When autumn arrives, reminders typically start going out for people to get their annual flu shot. The vaccine changes each year based on what strain of influenza is likely to be circulating then. Sometimes, it’s a good match, and other times, it’s not so good. But what if you could get one vaccine that would confer lifetime protection against the flu and its ever-changing strains?
Scientists at Oregon Health & Science University are working on advancing that goal by developing a new way to deliver vaccines against flu viruses. The vaccines are delivered through a harmless virus that most people are exposed to at some point in their lives. The technology stimulates the body to release cells that attack the internal machinery of the harmful virus instead of its outer surface which can evolve to slip past immune defenses. Joining us to talk about this research is Jonah Sacha, a professor at OHSU and the chief of pathobiology at the Oregon National Primate Research Center.
The following transcript was created by a computer and edited by a volunteer:
Dave Miller: This is Think Out Loud on OPB. I’m Dave Miller. In just a few months, many of us are going to be getting reminders to get our annual flu shot. The flu vaccine changes each year based on what strain or strains of influenza are most likely to be circulating. Sometimes it’s a good match, other times less so. But what if you could get a single dose that conferred a lifetime of protection against ever changing strains? That is what scientists at OHSU are hoping to create. And according to a recent paper, they are getting closer.
Jonah Sacha is a professor at OHSU and the chief of pathobiology at the Oregon National Primate Research Center. He joins us now. Welcome back to the show.
Jonah Sacha: Thank you for having me.
Miller: Can you explain the current model – how annual vaccines for flu are put together?
Sacha: Currently, we receive a vaccine that’s updated every year. And it’s sort of a best estimate by professionals who study the influenza viruses that are circulating within the animal pools that we know of. So within birds and pigs. It’s an educated guess of what’s going to be circulating in humans later in the year. And so they build this tailored vaccine every year based upon what they estimate is going to jump into humans from those animals.
Miller: And how does that vaccine work in our body? What does our body do in response?
Sacha: So when you receive one of these vaccines, it is essentially a killed or inactivated influenza virus. And what it does is to alert your body to, this as a pathogen that you want to remember. Our body is fantastic about recognizing foreign invaders and remembering them for later. The issue with influenza is that it’s not just one singular virus. It’s actually a large swarm of closely related yet genetically distinct viruses that are slightly different from each other.
Miller: But the model is to actually take an actual influenza virus and then inactivate it, or take a part of it, or a dead version of it, and use that to train our body then to make antibodies against it?
Sacha: Correct. So then your body sees this and it makes these small Y-shaped molecules called antibodies. And what they do is they physically attach to the outside of the virus and they prevent it from attaching to your cells and infecting you. And that’s how they protect you from getting sick with influenza.
Miller: And how effective are they?
Sacha: It really depends. They can range from as little as 30%, up to 75% or 80%. And it really depends on how closely what the vaccine is based on, to what virus actually emerges and then infects people in that influenza season. You can see something similar now happening with the SARS-CoV-2 or COVID vaccines, where it’s sort of a guess of what’s going to happen. And really the efficacy of the vaccine depends on how closely that vaccine strain matches what you actually get infected with later on.
Miller: In fact, it seems like we’re due for a new COVID-19 vaccine?
Sacha: That’s right. Interestingly, SARS-CoV-2 or COVID-19 vaccines are going to become sort of like an annual influenza vaccine. They’re going to follow that model. So we’ll be receiving annual influenza vaccines and then likely also annual COVID vaccines.
Miller: But you’re working on something to actually upend that model. What’s different about the vaccine model that you’re working on?
Sacha: As I mentioned, most of our historically successful vaccines work upon this idea that you can show the body a virus, the body will recognize it, remember it, make these Y-shaped molecules. Then when your body re-encounters that same virus later on, those Y-shaped molecules will attack that virus and prevent it from making you sick. The issue is that those sorts of vaccine approaches don’t work great when there’s a lot of diversity in the virus. And we see that with influenza. And we see that with SARS-CoV-2, the causative agent of COVID-19.
So the vaccine that we’re actually making has its origins in a vaccine approach that we were making for HIV. I came to OHSU 13 years ago to work on this exact vaccine vector. It’s based on another virus called cytomegalovirus or CMV, which is a quite innocuous virus that most people in the world are infected with. This virus is unique because, instead of making these Y-shaped antibodies, it actually trains your body to make a different type of immune response, one that is based on T-cells. You may have heard of them as killer T-cells. And these are immune system cells that will go around and recognize small pieces inside of the virus and then kill the cells that are infected with it. So our vaccine, based on CMV or cytomegalovirus, doesn’t use antibodies. Instead, it relies on these killer T-cells to do the work.
Miller: What’s different about attacking the inside of the virus as opposed to using antibodies to go for the outside?
Sacha: Yes, that’s a great question. And I bring this back to HIV because it’s sort of where all this started. But with HIV, with influenza, and with SARS-CoV-2, the theme is the same – these viruses are not just one single virus, but they’re rather diverse swarms. And they’re really adept at changing the outside of themselves. And when they do that, the body has difficulty recognizing that. So when you target the inside of a virus, it’s very difficult for these viruses to change the essential building blocks that allow them to form the virus particles.
A good analogy is that we train, with vaccines, our immune system to remember the color of the shirt of the bank robber. So if the bank robber comes in wearing a red shirt, your body is always going to say, “aha,” using antibodies, “I see that red shirt. I know that’s a bank robber. I will attack it.” However, these bank robbers, like the viruses, are smart. They change their shirts. And so now if the bank robber comes in with a blue shirt, your antibodies are no longer gonna work. But if you can train the T-cells to ignore the shirt, and focus on the fact that this person has glasses and a beard, then your body can recognize that bank robber much better.
Miller: This model is, as you noted, already being tested by your colleagues for HIV and for tuberculosis as well. How did you get the idea to try it for influenza?
Sacha: It’s a funny story that actually, ironically, harkens back to almost 10 years ago to the day. Ten years ago I was attending a conference called the International Aids Society meeting, which I just got back from last week in Germany. And 10 years ago, that meeting was in Melbourne, Australia. But when I came home, I didn’t realize that I was infected with H1N1 swine flu. And I wound up passing that virus to everyone in my household, including my wife and my son who, at the time, was three years old. He got rather sick and wound up in the hospital at OHSU.
In that moment, I remember thinking this is really unfortunate because we all took our annual influenza vaccines, but yet they didn’t protect us. And while I was thinking about why it didn’t work, I realized the CMV vaccine vector that we’re using for HIV actually parallels a lot of the same problems that we have with influenza vaccines. And that’s where the idea came out of – a very personal up-close experience with influenza in my household.
Miller: So to construct this new vaccine, my understanding is you put in pieces of the 1918 influenza virus, which was responsible for killing an estimated 50 million people around the world. Why choose this 106-year-old virus?
Sacha: So that is the oldest isolate that we have of influenza. I think it’s actually one of the oldest isolates we have of any virus. And we chose it, very specifically, because we wanted to make the test of our vaccine as rigorous as possible. So we picked the oldest possible isolate to vaccinate against. And then we came back and we challenged, with a virus, an avian influenza that was isolated in the early 2000′s. So that’s nearly 100 years of natural influenza evolution between the strain that we used to vaccinate with and the one that we used to challenge with. [Because] nearly 100 years of evolution would capture all of this sequence diversity or change within the virus, it would therefore be a very stringent test of our vaccine. And that’s actually why we chose it.
Miller: Is the thinking that if you had used, as the basis for the vaccine, a virus from five years ago, that you would actually confer even more benefit and it would let the body identify it with even more accuracy?
Sacha: That is exactly correct. So we chose the oldest strain we could to make it as difficult as possible. And that is where, actually, we want to go next, to then make the vaccine sequence that we use more optimal so that you get better coverage and make the healthy immune system recognize influenza even better – more accurately, as you put it.
Miller: Six of the 11 vaccinated nonhuman primates that were exposed to the H5N1 survived.
I think that was the language in the press release. Does that mean that five of them didn’t?
Sacha: That is correct. Again, this is due to our deliberate choice of this virus. So the H5N1 avian influenza isolate that we selected is incredibly pathogenic. It is uniformly lethal in these animals. In humans that have been infected with this, the mortality rate is around 60%. This is one of the most pathogenic viruses that we know of. Again, we chose this deliberately to make the test as difficult as possible for our vaccine.
Miller: I saw those numbers and it just made me wonder if a 55% survival rate, post-vaccination, is something to celebrate. Celebration is the wrong word, but it still is good news, given just how dangerous this virus is?
Sacha: Yes, that is one component. It’s good news given how dangerous this virus is, given the huge hurdle that we set up to make for the vaccine strain that we use coming from 100 years previously. We set the vaccine at the biggest disadvantage that we could to test the proof of concept because no one had ever really tried to make a T-cell based vaccine for primates before.
As I mentioned, the current vaccine approach is all based on antibodies, which is very powerful, but necessitates the vaccine having to change every year. So we’re pivoting away from that and deliberately trying a completely new approach to try and achieve a universal influenza vaccine.
Miller: Just stepping aside from this science for a second, what kinds of security and safety protocols do you have in place? As you said, this is a devastatingly effective virus that kills unvaccinated monkeys. But it would also kill many, many thousands or millions of humans, if it were to escape. And it’s not that far from the major population center of our state. How do you keep it in the confines of the Center?
Sacha: I’ll say three things. This challenge work was actually not done here but was done at the University of Pittsburgh in Pittsburgh. But that doesn’t change the fact that it’s still a population center. But we, as scientists in the United States, are under extremely strict regulations from multiple levels. And this is all done in what we call a Level 3 facility which has multiple checks and balances so that it would be very difficult for this to ever get out.
Secondly, I will say that this H5N1, if you zoom out and look at the United States or in the world, this virus is currently in our dairy population. So even if there were to be “a leak,” the virus is already out there in dairy cows already.
Miller: And it’s the same virus?
Sacha: It’s not the exact same virus. It’s H5N1, but is a different isolate than this one. But nevertheless, there is H5N1 that is out there circulating in animals and currently in our dairy cows.
Miller: So to go back to the possibility of this going from basic research to an actual vaccine people could take – what are the steps that have to happen before that?
Sacha: It’s a great question. So we sit at the interface of preclinical and clinical research. So with this result, this now gives us the ability to have the justification to proceed into clinical trials. Now, if we were starting from scratch, it would be years because the first thing has to happen is a phase-1 clinical trial which is to establish the safety of any such approach. Luckily, we are following in the footsteps of my colleagues who have been working on this vaccine for decades now.
This work was, like I said, why I came here to Oregon 13 years ago. This vaccine vector for CMV is now in clinical trials for HIV. And clinical trials for tuberculosis are starting soon. And because all of that work has already been done, the trail has already been blazed, so to say, our pathway forward is much quicker and much easier now because of that work.
Miller: Meaning … what’s a potential time frame?
Sacha: It’s difficult to say because a lot of this is out of my control. But if the HIV vaccine trials and the tuberculosis trials are successful, I could see this going into trials with people and potentially being tested for efficacy within five to 10 years. Again, there are a lot of factors that go into that. What’s unique about influenza is that you can run clinical trials where you can vaccinate people and then experimentally infect them. There are centers to test exactly this setup within the United States. So this could actually go quite quickly once the clinical vaccine is made to test.
Miller: Is there any reason this same model couldn’t be used for coronavirus as well, like the one that causes COVID-19?
Sacha: That’s an absolutely fantastic question. And as you can see, we’re facing similar issues here with SARS-CoV-2, with the COVID vaccine needing to change every year. And I would posit that, rather than us constantly trying to chase these viruses as they evolve and putting our vaccines where we think the virus is going to go, or where it just was, we aim at these conserved segments of the virus where we know it can’t move, and base vaccines off of that. So
yes, I think that this approach could be used and ideally should be used for these highly variable viruses like HIV influenza and SARS-CoV-2.
Miller: Just finally, if the brilliant nugget here is to go after the unchanging part of these viruses opposed to the quickly mutating parts, if these are “clever” evolutionarily pressured beings, what’s to say that they won’t mutate in some other way, given the new pressure that you’re gonna be putting on them?
Sacha: It’s a great question. Of course, they can. Viruses will always change and find a way. But what we’ve learned though is that when you target not one but multiple conserved regions of a virus, it’s very difficult, if not impossible, for a virus to escape those multi-pressures. The best analogy is the antiretroviral therapy drugs that we use for HIV. If you use one of them in isolation, the virus will simply mutate, sort of laugh at you and then keep replicating. But if you use two or three in combination, they can’t, and it simply can’t escape all three, and it stops the virus dead in its tracks. So with the vaccine, it would be similar to that. We have to take multiple targets at multiple conserved areas of the virus.
Miller: Jonah Sacha, thanks very much.
Sacha: Thank you for having me.
Miller: Jonah Sacha is a professor at Oregon Health and Science University and chief of pathobiology at the Oregon National Primate Research Center.
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