IN Conversation With Dr. Barney Graham

Dr. Barney Graham. Photo courtesy of the National Institute of Allergy and Infectious Diseases.

A native Kansan designed the structure for the highly effective Moderna vaccine just 24 hours after the genetic sequence of the Covid-19 virus was published by Chinese researchers back in January 2020, before most of us had even heard the term “coronavirus.”

Barney Graham, an immunologist, virologist, and clinical trials physician and a graduate of Paola High School and University of Kansas, was honored as a 2021 Hero of the Year by Time magazine in its year-end issue. A few weeks earlier, he was named Federal Employee of the Year. Graham was deputy director of the National Institutes of Health’s Vaccine Research Center and chief of the viral pathogenesis laboratory; he retired in August after a 20-year career at NIH.

Monique Young, a former colleague of Graham’s at NIH describes him this way: “He is a gentle giant. His knowledge is insurmountable, and he is humble. He is a great humanitarian. If I wanted anybody by my side, it would be him.”

IN Kansas City caught up with Graham by telephone at his new home in Georgia, where he and his wife moved to be closer to children and grandchildren. Several times during the conversation, the gentle-spoken doctor dodged opportunities to reflect on his grand accomplishment. Instead, he mused about how the miracle vaccine could have possibly stomped out the disease were it not for preventable problems in public trust and regional manufacturing capacities, problems he now intends to spend his time trying to fix, instead of accepting a lucrative private industry gig.

After you and your colleagues designed the structure of a vaccine on Jan. 11, 2020, was there a breakthrough moment when you felt sure it was going to work?
There were several breakthrough moments after January 11th, 2020, but we [already] had a good sense that it would work in 2019 because of work we had done on the MERS coronavirus.

However, a thousand things have to go right to get through a vaccine process all the way to licensure. So, the main milestones were: Making a spike protein for the first time on January 30 and seeing that it was well-behaved, and on the 31st seeing that it was uniform and in the right shape.

Then on Feb. 18, seeing strong antibody response in mice after a single dose.

On May 9th, we saw better-than-expected antibody data from the first eight subjects.

And finally, Nov. 8 when I heard about initial Pfizer efficacy data (95 percent), which is a very similar vaccine to ours, and Nov. 15th for Moderna (94.1 percent efficacy).

Dec. 22 was a milestone, when vaccinations began at NIH, just 11 months after the initial design. It was very gratifying to see the vaccine rollout, especially to see health-care providers having the protection they needed to keep caring for the sick.

Were you expecting the efficacy to be that high?
No. I had been expecting 70% efficacy and hoping for 80%. It is rare to get more than you hope for in vaccine development.

Let’s go back in time to life on your family’s farm in Paola during your teenage years. What kind of farm was it?
It started out as a quarter-horse farm, and then it transitioned to cattle, and then it transitioned to hogs. We raised about 2,500 head of hogs a year and farmed about 800 acres of crops to feed them.

Were there any signs when you were a little kid that you would end up a scientist and an inventor?
I don’t know. I liked to collect things and figure things out and build things. I collected coins and bottles, and I built furniture and fences and corrals.

Why did you decide to go into virology?
During my training at General Hospital, which was the public hospital in Nashville, and near the end of 1982, I saw one of the first patients with AIDS in Tennessee. That was the beginning of the HIV pandemic, and so a lot of people my age in training at that time decided that they had to do something about these kinds of diseases, and vaccines and virology were the obvious path.

A lot of vaccines like the polio vaccine work by injecting a small amount of live or dead virus into the body. How are mRNA vaccines different?
Historically a lot of our vaccines were based on growing up large amounts of virus and cell culture, and then killing the virus or doing something to attenuate the virus to make it so it wouldn’t cause illness.

Now, we can take the virus totally apart and look at one protein or one part of a protein. The protein on the surface of this virus, the spike protein, is the one that is used to get the virus into cells to start replicating, so attacking that is a rational thing to do to make a vaccine.

Antibodies recognize shapes and surfaces, so the minor surface contours of the protein really matter if you want to make the right kind of antibodies. And mRNA is a way of delivering that protein, especially if we do a little bit of engineering so that it stays in the right shape and it’s delivered into the system and shows the protein on the surface of a cell, and it looks very much like what it would look like if it was on a virus. So, the immune system gets to see something that’s very native, it’s the authentic shape of the spike protein that we want the immune system to attack. And mRNA allows us to do that in the simplest possible way.

What is the difference between the Pfizer and Moderna mRNA vaccines and the Johnson and Johnson and AstraZeneca vaccines? And what about the vaccine developed in Cuba?
The Pfizer and Moderna are very, very similar vaccines. Johnson and Johnson and AstraZeneca both use an adno-virus that’s been modified so that it really cannot replicate any more but it can deliver a payload; it can deliver a gene so that it can make the spike protein. They both work very much the same way. The mRNA and adno-virus vaccines are similar in that they are both delivering a gene that will allow the cell itself to make the protein.

In the other cases (like Cuba), you are making the protein in a laboratory and then giving the protein in the vaccine. In the other cases, the body itself is making the vaccine.

Gain of function research has become a controversial topic. What is it, and what is its purpose?
It’s not my field of interest, but I can say what it is: It means that you have used molecular biology techniques to modify a virus to make it do something else—to infect a different type of cell or do something it doesn’t do in natural life. Those kinds of experiments, a lot of times, are done mostly to try to understand how viruses work and what each element of the virus is contributing to the way the virus can make you sick.

Did gain of function research go into the development of your vaccine?
No. We never even had the virus in our laboratories. [The Moderna vaccine] is done entirely through synthetic chemistry and knowing the sequence of the spike protein.

Do you think it is important to determine the origin of the Covid-19 virus?
Yeah, I mean, you’re getting into very controversial areas that don’t really have good answers. In my opinion, this virus is something that could easily have come out of nature. It can be explained by viruses that you find in nature.

Regardless of whether Covid-19 was a lab leak, we know lab leaks are possible. Two separate cases of SARS leaked out in 2004. Knowing that, should we be looking at ways to minimize the risk of deadly viruses being created and possibly escaping?
I would say we face a lot more danger from Mother Nature than we do from laboratories. The procedures that are in place, that are enforced by all the institutions that I know about, are very strict in order to prevent these kinds of things. And as we have seen, the things that come out of nature are a lot more surprising and difficult for us to deal with than these kinds of things you’re bringing up.

There’s always been some vaccine hesitancy in America but it used to be a relatively small percentage of the public. Why do you think vaccine hesitancy has grown during the pandemic to close to 40 percent of the population?
It’s complicated. In some cases, there are historical reasons for people not wanting to trust institutions that are valid. In some cases, it’s just that people don’t want to be told what to do.

In this case, I think a lot of the hesitancy is driven by misinformation that is disseminated especially on social media, and those misinformation campaigns have increased hesitancy above what you would expect it to be.

“In this case, I think a lot of the hesitancy is driven by misinformation that is disseminated especially on social media, and those misinformation campaigns have increased hesitancy above what you would expect it to be.”

In a podcast with University of Kansas Medical Center, you said that in order to gain trust, institutions have to be trustworthy. What were you referring to?
There are historical incidents you can look at, like the Tuskegee syphilis incident [when treatment was withheld from African-Americans with syphilis without their knowledge] and some other things that happened like that in Guatemala [when the U.S. infected people with syphilis without their knowledge], and the Henrietta Lacks incident [where Johns Hopkins Hospital collected cells for research from a poor Black woman without her consent]. Those kind of events in our history are what cause people to not entirely trust biomedical institutions. Those are historical, true events, and we’ve been working for decades to try to get past those and regain trust.

Since science is constantly evolving and skeptical inquiry is crucial for advancement, do you have concerns about attempts to squash debate about vaccine safety and shaming people who raise concerns?
I’ve spent most of my life studying the safety of vaccines, and I don’t think asking questions is a problem. I think it’s important for everyone to ask questions. I don’t think there should be any resistance to answering questions.

In that spirit, let’s look scientifically at three concerns about vaccines that have been circulating. First, can mRNA vaccines change a person’s DNA?
The answer is no. The mRNA goes into the cell. It’s only there for a few hours while it is the template for making the spike protein. The spike protein then goes onto the surface of the cell and can be recognized by the immune system. That [the spike protein] is only there for a few days. mRNA never goes into the nucleus of the cell. It does not encounter DNA, so biologically it just isn’t credible to say the mRNA can change our DNA. And if you are worried about having your DNA changed by RNA, then you need to avoid infection as much as you can, because the virus infection itself is creating much more foreign RNA than the vaccine.

Does the vaccine inhibit the ability of our DNA to repair itself?
No. I can’t even understand why that would be raised as an issue.

Is there a danger the vaccine can cause infertility?
No. There has been no evidence that it has had any effect on the ability to conceive.

I think it’s important that people get their information from credible sources. I think one of the tragedies of this epidemic is that some people are getting infected and getting severe disease and dying who didn’t have to. When there is the ability to boost your immunity before infection to give you a better chance against the virus, and people don’t want to accept that, that is a tragedy.

Can you explain why it remains important for people to get vaccinated and boosted even though vaccinated people can still contract and spread the disease?
There are several reasons to get vaccinated. One is to protect yourself from severe disease. Secondly to protect those around you that you love and care about from getting infected. And the third one is because every time the virus infects [someone] and goes through a replication cycle, it has a chance to change. And it could change to escape the vaccines and antibody treatments we’ve already developed, and they would then have to be changed, or it could develop into the next variant of concern.

So, every time you can avoid an infection, you reduce the chance of the virus evolving into something even worse. People who are vaccinated can get infected. The vaccine was never really designed to completely prevent infection; it was designed to prevent you from getting sick. In vaccinated people the virus grows to a much lower level. There can be a thousand times less virus in the nose of a vaccinated person than in the nose of an unvaccinated person. And, the virus is shed for a much shorter period of time—only a few days instead of weeks in unvaccinated people.

So, people who are unvaccinated and get infected are producing a lot more virus, they have a lot greater chance of making a new virus that is more dangerous, and they have a greater chance of transmitting the virus to a loved one.

Now that you have the luxury of not running a lab on a daily basis, what would you like to work on in your retirement or semi-retirement?
I see two problems. One, we just talked about: vaccine hesitancy. So, I’d like to do some of my time doing community education, which I guess this interview counts as part of that…

I hope so.
And the other thing is, we need to have manufacturing available for more places around the world. Until we can vaccinate the world in three months instead of three or four years, we will continue to suffer from pandemics and from viruses evolving during the pandemics to escape our treatments.

There are two reasons to try to facilitate getting manufacturing to low- and middle-income countries. One is that many of the things that we are threatened by come out of tropical areas, which account for many of the low- and middle-income countries. Many of those things may not have commercial value or be of interest to the rest of the world, but they are of important globally. Having regional capacity to deal with regional problems before they become global problems is an important way to try to stop future pandemics.

The other reason is that if [poor, tropical regions] had that capacity, they could be the surge capacity to make sure enough vaccinations are available for situations like this, where less than ten percent of the African population is vaccinated. That means there’s a lot of virus still being spread and a lot of virus that has the chance to change and become more difficult.

The new mRNA vaccine approach changes what it takes to manufacture a vaccine. It’s gone from cell culture, which involves large equipment on big campuses, to simple chemical synthesis that requires a much smaller footprint and can be done on a much smaller scale. Using that approach is what I want to spend some time on.

A lot of people feel a great sense of despair that we are now two years into this thing and there seems to be no sign of life returning to normal. Are we doomed to living in a state of permanent pandemic, wearing masks indoors and getting tested before we fly, or do you think there is a way out?
There are ways out. Things have happened in those two years: We now have vaccines, we have therapeutic antibodies for treatment, we have antiviral drugs. But in order for those things to really be effective on a population level, people have to agree to participate and be part of the solution. I think if we had worked on this from the beginning as if we were all in it together, we would probably be much further out of this problem than we are. But it won’t last forever. Even the 1918 flu pandemic that killed 50 to 100 million people—eventually the human population got immune enough from the infections that the virus had to evolve away from that and after three or four years it went back to normal influenza season.

So, it will stop. And we now have tools we did not have ten years ago to respond to and stop future pandemic threats. It’s just a matter of utilizing those tools and being ready the next time.

Interview condensed and minimally edited for clarity.

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