The University of Montana campus was still humming with activity last February when Jay Evans got the call from the National Institutes of Health. Students and professors scurried to in-person classes and crowded into cafeterias, unaware how drastically their lives would change in the coming months. For Evans and his research crew at the Center for Translational Medicine, though, the message from NIH was clear: SARS-CoV-2 poses a serious threat, and the search for a vaccine is on.
By April, the UM campus resembled a ghost town. But on the third floor of the sprawling Skaggs Building, exempt from the statewide shutdown and chugging along on $2.5 million in crisp new NIH funding, Evans’ team was as busy as ever. A dozen members were tasked full-time to the coronavirus project. Data and materials began moving between UM and research partners at Boston Children’s Hospital and the Icahn School of Medicine at Mount Sinai in New York. As his microscopic world grew, Evans’ physical world shrank to Zoom meetings, his sunny corner office and the lab.
“Before the university was implementing mask policies and work-at-home policies, we had a ‘don’t come to work if you even have a sniffle’ policy,” Evans said. “We work in close quarters here.”
Evans can hardly believe the speed and scale at which scientists across the country have answered the call for the ultimate solution. More than 150 vaccine candidates for SARS-CoV-2 — the name of the specific coronavirus at the heart of this pandemic — are now in development, and seven of those have already entered the clinical trial phase. According to the World Health Organization, governments and vaccine manufacturers globally have committed $1.4 billion to research and development. Researchers are reviewing data in real time in an attempt to accelerate the trial process, and FDA Commissioner Stephen Hahn said in late August that he’s open to fast-tracking approval even before phase-three trials are complete, as Russia and China have already done. Evans, whose work with infectious diseases goes back more than two decades, calls the effort “striking” and “unprecedented.”
“If you asked me nine months ago how quickly I would think a COVID vaccine would have been ready, I would have said five years,” he said.
PIECES OF THE PUZZLE
That a university-based team of 45 researchers in a remote mountain town would be called into such an immense and global undertaking may seem unusual. But the fight against SARS-CoV-2 isn’t unfolding in some monolithic lab filled with hundreds of hazmat-suit-clad scientists. It’s taking place in pockets around the country and the world, in labs of varying sizes and with varying capabilities. And because there’s more than one way to build a vaccine, no two projects look alike. Some are going it alone, while others have built complex webs of collaboration.
Evans’ work falls into the latter category. The special sauce his team brings to the vaccine development table is its wealth of experience with adjuvants. These tiny agents act like the strobe setting on a headlamp, making it easier for the immune system to spot and target the invader adjuvant is attached to. In the case of SARS-CoV-2, the UM lab is tacking these adjuvants onto vaccine components called antigens that mimic the virus’ iconic spike protein. Evans’ partners at Mount Sinai are pros at building such antigens, making the collaboration something of an immunological peanut-butter-and-jelly partnership. The Mount Sinai lab also has a high enough biosafety clearance to work directly with SARS-CoV-2, allowing its researchers to test the effectiveness of different vaccine candidates by challenging vaccinated mice with the live virus to see how their immune systems respond.
“It’s not just vaccine design,” Florian Krammer, Evans’ counterpart at Mount Sinai, told Montana Free Press. “It’s also really understanding the immune response to the virus.”
Both labs say they’ve made significant progress over the past seven months, identifying several lead vaccine candidates. On a warm afternoon in late August, Evans pulled up a graph on his office computer showing the results of several different adjuvant-antigen combinations. One adjuvant dubbed 1007, which has shown promise in the Center for Translational Medicine’s in-development opioid vaccine, did increase the immune response to Mount Sinai’s antigens. But not nearly to the same degree as an adjuvant called 2002, a key player in Evans’ work toward a universal influenza vaccine. Evans noted that 2002 also happens to hold up well at higher temperatures. (By comparison, trial SARS-CoV-2 vaccines from Pfizer and Moderna have to be stored at -70 degrees Celsius.) The durability displayed by Evans’ adjuvant can prove invaluable in the vaccine world, not only lowering the cost of manufacturing, shipping and refrigeration, but making the vaccine more readily available to people regardless of race, class and geographic location.
“The U.S. has great cold-chain abilities” — the ability to transport and store at stable temperatures — “for our vaccines,” Evans said. “But not everywhere in the world does. If you want to send a vaccine to areas of sub-Saharan Africa or places in Asia where a cold-chain is hard to maintain, it’s hard to get good vaccines there.”
Evans has also sought help in determining whether particular adjuvants might improve a vaccine’s effectiveness in specific populations. Through his ongoing work on pertussis and influenza, he’s keenly aware that children and the elderly don’t always react well to vaccines that work in the broad swath of young, healthy adults. The same goes for pregnant women and people who have undergone chemotherapy, are currently taking steroids, or have diabetes or other underlying medical conditions. To explore that question, Evans partnered with Ofer Levy, a staff physician at Boston Children’s Hospital and professor of pediatrics at Harvard Medical School, who specializes in research on immunity at what he calls the “edges of life.”
Levy’s approach is particularly fascinating because he’s able to model immune responses outside the human body using infant and elderly blood samples in tissue cultures. Put another way, Levy told MTFP, “we can do clinical trials in a test tube.” That way, only the safest and most promising candidates move on to animal testing and eventually human trials.
Considering that there are hundreds of adjuvants — far too many for each to undergo a large clinical trial — Levy’s method could narrow the field of potential components for vaccines targeting specific demographics. Levy noted that most research labs working on the coronavirus aren’t looking too deeply into adjuvants, so he’s cast a wide net, searching for as-yet-undiscovered pandemic applications of adjuvants developed by Evans’ team and others.
“Adjuvants may have dose-bearing effects so that you don’t need as many doses to protect,” Levy said. “That’s a big deal. If you have 300 million Americans to immunize and you have to get them into the clinic not once but twice, it’s a punishing amount of logistics and cost. So if you could build a vaccine with an adjuvant that only requires one dose, it’s a big win.”
A UNIVERSE OF STRATEGIES
As if the network Evans has built in response to SARS-CoV-2 isn’t intriguing enough, one research project at the Washington University School of Medicine in St. Louis decided to tackle the novel coronavirus with a novel delivery system. In a paper published last month in the scientific journal Cell, WU professor and viral immunologist Michael Diamond and his colleagues wrote that a single intranasal dose of their experimental SARS-CoV-2 vaccine conferred “virtually complete protection against infection” in both the upper and lower respiratory tracts of mice. In other words, Diamond wants to vaccinate people through the nose, and so far the results look promising.
“If you give a nasal vaccine, not only do you generate systemic immunity, but you also generate this local immunity right at the site of the respiratory tract,” Diamond told MTFP. “And there’s an immunoglobulin, an antibody called IGA, and that IGA is able to get across and concentrate in the solutions of the respiratory tract, like your nasal solutions or the liquids that are lining the upper airway, and that will bind to and then directly neutralize the virus.”
To visualize Diamond’s tactic, think of a vaccine as the classic cartoon cat Tom, and SARS-CoV-2 as his perpetual rodent tormentor Jerry. You could station Tom on the couch and have him keep an eye out for Jerry, as a vaccine delivered by the more traditional shot-in-the-arm route would. Or you could position a dozen Toms in a circle around Jerry’s mousehole, ready to pounce the moment he enters the house. That’s how Diamond’s intranasal vaccine works — by creating what’s known as mucosal immunity. By attacking the virus at its point of entry into the body, Diamond intends for the vaccine to cut down on transmission as well, neutralizing SARS-CoV-2 before it has a chance to ride droplets back out and into the airways of other people.
From the moment he started down that path this spring, Diamond knew he had to start his tests in mice. But just as hospitals experienced early shortages of PPE and testing facilities struggled to acquire sufficient stores of reagents, some research labs faced their own supply-chain challenges. While mice are a historically valuable component in vaccine development, the cells in their respiratory tracts don’t contain the surface protein — known as ACE2 — that SARS-CoV-2 latches onto in humans. In order for Diamond to develop a model of how the virus works in mice, and then fashion a vaccine to disrupt that process, he first had to get his hands on modified mice that could actually be infected.
But SARS-CoV-2 isn’t the first coronavirus immunologists have encountered. The worldwide outbreak of SARS in 2003 prompted early research efforts into coronavirus vaccines. When that epidemic was contained, funding for that work mostly dried up. But not before coronavirus researcher Stanley Perlman at the University of Iowa bred a colony of mice with the necessary ACE2 protein. Perlman kept frozen sperm from those mice after closing down the colony, Diamond said, and sent those samples to biomedical research nonprofit Jackson Laboratories as soon as the threat of SARS-CoV-2 became apparent. By June, descendants of Perlman’s ACE2 colony were available, and Diamond had the animals he needed to begin his tests. It’s just one example of how early research on SARS and its cousin MERS, which emerged in Saudi Arabia in 2012, have helped immunologists get a jump-start on the current crisis.
“Each time this happens now, we go faster,” Diamond said. “Zika was much faster than whatever it was before, and now SARS-CoV-2 is much faster than Zika was.”
For some, however, even an effective vaccine won’t work fast enough. Enter the Defense Advanced Research Projects Agency (DARPA), the Pentagon’s beyond-the-cutting-edge science division. The agency was created in 1958 after the Soviet Union’s launch of Sputnik, with the mission of ensuring that the U.S. never encounter such a strategic surprise again. While others in the scientific community endeavor to unlock mysteries with research and gradual experimentation, DARPA seeks to make giant technological leaps by setting seemingly improbable goals. In the world of infectious diseases, that mission spawned a project in 2017 designed to stop a pandemic in 60 days. The agency dubbed the program Pandemic Prevention Platform, or P3, and rather than take the traditional vaccine angle, it began investing in replicating antibodies from a few tiny nucleic acids.
“The advantage to antibodies is that they’re immediately protective,” Amy Jenkins, program manager at DARPA’s biotechnologies office, told MTFP. “You can give them to somebody and almost immediately that person is protected.”
Jenkins likens the difference between vaccines and antibodies to the old proverb about fishing. Vaccines can teach your immune system to fish, instructing it on how to build its own antibodies. That process can take weeks and require follow-up shots. The kind of antibody treatment proposed by P3 — artificially creating an antibody using samples from the first recovered patient as a blueprint — gives your immune system the fish. Those antibodies aren’t a long-term solution, but they can last in the body for weeks or months. That meets DARPA’s needs nicely, enabling military personnel to quickly deploy to combat zones or humanitarian sites in regions known for disease without worrying that their bodies haven’t finished learning to fish. In a SARS-CoV-2 context, Jenkins said, such rapid immunity could also have civilian applications for frontline health care workers and even wildland firefighters (Jenkins noted that her sister works for the U.S. Forest Service).
Through P3, DARPA has funded rapid antibody treatment research at Duke and Vanderbilt universities as well as at pharmaceutical companies AbCellera and AstraZeneca. When SARS-CoV-2 began its worldwide spread, DARPA quickly pivoted to the challenge, tasking its P3 participants with developing an antibody treatment for this particular virus. They haven’t hit P3’s 60-day goal, Jenkins said, but all four labs were able to identify COVID-19 antibodies within 90 days. That’s a major achievement, she said, and takes DARPA one step closer to a future where a simple chain of molecules can be quickly decoded, documented and distributed to a planet in shared crisis.
“We see the potential to democratize the use of these very powerful molecules,” Jenkins said.
THE ETHICAL QUESTION
The quest for microscopic solutions to viral outbreaks is not without risks. A 37-year-old woman in the UK was hospitalized Sept. 5 after experiencing transverse myelitis, a neurological condition resulting in pain, weakness and difficulty walking. Fourteen days prior, she had received her second dose of an experimental SARS-CoV-2 vaccine from multinational pharmaceutical giant AstraZeneca. The incident temporarily halted the company’s huge clinical trial, involving more than 12,000 participants in multiple countries, and triggered an investigation in the U.S. by the NIH. Regulators in the UK and Brazil have allowed the trial to resume, and National Institute of Allergy and Infectious Diseases Director Anthony Fauci stated Sept. 15 that it’s “only a matter of time” before the U.S. follows suit. Still, the woman’s hospitalization and subsequent public reaction underscore an awareness that while the need for a solution is dire, the warp-speed nature of SARS-CoV-2 vaccine development has thrust the global population into new and potentially treacherous waters.
In an interview with MTFP, Art Caplan, founder of the Division of Medical Ethics at NYU’s School of Medicine, described the possible dangers of rushing to a vaccine: “We won’t get adequate safety data. We’re moving fast in the hope that we find something, but it turns out that the vaccine has side effects that don’t show up for months or maybe a year. We could be giving out a vaccine before we get a full picture.”
As a bioethicist, Caplan serves as the scientific community’s voice of conscience and caution, a Jiminy Cricket in a world desperate for a shot in the arm that will return it to normal. His concerns are manifold, from the staggering amount of research dollars that might otherwise gone to still-real threats such as cancer, malaria and AIDs to the apathy that promises of near-term vaccine availability may generate toward simple yet life-saving precautions such as face masks and social distancing. When a team of nearly a dozen researchers, several linked to bastions of scientific education including Harvard and MIT, dosed themselves with a DIY vaccine this summer and posted their formula in an online white paper for anyone to see, Caplan was appalled.
Caplan doesn’t downplay the severity of the pandemic, nor does he trivialize the public fear it has generated. But speeding up trials and releasing a vaccine too quickly could have implications far beyond undocumented long-term side effects or limited effectiveness. At a time when scientists are under constant social and political attack, he said, safeguarding public trust in objective, factual information — in science itself — is of paramount importance.
“The more you say, ‘We did this in a fast, speedy, warp-speed way,’ the more you make some people nervous that it’s not really trustworthy,” Caplan said.
The warnings Caplan has been expressing for months seem prescient in light of the results of a poll published Sept. 10 by the nonprofit Kaiser Family Foundation. Sixty-two percent of respondents confirmed they were worried that the FDA, under political pressure from the Trump administration, would approve a vaccine before ensuring its safety and effectiveness. Just over half said that if a vaccine is approved before Election Day and made freely available, they won’t take it.
“Public skepticism about the FDA and the process of approving a vaccine is eroding public confidence even before a vaccine gets to the starting gate,” KFF President and CEO Drew Altman said in a statement about the poll’s release.
Not everyone working on SARS-CoV-2 vaccines is racing to the finish line. Evans and Diamond are moving faster than usual, but neither expects to beat the likes of AstraZeneca, Pfizer or Moderna to market. They view their projects as “next-gen” vaccines, solutions that might fill gaps left by the current front-runners and provide more efficient or targeted protection that will enable society to live with SARS-CoV-2 in the long term. Done right, such vaccines might actually serve to counteract the erosion of faith in science.
“We have to guard against rushing in a way that contributes to cynicism and mistrust,” Elissa Weitzman, associate professor at Harvard Medical School and a pioneering researcher on public attitudes toward immunization, wrote MTFP via email. “This is hard as there is truly a public health crisis — we are not ‘wargaming’ this as a class exercise. If we manage the process well — following an accelerated timeline versus a rushed one … we could come out ahead in terms of public trust in and support for vaccine development.”
This story is part of continuing Montana Free Press coverage of community responses to COVID-19 supported by the Solutions Journalism Network.