What’s it like to be a medical researcher right now, pulled from your ongoing projects to work on COVID-19 as the whole world waits on tenterhooks for your results?
“It feels at the same time powerful and powerless,” says Dr. Daniel Hoft, the director of the Division of Infectious Diseases, Allergy, and Immunology and the Center for Vaccine Development at Saint Louis University, who was recently appointed to the National Vaccine Advisory Committee. “It’s wanting to do everything we possibly can yesterday but being frustrated by the fact that things take time.”
And so much has to be learned fast.
At first glance, COVID-19 looked like a respiratory virus that attacked the lungs. Then patients started reporting symptoms that suggested involvement of the gastrointestinal tract, heart, blood vessels, kidneys, liver, brain. Yet the virus wasn’t showing up in blood samples, so how had it managed to infect those tissues? And what explained the inflammatory disease affecting children well after the virus had seemed to run its course?
COVID-19 also looked as if it would be communicable only by people with serious illness. It turned out to be contagious even when people were asymptomatic, which is why it exploded a pandemic. Yet the novel coronavirus’ reproduction number (the average number of people each sick person will infect) went only as high as five at the start of the St. Louis outbreak, and that was the worst it got. The reproduction number for measles is closer to 18. The reason for the rapid contagion is that with COVID-19, many people don’t feel sick. They’re walking around talking and laughing…as the numbers keep doubling.
In less than six months, there were more than 4 million known infections on the planet.
SLU has one of the nine federally funded Vaccine and Treatment Evaluation Units, and it is one of the 58 sites around the world running the Adaptive COVID-19 Treatment Trial backed by the National Institutes of Health. Dr. Sarah George, the SLU site’s principal investigator for this trial, watched results pour in after seriously ill patients were given either a placebo or remdesivir, an antiviral drug developed to treat Ebola.
By interfering with the replication of the virus, remdesivir shortened the illness’s duration by 31 percent—four days. The death rate also dropped, but not statistically significantly so; researchers were hoping for better. Now the trial has entered phase II; the controversial placebo has been dropped and baricitinib added. “It’s an enzyme inhibitor that’s been shown, at least in vitro, to have a profound effect on blocking the release of proinflammatory cytokines,” Hoft explains. In other words, baricitinib could prevent the “cytokine storm” that whips the immune system into a self-destructive frenzy in end-stage lung disease.
“Baricitinib also has some impact as an antiviral,” he adds, “because it inhibits host factors required for viral replication, so it’s a twofer.” When shelter-in-place restrictions were loosened, in May, it looked likely that the study would have plenty of patients to recruit over the summer for its next phase.
Hoft, meanwhile, was preparing to evaluate the Moderna vaccine, a new platform that’s a sharp departure from tradition. Vaccines can be made with weakened virus, dead virus, pieces of a virus, or something that mimics a virus. But you can also simply introduce the RNA or DNA code and let the body manufacture the pathogen. This is faster and in some ways simpler, Hoft says: “You don’t actually have to grow the virus; you don’t have to make a huge batch that could escape and infect the whole continent. All you have to do is make the sequence on the computer and figure out how to clone it into a vector that can deliver that sequence.”
His team is also working with Epivax on a vaccine that targets T lymphocytes, or T cells. Most vaccines target the B lymphocyte, which floats through the body and, if it comes upon evidence of a foreign pathogen, blocks it. T cells are the other line of defense, but they have to wait until they recognize a bit of foreign protein that’s already attached itself to a cell’s surface. Some say this is less efficient, because theoretically a vaccine targeting B cells could stop the virus before it gets a foothold. “In my mind, that’s naïve,” Hoft says, dismissing the dream of a “sterile” response before the body is even infected. “Someone vaccinated 10 years ago likely will need the virus to amplify itself first in order to stimulate enough memory to have soldiers come out and, optimally, kill it.”
When SARS-CoV2 struck, Hoft was working on a universal flu vaccine that targets T cells present in all strains of influenza. “We have proof of concept already,” he says, “but it’s on hold because we only have data for half the world, and we need more funding.” Now he thinks it will also be possible to develop a universal vaccine against the three serious coronaviruses—SARS-CoV1, MERS, and SARS-CoV2—because they are genetically similar and have evolved along the same path, moving from bats to other mammals (a civet for SARS-1, a camel for MERS, possibly a pangolin for SARS CoV-2) and then to us.
The good news for any vaccine is that coronavirus genomes are relatively stable. Other RNA viruses, like influenza, mutate so fast, we have to be nagged to get a new flu shot every year. But coronaviruses are three times bigger, and those large genomes include a proofreading enzyme that catches and corrects errors. In its first six months, SARS-CoV2 mutated only a few times. Cynics who point out that an HIV vaccine was supposed to be developed by 1986 forget how swiftly HIV mutates and how many strains (15) are already circulating.
So far, the solution for HIV has been to use combinations of antiviral drugs developed specifically for HIV. That could happen for COVID-19 as well, but more traditional vaccines are also possible. The virus will still mutate to escape them, but the vaccines ought to be able to keep up.
How do we fast-track those vaccines and still know they’re effective? Vaccines are usually tested by giving them to animals, then exposing those animals to the disease. Thousands of people have already volunteered to serve as human guinea pigs and speed the process, but in Hoft’s mind, a human challenge study would raise major ethical issues—unless and until we can develop a highly effective treatment to rescue participants in whom severe disease develops.
Dr. Sean Whelan, chair of molecular microbiology at Washington University, agrees, adding that even the possibility of a study participant’s dying could undermine what’s left of public trust among those already suspicious of vaccines, science, and public health efforts.
Until December, Whelan was on the faculty at Harvard University, where he headed the virology program. He was alarmed by the mysterious new virus in Wuhan, and soon after he moved to St. Louis, he struck up a conversation with one of his new colleagues, Dr. Michael Diamond, who’d done pioneering work on the Zika virus while Whelan was working on Ebola. “Are you going to study this one?” Whelan asked.
“I’m thinking about it,” said Diamond, associate director of the university’s Bursky Center for Human Immunology & Immunotherapy Programs.
“Yeah, I am, too,” Whelan said, and they decided to compare notes every Monday morning.
Two months later, that 8 a.m. Monday meeting of a handful of scientists had to be conducted on Zoom, for safety’s sake, and it had expanded to include participants from nearly 40 labs across Wash. U. Many had dropped their own research to study the basic biology of the virus, how it replicates, the structure and function of its proteins, the clinical course of the disease. Why was it so severe in some and mild in others? What was the common denominator in otherwise healthy people who became severely ill? Other Wash. U. researchers were developing vaccines, better diagnostic tests, tests for antibodies, cocktails of antibodies targeting different parts of the virus, and a treatment, already approved by the FDA for critically ill patients, involving the use of plasma from people who have recovered.
Until this year, not many researchers around the world had chosen to focus on coronaviruses. “That’s understandable, I guess,” says Whelan, his tone far from convincing. “A lot of people’s research focus is on medically relevant pathogens. But three serious human coronaviruses have emerged in this century. There’s an enormous number of these viruses out there, and there are so many things we don’t understand about their fundamental biology.”
Whelan helped lay the foundation necessary to create the Ebola vaccine by developing genetic approaches to manipulate a livestock virus, harmless in humans, and change its surface protein. He’s now applying a similar approach to COVID-19, changing the surface protein so the virus looks like SARS CoV-2 on the outside but with a harmless interior. The exterior of the vaccine is so similar to the clinical isolates of COVID-19 that it should generate the same sort of immune response a natural infection would—and therefore protect against such an infection.
He has also been involved in the development of apilimod, a promising drug that works by inhibiting a host enzyme, thus blocking SARS CoV-2 from entering cells. Apilimod was developed to manipulate inflammation and was tested in Crohn’s disease. Remdesivir was originally developed for Ebola. As for the hydroxychloroquine–azithromycin combo that was christened a game-changer and gulped by the nation’s president, the clinical trials at Wash. U. have shown no positive outcomes, “and in fact there has been an association with cardiac problems,” Whelan says.
“One of the big strategies people are pushing right now is to ask if any existing drugs inhibit any aspect of this virus,” he notes. (Tests of Gilenya, Celebrex, and even Viagra are underway.) “But if you look at how antiviral drugs have been developed historically, what has worked in the past is to understand the biology of the virus and develop a drug specifically for that biology. We’re going to have to do that multiple times with multiple different targets for this virus.”
For Zika, Diamond helped develop a mouse model of the viral infection, identifying an antibody that’s now used as part of a diagnostic test. Now, for COVID-19, he has generated mouse models to test the effectiveness of human antibodies as a possible therapy. What we still don’t know, he says, is how protective an immune response is against subsequent infection: Are you protected only against developing disease, or are you completely protected against infection, so you don’t transmit? And if your immune system’s response is less than vigorous, are you more vulnerable to subsequent infection? “We speculate that robust responses will be protected for some durable period of time,” he says, “but we still do not know.” Those answers will have to come from clinical studies.
Diamond’s team is also evaluating possible vaccines and treatments to see how powerful and lasting their protection might be. “How you can tell ahead of time that something is going to be protective rather than just hope it will be?” he asks. “Are there measures—certain levels of antibody response, of T-cell response, which can predict whether that individual will be protected? That’s what you need to know in order to know which therapies or vaccines should be introduced en masse to try to curtail the pandemic.”
Whelan would like to see many vaccines, all with different characteristics. Ideally, there would be, say, 10 vaccines, because making 700 million doses is a lot more manageable than making 7 billion. And at least some of these vaccines would be shelf-stable, not requiring constant refrigeration, and deliverable without injection in countries with limited health resources.
The CEO of Sanofi, a French pharmaceutical company, outraged the French government in May when he said that the first doses of a successful vaccine would likely go to the U.S., which had funded its research. “It would be unacceptable for there to be privileged access of any country based on financial reasons,” snapped the French deputy finance minister, Agnès Pannier-Runacher.
Researchers are ignoring the political tug-of-war and posting raw data on free international servers as soon as it’s ready so colleagues in other countries can see what they’ve found, critique it, use it. “There’s been remarkable cooperation and interaction,” says Diamond, “but this is a remarkable time.”
Whelan—who was still living in a hotel six months after he moved here, his house in Cambridge unsold, his partner stuck in Canada—refuses to believe “that any nation that has developed a vaccine could not share the technical ability to produce it. We would all like our lives back. We are in this as a species, together.”
