Yale Public Health specialist addresses often asked questions about the newly emerging COVID-19 vaccine’s safety and effectiveness. In March, at the dawn of the COVID-19 pandemic, there was an agreement between health care professionals and public health authorities that a vaccine that gave full immunity to SARS-CoV-2, the virus that triggers COVID-19, would bring an end to the pandemic. Experts showed that developing a safe and efficient COVID-19 vaccine could be achieved in 12 to 18 months, even though vaccine formation typically takes about ten years. The fastest vaccine ever developed—a mumps vaccine—still lasted four years.
However, owing to the severity of this global pandemic—and the severe disease and mortality rates associated with COVID-19—preclinical and clinical studies to assess the effectiveness and safety of COVID-19 vaccine candidates are taking place at a fast, almost frantic speed. Which leaves many concerned about how effective a COVID-19 vaccine is going to be. The percentage of Americans who expected to receive a COVID-19 vaccine fell from 72% in May to just 51% in September. Also, according to the survey, 78%, when asked about the speed of the vaccine certification process, say their major concern “is that it will lose momentum, without fully determining safety and effectiveness.”
When Were Concerns Raised About the COVID-19 Vaccine?
This concern emerged early in September when the Centers for Disease Control and Prevention (CDC) instructed state officials around the country to brace for the delivery of the COVID-19 vaccine by 1 November, just days before the presidential election. It is unclear if this vaccine will be legally approved by the Food and Drug Administration (FDA) or released by the Emergency Use Authorization (EUA)—a tool by which the FDA may authorize the use of generic medicines, including vaccines that have not undergone clinical trials.
However, the announcement raised questions about the disproportionate political impact of introducing the COVID-19 vaccine. This prompted the Chief Executive Officers of nine pharmaceutical firms to make a collective promise to protect and ensure the well-being of vaccinated patients’ highest priority.’ They also announced that they would only seek a vaccine if the Phase 3 trial showed it was both safe and successful. The commitment was meant to convince the public that any approved vaccine must have met both protection and effectiveness tests. Yet, many remain cynical and puzzled.
Saad Omer, MBBS, Ph.D., MPH, Director of the Yale Institute for Public Health, sat down to address several questions. Dr. Omer heads the World Health Organisation (WHO) group to assess the efficacy of VOCID-19 vaccines. He offered answers to concerns regarding the production of the COVID-19 vaccine.
This is the Interview that Has Been taken from Three Conversations.
Q: Why do we need a COVID-19 vaccine?
And this is the endgame. If you want to continue the day-to-day habits of life—eat in restaurants, go to movies, all the other things you want to do without taking dramatic action—then you need a “population-level” of immunity. So there are two ways to do this. One is to make the total population—or many people—be contaminated with COVID-19. This will cause a great deal of death; many people die, which is unacceptable. The other way around is by vaccines.
Q: Do you know if the vaccine is going to be like the annual flu vaccine, that we need to have it every year, or if it will provide lifelong immunity, like the MMR vaccine?
We don’t know that, though. But I would be shocked if it were a year-to-year vaccine. I expect security to last for at least a couple of years. Beyond that, we’re going to wait and see.
Q: COVID-19 vaccines are being produced in a compressed time frame. Why isn’t this sacrificing safety?
Well, the pace has so far been improved by process reliability rather than cutting corners or removing the individual steps from production.
Q: In this case, what is an example of process efficiency?
Steps usually performed sequentially are taken in parallel, while achieving the same effect of providing usable results. E.g., a Phase 1 and Phase 2 joint trial will be completed. They will conduct animal trials with clinical studies, speed up target identification—and vaccine production facilities will be ready before they complete the vaccine.
Q: So if you’re doing a mixed phase of the experiment, isn’t there a larger chance for individuals who are taking part in a later phase trial without first understanding the outcome of the earlier phase test?
No, there’s just a subtle change in how the trials are going. If the experiments were independent, the full results would be released, and they would enroll a new group of participants. With a joint study, the evidence and safety review board will analyze the preliminary data and decide if it is still worth pursuing the trial.
This ensures that whenever their Phase 1 and Phase 2 experiments are merged, independent data analysis panels blindly track safety data. These commissions are appointed—usually academics or other specialists who are not interested in the proceedings. They deal closely with research statisticians, and those sessions are not confidential to the primary investigators of the study. The committee is also studying the test. If they see trends and patterns, they can prevent or delay the trial and then re-test them as required.
Q: What occurred recently with the AstraZeneca and Johnson & Johnson trials.
Yes.
Q: Many people are worried about the compressed schedules of the Phase 3 trials. If they usually last 6 to 8 months, for example, but they approve the vaccine by November—in only a few months—how can we be sure that there is no missed evidence on side effects and efficacy?
The effectiveness aspect is more convenient to acknowledge. Essentially, there are two options to conduct the trials: follow up with the trial subjects for a prolonged period. You can also do what they call “event-driven trials,” where you enroll a bunch of participants so you can get cases [people getting sick with COVID-19] from a variety of people. Event-driven trials are one way to achieve performance.
Q: How does this translate into efficiency?
The statistical detail, rather than the size of the survey, is calculated before these experiments. This means that the enrollment measure scale depends on the rate of incidents that need to occur to ensure that the vaccine has an effectiveness rate of at least 50%.
So if you require 130 to 150 activities to validate the vaccine’s effectiveness rate, you will recruit 30,000 patients. Faster accumulation ensures you can hit the exercises faster, saving an enormous amount of time.
Q: What’s about safety?
Health is a matter of control and accountability. Since this is a public health emergency, independent panels may have looked at the evidence earlier. This is where two boards, the DSMB [evidence and protection monitoring board] trial, and the VRBPAC [Vaccines and Associated Biological Products Advisory Committee]—a regular committee that looks at the results before they grant the authorization license—come into action. The FDA Commissioner has announced that they would hold a meeting at the end of October—and that it will be available, implying that openness is essential.
Saad Omer, MBBS, MPH, Ph.D., director of the Yale Institute for Public Health, says we can not believe that the approved COVID-19 vaccine would only be 50 percent effective because it is the minimum approval condition of the FDA. The FDA recently said that at least two months of median safety follow-up evidence from vaccine producers would be expected before they even recommend the EUA, and that’s a positive thing; it’s more stringent requirements.
There are other separate protections in operation. Technical organizations like the American Academy of Pediatrics should issue or withdraw their endorsement statements. If the data is not adequate, they will find it out. From a data standpoint, this is a post-marketing screening phase where vaccines are closely checked to determine whether there are early signs of adverse events. But even before that, there is some necessary follow-up that many people would have to give us trust in the vaccine’s efficacy. We, as experts in public health, would also like to have access to these results.
Q: Returning to the simplified timeline issue, is it safe to conclude that if there are no adverse reactions observed in these Phase 3 trials—however shortened they might be—we should presume that there will probably be no long-term adverse effects?
Well, we realize that most of the adverse events that occur accumulate early. That is usually during the first six months, so yes. And the plan is to be preemptive—to make sure you’re able to identify any signs and minimize and adjust the suggestions.
So, you follow the study subjects for something that appears like an illness or other things of interest, such as allergic reactions, among others. When the committee believes that there are no minor or significant adverse events, it is comforting.
Another factor is that ample follow-up has taken place to assume that it’s okay to vaccinate people safely. It is a risk-benefit scenario, and the benefits can be considerably more significant than the costs. Since it’s a pandemic, we don’t have the option of years and years of waiting.
Q: We are exploring new platforms that have not previously been used for licensed vaccines. You noted that the cluster of adverse effects in the first few months had eased concerns about a shortened timetable with alternative vaccines. Can we know the same thing to be true for these new platforms?
We don’t know, but they’re new platforms, not modern biology. They use the processes of nature to cause immunity. And we have experience with early phase experiments. Thus, it is crucial to note the difference between severe adverse effects and the subcategory of first events that are not serious and are standard with vaccines—things such as injection discomfort or fever that arise within one to two days of getting the vaccine and then overcome. These are not necessarily linked to severe cases.
Q: Is it possible to figure out the vaccine candidates are more promising than the others?
No, not correct at this moment. We have a wide variety of items in the early stages. They all display potential, but it remains to be seen, which will be more competitive or more mature and more effective.
Q: Why is it important to represent minorities—who have been disproportionately impacted by COVID-19—in vaccine trials? People with risk factors such as obesity or advanced age may respond differently to a vaccine. It seems like we do not yet know if there is a genetic or biological correlation between these classes and the extreme cases of COVID-19.
We know little about the evolutionary component of it. Yet, we know there’s a significant racial dimension to it. There is a need for generalizable evidence on protection and effectiveness in all populations. Still, particularly in the overwhelmingly affected communities, the vaccine’s affect—the vaccine’s effect – differ because of biological and social reasons. So I could not overemphasize the significance of enrolling the populations most threatened by the outbreak; they should be reasonably well-represented.
Q: The FDA has confirmed that if a VOCID-19 vaccine has an efficacy rate of at least 50%, they will approve it. Fifty percent is also the minimum effectiveness rate for the WHO aim product profile, although they agree that 70 percent is optimal. Could you reconcile the difference?
It speaks of why there are separate mechanisms such that various entities, such as the WHO or the U.S. administration, will arrive at a target percentage—and sometimes intersect. But the WHO is working with a broader population where they require a more potent vaccine to have more immunity. I think it’s fair for the U.S. to say that 50 percent isn’t perfect, but it’s decent enough.
Q: Is 50 percent strong enough to grant us herd immunity?
It depends on the rate of immunization and who receives the vaccine. People assume the herd immunity is binary—yes or no. Although in these kinds of cases, even with a 50% successful vaccine, you will have “indirect effects” when you slow down the disease without extinguishing it.
Q: We will also have to take steps, such as wearing masks, washing our mouths, and exercising social distancing.
Yes. But it’s necessary to note that 50 percent is the lowest floor set by the FDA. If the licensed vaccine is more effective than 50%, there is more scope to relax restrictions. So it’s not expected to be a 50 percent effective vaccine because that’s the FDA’s minimum standard for approval.
Q: Is there a danger that if we have a useful vaccine at or near 50%, it will slow down the production of a 100% effective vaccine?
Okay, once you have a 50 percent effective vaccine that is widely used, it becomes what they call the “standard of care.” So for ethical reasons, instead of giving a placebo to patients in the control arm trial, send them a 50 percent effective vaccine.
Ultimately, it may affect potential test sizes. Depending on whether you are searching for effectiveness and disease incidents (they will be larger) or the form and level of immune response associated with defense (they might be smaller)—and recruiting attempts. But I don’t think it’s a problem.
Q: So, if a 50 percent successful vaccine would not entirely prevent infection, does it protect against serious illness?
Yeah, this is the primary endpoint. They do not intend the experiments to assess the vaccine’s effect on transmission; they design them to look at disease outcomes. However, it could well be that this does not interrupt or decrease transmission but decreases the disease.
Q: Do people who have been treated with and healed from coronavirus continue to undergo a vaccine?
I’m hoping to research the issue myself, but we don’t know it yet.
Q: In September, the FDA announced it might recommend a vaccine before the conclusion of Phase 3 trials. Others accompanied this controversial judgment surrounding the EUA Agency on convalescent plasma and its arguments. What are you doing with these cases, and what can we do to defend ourselves?
This is an outstanding question. In terms of convalescent plasma, researchers have vociferously expressed their problems. There have been a lot of pushbacks. Most of the experts were okay with the USA; they were dissatisfied with the results’ over-interpretation.
The FDA has recently removed itself; it has put out the right signals to pursue the approved, mainstream process. The proof that they would expect to vote on is promising. The signs are optimistic because, amid some political interference, the FDA’s career staff will probably follow by-the-book procedures.
Yet, the public doesn’t have to view the results on their own. Look at the people who have been investigating this issue—and not by a Google search—looking at the very initial scholars who have worked on government advisory committees. See what they’re showing you. Similarly, watch how data is shared, how it is viewed, and look for clarity.
Q: Is there an optimistic message that you’d like to say?
Initial tests have shown that an effective vaccine for this virus could be available. So far, I have seen no critical dead ends in the production of vaccines. Animal experiments and human results in early trials are promising but not conclusive in terms of safety. It’s going to take a long ride to find decent conditions in the first part of the journey.
