A serendipitous discovery advances COVID research – and makes a cameo in Congress

Caption: National Institute of Allergy and Infectious Diseases Director Dr. Anthony Fauci holds up a copy of a Cell paper as he testifies before a US House of Representatives committee on the coronavirus response. (Watch the video aired by CNBC below.)

While much of the world was watching Dr. Anthony Fauci testify before Congress, Prof. Shane Crotty opens in new tab/window was in a Zoom meeting with his research colleagues at the La Jolla Institute for Immunology in California. Then an email caught his attention: rumor had it that Dr. Fauci held up a paper they co-authored in Cell opens in new tab/window.

The rumors turned out to be true.

Rep. Mark Green of Tennessee, a physician on the Coronavirus Select Committee, had asked Dr. Fauci to “educate America … and all of us” on T cell immunity and its ramifications for a pandemic response. Dr. Fauci explained:

There are two limbs of the immune response. One is an antibody, which is a protein that is made by the cells of the body to bind to the virus and is usually the hallmark of protection against infection. (The other is) the cellular immune response of T cells, and those T cells have the capability of essentially suppressing or killing cells that are infected and preventing the cells that are infected form making new viruses.

Then Dr. Fauci held up a copy of an article in the journal Cell opens in new tab/window to illustrate a finding that could change our understanding of COVID-19 immunity: people who have not been exposed to SARS-Cov-2 but were exposed to other coronaviruses – like those that cause the common cold – have T cells with cross-reactivity to SARS-Cov-2.

This is work we really need to pursue; we’re just at the cusp of understanding the importance of this type of response in Covid-19.

This finding, published online on May 20, could explain why some people are much more affected by COVID-19 than others – and how vaccines could function to be more effective.

Read Dr. Fauci’s new perspective in Cell opens in new tab/window

“A lot of scientists have really stepped up …”

Shane is a Professor and Principal Investigator at the La Jolla Institute, where he and his team investigate how the immune system remembers infections and vaccines. Prof. Alessandro “Alex” Sette opens in new tab/window heads a lab one floor above that identifies the chemical structures the immune system recognizes, using that knowledge to measure and understand immune responses.

So that was the first question they set out to answer. They would measure the immune responses of average COVID-19 patients as a reference point for all the labs and companies that were trying to develop vaccines.

For Shane, the ideal collaborator was right upstairs:

Alex Sette is probably the number one expert in the world at predicting and identifying T cell epitopes to viruses. That's something that he's been doing for decades.

In fact, Alex had just co-authored a paper on that topic in Cell Host & Microbe opens in new tab/window.

Meanwhile, the researchers on Shane’s team are experts in other aspects of viral immunology and measuring immune responses.

Also, both labs have extensive experience in human subject studies on vaccines and infections.

Still, a major hurdle remained:

You need the patient samples, and getting patient samples is always a big deal and a big challenge. So we reached out to our colleagues across the street at the University of California, San Diego and said, ‘Look, we really think we can do some important things … if you can point us to patients that might be willing to volunteer for this study.

They also knew they wanted to measure the T cell and antibody responses at the same time, so they thought of Prof. Florian Krammer’s lab at the Icahn School of Medicine at Mount Sinai opens in new tab/window. His was the first group to develop an academic antibody assay for COVID-19. They had not published the research in a peer-reviewed journal yet, so to get it out as quickly as possible, Florian tweeted the preprint with his explanation on a Twitter thread opens in new tab/window. The ensuing conversation has had more than 2.8K retweets.

Shane, who was working with Florian on other research, said he emailed him to ask if he would share his protocol and proteins:

Normally, that would be a very long and involved process, but instead, he sent it the next day. It’s been a world-on-fire type of situation, so a lot of scientists have really stepped up to move as fast as possible and to be as generous as possible.

A serendipitous discovery

With the key players on board and human subjects lined up, Shane and Alex still needed blood from a control group – people who never had the disease. For this, they used blood samples collected in previous years, before SARS-CovV-2 emerged.

What they saw shocked them: people who had never had the virus still had some T cell reactivity against it.

That was a major finding with implications for vaccine development and the possibility of herd immunity. Since then, they’ve been interviewed by media outlets around the world, including this recent article by CNN opens in new tab/window.

Resting on their laurels? Well, not just yet …

After seeing Dr. Fauci wave their paper before America’s lawmakers in the Congressional hearing, both researchers tweeted the news:

Read Prof. Shane Cotty twitter post opens in new tab/window

Read Alessandro Sette twitter post opens in new tab/window

Of course, with the frantic work pace of the past months, it was tempting for Shane to rest on his laurels.

“I told my wife “Ok, I am done for the year!” he said.

“She replied, ‘Actually, Tony Fauci specifically said you are not done – on TV… to Congress.’

"And she’s right.”

What’s next?

Now, Shane, Alex and their teams are following up on key findings.

“One finding was that actually people with average cases of COVID-19 made a pretty good immune response,” Shane said, adding that antibodies as well as CD8+ and CD4+ T cells were found in their blood after they had recovered.

With this data as a benchmark, they then looked at patients who had a more acute response – those who were hospitalized. As Shane explained:

There's been a lot of concern about those (cases) and desire to understand them, of course, because those are really sick people – and why are they getting so sick? The immune system’s a really complicated place, and so people have proposed that perhaps people are getting so sick because of the immune response. Or they're getting so sick because they're not having a response – or complicated variations of those two.

That study is now under review for publication.

But there’s still another important puzzle to solve: after analyzing the data from their serendipitous discovery, Shane and Alex found that about 50 percent of healthy and infected subjects had T cells that could recognize SARS-CoV-2. Since then, they confirmed opens in new tab/window that these are indeed memory cells that recognized common coronaviruses.

Now for the clincher – “the big one,” as Shane calls it: question that remains unresolved: “Do the T cells matter?”

If you do already have some immune memory that can recognize the virus, does that help you out? Does it not matter at all? Or does it hurt you in some way? Again, the immune system’s a complicated place.

Of course, the complicated nature of the immune system and the T cell question has not stopped people from speculating on everything from the applications for vaccine development and the possibility of achieving herd immunity:

There’s been a huge amount of speculation and a huge amount of news coverage on this topic, which is fine, it's totally interesting. And it's easy to quickly come up with really interesting hypotheses about how this might connect to what's going on in the world.

But we keep pointing out that we have no data, and neither does anybody else, about whether these T cells matter or not. We're going as fast as we can, and we're encouraging other people to study it as well.

Related research

• Read the paper Shane Crotty and Alessandro Sette co-authored: Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals opens in new tab/window, Cell (May 14, 2020)

• Read Dr. Fauci’s new perspective in Cell, co-authored with David M. Morens, MD: Emerging Pandemic Diseases: How We Got To COVID-19 opens in new tab/window, Cell (August 15, 2020)