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With COVID-19 vaccines currently in the final phase of the study, you’ve probably been wondering how the FDA will decide whether a vaccine is safe and effective.
Based on the status of the phase 3 trials currently underway, it is unlikely that the results of these trials will be available before November. But it’s likely that not just one, but several of the competing COVID-19 vaccines will prove safe and effective by the end of 2020.
I am a scientist and infectious disease specialist at the University of Virginia, where I care for COVID-19 patients and conduct research on the pandemic. I am also a member of the Group of Experts of the World Health Organization on Prioritization of COVID-19 Vaccines.
What is the status of COVID-19 vaccines in human clinical trials?
Phase 3 studies are underway for the Moderna and BioNTech / Pfizer vaccines and the Oxford / AstraZeneca viral vector vaccine.
Each of these vaccines uses the SARS-CoV-2 spike glycoprotein, which the virus uses to infect cells, to activate the immune system to generate protective antibodies and a cellular immune response to the virus. Protective antibodies work by preventing the spike glycoprotein from attaching the virus to human cells, thereby neutralizing the SARS-CoV-2 virus that causes COVID-19.
In the case of Moderna’s nucleic acid vaccine, the messenger RNA encoding the spike glycoprotein is encased in a blob of fat, called a liposome, to protect the mRNA from degradation and allow it to enter cells. Once these instructions are inside the cells, the human cellular machinery reads the mRNA and converts it into many spike proteins so that the immune system can respond and start producing antibodies against this coronavirus.
The Oxford / AstraZeneca uses a different strategy to activate an immune response. Here, an adenovirus found in chimpanzees carries the instructions for making the spike glycoprotein in the cells.
The phase 1 and 2 studies by the pharmaceutical companies Janssen and Merck also use viral vectors similar to the Oxford / AstraZeneca vaccine, while the Novavax and GSK-Sanofi vaccines use the peak protein itself.
Animal Tests Show Vaccines Protect Against Coronavirus Infection
Studies in animal models of COVID-19 provide compelling evidence that vaccination with the spike glycoprotein will protect against COVID-19. Experiments have shown that when the spike protein, which alone cannot trigger disease, is shown to the immune system, the immune system will generate an antibody response that protects against SARS-CoV-2 infection.
In hamster studies, an adenovirus viral vector was used, the approach used by Oxford / AstraZeneca, for example, to immunize with the Spike glycoprotein. When the hamsters were infected with SARS-CoV-2, they were protected from pneumonia, weight loss, and death.
In nonhuman primates, DNA vaccines, which deliver the spike glycoprotein gene, reduced the amount of virus in the lungs. Animals that produced antibodies that prevented the virus from binding to human cells were more likely to be protected.
What have the first Phase 1 and Phase 2 studies in humans shown?
Overall, vaccination has triggered a stronger neutralizing antibody response than even that seen in patients recovering from COVID-19.
This has also been the case for Moderna’s vaccine currently in phase 3 trials, and for the CanSino Biologics and Oxford / AstraZeneca vaccines.
What side effects have been observed?
Clinicians have recorded mild to moderate reactions when subjects were observed up to 28 days after vaccination. These side effects included mild pain, warmth and tenderness at the injection site, and fever, fatigue, joint and muscle pain.
But Phase 1 and 2 studies are small by design, with only hundreds of participants. Therefore, these trials will not be large enough to detect rare or uncommon side effects.
The emphasis on safety as a primary endpoint was recently demonstrated in the Phase 3 Oxford / AstraZeneca vaccine trial, in which a vaccinated individual developed inflammation of the spinal cord. It is not clear if the vaccine caused this reaction, it could be a new case of multiple sclerosis unrelated to the vaccine, but the phase 3 trial has been stopped in the US until more is known.
How does the FDA ensure that a vaccine is safe but produced quickly?
The FDA has issued guidance to the industry on the steps necessary to develop and ultimately license vaccines to prevent COVID-19; these are the same rigorous safety standards that are required for all vaccines.
However, there are ways to speed up the approval process that focus on “platform technology.” What this means is that if a vaccine uses an approach like an adenovirus that has previously been shown to be safe, a company may use previously collected data on toxicity and pharmacokinetics to speed up the approval of clinical trials.
While speed and safety may seem contradictory goals, it is also encouraging to note that rival vaccine manufacturers have jointly pledged not to bow to any political pressure to rush vaccine approval, but to uphold the most rigorous safety standards. .
What level of protection must a vaccine have to receive FDA approval?
The FDA has set the bar for the primary endpoint of a phase 3 trial of 50% protection for the approval of a COVID-19 vaccine.
Protection is defined as protection against symptomatic COVID-19 infection, defined as laboratory-confirmed SARS-CoV-2 infection plus symptoms such as fever or chills, cough, shortness of breath, fatigue, muscle aches, loss of taste or smell, congestion or runny nose, diarrhea, nausea or vomiting.
This means that an effective vaccine is considered one that will cut the number of infections in vaccine recipients by half. This is the minimum protection expected to be clinically useful. That’s, in part, because lower levels of efficacy could paradoxically increase COVID-19 infections if it leads vaccinated people to decrease mask use or social distancing because they believe they are fully protected.
Since a vaccine could be more effective in preventing severe COVID-19, the FDA indicates that protection against severe COVID-19 should be a secondary endpoint.
How many people must be vaccinated to know if a vaccine works in Phase 3?
Current Phase 3 trials are enrolling between 30,000 and 40,000 subjects. Most of these participants will receive the vaccine and some a placebo.
The exact time when the results of phase 3 studies will be published depends largely on the infection rate in placebo recipients. The way these vaccine studies work is that they test whether new naturally acquired coronavirus infections are lower in the group that received the vaccine compared to the group that received the placebo.
So while it’s good news that COVID-19 infections have recently declined in the US from 70,000 to 40,000 cases per day, this decline in new infections may delay vaccine studies.
Will the emergency use authorization expedite the vaccine?
In an emergency like the one we face with the COVID-19 pandemic, with approximately 700 new deaths and 40,000 new cases per day at this time, the FDA is authorized to allow the use of unapproved products for the diagnosis, treatment and prevention of disease . That includes a vaccine.
The standard approval process for vaccines may require more than one year of observation after vaccination. If the short-term safety is good and the vaccine works to prevent COVID-19, then the vaccine should be approved for use under an Emergency Use Authorization while it is still being studied.
Under the Emergency Use Authorization, FDA will continue to collect information from companies that produce vaccines for benefit and harm, including surveillance for improved vaccine-associated respiratory disease or other potentially rare complications that could be seen in just one at a time. million.
What should we expect in terms of approvals?
I hope that the FDA will approve several vaccines by the end of 2020 under its Emergency Use Authorization authority so that vaccination can begin immediately, starting with high-risk groups, including first responders, healthcare personnel, and the elderly. and those with pre-existing medical conditions.
This will be followed quickly with the implementation of vaccination in the general population, while throughout the time the FDA and vaccine manufacturers will continue to monitor side effects and work to improve these early vaccines. This process is expected to take months.
Life may not return to normal next year, but all signs point to a healthier 2021.
