Opinion | Faust Files: What Comes After mRNA? Vaccines of the Future

In this video, Jeremy Faust, MD, editor-in-chief of MedPage Today, discusses new vaccine technologies and their impact on future vaccination strategies with Peter Hotez, MD, PhD. Hotez is dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston, and a co-creator of Corbevax, a protein-based COVID vaccine designed to achieve global, low-cost scalability.

The following is a transcript of their remarks:

Faust: Hello, it’s Jeremy Faust, medical editor-in-chief of MedPage Today. Thank you so much for joining us today.

We are going to be speaking with Dr. Peter Hotez, the dean of the National School of Tropical Medicine, and professor of pediatrics and molecular virology, at Texas Children’s [Hospital] Center for Vaccine Development at Baylor College of Medicine.

Dr. Peter Hotez, thank you so much for joining us.

Hotez: It’s great to see you, Jeremy. It’s fantastic.

Faust: Likewise. Let’s talk about the White House next-generation vaccine summit, which you just attended and got back from. What did you learn there?

Hotez: Well, I think it was really to kind of begin the long process of making a game plan for the nation, and globally, what we do about vaccines. I think there are long-term issues, and I think there are short-term things we need to think about. I think in the long term, there’s a lot of enthusiasm for building next-generation, universal coronavirus vaccines, and a number of groups have now proposed interesting concepts for that, including our group.

We’re also, in addition to our COVID vaccine — about 66 million doses have been given in India — we’re also interested in a universal coronavirus vaccine, as well as the potential benefits of alternative delivery platforms like intranasal vaccines or vaccines delivered on a skin patch.

So that’s the big picture. Then, the question is whether there will be the adequate funds to actually support that either through NIH or BARDA [Biomedical Advanced Research and Development Authority] and other mechanisms. Then if so, what kind of timeframe are we talking about? I offered that I can’t imagine those vaccines would be ready any time before 2024. Others said that was optimistic and we’re probably looking at 3 to 5 years. Then my good friend, Eric Topol, was more optimistic; he thought the fact that now, at least for the intranasal vaccine, some of them are in phase II or III trials and we can move even faster. So [there are] some differences in perspective on how quickly that can mobilize.

But I said, ‘Look, no matter what, you’re still going to need an interim strategy.’ That’s also missing, because the only thing really being discussed right now is a bivalent booster; an mRNA booster where one RNA is to the original lineage and the other is to BA5. I’m not very enthusiastic about that kind of bivalent booster because I think, by the time it’s available in the fall, BA5 may be behind and we could be dealing with something else.

So I’ve said that I think we need another type of alternative booster strategy, one preferably where we could boost, and then we would have a year or two of protection because that’s ordinarily what we’ve come to expect from boosters before COVID, right? You know, you vaccinate your kids with a series of primary immunizations, you wait 6 months to a year, and then you get protection for 5 to 10 years.

That’s what we should be expecting, but it’s not happening with the mRNA technology. Whether it’s purely because of the technology or whether it’s because of all of the antigenic variation from these COVID subvariants, I don’t think we know, but I think we need to put a program in place where we look at alternative boosters, even including our vaccine [Corbevax] as well. So those were kind of the big picture discussions.

Faust: I think the thing that I’m interested in the most right now is that sort of pipeline for this new technology, or these new technologies. I myself am impatient and I have the sense that everyone else is as well. They say, ‘Look, we had Operation Warp Speed, no one had ever seen an mRNA vaccine go to market or be available, and then within the calendar year, we did it.’ And they’re working great for their stated purpose.

Why the longer timeframe now for these other technologies, which as far as I’m concerned, we have done mucosal vaccines before, that’s not new, so why the longer runway?

Hotez: Remember, making a COVID vaccine, in terms of low-hanging fruit or difficult vaccines, a coronavirus vaccine is relatively straightforward, right? You get enough virus neutralizing antibody to the spike protein or its receptor-binding domain, you get memory B-cell and T-cell responses, and you’ll have a vaccine. That’s why there are multiple ways to skin the cat. That’s why our vaccine works, why mRNA vaccines work, why adenovirus-vectored vaccines work.

The issue around the universal and the mucosal [vaccines] are two separate issues. With universal, since you can never anticipate all of the different coronaviruses that are out there, you have to find a way to get broadly neutral antibodies that are broadly neutralizing, and we’ve learned from HIV/AIDS that that’s easier said than done.

We have a strategy where, for instance, we’ve made the SARS-1 and SARS-2 equivalent of our COVID vaccine, as well as some others, so by combining them in a polyvalent strategy, we think that’s one way to go. Others, like the group at Caltech, have been working on trying to put multiple epitopes on a single particle, and it’s a really cool idea. The question is, can you do it at scale up and can you do it under a quality control, to control the stoichiometry of how many molecules of each go on, so there are some technical complexities there.

With mucosal delivery and skin patch, those ideas have been around for decades. I mean, when I was getting my MD/PhD a hundred years ago, we were talking about that. But the actual number of licensed vaccines that have gone through the gauntlet that actually do mucosal delivery — I mean, there’s FluMist — there are not many things out there, so, a lot of good ideas, a lot of cool concepts, but not nearly as much successful product development. That’s the reason for the more cautious timeline.

Faust: Anyone under [age] 50, I think, does maximize their benefit after two, maybe three, [COVID vaccine] doses.

For anyone over 50, the way I see it is you have to stay up to date because you might not get hospitalized for COVID pneumonia, but you might get hospitalized for something else.

Hotez: The only asterisk I would put on that statement is a lot of times we have the data first on those over the age of 50, and that becomes the tip of the spear. Then only later on do we learn about what’s happening under 50. So I’m still supportive of universalizing. Anyone who wants to get a second booster should go ahead, given the fact that we’re throwing away a lot of vaccines anyway. Better to use it rather than lose it.

Faust: Okay. Rather than do a journal club on that, what I would ask is, given that that is your opinion, do you think that someone who’s hearing that message, who’s 20, 30, or 40 years old, should get a second booster now, here it is late July [when this interview was done]? Or should they wait for the bivalent, which is probably going to be available in 8 weeks, and they certainly wouldn’t want to miss out on this better protection, if that’s how you read the literature.

Hotez: I still don’t think it’s a slam dunk that those new vaccines are going to come out. Because what happens if by — let’s say it’s 8 weeks, which is a pretty optimistic timeframe — let’s say it’s October/November, and BA5 is long gone. Are the ACIP [CDC Advisory Committee on Immunization Practices] and CDC going to still recommend it? I don’t know.

So I think there’s too much of an unknown, and now BA5 is accelerating, so if you’re going to do something as an intervention, I think now is the time to do it. I think BA5 may be way past us based on the history of other variants.

Faust: Right. And the question, which we can’t know the answer to, is what’s going to replace it, something similar or something completely different? So there’s always a bit of a gamble to any approach at this point. You can’t know.

Hotez: And that’s why I think we need a longer-term strategy that looks past mRNA to see if there are other technologies that we could boost with now that will give us more durable protection while we’re waiting for the universals, and the mucosal deliveries, and everything else.

Faust: Right. This is the promise of the sort of pan-vaccine/multivalent vaccine. Right now, we’re looking at the bivalent boosters, but I mean, I don’t think anyone’s looking at the question of a bivalent primary series or a polyvalent primary series. If they are, I certainly don’t think we’re going to have a change at the policy level anytime soon, do you?

Hotez: Well, I mean, that could wind up being what the universal coronavirus vaccine is. And then how would that work on a background of people who got immunized with the original COVID lineage? I think that is an unknown.

Faust: Dr. Peter Hotez — by the way, your book Preventing the Next Pandemic: Vaccine Diplomacy in a Time of Anti-Science; I am midway through it — it’s a very interesting book about your life as a scientific envoy and a longtime vaccine advocate. Not late to this fire; early on, you’ve been on this. I recommend it to everybody, and thank you so much for joining us.