Marion Gruber, Changemaker

Marion Gruber, Ph.D., M.S., is vice president, public health and regulatory science, IAVI. She joined the organization in 2022 following nearly 30 years with the U.S. Food & Drug Administration. Credit: IAVI

In 2009, when the H1N1 influenza virus known as swine flu was declared the first flu pandemic of the 21st century, Marion Gruber was serving as Deputy Director of the Office of Vaccines Research & Review at the U.S. Food and Drug Administration (FDA). Swine flu spread extensively, eventually infecting an estimated 700 million to 1.4 billion people worldwide, what was then as much as 21% of the global population, and it changed the way Gruber and her colleagues at the FDA thought about vaccine approvals in response to rapidly spreading pathogens.

The same would be true just five years later in response to an outbreak of Ebola virus in west Africa, which would end up being the largest outbreak of the Zaire strain of the virus ever recorded.

“The 2009 H1N1 pandemic, as well as the large Ebola outbreak of 2014-2016, were both unprecedented, at least looking at my time at the FDA,” recalls Gruber. And that time was substantial. She spent more than 30 years at agency and was appointed Director of the Office of Vaccines Research & Review in 2011.

After growing up in Germany and obtaining a Ph.D. in immunology, she completed her postdoctoral work in the U.S., first at the Oklahoma Medical Research Foundation and then at the Center for Biologics Evaluation and Research at the FDA, where she was introduced to the vaccine regulatory work that would become the focal point of her long and storied career.

Today, Gruber is a world-renowned expert in vaccine development and regulation. She oversaw the review and approval of numerous life-saving vaccines, including the first U.S.-licensed Ebola vaccine, as well as the first vaccines against COVID-19.

It turns out that the H1N1 pandemic and the Ebola virus outbreak weren’t the only serious infectious disease outbreaks Gruber would face while at the FDA. Still at the helm in 2020, she was thrust into the race to develop, authorize, and license vaccines against SARS-CoV-2, the novel virus that causes COVID-19, which went on to become one of the seven deadliest plagues in human history. By applying some of the lessons from flu and Ebola, Gruber and her team were able to prioritize safety and efficacy of COVID vaccines while drastically streamlining the authorization process. It turns out this was truly unprecedented territory, both in terms of the political pressure placed on Gruber and her FDA colleagues, as well as the speed with which the first vaccines were authorized.

In October 2021 Gruber left the FDA and the following year she joined IAVI as Vice President of Public Health and Regulatory Science. I recently spoke with her over Zoom, just days after she recovered from her latest bout with COVID-19, about how the regulatory process evolved during her time at the FDA and what she hopes to accomplish in her role at IAVI.

An edited version of our conversation appears below.

How did the H1N1 influenza pandemic change the way you viewed flu vaccine licensure at the FDA?

When the H1N1 virus started to circulate in the Americas in 2009, we saw a rapidly rising number of cases. We knew that this H1N1 influenza virus was sufficiently different in terms of its virulence from the H1N1 strains we put in the seasonal influenza vaccines, thus, the public health agencies were on high alert, and so was the public. So, we talked to the vaccine manufacturers who had licensed seasonal influenza vaccines and they said they were willing to develop vaccines against this strain, but we all realized that it had to be done quickly. Modeling at the time had shown that there may be a big wave of disease by the fall of 2009 and so we had to get these H1N1 vaccines out as fast as possible.

What helped us was the approach we used to license seasonal influenza vaccines. The influenza virus changes so frequently that we have to adjust the seasonal vaccines on an annual basis to try to match the vaccine strain to the wild-type strain that is circulating. We do this by a mechanism that we call a strain change. Licensed influenza vaccine manufacturers already have accrued safety and efficacy data with their original products. So, as regulators, we say that in order to update the vaccines they only have to provide manufacturing information for the new strain and then we can license these vaccines without any new clinical data. And that, of course, accelerates the availability of these products.

At the FDA, what we decided was that we could use this same process with the H1N1 vaccine because it consisted of the same influenza A subtype (H1N1) included in the seasonal vaccine. So, the vaccine manufacturers made these monovalent H1N1 pandemic vaccines and we were able to release them by September of that year. This illustrated that having a proven platform and regulatory approach for making these vaccines dramatically accelerated authorization of a new vaccine specific to this pandemic strain.

What about when the Ebola outbreak occurred in West Africa? What allowed the FDA to act quickly then to allow companies and organizations to proceed with safety, immunogenicity, and efficacy trials and eventually license the first vaccine against the Ebola virus?

When the Ebola outbreak happened in 2014, there were no licensed vaccines because the previously sporadic outbreaks of the virus didn’t really stimulate enough interest by vaccine manufacturers to develop vaccines and see them through the licensure process. However, there were a couple of candidates in development that were licensed by the NIH and by the Public Health Agency of Canada, which had early preclinical data indicating that their vaccine protected monkeys against challenge with Ebola virus. So, when the West Africa Ebola outbreak began in 2014, two vaccine manufacturers took over the development of these two vaccine candidates — one was Merck and the other was GSK. The Merck vaccine was the one that we eventually licensed.

We recognized that people were dying and falling ill and so we decided we really needed to look at creative clinical trial approaches to demonstrate vaccine safety and efficacy to support licensure of these Ebola vaccines given the public health emergency that was unfolding, and so many entities came together and did Phase I safety studies with these two vaccine candidates. Then the WHO [World Health Organization] started the ring vaccination study in high-risk groups of people who were close contact to people diagnosed with Ebola and this is what eventually demonstrated efficacy of the Merck vaccine. We started reviewing the efficacy data at the FDA before we even received the complete license application from Merck. This close collaboration between public health agencies, vaccine manufacturers, and regulators was how we were able to license this vaccine.

Then comes COVID-19. What lessons from these experiences with H1N1 and Ebola were you able to apply to rapidly authorize the first vaccines against SARS-CoV-2?

I think one of the lessons learned from the Ebola outbreak, and even the H1N1 pandemic, that served us well during COVID was the idea that we could accelerate trials using seamless designs rather than applying discrete stages of clinical development. We didn’t do discrete stages of product development during COVID. Rather, we just expanded Phase I trials directly into Phase II trials and then expanded those into these large Phase III efficacy studies. In addition, in some cases, we could even forego some preclinical trials if the vaccine candidate was based on an existing platform technology.

That of course worked well in 2020 because cases of COVID were rising so rapidly and many people wanted to participate in these studies, which meant they accrued COVID cases rather quickly and this allowed them to determine the efficacy of these products within really compressed clinical timelines. At the FDA, we all worked around the clock reviewing data and providing advice and guidance and again and again regulators across the globe came together to align on requirements for authorization and licensure of these products.

We were also under a lot of political pressure given 2020 was an election year in the U.S. Usually when you do a clinical study, the FDA requires six months of safety follow up of subjects enrolled in clinical trials. But we knew from decades of vaccine regulation, that adverse events that are truly attributable to the vaccine usually occur within the first six to eight weeks post vaccination. This was why we were able to require two months of safety follow-up for at least half of the volunteers in the efficacy trials of COVID vaccines in order to consider an emergency use authorization. We had to balance the gravity of the public health emergency with having enough safety and efficacy data, and this eventually pushed the vaccine authorizations past election day. But this had nothing to do with politics. It was just that the clinical trials were not advanced enough that we could say we had enough safety data before that time.

With COVID, there was also the benefit of Operation Warp Speed, which help tremendously in de-risking the manufacturing process and investment for the vaccine manufacturers.

Does all of this make you confident that when the next outbreak occurs, we will be more prepared?

Well, I think if you look at the situation with Ebola and COVID, there is an important lesson there. We can’t stop working on a pathogen or a related pathogen because the outbreak is over. Some groups are still working on developing broadly protective coronavirus vaccines, but there must be political will to invest the resources needed to really be better prepared.

We also need to invest in technologies now that will benefit us during the next outbreak. The mRNA technology that served us so well during COVID didn’t come overnight. There were decades of research leading up to that. Beyond that, we also have to investigate more modern approaches to clinical trials, including these seamless studies, as well as other new methods. There is also a need for continuous global collaboration.

What is your focus now that you are at IAVI?

I think the COVID pandemic showed us how to collaborate to develop vaccines fast. But, at the same time, I think it was also a very bad model because there was such inequity in making these vaccines available. And to make a long story short, I was bothered by this inequity and that was one of the reasons I came to IAVI.

We need to make sure that if there is a public health emergency that vaccines are going to be made available for everybody and not just a few privileged, select parts of the global population. That is why IAVI’s mission really spoke to me and so I wanted to lend my regulatory expertise to making these emerging infectious disease vaccines available for under-resourced countries. This means heading up the regulatory science program here, but also wearing a public health hat and working as an advisor with various groups and regulators across the globe. Global collaboration really is key to making a difference. We’re not going to change the world all at once, but perhaps in one country at a time, or even one region at a time, we can make a difference.

To learn more about her life and career, watch Marion Gruber: Preparedness is Prevention, a short documentary produced by the Vaccine Makers Project.