In early December, the first of the COVID-19 vaccines arrived at the Brigham. With the authorization of the Moderna vaccine last Friday, the world gained a second weapon in the fight against the pandemic. These feats — achieved in a remarkably short period of time — were in part due to the tremendous efforts of research communities around the world, including at the Brigham.
Over the past six months, multidisciplinary teams from across the Brigham have contributed significantly to the Coronavirus Efficacy (COVE) study, which evaluated Moderna’s mRNA-1273 vaccine. As part of the National Institutes of Health’s COVID-19 Prevention Network, the Brigham enrolled more than 600 of the trial’s 30,000 participants.
Additionally, the Brigham is a trial site for the phase 3 vaccine trial of Ad26.COV2.S, a COVID-19 vaccine candidate developed by Janssen Pharmaceutical Companies of Johnson & Johnson. That trial, known as ENSEMBLE, recently completed enrollment. Results are expected in the early months of 2021.
During the spring and summer months, infectious disease expert and co-principal investigator of COVE, Lindsey Baden, MD, MMSc, and vice president of research operations Allison Moriarty, MPH, began assembling a team to manage the logistical aspects of running large-scale COVID-19 vaccine trials, building off previous experiences managing other vaccine trials. Their tasks included determining how to recruit participants during a pandemic, scheduling participants six days a week, working with clinicians and pharmacists at each trial site to monitor patients in accordance with trial protocols, ensuring the availability of proper personal protective equipment, and deciding which medication and equipment should be on site in the event of an adverse reaction to a vaccine.
Brigham researchers trained in infectious diseases and vaccine development, pharmacists overseeing vaccine administration processes, physicians and nurses documenting the health of participants, outreach workers and educators who promoted trust-building and representation within the trial, and research assistants who supported all of these daily activities and more were among the many people who made these large-scale trials possible.
Beyond speed, safety has been of utmost priority in the vaccine trials. Each clinical trial has detailed, rigorous protocols, designed to ensure both the safety of the research participants and the integrity of the data being collected. Every aspect of how the vaccine trials were conducted needed to meet these standards, including how the vaccines were received, managed and dispensed, how the study team interacted with study partipants at each of the many study visits, and how the trial data was collected, managed and ultimately analyzed.
“There was an incredible amount of motivation to not only get this study done, but to get it done properly and safely. At the same time, we had to be flexible in the way we designed our plans in order to prepare for the unexpected,” said Lewis Novack, MS, PgCert, a clinical epidemiologist and one of the managers of the vaccine trial at the Brigham. “We always had to be on our feet.”
Beyond addressing logistical complexities, the vaccine trial team at the Brigham handled challenges related directly to the vaccines themselves and their rigorous trial protocols. Because the vaccine and the saline placebo are visually distinct, pharmacists needed to tape the syringes to preserve the integrity of the double-blinded trial. Furthermore, the Moderna trial protocol required that a blinded individual transport the inoculations from the pharmacy to the trial site while an unblinded vaccinator was needed to administer it to participants, creating additional logistical and staffing considerations. And finally, the trial teams had to work under tight, daily time constraints: after thawing the vaccine, stored at -4 degrees Fahrenheit, researchers only had a six-hour window to use it.
Pharmacy Services played a key role, securing the vaccines from the manufacturer and preparing them for administration, ensuring the maintenance of the blinded trial, and in some cases assisting with the injections themselves.
“Our pharmacists have really worked hand-in-hand with the clinical investigators as information came forward about the vaccine products,” John Fanikos, RPH, MBA, director of Pharmacy Services, said. “We provided as much knowledge as possible to our staff, which positioned them well to support the needs of these clinical trials. Our hospital leaders have been heroic in organizing people to be prepared.”
A Commitment to Scientific Rigor
Clinicians and research assistants have also been involved in the daily activities of the vaccine trials as they engaged with study participants and monitored their health.
The team of clinicians handling these tasks was small: two registered nurses, two physician assistants, five nurse practitioners, and five doctors worked six days a week, often 12 or more hours a day. They provided education about the study, conducted safety calls with patients, and treated and documented side effects and illnesses. Approximately 20 research assistants joined them in these activities and others.
“If you would have asked me, ‘Can our team handle over 600 people in a couple months?’ I couldn’t have imagined it,” said Haley Schram, NP, referring to the Moderna trial. “It’s amazing how a team can come together. Being at the Brigham, I’m fortunate to work with a group of people who stepped up to the plate and joined hands to make this possible.”
“It was the hardest I’ve ever worked for a study,” said her colleague Jane Kleinjan, NP. “But when we heard of the initial results in the news, we were all elated. It made it all worth it.”
The patient care administered as part of a clinical trial is subject to intense auditing and scrutiny. “Every two weeks, one or two monitors go through participants’ charts, looking at them page by page, entry by entry, symptom by symptom, blood pressure by blood pressure,” Jon Gothing, NP, said. “The i’s have to be dotted; the t’s have to be crossed. As a clinician, you must provide excellent care, on top of making sure that everything is entered precisely and accurately.”
Meticulous bookkeeping provides the trial’s infectious disease experts with the bread and butter of their work. Michaël Desjardins, MD, an infectious diseases fellow, was one of four co-investigators working alongside Baden to analyze the clinical data of the 600+ enrollees. Their team carefully monitored reported side effects and facilitated follow-up appointments with participants when phone-assessments of unexpected or concerning health reports were insufficient.
“We, as study physicians, don’t know whether the participants received a vaccine or placebo. We carefully review each adverse reaction that participants experience during the trial and we assess if these reactions may be related or not to the injection,” Desjardins said. “We work as a team of five infectious disease physicians, including Dr. Baden, who has a lot of experience with vaccine clinical trials. We frequently discuss together and sometimes reach out to colleagues from other specialties to get the most accurate assessments, as participants’ safety is our top priority. When all this data is accumulated for the 30,000 participants over time, we are then able to precisely determine the safety profile of the vaccine.”
Careful clinical observation at every level bolstered the scientific rigor of the study. Additionally, building trust around vaccination has been integral to the vaccine trial team’s commitment to assemble a diverse participant pool.
“There are hundreds of examples of racism in medicine and medical research, and then you add to that what has happened with COVID-19, where patients who are black and brown have suffered and died at much higher rates than white populations,” said Elizabeth Karlson, MD, co-principal investigator of the New England consortium of the All of Us Research Program, an NIH-backed initiative to create a diverse health database comprised of over one million individuals from diverse backgrounds. “There’s a lot of anger about the impact of COVID on communities of color, and the anger is feeding into mistrust.”
Karlson worked alongside primary care physician and epidemiologist Paulette Chandler, MD, MPH, who led the trial’s community engagement and recruitment efforts. Chandler facilitated patient education initiatives and events designed to reach communities that have historically been excluded, under-represented, and harmed by research and institutional medical practices. Some of the All of Us research assistants also provided support to the vaccine trial team by helping to recruit participants from community health centers.
Nicole Taikeff Gabela, a lead research assistant from All of Us, helped recruit participants from the COVID-19 testing site outside the Brookside Community Health Center, which serves a large Spanish-speaking population. A native Spanish speaker, she had previously recruited at Brookside for the All of Us program.
“The biggest challenge for me, personally, was breaking down misinformation so that people understand where I come from as a researcher, but also recognizing that in general, research is not inclusive enough and has not been respectful of communities of color,” she said. “There’s always going to be a tension there.”
Taikeff Gabela added that it was helpful to have pre-established relationships with the health center and its surrounding community. Even when the pace of the testing line curtailed a conversation, having the opportunity to connect with individuals and their family members over the course of several weeks bolstered familiarity and mutual understanding.
“When someone would say to me, ‘I want to do the trial pre-screening survey now,’ and they would say they want to do it because they care about their community and they care about finding a vaccine, that for me, was a triumph — doing the survey there, on the site,” Taikeff Gabela said. “It’s about reconstructing generational trust between scientists and researchers with patients and their communities. I know that what I do at the community health center is going to have an effect on the next research assistant who comes to recruit for the next research study, or the next trial.”
In it for the Long Haul
Brigham team members from across these groups described the excitement they felt upon learning of Moderna’s promising results. “The whole clinic lit up,” Bruce Bausk, a senior research assistant, recalled. “All of this work that we had been putting into the trial, all those hours of overtime, suddenly felt worth it, knowing that we were able to make a tangible impact on the vaccine landscape.”
The Brigham will continue to monitor the health of trial participants for two years, even as vaccine distribution accelerates.
“These trials aren’t over after we get preliminary results,” Bausk said. “There’s still a lot that we can learn about these vaccines. We’re in this for the long haul.”