Ask a Caltech Expert: Christopher Barnes on Antibodies

Barnes was a member of the lab of Pamela Bjorkman, the David Baltimore Professor of Biology and Bioengineering, and is now an assistant professor at Stanford University. He uses high-resolution imaging techniques to investigate how viruses infect humans, and how the body's immune system responds to viral infections. At Caltech, he focused on the study of antibodies to neutralize HIV-1 and SARS-CoV-2.

Here, Barnes talked with Caltech content and media strategist Lori Dajose (BS '15) about how his work could help improve COVID-19 vaccinations and make treatments better.

The questions and answers below have been edited for clarity and concision.

Let's start with the basics. What is an antibody?

Antibodies are nothing more than proteins that our body produces. These are produced by our immune system in response to specific antigens or pathogens, whether this is a virus, bacteria, or even pollen. They typically have a Y-shaped form in which the ends of the Y are used to grab onto that pathogen. Once attached, the antibody can either block the pathogen—a virus in the case of SARS-CoV-2—from infecting your cell or it can signal other cells in the immune system to respond and to dispose of that antigen.

These antibodies typically are produced within 7 to 10 days upon encountering an infection or virus. They play a very important role in our adaptive immune response in both neutralizing the virus or bacteria and giving us a memory so that we can be protected when we get challenged again by that same pathogen.

How do vaccines teach the body to make protective antibodies against viruses and other pathogens?

There are three things to think about when it comes to antibodies, and those are specificity, diversity, and memory. There's a diversity of immune system cells circulating in our body at any given point. Because of this diversity, you can get very specific immune responses when you're exposed to or challenged by a certain virus or antigen. Your body then drives a response that is very specific to that antigen and begins to make more cells that produce the antibodies that recognize it.

What we're trying to do with a vaccine is to produce antibodies by giving the body a piece of the virus. In this case, with SARS-CoV-2, we give it a piece of the virus known as a spike glycoprotein, the large protein on the surface of the virus. When we give the body this piece, cells that are very specific and can recognize that spike protein begin to proliferate and we start making more of them.

Now when we are challenged with the virus—when we're out in public after being vaccinated and the virus enters our body—our immune system has more of these cells available to go and attack and create antibodies that will be specific to that spike protein. That's what we're trying to do in the case of a vaccine: to expand this very specific population of cells that give rise to antibodies that will then help protect us.

You recently published research in collaboration with Rockefeller University about antibodies and their effectiveness against the SARS-CoV-2 variants. Can you discuss this work?

We wanted to explore what was happening after natural infection. How are the antibodies from recovered individuals functioning to neutralize a virus, and what can that tell us about ways we can engineer these antibodies to be better?

In Pamela Bjorkman's group, we utilized an imaging technique called single-particle cryo-EM. In this case, we take that spike protein and mix it to form a complex with potent, strongly neutralizing antibodies that have been isolated from people. Once we have this complex, we can look at it and image it and say exactly how this antibody is targeting the spike. Is it targeting it to block it from interacting with the receptor the virus needs for entry into our human cells, like the lung cells, or is it targeting a different region?

Through our work, we can begin to understand exactly where these antibodies bind, how they function in neutralizing the virus, and begin to tell a complete picture of what's happening within our immune response upon infection. Now that we know exactly how these antibodies bind and how they function, we can begin to think about ways in which we can combine them and make therapies. Even antibodies that we consider to be weak as a single antibody can be very potent and neutralize the virus within the mixture of antibodies that you would actually see after infection. That's important when we start to talk about the SARS-CoV-2 variants and how our antibodies deal with these variants.

Antibody Treatment Availability
Barnes suggested the Antibody Infusion Locator Tool: covid.infusioncenter.org, as a resource for members of the public who are interested in access to antibody treatments.

You were working on HIV before the COVID-19 pandemic. What was it like making the transition to SARS-CoV-2? How are the two viruses alike?

As structural biologists, we have worked out ways to image and understand antibody–antigen complexes using the technique I mentioned, single-particle cryo-EM. So, as long as we can understand the biochemistry, make the proteins that we wanted to study, and form stable complexes, then the imaging portion of it—with the microscopes and the facilities we have here at Caltech—allows us to transition easily and rapidly.

It wasn't too difficult, given the similarities between these viruses. The coronavirus is very similar to HIV in that both are [so-called] envelope viruses displaying a surface glycoprotein. That allowed us to quickly learn more about this virus.

You gave a talk about the COVID vaccine rollout and COVID's impact on the Black community. Can you discuss that a bit?

There's a degree of hesitancy within certain communities about vaccination and treatments, but this hesitancy doesn't completely explain the [initially] low numbers of people of color being vaccinated. We need to have more equitable practices for vaccine delivery into communities of color.

Our discussion that day was to help people understand exactly what the vaccines are, how they were tested, and to let people know that these vaccines are very safe and very effective. Unfortunately, there's a lot of misinformation circulating in the news and social media. As scientists, it's our job to go out and help people understand. There's a lot of information incoming even for us, as scientists, to deal with. So how can we expect the communities to parse these data themselves and understand them?

I value those types of events that allow us, as scientists doing the work, to get in front of the community and to explain exactly what we're doing and how the work will benefit you and your families and friends. I learned a lot about public health here in Pasadena, and I think the city is making great strides to make sure that people are being vaccinated equitably.

Here are some of the other questions addressed in the video linked above:

• What are antibody cocktails and how do they work?
• For a virus particle to be neutralized, do all of its surface spike proteins need to be bound by antibodies?
• Why do some vaccines result in lifetime immunity while others need a vaccination booster from time to time?

Learn more about vaccines and antibodies on the Caltech Science Exchange:

• How Do Vaccines Work?
• What Is Passive Immunization?