Understanding the COVID-19 Vaccine, part 2: The Road to Approval - How a Vaccine is Tested & Approved
In this blog series about the new COVID-19 vaccinations, we will discuss what vaccines are, how a COVID-19 vaccine works, what side effects to look out for, and work to clear up some of the myths and misinformation that’s currently floating around about these immunizations. This is an exciting and promising step that can help us stop the spread of COVID-19 and protect those of us working on the front lines as well as our patients, friends, family, and loved ones.
In case you missed it, you can read the first post in the series to become acquainted with immunology and vaccination basics. Today let’s discuss how vaccines are tested and granted approval in the United States.
The pre-clinical stage (animal testing)
As we discussed in the first post of the series, the most important thing a vaccine must do is trigger an immune response within our bodies by introducing some component of the pathogen. In order to determine what component of the pathogen will trigger the best immune response, several different formulations are first tested on animals. During this time, researchers are evaluating not only the immune response (how well the vaccine works), but the safety of the vaccine. Once a strong immune response is demonstrated in the animal subjects, it’s time to begin human trials!
The clinical stage
During phase 1 clinical trials, the vaccine is given to a very small number of people — typically between 20 and 100 participants. Researchers look for the same thing as during the pre-clinical phase: does it work (is there an immune response) and is it safe (are there any major adverse effects).
If there are no significant safety concerns, the research will move on to Phase 2. Phase 2 requires hundreds of clinical participants. In order to see how the vaccine affects certain populations such as the very young or very old, these participants are separated into groups. Building on their findings from Phase 1, researchers are looking to make sure the vaccine works and is safe.
Researchers are also working to find the most effective dosage. During this phase, the participants report any symptoms that occur within the first seven days of receiving the vaccine. Researchers re-evaluate the participants a month later and continue to monitor them long term.
The third phase of vaccine trials are the most well publicized, because thousands of clinical participants are involved in the testing. Between the Pfizer and Moderna COVID-19 vaccines, which are the two currently available in the US as of this writing, about 75,000 people were involved in the Phase 3 trials. This is important to note because while it seems like a small sample size when compared to the global population, it is actually a statistically significant sample size for a clinical trial. More people were involved in the testing of these two vaccines than live in some small cities!
During Phase 3, a really important step of the process begins: double blinding. The process of double blinding means that neither the researchers nor the participants know who receives the real vaccine, or a placebo such as normal saline. The placebo contains absolutely no active ingredients and cannot protect the participants from the targeted pathogen. Using double blinding is crucial because it keeps participants and researchers from accidentally influencing the results of the study.
For example, if a researcher is really hopeful about this vaccine, they might accidentally minimize symptoms or exaggerate benefits if they know which participant receives the real vaccine. But if they are “blind” to which participants received placebo versus active vaccines, they can objectively collect and report the data. Once the trial ends and all of the results are final, the researchers and participants are informed about who received the vaccine and who received the placebo.
At this point in the clinical trials, the safety of the vaccine is pretty well understood from the earlier phases, however with a sample size this large, researchers can more fully examine the vaccine safety. The most important part, however, is collecting information about the vaccine efficacy, meaning how well it works. By comparing the placebo group with the vaccine group, researchers can compare the rates of infection of the targeted pathogen between the two groups.
For example, of the 18,198 Pfizer vaccine recipients, only 8 contracted COVID-19, while of the 18,325 Pfizer placebo group 162 went on to contract COVID-19 (Polack et al., 2020). This demonstrates high efficacy rates since the vaccinated group contracted COVID-19 at a much smaller rate than the placebo group.
As the results of the Phase 3 trials become available, the researchers and manufacturers are able to submit applications to regulatory bodies such as the Food and Drug Administration (FDA) in order to be approved. These regulatory agencies will review the safety and efficacy data from the Clinical Phases, and ask the manufacturers to prove that they will be able to handle the large scale production of the vaccine. If all the stipulations for approval are met, the vaccine is granted approval from the regulatory authorities and the manufacturing and distribution begin.
The research doesn’t stop after the vaccine is available. In Phase 4 trials, also known as “postmarketing surveillance trials,” researchers continue to monitor the safety and efficacy of the vaccine along with any side effects and adverse effects. This ongoing evaluation allows long-term vaccination data to be gathered and studied.
Why was the COVID-19 vaccine created so quickly?
This is probably one of the most commonly asked questions: why does it take years for most vaccines to be created, studied, and approved, but it took less than a year to get COVID-19 vaccinations to frontline healthcare workers?
Money! The biggest hurdle to scientific advancements usually isn’t the science but rather the funding. Many clinical trials stall out, pause, or are even scrapped entirely if the funding for them cannot be obtained or sustained. However when there is a global pandemic, people are more willing to fund the science to combat it.
“Operation Warp Speed” was put into place by the US government, creating a carefully laid out plan to fund and develop the vaccines while still adhering to safety and efficacy standards. Funding doesn’t typically come from individuals, but even Dolly Parton donated a million dollars herself to fund the Moderna vaccine. With all the funding requirements met, there were no financial hurdles to overcome.
Concurrent phases. With other vaccine trials, there’s no need to run concurrent (simultaneous) phases. When a global pandemic is bearing down on us, though, there is a need to work smarter, not harder. Thanks to Operation Warp Speed, Phase 1 and 2 were run concurrently in some trials allowing researchers to work through multiple phases in parallel rather than sequentially. Remember that Phase 3 is what truly determines safety and efficacy across a large sample size, so running Phase 1 and 2 together speeds up the time it takes to get to Phase 3. This does not mean that any steps were “skipped.” COVID-19 vaccine trials followed the same steps, but running concurrent phases allowed them to take up less time.
This is not new technology. In our next blog post we’ll discuss the mRNA technology in depth, but for now it’s important to note that mRNA tech has existed for 30 years. Vaccines have been around since Edward Jenner used cowpox to provide smallpox immunity back in 1796. The new technology in this vaccine was simply isolating the specific sequence of genetic material that codes for the “spike protein” antigen on the surface of this virus. By using the known mRNA technology that has existed for three decades along with utilizing existing vaccine technology, there wasn’t too much “new” that had to be made.
Think of it this way: it’s pretty simple to bake a cake by adding eggs to a cake mix. If I asked you to create a cake recipe, gather all the ingredients, and try over and over to bake the perfect cake, it would probably take you much longer. When it comes to the COVID-19 vaccine, we already had the cake mix; we just needed to add the eggs!
Be sure to check back for the next post in this series, where we’ll take a deep dive into the incredible mRNA technology utilized by the Pfizer and Moderna vaccines!
Polack, F. P., Thomas, S. J., Kitchin, N., Absalon, J., Gurtman, A., Lockhart, S., Perez, J. L., Pérez Marc, G., Moreira, E. D., Zerbini, C., Bailey, R., Swanson, K. A., Roychoudhury, S., Koury, K., Li, P., Kalina, W. V., Cooper, D., Frenck, R. W., Hammitt, L. L., … Gruber, W. C. (2020). Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. New England Journal of Medicine. https://doi.org/10.1056/nejmoa2034577
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