Leading Pfizer Scientist Answers Key Vaccine Questions

John Whyte, MD; William C. Gruber, MD

Disclosures

August 05, 2021

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JOHN WHYTE: The COVID pandemic has infected more than 35 million Americans, resulting in over 600,000 deaths. The vaccines, developed in record time, are helping to curb the pandemic. And hopefully, we'll end it soon. Yet millions of Americans are skeptical. They seem to have been developed too fast. The side effects are serious, might be risky. Maybe you just don't know who to believe.

I had an opportunity to sit down with Dr. William Gruber -- he's Pfizer's senior vice president of vaccine clinical research and development -- to address these very issues, as well as answer the questions that are on your mind.

Dr. Gruber, thanks for taking the time today.

WILLIAM C. GRUBER: My pleasure to be here.

JOHN WHYTE: I want to start off with, why did Pfizer choose an mRNA technology for a vaccine development program, where history had shown that many vaccine development programs that used mRNA had failed? And we're talking about a pandemic.

WILLIAM C. GRUBER: Yeah. So it was clearly an ambitious undertaking. But it was driven by a need to develop a vaccine in record time. It was recognized at the time of the first wave of the pandemic that this would likely not be the last. And so speed was of the essence to deliver a vaccine in an unprecedented period of time, by December of the same year in which we started.

The relationship we established with by BioNTech and Pfizer occurred in March. And we were solving to develop a vaccine by the end of the year.

JOHN WHYTE: Did you consider other technologies, or pretty early on, you felt this was the way to go?

WILLIAM C. GRUBER: Yeah, pretty early on, we decided this is the fastest way to go. And it's really borne fruit. When you look at the other types of technologies out there, vector-based technologies also we're fairly rapid, but subunit or protein-based technologies have lagged. And we still don't have, at least in the United States, a licensed vaccine using that more conventional approach.

JOHN WHYTE: But Dr. Gruber, this should be a story of innovation in terms of how you brought a vaccine to market in record time. But many people are saying it's too fast. And that's contributed to vaccine hesitancy. So can you walk us through the steps that allowed you to develop it, as you describe, in record time?

WILLIAM C. GRUBER: Yes. I think it's important for the public to understand we took no shortcuts regarding our ability to demonstrate that the vaccine was likely to be safe and effective when applied to the population at large. What was really done was to remove a great deal of the white space that typically exists between each stage of development.

So we worked very deliberately in phase one to assure ourselves in small numbers of individuals about the safety of the vaccine and that we were getting the right sort of response that would be associated with protection. But we removed what typically are these intervening periods where we would go back and forth with regulatory agencies in decision-making and review of documents. It's a real credit to the regulatory agencies that they basically worked with us in real time, removing some of the typical periods that are required for that type of review.

So no shortcuts. We worked through deliberately until we were confident about the safety and immune response. And then we expanded quickly to a large-scale trial where we continued to collect safety information as well as information about the efficacy of the vaccine.

And I should say, we still do that. Post-licensure, we continue to look at information that we're getting from our trials and from the population at large to give us confidence and give the public confidence about the safety profile.

JOHN WHYTE: So these vaccines, as you know, are authorized by the FDA under an emergency use authorization, which is allowed under a public health emergency. You talk about the data and how the data has been convincing. Why aren't these vaccines fully licensed, a BLA [biologics license application], by the FDA? Some experts, such as Dr. Topol, have said it's contributing to vaccine hesitancy. I'm not sure if that's the case, if that's why people are holding out. But why aren't they fully approved?

WILLIAM C. GRUBER: Yeah. So I think the process of approval is a very deliberate one in which the FDA is obviously interested in gaining as much safety information as they can and as much efficacy. And of course, it probably makes some sense to talk to the FDA themselves about their perspective.

But it was quite clear that for essentially all vaccines, there is interest in having not only a large population for which you've got safety data, but also prolonged follow-up in that population. And so recognizing that we had to do things to solve for, one is getting a vaccine out to the public as soon as possible while still assuring safety.

The FDA reached a point where they recognized, OK, we will accept 2 months of follow-up for a significant proportion of the population for the safety assessment as a basis for emergency use. But as for other vaccines, we still want 6 months of follow-up to basically guarantee that there are really no longer-term effects.

Now, I think the data that we already have indicates -- and of course, this has now been submitted for the BLA -- is that, in terms of tracking for adverse events, the likelihood that you would see it only at 6 months and not see it at 2 months is very remote. But nonetheless, the FDA has chosen, and I think appropriately, to just provide the greatest confidence possible that they have followed both short-term and long-term to assure a safety profile. And I think we're confident with the data that's now been submitted for BLA, which the FDA now has under review, that the safety profile will be confirmed.

JOHN WHYTE: But can you see how it can contribute to vaccine hesitancy, because we're saying it's safe and effective, but then we're saying, oh, wait, we want to look at more data? Do you see the confusion that may result?

WILLIAM C. GRUBER: Well, I think the public should be reassured that it's not only the clinical trial data that's being examined. We've now, I guess across the world, across all vaccines, given over, I think, 3 billion doses and many hundreds of millions of doses now for the Pfizer vaccine itself. So that in itself lends itself to reassurance because the CDC, ourselves, other regulatory bodies, are basically monitoring that data in real time.

So now you've got hundreds of millions of individuals who have the opportunity to report back any sort of safety event. So you can look for those rare circumstances you otherwise can't pick up in clinical trials. And to this point, it's been clear that when one looks at all the potential adverse events associated with the vaccine versus the benefits, the CDC continues to come forward and recommend that everybody, at least in the case of the Pfizer vaccine, 12 years and above receive the vaccine.

JOHN WHYTE: Let's talk about some of those myths out there that are contributing to people's hesitancy. And two of the biggest myths -- let's start with the first one, is it changes your DNA. So Dr. Gruber, what can you say to people who believe it changes your DNA?

WILLIAM C. GRUBER: Yeah. So the first thing is that it does not change your DNA.

JOHN WHYTE: How do you know? That's what people are going to say: “How do you know?”

WILLIAM C. GRUBER: What evidence do we have for this? Well, first, mRNA basically is contained within the cytoplasm. So it doesn't get into the nucleus where the DNA resides. Secondly, there's no mechanism, either based on the host or the mRNA that's making its way into individual cells, for it to integrate.

So I think we have great confidence that there is no real risk there for integration. And we continue to obviously monitor populations for safety. There's been no evidence to suggest that there is a risk.

JOHN WHYTE: Let's talk about the other big myth: issues of fertility. And ACOG, or the American College of Obstetrics and Gynecology, put out a note that said women of reproductive age or even women that are lactating should not be denied access to the vaccine. Some people will say that's hard to understand exactly what that means. So what's the data that we have on issues of fertility and mRNA vaccination?

WILLIAM C. GRUBER: So to date, we've not identified, nor would we expect any impact on fertility. There's no basis in terms of our understanding of the construct that would be associated with a fertility risk. Some have pointed out that there may be some similarity between a protein that exists in the placenta versus the vaccine. But that similarity is small. And the peptide is very small. So there's no real even theoretical risk that should rise to the level of individual concern, in addition to which, we now know that, again, with the hundreds of millions of people that have been vaccinated, pregnant women have, in fact, been vaccinated.

The CDC has tracked that and has seen no evidence of either adverse outcomes of pregnancy associated with the administration of vaccine nor, in terms of the population at large, any evidence that fertility has been affected. And our own data reflects that. Pregnant women as well as women that are lactating after pregnancy should feel comfortable and reassured that the safety profile supports that they should be vaccinated, and particularly given that pregnant women have a likelihood of more severe disease if they get COVID-19.

JOHN WHYTE: For vaccines in general -- you've been studying vaccines for a long time. How much data is enough? You kind of referenced that normally, we like to see 6 months. But approval was based on 60-day fully immunized. Do we know how much data is enough?

WILLIAM C. GRUBER: Yeah. So I think the data that's been provided was enough for emergency use authorization. It will be enough for a BLA. But we will continue to be able to collect data to reassure ourselves and the public about the safety of the vaccine.

JOHN WHYTE: And in the history of vaccine development across different disease states, typically when we see serious adverse events, it is in those first 60 days, correct?

WILLIAM C. GRUBER: Yes. I think in most circumstances, we typically see them -- and in fact, many of them occur very proximate to vaccination, well before the 60-day period. So the likelihood, as I said before, that we would see anything that we have not picked up in the first 2 months, between 2 and 6 months, is remote.

JOHN WHYTE: Dr. Gruber, let's talk about what's on everyone's mind: boosters.

WILLIAM C. GRUBER: Yeah.

JOHN WHYTE: And there's been some conflicting information -- I'm just going to put it out there -- in terms of what we're hearing. But let's take a step back. I need to ask you: How long does immunity last from the vaccines?

WILLIAM C. GRUBER: Yeah, so we're still learning, frankly, how long immunity lasts. I think we can be reassured that in almost all circumstances, individuals that are hospitalized are in fact individuals that are unvaccinated. And the deaths almost exclusively seem to be occurring in individuals that are unvaccinated. And that's even in the setting of this new Delta variant that's created concern.

So I think the nature of the efficacy that we're seeing in the population at large provides some confidence that, in fact, the protection is durable. We have some data, in fact, that shows, even though antibody is declining, that the efficacy does not seem to decline at the same rate.

Now, how long that will continue is a reasonable question. So we need to answer it in two ways as to whether or not a booster would be required. First of all, can a booster restore a level of immunity like that seen after the first two doses? And so that's one of the things that we're exploring now actively with clinical trials, to look at a third dose to see what happens in terms of our ability to generate an appropriate immune response.

And can we do that safely? And I think we've reported publicly that, in fact, we are seeing a boost in that antibody response. And in fact, we are seeing that the safety profile looks very similar to what we saw after the second dose. So I think that's one piece. Can you do it?

Now the question is, when do you do it? And again, the data that we're hearing about, some of which I just referenced in terms of what's happening with the overall efficacy and where the breakthrough cases might be occurring, will help us learn better when an appropriate boost might occur.

And here again, we're not solely waiting for what occurs out in the population at large. We're also conducting a study of now 10,000 individuals, half of whom received the original two doses of the vaccine as part of our pivotal trial, and the other half will get a third dose. And we'll be able to compare those groups -- that group that's now farther and farther out from their original two doses of vaccine versus the newly third dose-vaccinated group -- and see: Is there really a benefit to be gained? And how much is it? And when does it occur in those that are vaccinated?

JOHN WHYTE: Do you expect that those persons that are immunocompromised will likely need a booster?

WILLIAM C. GRUBER: Yeah. I think if you were going to pick a population that would be most likely to fall in that category, it would likely be the immunocompromised because as you say, there is some data suggesting that two doses is not yielding the same level of antibody response, which again, we don't know that is the antibody itself that's so critical. But it does serve as a marker, along with all the other goodies -- the cell-mediated immune response, the memory that comes along with it -- to give us some indication of what might be required.

And so we're actually very much in support. And we've obviously communicated with the NIH [National Institutes of Health] about their plans. We have our own plan for studies looking at immunocompromised populations to better tease out what the best approach to those populations would be.

JOHN WHYTE: What do you say to those people that did get COVID, survived, and say, I don't need to get vaccinated, or maybe I just need one shot because we do know tens of millions of people have not come back for that second shot? What's your message to them?

WILLIAM C. GRUBER: Yeah. So again, there's data beginning to accumulate that I think supports that the level of efficacy seen with natural infection is well below that that's associated with vaccination. And I think that will help convince individuals.

But the CDC and others who have clearly recommended, whether or not you've had infection in the past, it's recommended that you receive the vaccine. And I think that's good advice.

JOHN WHYTE: What about this issue of interchangeability? We're not seeing it here in the United States. But some other areas of the world where there still are some shortages, even in Canada, you might get Pfizer the first time and Moderna the second time or vice versa. What are your thoughts on that?

WILLIAM C. GRUBER: Yeah. So from our perspective, of course, our emergency use authorization and what we're authorized to represent is two doses of the Pfizer vaccine. And we think that's important for protection. However, we welcome the fact that others are looking at the potential for interchangeability of vaccines to try to determine what might be the best regimens for the particular circumstances at hand in relationship to vaccine supply issues, et cetera.

So I think from our perspective, the best approach that we can stand behind now, based on the data that's available, is two doses of the mRNA vaccine where we have 95% efficacy.

JOHN WHYTE: But most experts don't recommend it. If it's something that has to be done, there's not objection to it, correct? But it's not something that should uniformly be done until we have more data, is that correct?

WILLIAM C. GRUBER: Right. I think the notion is, everything that we do -- and this is something I think we take great pride in at Pfizer -- everything that we do should be evidence-based. So you don't want to be too soon, nor do you want to be too late. You want to be able to gather the information as quickly as possible to make informed decisions and let that guide your judgment.

JOHN WHYTE: That's good advice. Dr. Gruber, thanks for taking the time today.

WILLIAM C. GRUBER: OK, thank you.

This interview originally appeared on WebMD on August 05, 2021

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