In just a few days, Cambridge, Massachusetts-based biotech Moderna will begin the first clinical trial of its kind, a massive placebo-controlled study to definitively determine whether an experimental vaccine can thwart the disease caused by the novel coronavirus.
But Moderna won't be alone in the spotlight for long. By the fall, four other like-sized trials from other coronavirus vaccine developers are also expected to begin in the U.S. Combined, they are looking for a specific group of about 150,000 total volunteers, and aiming to amass enough information from them within months to back potential approvals for emergency use.
Other, similarly large trials have been run before to test vaccines. But never have so many been done, simultaneously, for the same disease during a pandemic. Those factors make for one of the most logistically challenging research initiatives in history.
"What's unprecedented here is the speed," says Kathleen Neuzil, the director of the University of Maryland School of Medicine's Center for Vaccine Development and Global Health.
Neuzil is co-running the vaccine testing that will take place as part of a new National Institutes of Health initiative meant to help coordinate efforts of different developers. Called the COVID-19 Prevention Trials Network (CoVPN), the initiative, announced on July 8, merges multiple existing NIH-backed "clinical trial networks," or groups of researchers from different institutions working together to run trials.
CoVPN is building off of years of work putting these networks together to run tests of vaccines for HIV and other infectious diseases. More than 80 trial sites in the U.S. and abroad are involved, and the list is growing. But they'll all have to work through a long list of challenges unique to the coronavirus pandemic to "harmonize," and gain clear answers from multiple, simultaneously run trials for different types of vaccines in record time.
Vaccines are an "absolute necessity" to "return to a semblance of previous normality," wrote National Institutes of Allergy and Infectious Diseases director Anthony Fauci, NIH director Francis Collins and others in a Science editorial in late May. Achieving this goal, they wrote, will require governments, drugmakers and philanthropic groups to collaborate closely.
Finding the “at risk” recruits
Upon its formation, CoVPN immediately set up an online registry to find study volunteers. Some 180,000 have registered thus far, said Jim Kublin, executive director of the operations program for the CoVPN, which is coordinated by Fred Hutchinson Cancer Research Center in Seattle. Trial sponsors and investigators will filter through the entries for the right participants.
The hope is the registry will enable trial sponsors to move and pick volunteers faster than they would otherwise. Kublin noted, for instance, that the Hutch had to recruit 45 people from 10,000 volunteers for a Phase 1 coronavirus vaccine study in Seattle. "That was the impetus for the registry," he said.
Indeed, one of the most daunting tasks CoVPN faces, he said, is to quickly enroll the people "at risk" of the worst outcomes from COVID-19. He expects it’ll take “millions” of people to volunteer to find them.
Kublin pointed out the "disproportionate impact" COVID-19 has had on the elderly, African American and Latinx people, frontline workers, people with pre-existing medical conditions and those of low socioeconomic status. While early studies focused on safety largely consisted of healthy, young, white adults, developers need to enroll a much more diverse group of participants to best gauge the effectiveness of the vaccines in a broad population.
To do so, CoVPN will have to convince many people who may be skeptical of biomedical research or have historically been taken advantage of to voluntarily provide their information and participate in the registry, he said.
They plan to lean on a broad group — such as historically black medical colleges, professional sports organizations and religious leaders — to help with community outreach and advertising campaigns. But Neuzil cautions it is critical to appeal to participants without being too "coercive."
"Trust is built over time," she said, "and that is very challenging because we don't have the time."
Ebbs and flows
In an editorial published in the New England Journal of Medicine this month, Penny Heaton, the CEO of the Bill & Melinda Gates Medical Research Institute, worried that the "undulations of the pandemic" would make it particularly tough to run large vaccine trials. Disease outbreaks can come and go in certain geographic areas, meaning trial sponsors have to move fast to recruit when the timing is right.
"It’s going to be a challenge," she told BioPharma Dive, not just to enroll a large number of people, but "match the vaccinated individuals with where the pandemic is surging."
Developers need to be open to enrolling more patients, if necessary, to see enough cases develop to properly assess the effectiveness of the vaccine. "It would be just tragic if you decided on a fixed number to enroll," but don’t end up with enough cases to get clear answers, Heaton said.
Vaccine developers, then, will have to battle, sometimes within the same locations, to find enough participants. They’ll need to be tracked, closely, so it’s clear when symptoms of COVID-19 arise or any side effects occur. That’s one of the issues the CoVPN is helping to coordinate. Trial sites will be in a wide range of geographies, some of which will be selected by "chasing hot spots," while others aren’t, Neuzil said. Recruitment will be prioritized for studies with the first start dates, and for trial sites that are already activated, Kublin added.
"This is where the local outreach is so important," he said.
There are other challenges. New treatments could emerge for COVID-19. That means a company starting a large vaccine trial a few months from now could be dealing with a different other preventive options, such as engineered antibody drugs, that could conceivably prevent patients from progressing to mild or severe disease.
What’s more, some vaccines may require one dose, others two. Some vaccines may work differently in different populations. While a lot of work is going into "harmonizing" the studies, Neuzil says, “our intent isn't to have the exact same trial.”
It’ll be a daunting effort, one that aims to compress into months what typically takes much longer. The HIV Clinical Trials Network, for example, has started five vaccine efficacy trials over the past three years, according to Kublin.
"We're starting five much larger [coronavirus] vaccine trials in as many months," he said.