The pandemic pushes global efforts to study the side effects of a rare vaccine Science

Scientists in more than 20 countries, on every continent except Antarctica, have begun collecting data for the largest ever vaccine safety project. Members of that effort, called the Global Vaccine Data Network (GVDN), have unsuccessfully sought funding after the project was conceived more than 10 years ago. But 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 the rare complications associated with COVID-19 vaccines in hopes of improving the prediction, treatment, and potential prevention of these side effects.

“You really need global data to understand ‘rare vaccine side effects,'” says Gregory Poland, MD, a vaccinologist at the Mayo Clinic. Poland, who was not involved in GVDN, developed severe tinnitus about 90 minutes after the second vaccine dose, which is suspected to be related to the injection. He says studying the potential complications of a vaccine is a “very neglected area”.

Bruce Carlton, a clinical pharmacologist at the University of British Columbia, Vancouver, and head of the GVDN genomics effort, is making an analogy for air travel safety. There, improvements often come after crashes in high-speed flying. Carlton says the planes were powered by “learning from those events, not denying them.” With billions of doses of COVID-19 vaccines being administered, the vaccines are clearly “very safe for most people,” he continues. At the same time, “there are likely to be patients who might actually be harmed.”

Conducting this research comes with severe scientific hurdles, among which is the dearth of serious problems. The largest vaccine studies involved about 1 million people, and even this may be too small to eliminate the side effects. “If you had something that happened naturally to 1 in 100,000 people, and you wanted to see if the vaccine doubled the risk, you would need a study with about 4 million people,” says Helen Petosis-Harris, a vaccine specialist at the university. Jointly GVDN with Stephen Black, a pediatric infectious disease specialist formerly at Cincinnati Children’s Hospital.

The idea for a GVDN came to Black around 2009, when the H1N1 influenza pandemic broke out and a massive vaccination campaign began. Some countries have discovered an increased risk of narcolepsy from the vaccine called Pandemrix, but others have not. This disparity may reflect differences in vaccine surveillance, which vary geographically, with some countries relying on negative reporting and others combing through health records for patterns. Or, scientists have come to suspect that the immune response to the vaccination may have somehow interacted with the flu infection to trigger narcolepsy. Consistent statements of black thought can help solve such puzzles.

He initiated the globalization of vaccine safety research. Funding, however, was nowhere to be found. Then in 2019, the Bill & Melinda Gates Foundation provided initial funds for the meeting. About 60 vaccine safety professionals descended on a lakeside village in France and the GVDN was born. The network got off to a solid start with support from Petousis-Harris University and Auckland UniServices Ltd. It is a non-profit organization owned by the Foundation.

Carleton and Daniel Salmon, a vaccine safety researcher at Johns Hopkins University, brought up his first project: studying the potential risk of Guillain-Barré syndrome, a rare neurological condition, from influenza vaccines. In early February 2020, just as COVID-19 was spreading, they submitted a funding proposal to the National Institutes of Health (NIH), briefly stating that should a pandemic emerge and vaccines be developed, their network would be well suited for the study. No side effects. The request was denied, as were subsequent requests to the World Health Organization and the National Institutes of Health.

Then in April 2021, with the COVID-19 vaccination campaigns underway, the Centers for Disease Control and Prevention (CDC) awarded $5.5 million in GVDN over 3 years to study the safety of vaccines. It was a small but sufficient budget to design several projects, each of which relied on large health systems, regions within the country, or in some cases, as in New Zealand, the entire population of the nation. One will study carditis associated with the messenger RNA vaccines from Pfizer and Moderna. Another will examine vaccine-induced thrombocytopenia, a serious clotting disorder linked to vector vaccines made by AstraZeneca and Johnson & Johnson. The network will also examine the risks of developing Guillain-Barré syndrome after vaccination against the COVID-19 virus, among other projects.

“We’ve been trying for a long time” to start projects like this, says Robert Chen, scientific director of the Brighton Collaboration, which studies vaccine safety, and former director of the CDC’s Vaccine Safety Program. Chen notes that those who advocate for improved vaccine safety have “unfortunately been incorporated into anti-vaccine combinations” on occasion, although their goal, he says, is to make rare side effects even rarer.

Putting the project together was “anomalous,” Petosis-Harris says. It means conference calls in the middle of the night across a dozen time zones, and spending months coordinating the definition of a health condition, such as myocarditis, across hospital systems and countries. The exposure to an increased risk of complications after vaccination is also statistically complex. Some studies do this by comparing a vaccinated group with an unvaccinated group and assessing whether more affected populations have, for example, myocarditis. But unvaccinated people differ from vaccinated people in other ways, which can obscure results. Instead, GVDN will use a method called “autonomous state chain”. For example, they will recognize everyone who has had myocarditis in the 60 days since the last dose of the vaccine. The statisticians could then examine whether and to what degree participants were more likely to develop heart disease immediately after vaccination compared to weeks later.

A huge set of data can also begin to solve other mysteries – in particular, who is at risk. Is myocarditis more likely to develop after a vaccine, for example, if someone has another health condition or takes a certain medication?

Another dream is to understand the biology that underlies the side effects. Ideas could come from another emerging global effort, called the International Network for Special Immunization Services (INSIS), which is now finalizing funding agreements. While the GVDN aims to collect and analyze COVID-19 vaccine data worldwide and address genomic questions, INSIS will examine the biology and immunology of post-vaccine problems as they unfold. Network leader Karina Taub, a pediatric infectious disease specialist at Dalhousie University, is working with GVDN to identify patients and share data.

Currently, the new efforts do not include hard-to-diagnose health problems that may be related to vaccines. Some people described symptoms similar to Long Covid, such as chronic headache, irregular heartbeat and blood pressure, soon after vaccination, but studying this phenomenon is much more difficult. Headaches, for example, are so common that no vaccine surveillance system can detect an imbalance, says Rebecca Chandler, who works on vaccine safety for the Coalition for Epidemic Preparedness Innovations. To distinguish patterns, she says, it is necessary to review not just single words in vaccine safety reports, but the accounts of doctors and patients.

“Personal reports should not be dismissed as meaningless or irrelevant,” Carlton says. He and others hope that GVDN and INSIS will expand their reach over time, if funding permits.

Carlton suspects that much of a person’s risk is due to genes. With a GVDN, he will test whether certain genetic variants increase the risk of post-vaccine complications. He’s also planning a solo project, creating a website for anyone who thinks they’ve experienced a post-COVID-19 vaccine adverse event, inviting them to ship a saliva sample and health records.

The GVDN team hopes to have preliminary data by late summer. “I sincerely hope that once we prove the value of something like GVDN, we can secure long-term sustainable funding,” says Anne-Marie Navarre, MD, a cardiologist at the University of Texas Southwestern Medical Center and a GVDN researcher. Chen, an INSIS consultant, is cautiously optimistic, but he knows the road ahead may be bumpy. “Unless we find a way to stabilize” the financing of these projects, “it’s very easy for them to fall apart,” he says.

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