CHR researchers have been working to ensure the COVID-19 vaccines are safe
By Neon Brooks, Senior Scientific Editor
With three vaccines for COVID-19 now approved in the United States, we are entering a hopeful phase of the pandemic. While the development of the relatively new technology behind these vaccines began decades ago, the development and testing of these vaccines against COVID-19 specifically has happened over the last year. This has required the expertise of specialists in both vaccine development and in testing and monitoring their safety. As experts in clinical trials and vaccine safety monitoring, CHR researchers have made critical contributions to these processes and have provided us with a front-seat view of how much attention and care has been given to evaluating the safety of the COVID-19 vaccines.
Overview of the technology used in the COVID-19 vaccines.
Understanding how the COVID-19 vaccines work is important for understanding what researchers are looking for when evaluating safety. All three approved vaccines in the U.S.—the Pfizer-BioNTech, Moderna, and Johnson & Johnson vaccines—involve injecting genetic material (messenger RNA or DNA) into the body. This material instructs cells to make a protein that resembles the “spike” on the virus that causes COVID-19. When the immune system discovers the spike proteins, it activates to destroy them, creating antibodies specialized to fight the spike protein. The body then “remembers” how to create these antibodies so it can launch a quick attack should it later be exposed to the real virus. While these vaccines are some of the first uses of this technology, the technology has been studied and developed over the last 25 years because of its ability to be used to rapidly develop vaccines to specific viruses.
It is impossible for these vaccines to give you COVID-19. While a few vaccines, like the vaccine for varicella (chicken pox), contain weakened versions of the virus they protect against, that is not the case for any of the COVID-19 vaccines available in the U.S. The spike proteins that the body generates in response to the vaccine do not have the ability to cause COVID-19 on their own. Additionally, the genetic material in the vaccines never enters the nucleus of the cell, where our DNA is kept, and does not interact with our own genetic code in any way. Instead, this genetic material simply uses our body’s ability to “decode” genetic information to make proteins.
COVID-19 vaccine clinical trials tested their efficacy and safety in tens of thousands of people, including at CHR.
Phase 1 and 2 clinical trials give researchers and regulators an initial sense of whether a drug works and is safe. Phase 3 trials involve many more participants and provide the best data on whether a vaccine is safe and effective. Phase 3 trials for each of the three COVID-19 vaccines in use in the U.S. involved 30,000-43,000 participants from all racial and ethnic backgrounds.
CHR was one of many sites across the globe in the Phase 3 clinical trial for the Pfizer-BioNTech vaccine, enrolling 98 participants from the Portland, Oregon, area. Participants were randomly assigned to receive the vaccine or a shot of salt water (placebo) – neither the participants nor researchers knew who had received the real vaccine. Researchers worked closely with participants to track all symptoms and medical events that occurred any time after they received their first shot. This symptom data was used both to evaluate safety and to determine when patients needed to be tested for COVID-19. “The meticulous nature of the data collection is mind-boggling” said Tara Beatty, RN, a CHR research nurse who worked closely with participants to track symptoms. “You gather anything that happens. So if somebody falls and hurts themselves, you record that information, even if you don’t think it is related to the vaccine. All that data gets aggregated in case there is some wild side effect that nobody would expect.” These data were reviewed daily by the team of medical doctors who were leading the study.
Results from Phase 3 trials for all three approved vaccines all showed surprisingly high efficacy at preventing COVID-19 illness, reducing the rate at which participants were diagnosed with COVID-19 by 72%-95%, and almost completely eliminating risk of hospitalization and death. Mild to moderate but short-lived side effects were common, especially for the Pfizer-BioNTech and Moderna vaccines, with most people experiencing pain at the injection site and as well as symptoms like headache and fatigue. However, no serious safety concerns were found.
These clinical trials were conducted in a record amount of time following the discovery of COVID-19 at the end of 2019. This was possible in part because steps that would typically occur in sequence happened at the same time: for example, Pfizer-BioNTech contacted sites to begin administrative, staffing, and scientific preparations for the Phase 3 trial in March, while the Phase 1 trial was still underway. Enrolling a very large number of participants during a period where COVID transmission rates were high also sped up the trials, by shortening the amount of time it took to see a difference in infection rates. A side benefit of this approach is that the safety of the vaccine was tested in a very large number of people. “Based on our direct experience with the Pfizer-BioNTech trial I can say that the science was never compromised,” said Stephen Fortmann, MD, Senior Director of Science Programs at CHR. “The trials were as thorough as any. The speed of the trial completion was achieved by strict requirements for getting the study data into the electronic databases fast, and the large sample size.”
CHR’s clinical research has also included trials of COVID-19 treatments, and a trial testing a new version of the Pfizer vaccine that is intended to provide better protection against the South African variant of the virus. If you are interested in participating in future vaccine and/or treatment trials, join CHR’s research study registry.
FDA approval demonstrates that the vaccines have met rigorous safety standards.
An essential part of the mission of the US Food and Drug Administration is to protect the public health of Americans by ensuring the safety, efficiency, and security of all drugs. The FDA is heavily involved in the clinical trial process for all drugs that it approves, reviewing and approving all research protocols and reviewing data through every phase. The FDA also tours manufacturing facilities and conducts quality assurance on approved products.
The FDA has rigorous scientific standards for safety, effectiveness, and quality that all vaccine trials must adhere to. The Pfizer-BioNTech, Moderna, and Johnson & Johnson vaccines have received Emergency Use Authorizations (EUA) from the FDA, indicating that “the known and potential benefits outweigh the known and potential risks.” The EUA allows the FDA to approve use of the vaccines before the Phase 3 trials have completed planned data collection. EUA criteria require that vaccines have completed Phases 1 and 2, and have at least 2 months of safety data for half of the participants in the Phase 3 trial. Once the trials have completed at least 6 months of data collection for all participants, the vaccines will be eligible for full approval and licensing by the FDA. This will allow the FDA to evaluate how long the vaccines are effective and how frequently booster shots may be needed. Follow-up of study participants will continue for two years after vaccination.
What about long-term safety concerns? “We’ve been looking for decades for long-term health consequences of vaccines in the Vaccine Safety Datalink, and we haven’t found any.” Said Allison Naleway, Ph.D., an epidemiologist and Distinguished Investigator at CHR who has been conducting vaccine safety research for over 21 years. “If a vaccine reaction is going to happen, it usually occurs in the first six weeks after vaccination.”
CHR researchers and many others track and monitor vaccine safety after FDA approval.
Many people don’t realize that evaluation of vaccine safety does not stop when a vaccine is approved by the FDA. The U.S. has several systems that leverage information from the millions of Americans who have been vaccinated to identify and evaluate safety concerns.
Passive safety monitoring systems monitor negative health events that could be related to vaccination. The Vaccine Adverse Event Reporting System (VAERS) allows anyone to report medical events that happen after vaccination; healthcare providers and vaccine manufacturers are also required to report certain types of medical events that could be related to vaccination. A new system, V-Safe, uses text alerts to collect symptom data from people who get a COVID-19 vaccine and sign up to participate.
Active vaccine surveillance networks, including the Vaccine Safety Datalink (VSD), ask specific questions about the safety of vaccines using data from vaccinated and unvaccinated individuals in large population-based databases. The VSD relies on electronic health record data from eight health care systems, including Kaiser Permanente Northwest and four other Kaiser Permanente regions, to answer vaccine safety questions that are a priority for the CDC. Currently, these data include over 2 million individuals who have received a COVID-19 vaccine, and millions of others who have not. The CHR VSD team has been working overtime to evaluate the safety of the COVID-19 vaccines: they are currently running more than 13 studies focused on COVID-19. This includes a weekly review of electronic health record data looking for a specific list of rare medical events that have been linked to vaccines in the past, such as severe allergic reactions, and a broader study looking for any possible differences in health outcomes between people who have and have not been vaccinated. They are also conducting research on the safety of the vaccines during pregnancy. “We always have a lot of VSD studies going on, but this level of response to a new vaccine is unusual. The CDC is taking the look at safety very seriously,” said Stephanie Irving, MHS, a CHR research associate who works on VSD studies.
The vaccine safety monitoring system was recently activated when VAERS reports showed that six women who received the Johnson and Johnson vaccine had experienced a rare form of blood clotting disorder. The FDA and CDC responded by pausing the use of the vaccine while they investigated the issue. During this period, in part through review of VSD data, an additional nine cases of the disorder were identified that were linked to the vaccine, all in women. In total, this amounted to 7 cases per million doses for women between the ages of 18 and 49, and 11.8 cases per million doses for women between the ages of 30 and 39 specifically. Based on modeling of the risks and benefits of the vaccine, the FDA and CDC ended their pause on April 23rd, requiring Johnson & Johnson to add a warning label to the product alerting potential users to the small risk of blood clots. Going forward, the VSD and other active surveillance networks will be used to continue to monitor this safety concern.
One other rare safety issue that has been identified through surveillance is anaphylactic reactions: severe allergic reactions appear to be somewhat more common with the Pfizer-BioNTech and Moderna vaccines than with other vaccines: while about 1 in a million people have an allergic reaction to the average vaccine, the rate is closer to 5 to 11 cases in a million with the Pfizer-BioNTech and Moderna vaccines. For this reason, extra precautions are being taken to ensure allergic reactions are quickly identified and treated after vaccination.
With over 300 million COVID-19 vaccine doses delivered to Americans, vaccine safety surveillance systems are now able to detect even these very rare safety issues occurring in fewer than 15 cases per million vaccines given. This arms clinicians and patients with the information they need to feel safe taking a vaccine that is a good fit for them, and to take appropriate precautions when warranted. The VSD continues to actively monitor vaccine recipients to identify blood clots, anaphylaxis, and any other potential vaccine side effects.
The COVID-19 vaccines represent an enormous scientific achievement, and CHR is proud to play a role.
“The work we are a part of will help to ensure that COVID-19 vaccines are safe, and hopefully earn the trust of the public, leading to higher vaccine uptake,” said Stephanie Irving. “It’s such an honor to be able to play even a small role in helping to end the pandemic.” For Danielle Millay, the project manager of the Pfizer-BioNTech trial at CHR, the significance of her work on the trial didn’t fully hit home until she received her own vaccine. “Usually the results of a trial and drug approvals take years to happen and we might not know the results; this was my first time getting a product from a trial I worked on. I felt a lot of hope at the vaccination site listening to the people around me: the volunteers who were happy to be there and the vaccine recipients expressing their hope and gratitude about being able to receive the vaccine. It was a surreal moment knowing we had helped contribute to that moment, and I am grateful to have worked with such a wonderful team to make it happen.”