Scientists in more than 20 countries, on every continent save Antarctica, have started to gather data for the largest ever vaccine safety project. Members of the effort, called the Global Vaccine Data Network (GVDN), fruitlessly sought funding after conceiving the project more than 10 years ago. But the mass vaccinations during the COVID-19 pandemic breathed new life into the project. With the ability to draw on data from more than 250 million people, the network will investigate rare complications linked to COVID-19 vaccines in hopes of improving prediction, treatment, and potentially prevention of these side effects.
“You really need global data in order to understand” rare vaccine side effects, says Gregory Poland, a vaccinologist at the Mayo Clinic. Poland, who’s not involved in GVDN, himself developed severe tinnitus about 90 minutes after his second vaccine dose, which he suspects is related to the shot. Studying potential vaccine complications “is a very neglected area,” he says.
Bruce Carleton, a clinical pharmacologist at the University of British Columbia, Vancouver, and head of the GVDN genomics effort, draws an analogy to air travel safety. There, improvements often came after ultrarare crashes. Airplanes, Carleton says, were shored up by “learning from those events, not denying them.” With billions of doses of COVID-19 vaccines administered, it’s clear the vaccines are “very safe for most people,” he continues. At the same time, “There probably are patients that may, in fact, suffer harm.”
Doing this research comes with steep scientific hurdles, among them the rarity of serious problems. The largest vaccine studies have included about 1 million people, and even that can be too small to nail down side effects. “If you had something that happened normally to one in 100,000 people, and you wanted to see if the vaccine doubled the risk, you’d need a study with about 4 million people,” says Helen Petousis-Harris, a vaccinologist at the University of Auckland who jointly heads GVDN with Steven Black, a pediatric infectious disease specialist formerly at Cincinnati Children’s Hospital.
The idea for GVDN came to Black around 2009, when the H1N1 flu pandemic hit and a mass vaccination campaign began. Some countries detected an increased risk of narcolepsy from the vaccine, called Pandemrix, but others did not. The variability might have reflected differences in vaccine surveillance, which varies geographically, with some countries relying on passive reporting and others combing through health records for patterns. Or, scientists came to suspect, the immune response to vaccination might somehow have interacted with flu infection to trigger the narcolepsy. Black thought consistent data could help solve such mysteries.
He set out to globalize vaccine safety research. Funding, however, was nowhere to be found. Then in 2019, the Bill & Melinda Gates Foundation offered seed money for a meeting. About 60 vaccine safety specialists descended on a lakeside village in France and GVDN was born. The network got a jump-start with support from Petousis-Harris’s university and Auckland UniServices Ltd., a nonprofit owned by the institution.
Carleton and Daniel Salmon, a vaccine safety researcher at Johns Hopkins University, conjured up its first project: a study of the potential risk of Guillain-Barré syndrome, a rare neurologic condition, from flu vaccines. In early February 2020, just as COVID-19 was taking hold, they submitted a funding proposal to the National Institutes of Health (NIH), briefly noting that if a pandemic emerged and vaccines were developed, their network would be well-suited to studying any side effects. The application was turned down, as were subsequent applications to the World Health Organization and NIH.
Then in April 2021, with COVID-19 vaccination drives underway, the Centers for Disease Control and Prevention (CDC) awarded GVDN $5.5 million over 3 years to study the safety of the vaccines. It was a shoestring budget but enough to design several projects, each drawing on large health systems, regions within a country, or, in some cases, as in New Zealand, a nation’s entire population. One will study heart inflammation associated with the messenger RNA vaccines from Pfizer and Moderna. Another will probe vaccine-induced thrombotic thrombocytopenia, a dangerous clotting disorder linked to viral vector vaccines made by AstraZeneca and Johnson & Johnson. The network will also examine the risk of Guillain-Barré syndrome after COVID-19 vaccination, among other projects.
“We’ve been trying for so long” to get projects like these started, says Robert Chen, scientific director of the Brighton Collaboration, which studies vaccine safety, and a former director of CDC’s vaccine safety program. Chen notes that those who advocate for improved vaccine safety “have unfortunately been lumped into the antivaccine groups” at times, even though their goal, he says, is to make rare side effects even rarer.
Pulling the venture together has been “gnarly,” Petousis-Harris says. It’s meant middle-of-the-night conference calls across a dozen time zones, and months spent harmonizing the definition of a health condition, like myocarditis, across hospital systems and countries. Getting at the risk increase of complications after vaccination is also statistically complex. Some studies do this by comparing a vaccinated population with an unvaccinated one and assessing whether more of the former develop, say, myocarditis. But unvaccinated people differ from vaccinated ones in other ways, which may cloud the results. Instead, GVDN will use a method called a “self-controlled case series.” For example, they will identify everyone who suffered myocarditis in the 60 days that followed their last vaccine dose. Statisticians can then examine whether and to what degree participants were more likely to contract the heart condition immediately after vaccination versus weeks later.
A massive data set could also begin to crack other mysteries—in particular, who’s at risk. Is postvaccine myocarditis more likely, for example, if someone has another health condition or takes a certain medication?
Another dream is to understand the biology underpinning side effects. Insights could come from another nascent global effort, called the International Network of Special Immunization Services (INSIS), which is now finalizing funding agreements. Whereas GVDN aims to scoop up and analyze COVID-19 vaccine data worldwide and tackle genomics questions, INSIS will examine the biology and immunology of postvaccine problems as they are happening. The network’s leader, Karina Top, a pediatric infectious disease specialist at Dalhousie University, is working with GVDN to identify patients and share data.
For now, the new efforts don’t include difficult-to-diagnose health problems that may be linked to the vaccines. Some people have described Long Covid–like symptoms, such as chronic headaches and irregular heart rate and blood pressure, soon after vaccination, but studying this phenomenon is far more difficult. Headaches, for instance, are so common that no vaccine surveillance system would detect an imbalance, says Rebecca Chandler, who works on vaccine safety at the Coalition for Epidemic Preparedness Innovations. She says that to discern patterns, it’s crucial to review not just single words in vaccine safety reports, but narratives from doctors and patients.
“The subjective reports should not be discounted as meaningless or unrelated,” Carleton says. GVDN and INSIS, he and others hope, will expand their scope as time goes on, funding permitting.
Carleton’s suspicion is that much of a person’s risk comes down to genetics. Through GVDN, he’ll test whether certain gene variants raise risk of postvaccine complications. He’s also planning a solo project, setting up a website for anyone who believes they’ve suffered a post–COVID-19 vaccine adverse event, inviting them to ship him a saliva sample and health records.
The GVDN team hopes to have initial data by late summer. “My sincere hope is that once we prove the value of something like the GVDN, we can secure longer term sustainable funding,” says Ann Marie Navar, a cardiologist at the University of Texas Southwestern Medical Center and a researcher with GVDN. Chen, who’s advising INSIS, is cautiously optimistic, but knows the road ahead could be bumpy. “Unless we find a way to stabilize” funding for these projects, he says, “it’s very easy for them to just collapse.”
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