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The arrival of SARS-Cov-2 in the winter of 2019 caught most people by surprise, but not coronavirus experts. Less than a decade separated the zoonotic emergence of SARS in 2003 and MERS in 2012, and the appearance of a third novel coronavirus seven years later was more or less on schedule. If the pattern holds, a fourth coronavirus with pandemic potential can be expected to jump the species barrier around 2027. Whether this comes to pass or not, the scientific community will not be caught as flatfooted as it was in 2019. Even before the first candidate vaccine for COVID-19 was developed, researchers were already thinking about how to get ahead of a possible COVID-27 by developing a pan-coronavirus vaccine.

In the U.S., this effort was formally launched in November 2020 when the N.I.H.’s Institute of Allergy and Infectious Diseases put out a call for grant proposals. In late September, the largest of those grants—totaling $36 million—were awarded to laboratories at Boston’s Brigham and Women’s Hospital, Duke University, and the University of Wisconsin, Madison, which last year launched a Center for Pan-Coronavirus Vaccine Development. While the Boston team will be focused on how to achieve durable immunity, the Duke and Wisconsin teams will use the money to expand their work on candidate vaccines in development.

These projects are part of a larger and sustained global effort that is overdue, says Dr. Sonia Navas-Martin, an immunologist and microbiologist at Drexel University in Philadelphia, as well as a member of the international Pan-Coronavirus Task Force. Navas-Martin has been studying coronaviruses since long before they were cool. As a young PhD in the late 1990s, she made a specialty of mouse coronaviruses. When the SARS threat receded in 2003, and then again after the MERS outbreak in 2012, she warned against letting research interest dissipate. But that’s exactly what happened. As a result, she says, we lost 15 years of research before the arrival of SARS’s and MERS’s cousin, SARS-CoV-2.

Roundtable spoke with Navas-Martin by phone about the quest for a pan-coronavirus vaccine, why it took so long to get underway, and the importance of cracking the mysteries of human immunity.

There is a lot of activity taking place around the search for a pan-coronavirus vaccine. How do you explain the long runway dating to 2003?

Over the last 18 years we’ve faced three highly pathogenic zoonotic coronaviruses. With the first SARS in 2003, we were lucky it didn’t have efficient human-to-human transmission. Asymptomatic carriers and people without clinical symptoms did not shed the virus, so quarantine was effective. So, after it was contained, research into SARS and the human immune response stopped. That was a mistake. Then, in 2012, another pathogenic coronavirus, MERS, jumped from bats to camels to humans in Saudi Arabia. When it was also contained, interest in research again receded. Another mistake.

It was COVID-19, the third coronavirus and the one that caused a global public health emergency, that pushed everything forward. It made the research community realize we have to advance our understanding of the human immune response against coronavirus infections, in particular the betacoronavirus group. There are four main groups of coronaviruses—alpha, beta, delta, and gamma—and SARS, MERS, and Covid-19 are all from the beta group.

Now that sustained work is underway, what are its most important facets?

The human immune response is the key mystery. How do our cells respond to these infections? We can see that the current vaccines are working, but we still don’t understand the complexities of breakthrough infections, or how long immunity will last. The immune response is not just about developing antibodies. We have to understand how the vaccines induce T-cell responses. The weakest aspect of the current vaccines is that the T-cell responses are perhaps not as efficient as they could be.

But developing a pan-coronavirus vaccine with durable immunity is very complex. The first thing is we need to understand is the target. Of course, the spike protein is the main target for developing neutralizing antibody response, but we need to explore a number of avenues and combine the expertise of scientists across multiple disciplines. Not only virologists and immunologists, but also specialists in bioinformatics and structural biology.

Is there anything to suggest whether those infected with SARS and MERS may still have cross-antibodies that protect them against Covid-19?

There are papers here and there, most based on in vitro samples that show [small amounts] of antibodies, but no human studies that prove cross-antibodies are effective. Think about the regular colds people get every winter. Do we develop antibodies? Yes. But how many? And for how long? Is it the same strain as next year? We don’t really know the answers, because nobody has ever been interested in studying the main coronaviruses that infect humans—who cares about sneezing a little bit? But we do know that it’s not enough for the following season. We still get colds. Again, understanding the immune system response is crucial. We need to put a lot of effort on this. Based on what we do know, I don’t think we can’t assume there is cross-protection between SARS, MERS and SARS-CoV-2 antibodies.

How would you rate our current understanding of the human immune response on a scale of one to ten, with ten being the highest? And what is the prognosis for ultimate success?

Maybe a four. We just don’t have the human studies yet. After the SARS and MERS threats passed, we returned to studying the coronavirus immune response in the livers and brains of mice and ferrets. These studies provide us with a framework, but in the end, they are models. We should have continued to research the human immune response.

The research taking place now will lead to huge advances in our knowledge in many areas, including the immune response. We could be five years, maybe a decade away from identifying an effective pan-coronavirus vaccine. I am going to be optimistic. But the lesson of the past is there will be other coronaviruses. Whether it’s a new virus, or emerges from the circulating strains of COVID-19, we need to be prepared.