Early on in the coronavirus pandemic, infectious diseases expert C. Buddy Creech caught coronavirus, as did his wife and his three children. Each family member was struck differently by the virus, some more severely than others. Creech wrote in an October 2020 essay published by Vanderbilt School of Medicine that his family’s varied experiences “illustrates the wide spectrum of disease caused by the virus.”

Researchers like Creech have learned so much more about this strange virus in the year since the global battle against COVID began. They’ve developed an arsenal of weapons and tactics to fend off COVID. Masks, for instance, are still relevant, says Creech, as is Remdesivir. Most importantly, vaccines against COVID were developed and approved for emergency use at record speed. Three months into the US vaccination effort, about 25 percent of the US population has had at least one dose of one of the available vaccines. Pew Research Center reports that 69 percent of Americans intend to get vaccinated, an increase from 60 percent in November 2020.

Race has played a role in who is getting the vaccine. More white Americans are being vaccinated than people of color, even as Blacks and Hispanics are still disproportionately affected by the virus. As director of the Vanderbilt University Vaccine Research Program, Creech and his team have been working on ways to help alleviate racial disparities, but as he says, “We’ve got years of missteps, dating back 50 to 75 years ago, that we’ve got to recover from. And that just takes communication; it takes trust; it takes transparency.”

I spoke to Creech about what we’ve learned about the virus since the pandemic began, how to make vaccine access more equitable, whether or not a vaccine for children is on the horizon, and why he describes this time as the dawn of a golden age of vaccinology.

Yvonne Bang: In an essay published in October 2020, you shared your experience contracting COVID in the early days of the pandemic. So much has changed in the year since you recovered. What are your thoughts about what has been accomplished in that time and what you know now about how the virus works?

C. Buddy Creech: I think one thing that we understand is that it’s not going away on its own. There were some who thought maybe this would go like the original SARS did in the early 2000s, where it threatened human health considerably and then, in large part, just sort of fizzled out. I think a lot of people hoped that would happen. It certainly didn’t.

The second thing is that we never historically have been able to prove that mask wearing is something that has benefits outside of the healthcare system. We studied it for influenza and for other respiratory viruses, and I think that formed the basis of our public health stance very early in the pandemic, in February and early March. But then I think it became crystal clear that communities that took seriously these efforts of distancing and mask wearing really had decreased disease. And if you look at the cadence of the pandemic over the year, you saw these rises and falls that often correlated with how compliant our local communities were with these basic measures.

Mask-wearing is still a heated issue.

Quite frankly, I don’t like them. No one likes them. The question is whether or not there is sufficient evidence to suggest their use and then to mandate their use. As we look back, I hope we will recognize that the way we message things is really important to those outside the healthcare system. I hope that we can look back and say that we need to be very transparent with our science. When there is an issue, we need to speak blatantly to people; when there’s a lack of information, we need to speak plainly, and then we can appeal to our common goals. I think we’ll look back and wish that our early messaging had been: we don’t know for certain that this will work, but we think it will, so can everyone just chip in and do this for a little while and let’s see if it works.

That’s a very different model than the bifurcation that we had, which said masks infringe upon my personal freedom, versus, if you don’t wear a mask you’re killing people. Those extremes don’t help when we’re dealing with the 60% in the middle. Hopefully what we will see is that we can reduce some of these issues as we get more people vaccinated.

Many people still have concerns about how quickly the COVID vaccines were developed. What factors sped up vaccine development?

The three categories are money, time, and pride. We poured a terrific amount of resources into this from a financial standpoint. We provided funding to the research sites that needed to do these clinical trials. We provided risk mitigation to manufacturers, to industry partners here in pharma, to make vaccines without feeling like their profit lines were just going to get destroyed. It wasn’t just on them. We were funding the trials on a public level. We were buying vaccines even before they were proven to be effective. So, some of it was the financial investment.

The second is time, and that time issue is really important. For the last year, we eat, sleep, vaccinate—that is our rhythm. And it has been a really important year for COVID. Admittedly other diseases, other clinical trials, have taken a back seat, and that’s just the way it is. But it shows us what we can do when we hyperfocus on one pathogen or one disease. It’s interesting, and it might be a model that we want to pursue for other scourges of the globe.

The third one is one that I kind of jokingly say: pride. But it basically was a combined effort. When all of our noses are pointed in the same direction, we can really do some good things. And whether that’s Merck coming alongside and helping make the Johnson & Johnson vaccine, whether that’s Pfizer and BioNTech getting together and forging a collaboration, I think the other piece is making available the really important basic science discoveries that have occurred in the last 20 years.

So, for instance, the story I like to tell with mRNA vaccines is that these didn’t happen quickly—it’s taken 20 years. It’s been 20 years since we learned that the spike protein is the most important part of the virus from an immune standpoint, and in fact, it’s the shape of the protein before the virus docks with your cells that we really need to make an immune response to. It took some time to figure out how to stabilize that shape of protein. But Barney Graham and his colleagues at NIH figured that out.

At the same time, it’s been years in the making that we’ve been working on mRNA vaccines for a variety of applications. So, taking 20 years in each of those two columns, and then adding pride and removing barriers and slamming those two together, now all of a sudden we have two mRNA vaccines for the spike protein. I think that’s huge.

You have already had COVID. Did you get vaccinated, and should other individuals who have already had COVID?

Yes, I think they should. I’ve been vaccinated. The variability in the robustness of the immune response after disease is really important. So, even in my own family, there were three of us, of our five, who had antibodies measured in our research laboratory. My daughter had next to no disease, maybe felt bad for a day or two, and her [antibody] level was four times normal. And then my wife, who was sick for about a week, flu-like illness, lost her sense of smell, she was 70 times, so hers was 7,000. Mine was 25,000, and I was the sickest of our group, having fever for over two weeks. So, we know that the severity of infection is correlated with the height of immune response.

So, just having a positive test doesn’t tell me much. What I think we need to be doing is: those who have had mild disease, they absolutely need to be vaccinated. We may get to the point where we realize that those with more substantial or more severe disease, maybe they only need one dose. But I still think a boost is really important, especially since we’re seeing these variants emerge that may require a higher number of circulating antibodies to be protective; and because we probably will see things—like transmission or asymptomatic infection—[that] are going to be prevented for longer when we have higher antibody tiers.

Are vaccines protecting people against COVID variants?

Yeah. We have indirect evidence in the clinical trials from Pfizer and Moderna studies, because they were done prior to these variants really taking root. But serum from these individuals neutralize the virus in laboratory assays. Then, when we’ve seen them launched in the wild, we certainly are seeing decreases of disease activity even in those areas where variants are plentiful.

The Johnson & Johnson study gives us direct evidence, particularly for variants that are circulating in Brazil and the B.1.351 that’s circulating in South Africa. There was 100% efficacy against COVID-related hospitalization in death, even when that variant represented over 90% of circulating strains. So, I think that gives us the most direct evidence that this particular vaccine construct, however it is delivered, whether it’s mRNA or viral vector, is going to protect against severe disease due to the variants.

Part of your work involves testing the immunity of patients who have recovered from the virus. What is different about immunity via vaccine and how the natural body responds to the novel coronavirus? We know the mRNA vaccines work in a certain way. Does the human body also work in that way?

When you see coronavirus naturally, you not only make an immune response to the spike protein, but to a number of other important proteins that are in the virus. We don’t know what the relative contributions of each of those proteins are to disease going sideways, but what we do know is that if you are immune to the spike protein, that protects you and we know that following infection, the spike protein has proven to be the immuno-dominant protein of the virus. So those things are important.

The reason I think we’re having such success with the vaccines that have been out there so far, is that we are presenting, to your body, the genetic code corresponding to that spike protein, and your body is making that protein just like it would if it were infected by COVID, but we’re not letting it see the rest of the virus. So, you can’t get COVID from the vaccine, of course, and it’s not going to keep making that protein. But it’s really interesting that we’ve been able to turn the deltoid muscle cell, where you get the shot, we’ve been able to turn that into the manufacturing plant for this vaccine.

You think about other vaccines, where we have to grow them in chicken eggs or we have to make them in some sort of manufacturing facility in Michigan. This is different because, when we make them that way, we have to make sure that the protein is folded correctly; we’ve got to make sure that it’s pure; we’ve got to make sure that everything worked the way it was supposed to. In this system, the mRNA and the viral vector systems, we’re giving our body the recipe; it’s going to make it because that’s what it does.
So, if you will, the purity of the vaccine, it’s just a trim, lean way to tell your body, “I’m going to trick you for a few hours into thinking that you’re infected with this virus.” You may have some fevering, you’re probably going to have some heart pain and some feeling yucky for a day. Then it’s going to be over and because we gave you just the one target, you’re now going to be immune and you’re going to recover very quickly from those symptoms. It’s a brilliant strategy, and I think that’s why I’ve called this time for us the dawn of a golden age of vaccinology, because these are tools that are going to be used for a number of pathogens.

The vaccines in circulation today have not been given FDA emergency approval for use with children, or any approval for use with children, what do you think are the next steps as far as vaccinating children is concerned?

Well, you have to recognize that children have been under-affected compared to older adults and those with ongoing medical problems. And when we do see children affected, we see really two things, we see adult type disease and those with underlying medical problems, particularly obesity, and then the second is that we do see this multisystem inflammatory syndrome that resembles Kawasaki disease. So, those are two things that are very important for us.

We also know that, societally, vaccinating children will provide even more of a cocoon of protection around our older adults like grandparents, but also around essential members of our communities like teachers and others. So, I think it’s important for us to understand how we can deploy the vaccine in children and then, once we know that we can, we can make decisions about whether we should.

We know that we can give the Pfizer vaccine down to 16 years of age. We know that both Pfizer and Moderna have studied the vaccine down to 12 years of age, and have completed enrollment for their studies in their teenager cohorts. That’s the first step, because I think it’s probably most important for us to get teenagers vaccinated. And we may be able to see teenagers vaccinated by this summer, and I think that’s a really powerful next step.

The next step is to then very steadily and methodically study the vaccine in different age groups of children so that we can carefully define whether or not the side effect profile looks the same. Maybe they have fewer side effects than adults, maybe they have different side effects from adults. Certainly with flu vaccine, we might see more fever in children, whereas we see more arm pain in adults. So, that’s one issue.

Then the second is, we would have to be looking at those immunologic consequences of vaccination. Do they make the same immune response? Do we need to use a smaller dose? Do we need to use just one dose? Do we need two? Do we need three? There are a lot of unanswered questions as relates to younger children that we will be embarking on in the next little while.

One of the things about children’s response to COVID is that their immune system is handling it differently. It’s been described as the “innate immune system.” Do children’s relatively “immature” immune systems have more of a protective effect and can you explain when an innate immune system response starts to evolve?

That’s an important question. Everybody has an innate immune response that never goes away. Think about it like this: on every cell of our bodies, except for red blood cells, we’re always patrolling for stuff that’s not us. The example I often give to people is that when you teach bank tellers how to recognize counterfeit money, the way you teach them that is not by knowing all the counterfeit strategies, but teaching them what the real thing is so well that when there’s something that’s different from that, it raises a flag. And then it can be looked at more carefully, and then you can say, “Oh wait, nevermind, that was okay.” Or you can say, “Oh crud, this is something that I’ve got to care about.” That’s what the role of the innate immune response is, to just be on patrol for things that don’t look right, for things that we don’t make, like flagella that are on protozoans, or DNA strands that only bacteria make, or RNA strands that only viruses make. We’re always on patrol for that.

For kids and adults, probably the basis for the side effect profile that we see after vaccination is the innate immune response being triggered to say, “You just showed me something that I’m not sure what to do with, so I’m going to make some inflammation and over the next several days I’m going to now engage my adaptive immune response.” That’s the innate and adaptive. “I’m going to engage my adaptive immune response and do some things here.”

Back to children. Where children are really important is maybe in two or three areas. Number one, they don’t make, we don’t think, as much of that ACE2 receptor that serves as the docking station for the virus. They’re at less risk overall for disease, so that might be one of the reasons why there are different serums. In addition, they don’t have some of the underlying comorbidities, so they don’t have that chronic inflammation that might be the cause of some people’s immune systems just going haywire with COVID. Then third, they’re constantly seeing coronaviruses, since that’s the cause of probably 25% to 30% of the common cold. They’ve recently seen other coronaviruses and therefore they may have some pretty good immunity because of the fact that they’ve just seen them for the first time.

All of those factors may contribute to kids being less likely to have severe disease from COVID. Why that’s important is that, when we get the vaccine, we want to make sure that we don’t disrupt the normal type of coronavirus immunity that happens through natural exposure to what typically is an easily controlled virus.

People of color are receiving the vaccine at a much lower rate. Since people of color have been disproportionately affected by the virus, equitable vaccine distribution is key. How can we make vaccine distribution across the United States fairer for everyone?

I think we’re really working on this and it’s very challenging. We have a group here at Vanderbilt, led by Consuelo Wilkins, who is singularly dedicated to this right now because we want to make sure that access to vaccine is not limited to those who have a very high healthcare literacy, or literacy about how to game a system in terms of how to get access. We really want vaccines to be able to go to those who are being disproportionally affected. That’s been largely in our Hispanic and our Black populations, for a variety of reasons that we don’t completely understand.

I think it’s challenging, one of the things that we were very focused on during vaccine development was ensuring that we had diversity within our clinical trial participants. And not merely racial and ethnic diversity, but socioeconomic diversity, diversity of medical problems, a lot of factors, because we want people to say, when they go sign up for a vaccine, “Someone a lot like me was involved in the clinical trial, and therefore I can have confidence that things are on the up and up.”

I think that’s really critical for us moving forward. I think we’ve got years of missteps, dating back 50 to 75 years ago, that we’ve got to recover from. And that just takes communication, it takes trust, it takes transparency, and it takes intentionality. And that’s what we’re trying to do locally, and I’ll tell you we’re really proud of the fact that in our phase three Moderna study, we recruited far fewer non-Hispanic white individuals than we typically would, because we were trying to be very intentional about it.

About a third of Americans are saying they are unlikely or hesitant to get the vaccine, for a variety of reasons. Trust, which you mentioned, is key. What would you say is important for hesitant individuals to know about the vaccines?

Again, it comes down to trust and communications. When I’ve encountered individuals, whether it’s in my church or friend groups, who have some hesitancy around the vaccine, I just ask what their concerns are. If the concern is, I think there’s a microchip in there, then I have a very different approach than if they say, “I’m really worried about pregnancy issues.” Or “I’m really worried about the side effects profile.” Or what have you. I think it has to be personalized. I think we need to train up clinicians and public health officers to be able to answer these very specific questions.

There’s not much more personal than our own health, so my ability to give a one-size-fits-all answer is probably unfair, right? Because everybody has individual questions.
I can hopefully just provide facts. Some have a fear of the unknown and that’s harder, because there are still things we don’t know about this vaccine. It’s less than a year ago that the first participants received this vaccine. And then we go into a risk benefit calculation, right? If you’re an 18 year old, healthy individual, normal weight who is thinking about getting the vaccine but has concerns, we probably have some time to think through it and talk about it. If you’re a 45 year old, obese healthcare worker who has high blood pressure, that’s a different risk calculation, so we need to have a different conversation in terms of the urgency of it.

I think, for the most part, those who have high risk factors for COVID, we don’t see hesitancy. Where we see hesitancy are in those who have identified, potentially correctly, that they’re not at highest risk for complication. I think we can have different conversations there. At the end of the day, we will get through this pandemic more quickly the faster we can vaccinate everyone.

Does vaccine effectiveness increase if the doses are spread apart even more than the recommended length of time?

Kathy Edwards, my mentor, is fond of a phrase that is getting steamed here at Vanderbilt, “Your immune system’s like your mother-in-law, it never forgets,” so if that’s ever used, it has to be attributed to Kathy. The issue is that anytime you can space out vaccines, you typically get a better, more durable response. And that’s true of a lot of different vaccines. The problem is, you also extend the amount of time where someone might be vulnerable to the infection. If this were just any old, no-big-deal virus, yeah, give it the first day and then give it six months later and get a boost, totally fine.

But if you’re trying to get people protected from a potentially fatal virus, give it three, four weeks between and do your best, right? So, the reason we’re doing it a month apart is because three to four weeks is probably the fastest that we would want to do it. That’s just where that sits right now. This also should give people encouragement that, if they can’t make it to their second follow-up, it’s okay if they’re late by a little bit, it’s not going to hurt anything.

What’s your opinion about reaching “herd immunity,” what percentage would that be of people vaccinated? And when might we reach that?

Yeah, we don’t know is the answer! We’re taking a lot of cues from smaller countries and smaller communities where vaccines are going very well, like Israel. And as we see those groups get to 40%, 50%, 60% vaccination, I bet we’re going to see tremendous drops in that area. I think the other thing we can see is, if we can get a handle on how many of our 60+ year olds are vaccinated, 70+ year olds are vaccinated, and then look at disease rate in those communities, I think that will also tell us a lot about the role of population immunity.

I would assume that it’s going to have to be more than 50% to work. It might need to be somewhere around 70% or 80%. But let’s keep in mind, our goal is not to keep everybody from getting infection—that may not be possible, it’s a respiratory virus, those are really tough. Our goal is to keep people out of the hospital and to prevent fatal cases of COVID. The overall disease rates are a little less important than hospitalization rates, fatalities, and complications of COVID.

I think what we’ve got to do is hyperfocus on those that are at highest risk of disease. That’s what we’ve been doing. And then I think we’ll see sustained decreases in disease activity. When that happens, we can steadily start to reopen things in a very profound way, not only for those that are vaccinated, but also for those who are at lowest risk of complication.

Will this COVID become endemic, constantly circulating from year to year?

I personally do think it will. I think this virus is too good at being adapted to the human host and every indication would point to it maybe becoming our fifth circulating coronavirus. And again, if this virus only causes troubles the very first time you see it, that’s a pandemic we can answer. If it’s continuing to cause problems, that gets a little more challenging. But every indication is that this virus is going to be with us for a considerable amount of time, which is all the more reason to get vaccinated.

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