Safety of Live Attenuated Influenza Vaccine in Children With Asthma

​​​​​In this episode, C. Buddy Creech, MD, MPH, speaks about his team’s research titled “Safety of Live Attenuated Influenza Vaccine in Children With Asthma,” including supply chain issues with influenza vaccine, the difference between influenza vaccines, and the importance in vaccinating children with asthma against influenza.

Additional Resource:

• Sokolow AG, Stallings AP, Kercsmar C, et al. Safety of live attenuated influenza vaccine in children with asthma. Pediatrics. 2022;149(4):e2021055432. doi:10.1542/peds.2021-055432

C. Buddy Creech, MD, MPH, is a professor of infectious diseases at the University of Vanderbilt Medical Center and director of the Vanderbilt Vaccine Research Program (Nashville, TN).

TRANSCRIPTION:

Jessica Bard: Hello everyone. And welcome to another installment of Podcasts360, your go-to resource for medical news and clinical updates. I'm your moderator, Jessica Bard, with Consultant360 Specialty Network. People with asthma are at a high risk of complications from influenza, according to the Centers for Disease Control and Prevention. The CDC recommends that people, aged 6 months or older, get vaccinated for influenza every year, but the live attenuated vaccine is only approved for people aged 2 to 49 years. Dr Buddy Creech is here to speak with us today about his team's research, Safety of live attenuated influenza vaccine in children with asthma. Thank you for joining us today. Could you please give us an overview of this study?

Dr Buddy Creech: Well, I'm delighted to be here. Thanks for having me. We've been working in the influenza vaccine space for many years. We're one of the 10 NIH-funded Vaccine and Treatment Evaluations in the country. And as a result of being part of that VTEU network, we do a great number of influenza studies. We also wear another hat and that's part of a large vaccine safety consortium, called the Clinical Immunization Safety Assessment Project through the CDC. And those 2 represent the bulk of our work. On the one hand, we're developing new vaccines and therapeutics, and on the other, we're making sure that those vaccines are safe, when deployed out into the real world. This study was born out of that CDC-funded effort to say, "How can we either improve upon or evaluate more carefully the safety of vaccines in special populations?"

Dr Buddy Creech: That's the real bulk of what we did here. We said that there is a unique side effect to FluMist in young children, which is wheezing. And even though it's uncommon, it certainly is a precaution that we're all aware of and limits its use in some populations. What we didn't yet have full data on is whether or not kids with asthma, who were a bit older, had that same of wheezing. So, we set about to do a prospective randomized trial to ask the simple question, "Does giving FluMist or the injected influenza vaccine... Does one of those cause more wheezing or more asthma exacerbations than the other one."

Jessica Bard: How did this research topic come about?

Dr Buddy Creech: Well, it started many years ago, as we thought about supply chain issues with influenza vaccine. We really want to make sure that every child has ready access to a vaccine. And not only does that include making concessions for those who might have needle phobias and simply don't want to get an injection. It also means that there are some who have allergic reactions to certain vaccines, so we want to have options for them. And we also recognize that not every flu vaccine is made the same way, and there may be inherent advantages of some vaccines over another. And many listening to this podcast may remember that over the years we've made different recommendations for flu vaccine use in children. There was a year in which we said, "Let's preferentially use FluMist or the live attenuated vaccine," because of its ability to protect against drifted strains of influenza, where we might not have guessed the right vaccine make up for that year.

We also recognize there are some years where we've had to not recommend the live attenuated vaccine because of some manufacturing issues that led to it not being as effective as the inactivated vaccine. And even now we continue to do work to try to figure out whether growing it in chicken embryos or whether growing it in cells is a better way to induce the kind of immunity that we need for influenza. So, it's really born out of the fact that there are inherent differences to all of the different flu vaccines that we have. And for children who are at risk for influenza complications like children with asthma, we really want them to have all of the possible vaccines available to them. Now, the other reason we did this prospective study is that there were a number of smaller studies being done in the U.S. and Europe that suggested that, in fact, wheezing wasn't a common phenomenon after live attenuated vaccine in those kids with asthma.

Some of those were observational studies. Some of those were database mining through electronic medical records. And at the end of the day, we thought the best way to answer the question would be to very carefully evaluate these kids after vaccination and do it in a randomized way.

Jessica Bard: Could you elaborate on the results of the study, please?

Dr Buddy Creech: What we did in this study is we evaluated about 140 participants, and that was in the group that we had all of the data needed to be able to evaluate whether or not they had wheezing episodes after the receipt of their vaccine. And what we did is we evaluated their likelihood, not just of wheezing events that might take them to their provider, but also wheezing events that might cause them to contact their healthcare provider and get a prescription for steroids because they were having an asthma exacerbation. Or those asthma symptoms that aren't necessarily a true exacerbation, but do represent an acute worsening of their disease, like nighttime coughing or albuterol use, or some of the other validated questionnaires that look at, not just asthma severity, but asthma control on a daily basis.

And what we did is when we started the study, we simply said, "We want to stratify these children by age. We want to stratify the randomization based on which site they were at," because this study was done here at Vanderbilt with our colleagues at Duke. Chip Walter led the study there. And at Cincinnati Children's, Mary Staat led the study there. And what we did is we stratified also by asthma severity, those who had more severe asthma versus those who had milder symptoms at rest, not only severity but control. By doing that and by randomizing, we were able then to look for 42 days, using an electronic diary that we used through the REDcap system that we developed here at Vanderbilt, and we tracked their daily symptoms. And that was nighttime albuterol use, nighttime wakening, nighttime cough, trips to the ER, or the urgent care to their healthcare provider for asthma exacerbations.

And what we found is that when you look at either frequency of asthma symptoms or their change in peak flow, the peak flow meters that they use, or on these validated asthma control surveys or scores, if you look had them in the 14 days or the 42 days, so six weeks after vaccination, not only were the side effects of vaccine really similar between the two groups, but the rates of wheezing or asthma symptoms were really similar between the groups. And what we are able to say, statistically, is that receiving LAIV, or FluMist, was not associated with an increased frequency of asthma exacerbations or an increase in asthma-related symptoms or a decrease in peak flow when you compare it to kids who got the inactivated vaccine. And I think because of this, we're now poised to be able to take this type of prospective study, as well as the other studies that have been done recently and be able to hopefully make new recommendations about the use of FluMist in this particular population.

Jessica Bard: How would you say those results impact clinical practice?

Dr Buddy Creech: I think it gives providers another option for vaccinating kids, whether that means, maybe vaccinating some kids with asthma who historically have not gotten vaccinated because they simply do not want to get a shot. Whether that means, offering children with asthma an intranasal vaccine, that at least biologically has some advantages over the inactivated vaccine, right? Even though we know that the vaccine efficacy is different between products and it's different from year-to-year. We do know from some work that we did years ago with Dan Hoft at St. Louis University, that LAIV induces a cellular immune response that is distinct from what we get from the inactivated vaccine, at least in younger children. There's a bit more robust of an interferon-gamma response and a T-cell response in those who receive the live attenuated vaccine. And that makes sense, right? It's a full virus. It's replication-competent in the nose. It's not just the inactivated proteins of the virus.

Dr Buddy Creech: And so, because of that, there may be some biologic advantages to getting a live attenuated influenza virus vaccine. With that being said, we would never do that if there were a safety concern. And I think what this study now does is adds to the growing knowledge that we can safely give FluMist to kids with even severe asthma, particularly those who are under good control of their asthma, but even for those who have some degree of symptoms on a daily basis, FluMist does not appear to cause wheezing events anymore than an inactivated vaccine. And so, I think what we should be looking for is hopefully for the ACIP, the Advisory Committee on Immunization Practices of the CDC, to take up this information and potentially tweak the language about whether or not we treat this as an ongoing precaution against use in those with underlying asthma.

Jessica Bard: What would you say are the overall take-home messages from our conversation today?

Dr Buddy Creech: Well, I hope that every provider recognizes the importance of influenza vaccination in their children with asthma. This is one of the reasons why the study sample size wasn't larger than it was, is in part because of supply chain issues coming out of the manufacturing issues with FluMist. But some of it was because children with asthma were being vaccinated so early in the season, that by the time we approached them for enrollment, they had already been vaccinated. Okay, well, that's a really good problem to have in clinical research, that these children were the first in line to get vaccinated. I think that's the first take-home point. Asthma is a risk factor for complicated influenza. Number two, I think the take-home is that we have greater flexibility than we maybe once thought about the types of vaccines against influenza that we can use in this population.

And I certainly, as a pediatrician and as a PID person, would feel very comfortable offering a child with asthma an intranasal flu vaccine, particularly if that was the only way to get them vaccinated. But even with this study, I think we can treat them somewhat equally. Now, we've got to wait for the CDC to make some final recommendations around that and potentially modify the language, but I do think it gives us some options. And I think the third thing that's a good takeaway, is to say that even in the context of LAIV or the inactivated vaccine, if you look at the types of symptomatology that people had in the two to six weeks after vaccination, there was a lot of asthma symptomatology. There was a lot of nighttime wakening, a lot of wheezing, a lot of chest tightness. What that tells us because they were balanced between the two groups, is it wasn't vaccine that was doing that, it was their underlying disease state.

And so, for those who practice in an area where asthma is their bread and butter, they know this far too well, that asthma continues to provide daily symptoms and alterations in the quality of life for a number of children. Thankfully, by doing this type of randomized trial, we can cut through some of the noise of those daily symptoms or weekly symptoms that kids with asthma may have, and be able to separate that from that which might be provoked by the vaccine itself. And so, I think vaccines are safe in this population. They're effective in this population. They're necessary in this population. And now we have greater choices.

Jessica Bard: Is there anything else that you'd like to add today?

Dr Buddy Creech: I think the final thought that I would leave folks with is this idea of, we really struggle in medicine sometimes, to take things that are true and true, but are actually unrelated to each other and inadvertently assign causation. And so, one of the things that's really important to us who work in vaccine safety is to do these kinds of rigorous, controlled clinical trials. So that again, we can cut through that noise of what the baseline event rates of whatever symptom it might be, whether it's fever or headache that we often see after a vaccine, or whether it's wheezing in children with asthma, whether it's abnormal glucoses in children with diabetes, or flares in those with autoimmune diseases. We have to be very careful when we're evaluating the safety or reactivity of vaccines in these populations, to make sure that we don't inadvertently say that a vaccine is causing something, as opposed to it just representing what the natural ebb and flow of their underlying disease is.

So, what I hope is, that by us using our vaccine safety network, our CISA network, that the CDC sponsors, by using that kind of a network to be able to unravel side effects after vaccines and doing it even in special populations, I think that's going to be a really important path forward to give parents confidence that the vaccines that we're offering their children are not only effective, but they're very safe as well.

Jessica Bard: Well, thank you so much for your time today, Dr Creech. We really appreciate it. And thank you for all of the important work that you're doing on this topic.

Dr Buddy Creech: Thanks for having me. I really appreciate it.