A 60-Year Quest for An RSV Vaccine: A Conversation with Dr. William Gruber

For Dr. William Gruber, the development of an investigational vaccine for RSV (Respiratory Syncytial Virus) is deeply personal. Dr. Gruber, Senior Vice President of Pfizer Vaccine Clinical Research and Development, has been at the forefront of researching the virus since his days as a medical school student in Houston.

Each year, approximately 177,000 adults 65 years and older are hospitalized with RSV, and it is estimated that 14,000 die in the United States due to the virus.[1] Recent hospitalizations of children with RSV have spiked to levels not seen in years in the U.S.[2]

For many years, Pfizer has been advancing RSVpreF, a novel vaccine candidate for RSV. Based on late-stage trial results for adults 60 years of age and older, the company submitted an application for RSVpreF for the prevention of lower respiratory tract disease caused by RSV in this population and received priority review from the U.S. Food and Drug Administration (FDA), which reduces the standard review period by four months. The FDA is expected to make a final decision on whether to approve the vaccine candidate by May 2023. Pfizer also recently announced top-line results from its Phase 3 clinical trial of the RSVpreF vaccine candidate administered to pregnant individuals to help protect their infants. The company plans to seek regulatory approval from the FDA for this population by the end of 2022.

Investor Insights recently spoke to Dr. Gruber about RSV and the moments of serendipity that led to the development of the vaccine candidate. The conversation has been edited for length and clarity.

Investor Insights: Tell us about the recent history of RSV.

Dr. William Gruber: The story began in the 1950s. It was recognized for a long time that children were being hospitalized with a respiratory condition called bronchiolitis, but it was only in the 1940s and ’50s that it became possible to cultivate viruses successfully. It wasn’t until the mid-1950s that the pathogen was successfully isolated and named Respiratory Syncytial Virus.

Dr. Paul Glezen, who worked at a large Houston hospital affiliated with Baylor College of Medicine, said, “Well, wait a minute. Not every child gets bronchiolitis, but a lot of children get RSV. In fact, all children by the time they’re two years of age have had RSV at least once. So why is it that some children end up in the hospital while others don’t?”

Dr. Glezen thought it might depend on the quality of the children’s antibodies. So, he started to examine whether mothers who pass on more of the antibodies that neutralize the virus are able to protect their children, versus mothers who aren’t able to pass on that antibody to their infants.

Investor Insights: You worked under Dr. Paul Glezen during your residency. Is that what sparked your interest in respiratory viral pathogens?

Dr. Gruber: I was a medical student and then resident at Baylor College of Medicine. At that time, Baylor hosted a Houston maternity hospital that had about 23,000 deliveries a year including high-risk populations. Houston’s main hospital serving these newborns, Ben Taub, was across town.

While I was at Baylor, Paul Glezen had a great idea. If he could get cord bloods at the time of delivery, he could identify the amount of the RSV antibody mothers passed to their infants. Then, he could look and see what babies get hospitalized with bronchiolitis and thereby determine the relationship of the antibody to the condition. If moms pass on a lot of antibodies, is their baby less likely to end up with bronchiolitis?

When an infant was hospitalized with bronchiolitis, it became my job to help identify cases and notify Dr. Glezen. Paul could then track and match their cord serum, which would determine how much antibody they had, prior to being hospitalized. With this data, the investigative team could demonstrate that children who inherited a lot of antibodies weren’t often hospitalized, while those with low antibodies were. This suggested that if we could duplicate the levels of maternal antibody that reduced infection, we could create a treatment that provides similar protection.

That experience, among others, got me interested in pediatric infectious disease research.

Investor Insights: Your collaboration with the immunologist Barney Graham played a significant role in the discovery and development of an RSV vaccine. Can you explain the research breakthrough that advanced this development?

Dr. Gruber: Barney and I were roommates at Rice University. He went off to Kansas, got his medical degree, and ended up at Vanderbilt University. He was a groomsman at my wedding; I was at his wedding. We carried on the usual pleasantries of life. Meanwhile, not knowing at all what the other was doing as we moved along with our careers. One day, I go to a conference to present on RSV research, and I’m putting up a scientific poster. I see Barney Graham, right next to me, also putting up a poster about his RSV work.

My life continues to intersect at times with Barney. In 2013, he was locked out of his office at the National Institutes of Health because of a government shutdown. He said, “Well I’m locked out of my office, I might as well go up and see the foliage in the Northeast.” I get a message from Barney, telling me he’s in my area and asking to get together.

He comes over for dinner and I say, “By the way, Barney, I saw in Science magazine in April 2013 that you’d managed to crystallize the structure of the pre-fusion form of the F protein.”

Investor Insights: How did the ability to model that protein lead to the breakthroughs behind the RSV vaccine?

Dr. Gruber: Before the fusion protein attaches to the cell, it exists in a different state. The neutralization targets it expresses in this pre-fusion form are ostensibly different. Your goal is to intercede at that point, not after it attaches when it’s in a different form.

I said to Barney, “This has the potential to be a breakthrough.”

At that point, the protein wasn’t stable enough to withstand what we thought was needed, so we improved the construct further. Also, there are two subgroups of RSV, an A and B subgroup. We further improved the model by including both the A and B subgroups, making it a bivalent vaccine. And that’s the vaccine candidate that, between 2013 and today, we progressed through preclinical studies.

Investor Insights: Pfizer is currently the only company with an investigational vaccine for both older adults and infants, via maternal immunization. Can you speak to why it’s important to address both at-risk populations?

Dr. Gruber: We recognized we had two routes to develop this vaccine candidate. One was maternal immunization. That’s what got me in this business in the first place, trying to help protect babies less than six months of age against RSV. These infants are most likely to be hospitalized, most likely to end up in the ICU, and most likely to die worldwide.

At the same time, we recognized that after influenza, this is the next most common cause of potentially serious lower respiratory illness for older adults. So now we had a two-fer: an RSV pre-fusion F vaccine that could potentially generate sufficient antibody response to help protect both older individuals and infants.

It’s a wonderful story of perseverance with countless people. And here we are today, on the cusp of potentially protecting vulnerable older adults and infants against RSV lower respiratory tract disease (if approved), after a more than 60-year quest.

[1] Respiratory Syncytial Virus in Older Adults: A Hidden Annual Epidemic, A Report by the National Foundation for Infectious Diseases, September 2016

[2] Centers for Disease Control and Prevention. “Increased Respiratory Virus Activity, Especially Among Children, Early in the 2022-2023 Fall and Winter.” Accessed 12 December 2022.

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