The largest global vaccine safety study has linked COVID-19 vaccines with small increases in health conditions involving the brain, blood, and heart.

The international team of researchers emphasizes that the chances of getting any of these conditions are still very low. It's important to note that extensive research shows COVID-19 vaccines protect against serious illness, death, and long COVID symptoms.

Across just under 100 million COVID-19-vaccinated people in eight countries, potential links called safety signals were identified by comparing observed rates of 13 specific conditions following vaccination to what we'd expect to see based on prior rates, or 'background risk' of the conditions – the rates that these conditions are expected to occur in the absence of COVID-19 vaccines.

"The risk up to 42 days after vaccination was generally similar to the background risk for the majority of outcomes," the authors write in their published paper.

The authors say their multi-country analysis confirmed pre-established links between COVID-19 vaccinations and low risks of myocarditis, pericarditis, Guillain-Barré syndrome, and cerebral venous sinus thrombosis. But the enormous size of the study also meant there was a higher chance of them spotting rarer safety signals that prior studies may have missed.

Since the World Health Organization declared the COVID-19 pandemic on March 11, 2020, nearly 7 million people have died from the disease, including more than 1 million in the US. Over 13.5 billion doses of COVID-19 vaccines have been given, with at least 70.6 percent of the world's population having received at least one dose.

Vaccine rollouts usually identify common and moderate side effects, after excluding dangerous ones during clinical trials. But even in huge clinical trials, extremely rare side effects can go undetected.

"This unparalleled scenario underscores the pressing need for comprehensive vaccine safety monitoring, as very rare adverse events associated with COVID-19 vaccines may only come to light after administration to millions of individuals," the authors write.

Their study sought safety signals observed within the 42 days after receiving viral-vector vaccines (such as AstraZeneca) or mRNA vaccines (such as Pfizer-BioNTech). Health datasets from before the COVID-19 vaccines were used to determine the rates of these conditions that were expected in the general population prior to vaccine rollout, and the observed rates were derived from the same dataset after vaccination.

In the wake of viral-vector vaccines, the team discovered a statistically significant rise in cases of Guillain-Barre syndrome; a rare immune system disorder that affects nerves. Within the group that had these vaccines, 66 cases were expected, and 190 were observed. This increase was not seen after mRNA vaccines.

Following a first dose of the AstraZeneca vaccine, there was a 3.2 times greater-than-expected risk of cerebral venous sinus thrombosis (a type of blood clot in the brain) observed in 69 events, compared to an expected 21. The risks were 1.49 times higher after the Pfizer vaccine's first dose, and 1.25 times higher after second doses.

In March 2021, some countries in Europe suspended the AstraZeneca COVID-19 vaccine after observed versus expected analysis identified thrombosis with thrombocytopenia syndrome as a safety signal.

The analysis found a higher risk of heart inflammation called myocarditis after mRNA vaccines, with observed rates highest after a second dose of Moderna's vaccine. These vaccines instruct cells to produce a protein that resembles the SARS-CoV-2 virus, giving the immune system a preview and prompting it to create antibodies to protect the body.

In rare cases, this immune response can result in heart muscle inflammation. Though COVID-19 vaccine-induced instances have mostly been mild, 28 deaths have occurred.

After a first dose of mRNA vaccines, the risk for pericarditis – inflammation of tissue surrounding the heart – was 1.7 times higher than expected, and it became 2.6 times higher after a fourth dose.

Potential safety signals were found for transverse myelitis (inflammation of part of the spinal cord) after viral-vector vaccines, and for acute disseminated encephalomyelitis (inflammation and swelling in the brain and spinal cord) after both types of vaccines.

Compared to an expected two cases, seven cases of acute disseminated encephalomyelitis were observed after mRNA vaccines.

"The size of the population in this study increased the possibility of identifying rare potential vaccine safety signals," says first author Kristýna Faksová, an epidemiologist at the Department of Epidemiology Research in Denmark.

"Single sites or regions are unlikely to have a large enough population to detect very rare signals."

Vaccines have saved countless lives by preventing the spread of the COVID-19 pandemic, and there is strong evidence that they are safe in the majority of cases and effective. A recent study found that if everyone in the UK was fully vaccinated, about 7,180 out of 40,393 severe outcomes (including deaths) from COVID-19 could have been avoided.

"We have a number of studies underway to build upon our understanding of vaccines and how we understand vaccine safety using big data," says Steven Black, an infectious disease scientist at the Global Vaccine Data Network (GVDN).

Anyone can view the methodology and complete results of this analysis on the GVDN's interactive data dashboards.

The study has been published in the journal Vaccine.