Vaccines for COVID-19 are in the final stages of research, and you may be wondering how the FDA will decide if a vaccine is safe and effective.
Given the status of the ongoing Phase 3 trials, it is unlikely that the results will be available before November. But it is also very likely that not only a safe and effective vaccine for COVID-19 will be found by the end of 2020.
What is the status of COVID-19 vaccines in human clinical trials?
The Phase 3 studies are in development for Pfizer's Moderna and BioNTech vaccines, the Oxford vaccine from AstraZeneca and now the Johnson & Johnson vaccine.
Each of these vaccines uses SARS-CoV-2 spike glycoprotein, (used by the virus to infect cells), to activate the immune system and generate protective antibodies, a cellular immune response to the virus. Protective antibodies work by blocking it glycoprotein spike (spike glycoprotein) to attach the virus to human cells, thus neutralizing the virus COVID-2 caused by COVID-19.
In the case of the Moderna nucleic acid vaccine, the messenger RNA encoding the glycoprotein spike is enclosed in a fat droplet (called a liposome) to protect the mRNA from degradation and allow it to enter the cells. Once these instructions are inside the cells, the mRNA is read by the "mechanisms" of human cells and converted into many protein spikes so that the immune system can respond and begin to produce antibodies against this coronavirus.
Oxford vaccines from AstraZeneca and Johnson & Johnson use a different strategy to activate the immune response. Here an adenovirus found in chimpanzees closes the instructions for making the glycoprotein spike 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 and J&J vaccines, while the Novavax and GSK-Sanofi vaccines use the actual glycoprotein spike of the virus.
Animal tests show that vaccines provide protection against coronavirus infection
Studies in animal models with COVID-19 provide convincing evidence that glycoprotein spike vaccination will protect against the virus. Experiments have shown that when the glycoprotein spike - which alone cannot cause disease - appears in their immune system, the immune system produces an antibody response that protects against SARS-CoV-2 infection.
In hamster studies, an adenovirus vector - the approach used by Oxford / AstraZeneca, for example - was used to immunize with the glycoprotein spike. Hamsters infected with SARS-CoV-2 were protected against pneumonia, weight loss and death.
The animals produced antibodies that prevented the virus from attaching to the cells.
What have the first Phase 1 and 2 studies shown in humans?
Overall, the vaccine elicited a stronger neutralizing antibody response than that observed in patients recovering from COVID-19.
This also applies to the Moderna vaccine in Phase 3 trials and to vaccines from CanSino Biologics and Oxford / AstraZeneca.
What side effects have been observed?
Doctors have recorded mild to moderate reactions when subjects were observed up to 28 days after vaccination. These side effects included mild pain, slight burning and tenderness at the injection site, and fever, fatigue, and joint and muscle pain.
However, the Phase 1 and 2 studies are small by design, with hundreds of participants. Therefore, these tests are not enough to detect unusual or rare side effects.
The emphasis on safety as a primary goal was recently demonstrated in the Oxford / AstraZeneca vaccine phase 3 vaccine trial where a vaccinated person developed spinal cord inflammation. It is not clear if the vaccine caused this reaction, but Phase 3 trials stopped in the US.
How does the FDA ensure that a vaccine is safe but produced quickly?
The FDA has issued industry guidelines on the steps required to develop and eventually approve vaccines to prevent COVID-19 and are the same strict safety standards required for all vaccines.
There are, however, ways to speed up the approval process that focuses on "platform technology". This means that if a vaccine uses an approach such as an adenovirus that has been studied and proven to be safe, the manufacturer can use previously collected data on toxicity and pharmacokinetics for faster approval of clinical trials.
Speed and safety may seem like conflicting goals, but the encouragement is that rival vaccine manufacturers have jointly committed not to succumb to political pressure to speed up vaccine approval, but to maintain the strictest safety standards.
How protective must a vaccine be to receive FDA approval?
The FDA has set the line for the main endpoint of Phase 3 testing in 50% protection for vaccine approval.
Protection is defined as protection against symptomatic COVID-19 infection, which is defined as laboratory-confirmed SARS-CoV-2 infection and has symptoms such as fever, 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 reduce the number of infections in vaccine recipients by half. This is the minimum protection that is expected to be clinically useful. This is partly because lower efficacy levels could paradoxically increase COVID-19 infections if they cause vaccinated people to reduce their use of the mask or not care about social distance because they believe they are fully protected.
Because a vaccine may be more effective in preventing COVID-19, the FDA recommends that protection against COVID-19 should be a secondary endpoint.
How many people need to be vaccinated to know if a vaccine tested positive for Phase 3?
The current Phase 3 tests are performed on 30.000-40.000 people. Most of these participants will receive the vaccine and some placebo.
Exactly when the results of the Phase 3 studies will be released depends to a large extent on the rate of infection in the recipients of the placebo. The way these vaccine studies work is that they test whether the new infections received from the coronavirus are lower in the group that received the vaccine compared to the group that received the placebo.
Thus, while it may be good news that COVID-19 infections have recently declined in the US from 70.000 to 40.000 cases per day, this reduction in new infections may be slowing down vaccine studies.
Vaccine with emergency warranty?
In an emergency situation as we face the pandemic, with about 700 new deaths and 40.000 new cases a day, the FDA is authorized to allow the use of unapproved products for diagnosis, treatment and prevention. These include a vaccine.
The standard approval procedure for vaccines may require observation more than one year after vaccination. If the short-term safety is good and the vaccine works to prevent COVID-19, then it may be approved for use under the Emergency Authorization during its study.
According to the Emergency Warrant, the FDA will continue to collect information from the companies that produce the vaccines for the benefits and harms they cause.
What should we expect for approvals?
I expect the FDA to approve several vaccines by the end of 2020 under the Emergency Authorization, so that vaccination can begin immediately, starting with high-risk groups such as health care staff and the elderly with pre-existing medical conditions.
The FDA and vaccine manufacturers will continue to monitor side effects and work to improve the first vaccines. This process is expected to take months.
We may not have the life we knew next year, but it all shows a healthier 2021.