As Senior Vice President of Pfizer Vaccine Clinical Research and Development, Dr. Bill Gruber is responsible for the global clinical development of vaccines and led the Pfizer-BioNTech COVID-19 vaccine effort. He is also a pediatric infectious diseases physician and a longtime member of the Pediatric Infectious Diseases Society. I recently had the opportunity to talk to Bill about his career trajectory, beginning with his interest in respiratory syncytial virus and, more recently, with the development of an mRNA COVID-19 vaccine. This interview has been edited for length.
Dr. Kris Bryant: I understand your interest in science started as a child. I’ve heard you were fascinated with astronomy as a child, and you grew up in Houston, home of the Johnson Space Center. Growing up, did you envision a career related to the space program?
Dr. Bill Gruber: In the beginning, I had a real interest in astronomy. We were passing by a church at night, and there were a bunch of people with telescopes. My parents took me out there to look through the telescopes, and I first saw the rings of Saturn when I was about five years old. That made a major impression on me. In middle school, I actually built a telescope and entered some astrophotography into the greater Houston science fair. I still have that telescope that I built more than 50 years ago, and I guess you could say that sparked an interest in science.
Dr. Kris Bryant: You attended Rice University and majored in Math, right? What inspired you to choose a career in medicine rather than something related to space?
Dr. Bill Gruber: I was initially thinking I was going to be a physicist, but by the time I was in college, I began moving more toward mathematics and biology. I thought I could do more to help people in the context of a career in medicine. Interestingly enough, though, everything came full circle because I first learned about Bayesian theory in college, and the approach we used for the COVID-19 vaccine trial was a Bayesian approach rather than a frequentist approach for defining the endpoints and achieving the desired outcomes.
Dr. Kris Bryant: What sparked your interest in infectious diseases?
Dr. Bill Gruber: I went from Rice right across the street to Baylor College of Medicine. You know some of the people I encountered there, people like Ralph Feigin, Carol Baker, Shelly Kaplan. They were all sort of arriving (at Baylor) at the time I was thinking about what I wanted to do. It’s a wonder not everyone ended up in infectious diseases because of the nature of those people.
Dr. Kris Bryant: Very early in your career, you had a mentor who impacted your interest in respiratory viral pathogens?
Dr. Bill Gruber: Paul Glezen really shaped my interest in viral respiratory pathogens. He is a primary reason why I threw my lot in with the influenza research unit and vaccine evaluation unit at Baylor College of Medicine as a pediatric ID fellow. It started with work as a student and resident identifying babies hospitalized with RSV infection for which Paul had obtained cord sera. You know the rest of the story; Paul then wrote the seminal paper on the importance of maternally transferred antibody for the protection of infants against RSV. This became the basis for polyclonal (Respigam) and monoclonal (Synagis) prophylaxis against RSV, and the maternal immunization approach now in the clinic.
Dr. Kris Bryant: We’ll talk more about how you haven’t lost interest in RSV, but I want to know more about how you ended up working in the industry. Early in your career, you were following a traditional academic path. In 1999, you left Vanderbilt University to become the Vice President of Clinical Vaccine Research for Wyeth. Can you talk about why you made this change and the career opportunities that working in the industry has provided—opportunities that wouldn’t have been available if you’d stayed on the academic career path?
Dr. Bill Gruber: So I wasn’t looking to make a jump, but George Siber approached me about a job when Pfizer was establishing a creative relationship with the NIH around the development of live attenuated vaccines. George knew of my interest in RSV and of the other vaccine work I had done, and he reached out and asked me to come and take a look at that job. It was appealing, but I could do a lot of the same things in my job at Vanderbilt. I told him that I understood he was looking for someone to head clinical research, and if he was willing to give me a try, I’d be willing to consider that job.
Dr. Kris Bryant: What was the hook for you?
Dr. Bill Gruber: It was hard to come up with something they weren’t working on as far as vaccines were concerned. It was like a candy store. I could be involved with a number of different projects, see end-to-end development, from early phase all the way to licensure, and have global reach. My desire to have a big impact in terms of potential vaccine development could be realized by making that leap. It was not an easy decision. I was tenured, I had a productive research career, and I was working with good people like Kathy Edwards and Peter Wright. My former college roommate Barney Graham was there at Vanderbilt at the same time.
Dr. Kris Bryant: Barney Graham who has led the work at the NIH to develop the COVID-19 vaccine with Moderna? I think many will be surprised that he was your college roommate!
Dr. Bill Gruber: Neither of us imagined that we would end up on this path together! Well, it was a great mix of folks at Vanderbilt, but I decided to take the plunge, and it worked out. It proved to be as good or better than I thought it might be, although it was a hard decision to give up patient care. I jumped with both feet into vaccine clinical research and clinical development, and I’ve been fortunate to be part of a team that has had some success in bringing important vaccines to the world. It has been very fulfilling.
Dr. Kris Bryant: As a pediatrician, it must be very gratifying to look at the childhood immunization schedule and see what an impact you have made: conjugate pneumococcal vaccine, conjugate meningococcal vaccine, meningococcal B vaccine, live attenuated influenza vaccine. You and your team have worked on all of those. What is going to be the next big “breakthrough” on the immunization schedule?
Dr. Bill Gruber: RSV! It is clearly one of the main ones that are next. Frankly, it is one of the anchors for me and one of the main reasons I am not prepared to retire from at least this job and consider something else. We are in phase three development of a maternal immunization construct that, ironically enough, gave me an opportunity to work with Barney Graham. The pre-fusion protein construct came out of his lab, and our talented molecular engineers at Pfizer stabilized it and now it is in the clinic in phase 3 trials. It produces tremendous antibody responses, and we think we are really at a watershed moment in terms of providing protection.
We are working on a group B strep vaccine. We are just finishing the phase two trial and getting ready for phase three. Obviously, having been trained by Carol Baker, that is a key thing that I would like to see us be able to move forward. We are working on a next-generation pneumococcal vaccine. We’re working on a pentavalent meningococcal vaccine to bring the men B and quadrivalent together. We have a C. difficile vaccine that is in phase 3.
I think the mRNA platform, given this success (with SARS-CoV-2), really lends itself to further energize the work we were already doing. We acquired that capability by a partnership with BioNTech to work on flu vaccine, and that is what allowed us to leap to applying it to SARS-CoV-2.
Dr. Kris Bryant: So how surprised were you that we have a newly discovered virus and now a vaccine for that virus in less than a year? Did you think it could be that fast?
Dr. Bill Gruber: I could conceive of it occurring rapidly, perhaps not as fast as it did. But I think it speaks to the nature of what you can do if you remove a lot of the white space. I always want to make sure to emphasize that we did not cut any corners in terms of assessment of safety, on ensuring the integrity of the results, or documenting efficacy. But when you have everybody pulling together, not only within Pfizer but our investigators, our participants in the trial, and the government, you can accomplish really remarkable things.
There were several surprises. I hadn’t anticipated the efficacy being as high as it is. I thought with a mucosal pathogen, given the track record we have we flu and rotavirus, we might be in the 70% range, maybe 80% if we were lucky. We powered the study for 60%, thinking efficacy might be down in that range. It was a pretty overwhelming experience to have 95% efficacy documented. There are three reasons I think this is a watershed moment.
First, the mRNA technology is really living up to its promise. It produces a Th1-biased response. You get great CD4 cell responses, great CD8 responses and you get antibody. Perhaps we’ve really found a new technology that is incredibly enabling.
Second, the nature of the pre-fusion construct can’t be forgotten. The very thing we think will work for RSV seems to be working for coronavirus. The pre-fusion state where you have the necessary epitopes exposed that can induce antibody is key.
The least satisfying thing from a scientific point of view is that maybe that coronavirus is an immunologic wimp, and you only need a small amount of antibody. Both we and Moderna are seeing high efficacy and achieving antibody levels that are comparable to convalescent serum. Maybe you need a lot less antibody to be effective, and we’re potentially going to find that out with other modalities that are producing lower antibody levels. It could be a combination of all things.
Dr. Kris Bryant: A number of different strategies have been employed to develop COVID-19 vaccines. Why did you decide to develop a mRNA vaccine, and did you consider anything else?
Dr. Bill Gruber: I think we briefly considered other possibilities. Considering everything we knew based on work that had been done in the oncology space and the infectious disease space, this was likely to produce the best immune response. It was also going to be the fastest to make and to scale up. We’re talking about micrograms of mRNA in a lipid nanoparticle.
Some of the challenges that you face with peptide-based vaccines or other modalities just take longer. For our purposes, we were never very enamored with the vector-based approach by virtue of the challenges you face with with re-immunization and anti-vector immunity. We think this provides an opportunity to circumvent that, although maybe it won’t be necessary. Maybe everyone will get one or two doses of vaccine, and the virus will go away from the face of the earth.
I’m less sanguine about that, though. I think we are going to see some real durability of protection, but I think people may need to be re-immunized every so often and boosted. This technology really lends itself to being able to do that.
Dr. Kris Bryant: What do you see as your greatest achievement thus far? I emphasize “thus far” because you are not ready to retire. Is it this or something else?
Dr. Bill Gruber: It’s this, it’s this! I’m thrilled about some of the things I’ve done in the field, particularly the pneumococcal conjugate field, but to have done something like this in such a short period of time… something that has the potential to have such an immediate impact on public health and people being able to get their lives back to normal, it is hard to come up with something more gratifying.
I’ve never had so many personal notes come in. You can tell that individuals’ lives are really impacted, right from the moment they get the dose of vaccine, they know that their life is going to be different.
My hope is that we’ll get high uptake of the vaccine as fast as we can provide supply. We’re highly dependent on others like Moderna being successful because none of us can supply the whole world with the production capabilities that we have. This is really a team effort across sponsors, academic institutions, and people in the healthcare profession to get this vaccine delivered and to convince people to be vaccinated.
Dr. Kris Bryant: Match Day for Pediatric ID fellowship positions was in December, and about half of our available positions went unfilled. This is a concerning trend and people are worried that we are not going to have enough scientists in the decades to come. What would you say to a medical student or college student thinking about a career in pediatric infectious diseases?
Dr. Bill Gruber: The driver for me was being able to make a broad impact. There is no single medical intervention that has had a bigger impact on public health than vaccines. My hope is that some of these workaround COVID-19 vaccines will energize people to consider infectious diseases as a career because they realize they will have an opportunity to make an impact.
Dr. Kris Bryant: Training in pediatrics and pediatric infectious disease was good preparation for a career in vaccine development?
Dr. Bill Gruber: For me, it was an asset. As a pediatrician, I was very tuned into vaccines. People should recognize that there are a lot of career opportunities for individuals trained in pediatric infectious diseases, and certainly industry has provided a great opportunity for me to deliver on that desire to make an impact.
Trainees should know that there is still a lot of work to be done. We have yet to eradicate polio. Measles should be the next virus we knock off the face of the earth. Someone can be part of that solution. I’m hopeful that, in my lifetime, I’ll see an HIV vaccine. Someone is going to need to develop that.
Dr. Kris Bryant: What question did I not ask that you really want to answer?
Dr. Bill Gruber: I have a real sense of gratitude to the people who helped me to fulfill a dream to have an impact on public health including Ralph Feigin, Carol Baker, Shelly Kaplan, Martha Yow, Paul Glezen, Peter Wright, Kathy Edwards, Barney Graham. And I am grateful to the many mentors and colleagues during my academic days and at Wyeth (now Pfizer). Each of these people at various points in my career had a formative influence in terms of helping me grow.
I would encourage trainees and junior faculty to take advantage of opportunities to work with experts in the field, and then pay that forward in the context of helping other people grow in this discipline.