicit strong neutralizing antibodies should provide robust protection against the virus.”

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. Several of these monoclonal antibodies are promising candidates for clinical development as potential therapeutic and/or prophylactic agents against SARS-CoV-2.

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