Dr. Larry Corey is an internationally renowned expert in virology, immunology, and vaccine development and a leader of the COVID-19 Prevention Network (CoVPN), which was formed by the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health to respond to the global pandemic. He is a Professor in the Vaccine and Infectious Disease Division at the Fred Hutchinson Cancer Research Center, past President and Director of Fred Hutch, and a Professor of Medicine and Virology at University of Washington.

On Dec. 2, the New England Journal of Medicine published an article coauthored by many prominent medical scientists, including physicians, who advocated for extending the time in which volunteers in the placebo group enrolled in the Pfizer and Moderna COVID-19 clinical trials should be followed.  

Essentially, they are arguing that the study volunteers – people who sacrificed for the greater good to join the trials in the first place – should be prohibited from getting the actual vaccines, even after the vaccines become widely available under an EUA (Emergency Use Authorization), because there is “additional scientific information that can be learned.”

Of course, there are always new things we can learn from a clinical trial. But at some point, we know enough that the risk to persons not being given these markedly effective vaccines is greater than benefit that can be learned from withholding vaccination to these persons. 

As a physician and a scientist, I recognize no one clinical trial ever solves all the issues needing to be addressed for public health. However, in making decisions when to offer vaccine to placebo participants in a trial in which high efficacy has been demonstrated, one needs to carefully balance scientific interests with withholding the benefits of vaccination to clinical trial participants themselves.

We must consider the real issue of fairness, and perceptions of fairness, at both the individual and community level.

So, let’s discuss these issues.

First, let’s look at what’s to be learned from keeping people on placebo while the EUA is being evaluated and the early days of market authorization, when supplies will be scarce.

Both the Moderna and Pfizer studies, which enrolled 30,000 and 43,000 volunteers, respectively, have reached their goal. Enough information on the number of pre-defined cases of COVID-19 required to define the vaccines’ effectiveness has been reached. More than 150 cases of COVID-19 were found among participants in each trial, and the vast majority of those cases were in people who were on placebo.

The analysis which compared the vaccine to the placebo occurred nearly two months earlier than projected. We got the answer quickly because people at high risk of infection enrolled swiftly in trials, and the widespread epidemic of COVID-19 across our country meant we didn’t have to wait long for cases to appear among volunteers.

The endpoints were well defined. Scientists asked, first and foremost, whether the vaccine reduced the chance of people getting symptomatic disease. The most important secondary endpoint looked at whether the vaccine reduced severe disease (hospitalization).

The results were simply spectacular—approximately 95% efficacy in the primary endpoint; 100% in the secondary for the Moderna vaccine. Even more compelling is that the results were remarkably similar between both the Pfizer and Moderna clinical trials, which both are testing messenger RNA based vaccines.

That’s a key validation for this emerging type of vaccine technology.

To date, the only reported death related to COVID-19 in the trials was in the Moderna trial and that was in the placebo group.

These data are clear and compelling. It’s hard to believe any more data are needed to show that the vaccines reduce the likelihood of developing moderate-to-severe COVID-19. By keeping people on placebo, we are only subjecting them to a higher risk of contracting severe COVID-19 disease. Are we trying to show that hospitalization and/or mortality is only 90% rather than 100%? I doubt that.

Everyone wants to know how long the vaccine can protect people. More time is required to answer that question. But by the time January rolls around and more vaccine doses become available, we will have close to six months of data from the start of the clinical trials in late July.

As I’ll explain below, there is a very good way to assess vaccine durability. One way to assess continued vaccine effectiveness against COVID-19 would be by vaccinating the placebo recipients in a crossover design.

This literally allows people who were on the placebo to “cross over” to get the real vaccine in a second phase of an ongoing study. The participants, and researchers, would still remain blinded as to what they are getting.

By continuing in this way, we could ensure that everyone in the study is getting vaccinated, while we’ll also get the chance to learn something new what the difference is between early versus late effects of vaccination. These data can be obtained by vaccinating the placebo recipients in early 2021, rather than simply waiting and watching them as more and more of them acquire COVID-19 disease in the trial. 

Understandably, people want more safety data, and longer-term follow-up.

However, to assess the infrequent side effects of vaccination, it is not the vaccine cohort in the Phase III trials (about 21,500 for Pfizer and 15,000 for Moderna) that will discern this. Instead, this information will be gathered from the cohort of millions of people who receive the vaccine under the EUA and are then closely followed post-vaccination.

Respecting the thoughtfulness of the guidance documents from the FDA, regulators still want to know whether vaccination can result in enhanced disease. They also want to compare the background rate of severe pulmonary infection in placebo recipients. So far, there is no evidence in either trial of severe pulmonary disease from vaccination. In fact, it is quite the converse.

Between the two trials, there are between 40 to 50 cases of severe disease, and while the details of these cases are not known to me or the public (and such data are critical to unpack), it all says these pneumonias and hypoxemias are in placebo recipients.

Should we be more worried about a chance of enhanced disease from the vaccine – even though there’s no evidence to say that’s a real concern – or should we be more worried about exposing unvaccinated placebo recipients who self-identified as at-risk of COVID-19 infection?

In the Moderna trial, 30 (16%) of the 187 reported cases of COVID-19 were classified as severe over the four-month review period. Do we really want to see another 30 people get severe disease by watching them for four more months? 

The question in my mind is what scientific justification is there to not vaccinate placebo recipients who had participated in the trial in which there was 95% efficacy and 100% effectiveness from hospitalization?

One can mitigate these numbers by saying only the healthy, so to speak, should be left alone. The tactic of differential handling of placebo recipients is, however, problematic. To take placebo recipients who fall under the category of EUA eligibility—in other words, medical care or first-line workers, nursing home personnel, those who are elderly or essential workers—and provide the vaccine because they are in group 1 of the EUA in their state, or nationally, is logical. But to deny their companions who joined them in being a clinical trial participant is quite problematic both from a social justice, fairness, and public perception point of view.

First, trial participants are essentially a community bonded together in a clinical trial. Thirty to forty thousand people were grouped together and placed under common scrutiny and rules.  

We in clinical trials authenticate this bonding by calling them a study cohort. In this medical vernacular all are equal and each benefits from the other. The goal of the cohort is to achieve the study goal, which is not asking participants to get sick, but recognizing that in the course of human life some people will develop this disease.

Within the common community of trial participants, did the endpoints on the trial come from the medical workers or the non-medical workers? Was severe disease only in the elderly or in one group or the other? Does it matter? Does a medical worker who participated in the trial deserve vaccination more than the group of essential workers or someone who lived in the household of an essential worker who developed COVID-19 on the trial? Does either group feel good that the other is excluded when they entered the trial as equals in their own community? Differential access inserts nonequity among this “Band of Brothers and Sisters.” Are they being asked what they want? If so, would they say that they deserve the vaccine more than someone else in the trial? Did the medical worker who did not get infected sacrifice more than the bus driver who did or his friend who did not get infected?

Need I say more?

There are many dispassionate people who say we need and have a societal obligation to learn about the durability of the vaccine’s effectiveness. My colleagues at the CoVPN (COVID-19 Prevention Network) have, in fact, developed a proposal that would answer this quite effectively by vaccinating the placebo recipients, keeping the trial blinded, and following participants for signs of COVID-19 disease for the subsequent 18 months.

In this scenario, the people who got vaccine in the first place would get their blood drawn and be randomized to placebo injection. And those who initially got placebo would get their blood drawn and be injected with vaccine.

Let’s say we start in early January with the first dose, by the end of January after the second dose has been administered, everyone on the trial(s) would be vaccinated. Some could have been vaccinated last July 2020 at the start of the trials; some in January 2021.

By running the trial this way, we will be able to see the changes in durability in that six-month time difference, but everyone in the trials would then be vaccinated and therefore protected.

My colleagues and I feel this is best done blinded, but that is perhaps a lesser issue. The key point is that receipt of the vaccine is intended for all who originally signed up for the trials. Hopefully, most participants will want to continue with the study, and help answer this longer-term issue and continue to go to the clinic for COVID-19 testing and follow-up when they are ill.

With this proposed way forward, we can continue to learn about the efficacy and durability of the vaccine with the placebo group being vaccinated. It is medically difficult to justify keeping people on placebo when we don’t have absolute markers of risk — when we see that even some people ages 15 to 55 have been shown to experience severe disease, when we see increased hospitalization and death but have no clear marker of risk that can guide us as to who is at risk and who is not.

Keeping the vaccine from the very people who got us this far by participating in the trial, and who could benefit from it, is in my view, untenable. I, and almost all of my colleagues I surveyed who conducted these trials, honestly feel it is just not right.

Lastly, some people might argue that by vaccinating those in the placebo group, we would be taking vaccine away from others who are more deserving or who might have a higher risk. This is not the case. Vaccine vials labeled for research purposes are permanently labeled as such and are not those allocated to the general population.

If we’re going to adhere to the determinants of social justice; if we’re going to advocate for the underserved; if we’re going to declare the importance of altruism and act with principles of fairness, then we must treat all of the placebo recipients equally.

They themselves have become their own Band of Brothers…and Sisters, and we must honor their service to us all. 

Dr. Larry Corey is an internationally renowned expert in virology, immunology, and vaccine development and a leader of the COVID-19 Prevention Network (CoVPN), which was formed by the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health to respond to the global pandemic. He is a Professor in the Vaccine and Infectious Disease Division at the Fred Hutchinson Cancer Research Center, past President and Director of Fred Hutch, and a Professor of Medicine and Virology at University of Washington.

Larry Corey, MD

The Pfizer and Moderna vaccines are likely to secure Emergency Use Authorizations (EUAs) from the FDA by Christmas.

These are amazing gifts of science. They also arrive with high expectations from a weary public, especially since the clinical trials of these mRNA vaccines indicate near-complete protection from severe disease.

These first two vaccines arrive at the most tumultuous time yet in the pandemic. We are seeing a surge of people being newly diagnosed with COVID-19 across the country. More than 90,000 people are now hospitalized, and our healthcare capacity is being stretched to the limits. The death rate, after months of decline, is now heading back up. The upheaval in our daily lives has been with us for nine solid months. This terrible set of circumstances should help push back against the vaccine hesitancy we have heard about from public opinion polls.

The desire for protection from this sinister virus ought to prevail, and lead to a successful national vaccination campaign in the months ahead.

The demand for a vaccine is clear. Unfortunately, however, the demand for these vaccines will markedly outstrip their supply, at least for the next four to five months. That seems like an eternity, especially with the rate of community spread we are now seeing. Vaccine scarcity will be in the news for the next several months until one or two other types of vaccines — beyond the initial batch of mRNA vaccines — can meet the safety and efficacy requirements for an EUA distribution and become widely available.

How did we get into this predicament — where science came up with a couple of exceptional vaccines, but we can’t deliver them to everyone?

The pace of vaccine development has been unbelievably quick; quicker than anyone ever expected. This remarkable scientific accomplishment has outstripped the existing manufacturing supply chain. The conceptual framework of a victory against the virus exists, but in order to proclaim victory, we need mass vaccine manufacturing distribution and uptake.

Making and distributing vaccines is a complex process. There are many steps, and each step requires detailed quality control measures to ensure that each and every vial contains the right dose and right substance. To think of it in a more personalized way, what goes into every arm — including yours and mine — needs to meet manufacturing standards. That is not an easy task and one that takes specialized facilities and highly trained personnel, more than currently exist.

It’s especially difficult when you recognize that mRNA vaccines are an altogether new type of platform for vaccine development. Never before have they been manufactured at the scale of millions — even billions — of doses.

When we look at the number of doses being made versus what we need, it’s a daunting thought. Between Pfizer and Moderna, we expect only 20 million doses to be available in December; 30 to 40 million in January and February; and 60 million per month in March and April. Even if we reach 200 million doses, that’s only 100 million people vaccinated at best — less than half the U.S. adult population.

As I’ll describe below, these doses may not even cover the populations we feel most need the vaccine.

So, who’s in line for this scarce resource and who decides who gets vaccinated first? We knew that vaccine scarcity would be inevitable since the beginning of the Operation Warp Speed (OWS) program. Independent groups and other experts have been evaluating all along how to define and develop an equitable national vaccine access strategy.

The National Academy of Medicine, or NAM, the country’s premier independent group of scientists and medical policy makers, was commissioned by the National Institutes of Health (NIH) and OWS to evaluate this issue.

NAM divided access to effective vaccines into four categories and estimated the number of people in each of these categories. As shown in the first phase (1A and 1B), they prioritized health care workers and the elderly in high-density communities, such as nursing homes, followed by the elderly that have comorbidities like autoimmune disease or diabetes, which raise their risk of severe COVID-19. The NAM panel classified essential workers as the second group.

In both phases of distribution, the panel emphasized that economically disadvantaged communities must be given equal access in all situations.

The second group of experts enlisted was the Advisory Committee on Immunization Practices (ACIP). That’s the CDC’s arm that makes recommendations for public health authorities around the country. The ACIP is the committee that has defined populations recommended for vaccination for over 50 years. Its advice is linked to public health–funded programs and defines insurance coverage for vaccines.

This group has been discussing who ought to get the COVID-19 vaccines first for many weeks in open meetings. It has, in its first rendition noted below, suggested that essential workers and first responders and medical personnel be in the first group.

Essential workers comprise group 1B, for example grocery store workers and meat packers. The third priority group (1C) is the elderly and those people with comorbidities. These 3 groups of people alone comprise well over 150 million people.

That all adds up to a lot of vulnerable people – more than we can vaccinate right away. Estimates are we’ll have enough vaccine supply for about 90 million people by April 2021.

How does one handle this scarcity when a case for vaccination exists for a very large segment of our adult population?

ACIP Proposal

How does one choose between a healthy frontline essential worker with no comorbidities — someone with a lower risk of death but a higher chance of becoming exposed and infecting others — than an elderly person with comorbidities who has a much higher risk of death but could perhaps self-protect more by limiting exposure?

Is there a right answer to who gets vaccinated first or do we have to understand and practice principles of equity and patience until we have enough vaccine for everyone?

Both groups — the National Academy of Medicine and the ACIP — are advisory. They make recommendations to the public and executive branches of state governments. We have national-guidelines, but we don’t have a nationally controlled distribution plan.

Each state will make its own choice about allocation. We will see differences in distribution by locale. Understanding and communicating these differences to the public will be challenging. Some will call it confusing.

I’m sure there will be some disagreement, some of it loud and angry, about who should get the vaccine when.

One principle should be upheld; we should use every available vial. Nothing should get wasted.

The only real solution to overcome vaccine scarcity is, of course, to remove scarcity, which means that the remaining vaccines need to be made available. So, the AstraZeneca vaccine that you’ve heard about, which reports about 70% effectiveness; the single-shot Johnson & Johnson vaccine still being tested in a blinded pivotal clinical trial and others, will need to pass scientific muster and then be made widely available as well.

We are hopeful that answers on how these vaccines perform in the U.S. will be known by late January 2021 — less than two months from today.

For the time being, we’re going to have to get used to this issue of vaccine scarcity. However difficult it may be, we will have to be patient, and conscientious of broader societal needs, at least until more manufacturing capacity for the mRNA vaccines exists, or more likely, other types of vaccines become available for all of us. 

Dr. Larry Corey is an internationally renowned expert in virology, immunology, and vaccine development and a leader of the COVID-19 Prevention Network (CoVPN), which was formed by the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health to respond to the global pandemic. He is a Professor of Medicine and Virology at University of Washington and a Professor in the Vaccine and Infectious Disease Division and past President and Director of Fred Hutchinson Cancer Research Center.