Working Towards A Universal Flu Vaccine

Each year, you need a new influenza vaccination to protect against the ever-changing seasonal flu virus. Then there's more exotic influenza variants such as swine flu and avian flu. Gary Nabel, director of the Vaccine Research Center at the NIH, discusses the ongoing quest to develop one vaccine that could protect against all influenza variants at once.

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This is SCIENCE FRIDAY. I'm Flora Lichtman, filling in for Ira Flatow, who's out today. This week, the FDA approved a new influenza vaccine for this year's flu season, and soon enough summer will be over and you'll be standing in line again at your pharmacy or doctor's office, participating in that yearly ritual - your annual vaccination allocation.

But what if that didn't have to happen? Imagine a world without the seasonal flu shot. What if one shot could protect you against flu forever and protect you against all flus, including avian flu and swine flu?

Well, you'll have to keep imagining for a while yet because there's no universal vaccine, but researchers are working on it. And joining me now to talk about the effort is Dr. Gary Nabel. He's the head of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases - that's part of the NIH - and he's co-author of a paper this week in the journal Science Translational Medicine on the topic. Welcome to the program, Dr. Nabel.

GARY NABEL: Thank you.

LICHTMAN: So what's the difference between a universal vaccine and the one that I get every year?

NABEL: Well, an ideal universal vaccine would be one that would be similar to a childhood vaccine - for example, like a measles vaccine that you might get early in life, and that would then give you protection against all flu viruses that you might ever see in a lifetime. That's an aspirational goal. We may not get to a completely effective vaccine like that.

But another option would be to maybe get a vaccine once every five years or once every 10 years. The idea either way is to expand coverage so you don't have to go in for a yearly shot.

LICHTMAN: And would they work differently? Is the mechanism different?

NABEL: Well, yeah, there might be subtle differences in that something that's truly universal would need to target something that is very constant and unchanging in the virus and something that would be accessible to our immune systems. And in an ideal world, if we could target the vaccine to those kinds of structures, and we see those in the virus, then we'd have our universal vaccine.

But we may not be that lucky. We may end up not being able to get a clear shot at something that's completely (unintelligible) and if that's the case, we would redirect it to the parts that we could see, and then you might have a little bit of escape every once in a while, and so they would be targeted to different regions.

LICHTMAN: Give me a rundown of virus anatomy. What are we actually targeting with these vaccines?

NABEL: Well, there are different targets that various scientists are studying for universal flu, but the one that has gathered the most interest is the one that we call the hemagglutinin, which forms part of the outer spike of the virus. The spike is really the part that attaches the virus to the cell that it's going to infect, and so by interfering with attachment, you prevent the infection entirely.

LICHTMAN: And is that the H for H1N1, for example, is that where that hemagglutinin, is that how it manifests the name?

NABEL: Yes, that's right. When you talk about the H and the N terminology, the H refers to the hemagglutinin, the N to the neuraminidase.

LICHTMAN: So it interferes with the spike, and this is something that you're working on, right?

NABEL: Correct, yes.

LICHTMAN: How does your - your vaccine has two parts. Walk me through them.

NABEL: Well, the approach that has proven successful in our hands is to essentially deliver a one-two punch with our vaccine. We prime the immune system by using a genetic vector that delivers the hemagglutinin in isolation into the muscle.

Once that DNA is introduced into the muscle, it just makes the viral hemagglutinin and induces an immune response to it.

LICHTMAN: Let me jump in right here because this part I really want to understand. So you put DNA into our bodies, and then what happens exactly on the cellular level?

NABEL: Well, the DNA is taken up into the muscle, and essentially the muscle becomes the manufacturing plant for the hemagglutinin. It actually uses the genetic instructions from the DNA to make the hemagglutinin on the surface, and so essentially you're using the body's machinery to present the foreign antigen to the immune system.

LICHTMAN: It reads these foreign blueprints then.

NABEL: That's right, that's right, and we essentially within the DNA give the instructions for that cell to read out the viral protein.

LICHTMAN: OK, so you put the cell to work, and then what happens? What's the second stage?

NABEL: Well, then after a few months, we come back and we boost the immune response, and we can do that in one of two ways. We can actually inject the standard inactivated vaccine, the one that you and I get every year in our flu shot, or we can also do it by using a different type of carrier, a viral vector, an adenovirus, that can do the same thing.

In our human studies, we've actually done it with the standard flu vaccine.

LICHTMAN: And these antibodies are responding to the conserved part of that hemagglutinin, is that right?

NABEL: Well, when we generate the immune response to the hemagglutinin, we actually do generate antibodies to the entire hemagglutinin. But within the spectrum of antibodies that are made, are these antibodies to the highly conserved region to the - this region that is on the base of that spike, we call it the stem, and that's a region that has been identified by others previously to be highly conserved and susceptible to antibodies that are directed to that particular region.

LICHTMAN: How do you know when a vaccine is ready for primetime, that it's effective enough, I guess?

NABEL: Well, we do things in stages. With all vaccines, we look initially in small-animal models. Then we look in the animal models that are most relevant to the human disease. In the case of flu, it's a ferret model. And then we also will look at some of the immune responses in monkeys.

And when we see that we're getting the kinds of desirable immune responses that would give us improved potency, improved breadth, the kind that we see with these anti-stem antibodies, then we begin to take those steps to test them in people.

LICHTMAN: Are there variations from person to person about how effective a flu vaccine is, or is it more targeted toward the virus? That is, if it works on the virus, it's going to work for all people.

NABEL: That's a great question. There are differences from one - certainly there are differences from one virus to another. In fact, the flu virus makes its living by essentially getting a makeover every year so that the immune system won't recognize the new virus that it recognized the year before.

But having said that, there is variability in the population in terms of how well any one person responds to a given vaccine. In some cases people may be taking medications that could blunt their immune responses. In other cases there can be genetic differences in terms of how well you respond to a particular foreign protein.

So there is variation in the human population, and that in fact is one of the challenges for developing vaccines for broad use.

LICHTMAN: How has technology changed the way that vaccines are made? Is it easier to sort of see responses in living things as they happen now?

NABEL: Yes, the technology has improved by leaps and bounds. We have, in the case of influenza, now a variety of different ways that we can read out virus neutralization. The traditional way was done using red blood cells, and we would look at the clumping of red blood cells, which is called hemagglutination. And the antibodies to flu would prevent the agglutination of red blood cells.

That was used for decades as the best marker of an immune response. Now we can look with automated assays at neutralization of the virus.

LICHTMAN: What does that mean?

NABEL: Well, we can actually grow the virus in cell culture, and we can add antibodies to the virus and see if they block the growth of the virus in cell culture. It's a much more physiologic readout of virus inhibition.

LICHTMAN: So you can sort of watch the fight happening in front of you?

NABEL: Oh, absolutely, yeah, in a test tube, and then that gives us more confidence of how those antibodies might work in the body.

LICHTMAN: Now, your lab has worked on this vaccine for a couple years, and you reported the findings a few years ago. What did you report this week that's new?

NABEL: Well, what we found several years ago, in 2010, was that we - we were able to use this prime-and-boost vaccine approach to elicit this more broad neutralizing antibody to the stem region of flu. When we did those studies, though, we did them in animals that had never seen the flu virus before. And most people have seen the flu virus, either they've seen it because they've been infected, or they've seen it because they've had vaccines.

And so the question actually was raised by us and by others at the time - you know, would this approach work in settings where the immune system had already seen flu? In this study, we answer that question. We deliberately infect animals, we looked at both mice and at ferrets, or we deliberately pre-vaccinate them, and then we immunize them the same way we did in our previous study and ask if they're capable of making these broad stem antibodies that are a target for a universal vaccine.

And fortunately we found that there was no blocking of this immune response when animals had been exposed to influenza previously.

LICHTMAN: So it would work even if you'd had the flu before.

NABEL: Exactly.

LICHTMAN: So in people, if we fast-forward it, you wouldn't have to be a newborn to have a vaccine like this maybe work for you?

NABEL: That's exactly correct. If we had seen a problem of that sort, it might still work at a young age, but this now certainly would give us more reason to be optimistic that in people of all ages, regardless of whether they had been exposed to flu, that it would have a chance of working.

LICHTMAN: Dr. Gary Nabel, thanks for joining us today. We'll look forward to hearing more about this and following this in the news.

NABEL: Thank you, it's been a pleasure.

LICHTMAN: Dr. Nabel is the head of vaccine research, the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases, part of the NIH. And we'll be back more to talk with Maria Popova, super-blogger, uber-tweeter; and Danica McKellar after this break. Stay with us.

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