Caught on Camera: Neutralizing Antibodies Interacting with SARS-CoV-2

Work also continues on developing better therapeutics against SARS-CoV-2, the novel coronavirus that causes COVID-19. Though we’ve learned a great deal about this coronavirus in a short time, structural biologists continue to produce more detailed images that reveal more precisely where and how to target SARS-CoV-2. This research often involves neutralizing antibodies that circulate in the blood of most people who’ve recovered from COVID-19. The study of such antibodies and how they interact with SARS-CoV-2 offers critical biological clues into how to treat and prevent COVID-19.

A recent study in the journal Nature brings more progress, providing the most in-depth analysis yet of how human neutralizing antibodies physically grip SARS-CoV-2 to block it from binding to our cells [1]. To conduct this analysis, a team of NIH-supported structural biologists, led by postdoc Christopher Barnes and Pamela Björkman, California Institute of Technology, Pasadena, used the power of cryo-electron microscopy (cryo-EM) to capture complex molecular interactions at near-atomic scale.

People infected with SARS-CoV-2 (or any foreign substance, for that matter) generate thousands of different versions of attack antibodies. Some of these antibodies are very good at sticking to the coronavirus, while others attach only loosely. Barnes used cryo-EM to capture highly intricate pictures of eight different human neutralizing antibodies bound tightly to SARS-CoV-2. Each of these antibodies, which had been isolated from patients a few weeks after they developed symptoms of COVID-19, had been shown in lab tests to be highly effective at blocking infection.

The researchers mapped all physical interactions between several human neutralizing antibodies and SARS-CoV-2’s spike protein that stud its surface. The virus uses these spiky extensions to infect a human cell by grabbing on to the angiotensin-converting enzyme 2 (ACE2) receptor. The molecular encounter between the coronavirus and ACE2 takes place via one or more of a trio of three protein domains, called receptor-binding domains (RBDs), that jut out from its spikes. RBDs flap up and down in the fluid surrounding cells, “reaching up” to touch and enter, or “laying down” to hide from an infected person’s antibodies and immune cells. Only an “up” RBD can attach to ACE2 and get into a cell.

Taken together with other structural information known about SARS-CoV-2, Barnes’ cryo-EM snapshots revealed four different types of shapes, or classes, of antibody-spike combinations. These high-resolution molecular views show that human neutralizing antibodies interact in many different ways with SARS-CoV-2: blocking access to either one or more RBDs in their “up” or “down” positions.

These results tell us a number of things, including underscoring why strategies that combine multiple types of antibodies in an “antibody cocktail” might likely offer broader protection against infection than using just a single type of antibody. Indeed, that approach is currently being tested in patients with COVID-19.

The findings also provide a molecular guide for custom-designing synthetic antibodies in the lab to foil SARS-CoV-2. As one example, Barnes and his team observed that one antibody completely locked all three RBDs into closed (“down”) positions. As you might imagine, scientists might want to copy that antibody type when designing an antibody-based drug or vaccine.

Caption: Illustration showing the binding regions for the four classes of SARS-CoV-2 neutralizing antibodies. They bind to a part of the virus’s spike protein called the receptor-binding domain (gray). Credit: Christopher Barnes, California Institute of Technology, Pasadena

It is tragic that hundreds of thousands of people have died from this terrible new disease. Yet the immune system helps most to recover. Learning as much as we possibly can from those individuals who’ve been infected and returned to health should help us understand how to heal others who develop COVID-19, as well as inform precision design of additional vaccines that are molecularly targeted to this new foe.

While we look forward to the potential arrival of COVID-19 vaccines, each of us needs to remember to practice the three W’s: Wear a mask. Watch your distance (stay 6 feet apart). Wash your hands often. In parallel with everyone adopting these critical public health measures, the scientific community is working harder than ever to meet this moment, doing everything possible to develop safe and effective ways of treating and preventing COVID-19.

This article was written by Dr. Francis Collins, who is a physician-geneticist noted for his landmark discoveries of disease genes and his leadership of the international Human Genome Project, which culminated in April 2003 with the completion of a finished sequence of the human DNA instruction book. He is director of the National Institutes of Health in Bethesda, Maryland, United States.