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CDC Press Briefing: Study on Transmissibility of Avian Flu H5N1 in an Animal Model

Friday, July 28, 2006; 11 a.m. ET

Tom Skinner, CDC Media Relations: Thank you, Melissa, and thank you all for joining us today to discuss some important research on H5N1 and it’s published in the journal Proceedings of the National Academy of Sciences. I want to be clear before we get started today that the information we share today as well as the content of the article are embargoed until 5 p.m. on Monday, July 31st. We’ve been getting a lot of calls about the paper and we wanted you all to have more time to work on your stories prior to the embargo so that’s why we’re having the briefing today. Joining us on the call is the director of the CDC, Dr. Julie Gerberding, who’s going to give a brief overview of the current situation in regards to H5N1 and who will provide some general comments about the paper. And also joining us are the lead author of the paper Dr. Taronna Maines, as well as one of our lead researchers on influenza and a co-author of the paper, Dr. Jacqueline Katz. There’ll be providing details of the study, and then we’ll open up for questions. So with that, I’ll turn it over to Dr. Gerberding.

Dr. Gerberding: Thank you, thanks for your interest and for joining us. I am here with two of the CDC researchers, Dr. Maines and Dr. Katz who contributed to this work and we thank our collaborators in Spain and Indonesia [Editor’s note: and Vietnam] for their contribution as well and their co-authorship of the paper. To put this into context, what we’re here to talk about today is some laboratory research to evaluate the transmissibility of H5N1 avian influenza when it has exchanged genes with human influenza of a type that is readily transmitted from one person to another. This is one in a set of experiments ongoing at CDC to try to understand what makes some viruses transmissible and others not easily transmissible in people. As you know, three things are necessary to cause a pandemic. You need a new virus that has surface proteins that human beings don’t have antibodies to, and thus are susceptible to. You need a virus that is capable of causing infection and disease, and you need a virus that can move easily from one person to another. In the situation that we have today with H5N1, two of these three conditions are met. We have a new virus that we don’t have immunity to, on a global scale, and we have a virus that has infected people and caused disease 231 times, 133 of those people have died. So we do have the first two conditions met, but we have yet to see any evidence of efficient person-to-person transmission of this virus. So it’s important to go into the laboratory and try to understand what are the factors that might create the circumstances that lead to that effective person-to-person transmission. In general, these viruses evolve by two main mechanisms. In one case, they might make a set of genetic changes over time, becoming progressively more transmissible from one person to person, and that’s probably what happened in 1918 with the pandemic virus that caused influenza on a global scale back then. But the other way that viruses can become transmissible to people is by exchanging genes with strands that are already transmissible. In other words, an H5N1 virus could exchange genes with a human flu virus that’s already in the population and pick up the characteristics of that virus that then leads to enhanced transmissibility. So what the CDC scientists have done is to explore this latter possibility, that taking an H5N1 strain of virus and mixing through reverse genetics in the laboratory with strains from H3N2, which is the most common regular influenza virus circulating in the world today, that we may, in the laboratory be able to create reassorted viruses that contain some genes from each parent that would lead to enhanced transmissibility in an animal model. So, our scientists are going to describe for you today those experiments, but the first result that is being reported in PNAS that’s embargoed until Monday, is the result that shows that simple combinations of genes from both parent viruses have not led to enhanced transmissibility in the ferrets. The reason that we are talking with you today about this is because we want to make sure that this new science gets interpreted in the proper public health light. These data do not mean that H5N1 cannot convert to be transmissible from one person to another person. They mean that it is probably not a simple process and more than simple genetic exchanges are necessary, and that complexity is something that we will be working on in subsequent experiments at CDC. So again, it’s very important to understand as I stated (these results) do not mean that H5N1 cannot develop into a pandemic strain. It means that the genetics of that transformation are more complicated than a simple one-to-one exchange. We also want to remind you that we are far from out of the woods in H5N1 on a global scale. Just recently we’ve seen new cases reappear in Thailand, we have a new outbreak in poultry that may be ongoing in Laos, and as I said, we have a total of 231 known infected humans and 133 deaths attributable to this evolving strain. We also know that H5N1 continues to undergo microevolution, a series of genetic changes that are subtle but, just demonstrate again that flu is a virus that constantly evolves. It’s unpredictable. We don’t know what direction these changes will take us in, and we’ve got to maintain our preparedness. We are concerned about complacency. And when people hear news that, well maybe it’s hard for the virus to evolve, that gives them a reason to become complacent about pandemic preparedness. When people hear that there’s a new vaccine and we all celebrate the possibility that could be more effective at a low dose, such as the vaccine product that was in the news this week, that’s great news, but it’s not an excuse for complacency. We have a lot of work to do to prepare for a pandemic, and whether or not is an H5N1 pandemic or some other pandemic; it’s absolutely essential that we continue our preparedness efforts. And we will continue to do that at CDC and the entire Department of Health and Human Services, and the whole federal government. We’re also extremely pleased to see the work that’s going on at our state and local levels as well as the international scale. They continue to drive all of us to a point where every community and every part of the network is as prepared as we can be. So, let me ask our scientists to provide some more detail on the nature of the research, and I’m sure they can do a much more thorough job of explaining the significance than I can. But I just really appreciate your interest and I emphasize that we are not out of the woods on pandemic preparedness yet.

Tom Skinner: Thanks, Dr. Gerberding, and now I am going to turn the call over to Dr. Jackie Katz, that’s spelled k-a-t-z, who’s going to describe the various research that’s published in the paper, and then we’ll open it up for Q and A. So, Dr. Katz?

Dr. Jacqueline Katz: Thank you. I would first like to just give you two pieces of background information. As Dr. Gerberding mentioned, this research study was undertaken in order to better understand what genetic changes are needed for an H5N1 virus to acquire a property of efficient transmissibility. And we believe that we understand that the spread of influenza virus is through respiratory droplets that are expelled when infected persons cough or sneeze, is a major way in which human influenza strain spreads through the community during seasonal epidemics. And this is the property that a pandemic strain would have to acquire. The other piece of background information, as Dr. Gerberding said, is that the last two pandemics were caused by viruses that had a combination of both genes from an avian virus as well as those from a human virus. And so, it’s that approach that we have taken to address whether looking at such genetic changes with H5N1 virus might allow them to gain properties of transmissibility. The study was conducted in four experiments. The first experiment was done, and I should say that the experiments were done using the ferrets as an animal model because the ferret is susceptible to influenza in the same way that humans are susceptible to influenza. And so, it provides a unique animal model to assess the ability of viruses to transmit from one animal to another. We also used a specialized caging system that was designed to study the transmission through respiratory droplets. And finally, we used a process, a molecular technique known as “reverse genetics” to make reassorted or hybrid viruses that contain genes from both avian virus and the human virus in culture. So the first experiment was to assess the transmissibility of human H3N2 influenza viruses and avian H5N1 influenza viruses in the ferret model. And what we found was that the human H3N2 influenza viruses transmitted efficiently using the special caging system whereby the animals were placed in close proximity, but such that only transmission through respiratory droplets could occur. When we looked at a number of H5N1 viruses we found that these viruses were not able to transmit efficiently. And so, this told us that the model was working and reflected the transmission that we see of these two viruses in humans at present. So the next step was to generate reassorted viruses using the process of reverse genetics. And we made two viruses that contained the surface-like protein gene from the avian H5N1 virus and the internal genes from a human H3N2 virus. And, as Dr. Gerberding mentioned earlier, the H3N2 virus was used because it’s commonly, the common strain that circulates from season to season in humans. And we found that we could make these viruses, and that some of the viruses were viable and so the next step was to test them for their ability to transmit in the ferret model. But when we assessed the ability for transmission of these reassortant viruses, we found that they were not able to transmit efficiently. And, in fact, they were also not as able to cause severe disease as the original H5N1 virus. Finally, we wanted to ask an additional question, about whether additional genetic changes might be acquired if one of these hybrid viruses were “passaged” in from one ferret to another, would this give the virus a chance to acquire additional genetic changes that could increase its ability to transmit efficiently. So we conducted this experiment with one of the hybrid viruses and passed it from ferret to ferret through taking nasal secretions from one ferret and transferring it to the next. And we found that in this process that we, the virus did not acquire any additional capacity to transmit efficiently from an infected ferret to a healthy ferret. So overall, this work tells us that we have a good research tool to assess the ongoing genetic changes that H5N1 viruses may acquire, and that may enhance their ability to transmit efficiently. I want to stress that our results cannot be generalized, and they’re only relevant for the viruses that we used in the study. And the H5N1 virus that we used in the study was a 1997 strain. But we did see with this strain that when we created a hybrid avian human reassortant virus we were not able to see efficient transmission from an infected animal to a healthy animal. So we believe that this animal model is a useful tool to better understand the properties of transmissibility and the potential of H5N1 viruses to cause a pandemic in the future.

Tom Skinner: Thanks Dr. Katz. Melissa, I believe we’re ready for questions please.

Operator: Thank you, we will now begin the question and answer session. If you would like to ask a question at this time, please press star 1 on your touchtone phone. You will be prompted to record your name. To withdraw your request press star 2, one moment for the first question.

Operator: Helen Braswell with Canadian Press, please go ahead.

Helen Braswell: Hello, thank you very much for taking my question, and for doing this today. I wanted to ask Dr. Katz if we can tell from this work whether or not more contemporary strains of H5N1 would re-assort and create a more transmissible virus? I know you tested the model with more contemporary strains, but I don’t think you actually created reassortants using a contemporary strain, and I’m wondering if we know enough about the virus and the changes that have occurred since then to know whether or not what you’ve seen in the ’97 virus would also be expected to hold true in viruses that are circulating now.

Dr. Katz: Thank you, that’s a good question. As you said, we did test the more recent strains for their ability to transmit, and like the 1997 strain, they could not transmit efficiently from one animal to the next. I think we need to continue these studies and the first study has shown that we have now a good model to assess, for continued assessment of more recent strains for their ability to re-assort with human strains and that is work that is ongoing at the moment.

Tom Skinner: Question Monitor?

Operator: Yes, our next question comes from Maggie Fox, with Reuters, please go ahead.

Maggie Fox: Hi, thanks very much. I’m wondering if this answers the question, the theory that’s been going around that reassortment kind of “dumbs down” as Mike Osterholm likes to say, dumbs down the virus. Does this tell you anything about that? And I’m also wondering if anyone’s testing putting the two viruses together and organism, and letting things happen naturally, as opposed to doing it artificially in the lab?

Dr. Katz: Again, I want to stress that the results of our study can only be related to the 1997 H5N1 virus, but is true that the reassortant that we generated were less virulent when they had acquired a number of human influenza virus genes in the ferrets. Whether this would be true for the more recent strains, again needs to be investigated.

Dr. Gerberding: I think it’s also important to remember that the pandemics of 1957 and 1968 were caused by reassorted viruses, those were not dumb viruses.

Tom Skinner: Next question please?

Operator: Yes, our next question comes from Miriam Falco with Cable News Network.

Miriam Falco: Hi, good morning everybody, thank you for doing this. How long did this testing take? ‘Cause you said that this is a good model for other types of testing. How long would it take to test it on the other strains that are out there? Although, the way I understand it, the 1997 model isn’t that far from what we’ve seen in some parts of the country. And then, are you also testing it in other animals? Because, obviously humans aren’t the only mammals that this could re-assort in.

Dr. Katz: To do a one-transmission experiment and to collect all the data takes about two to three weeks, so what we’re saying is that this is a good approach to identify genetic changes that we can then look for in viruses that are circulating in nature. And then to answer the second part about different animal models, we are investigating another animal model, the guinea pig model as a model for transmissibility, but at this point we aren’t considering any other animals. But we do believe the ferret is one of the better model animals to use because of its susceptibility to current human influenza strains as well as the highly pathogenic avian strain.

Tom Skinner: Next question, please?

Operator: Yes, our next question comes from Anita Manning with USA Today.

Anita Manning: Hi. Can you explain to us the difference between the way that the ’57 and ’68 viruses changed to become transmissible? And the 1918 virus? And why this experiment doesn’t necessarily tell us anything about the 1918 type strain?

Dr. Katz: Well, the 1918 virus is a very different virus, and some people believe this virus was generated through more slowly accumulating changes in a virus a potentially wasn’t an avian virus to begin with, but over time it acquired multiple changes to become virulent and transmissible in humans. We’re looking at the approach of the 1957 and 1968 pandemics where there was a more sudden acquisition of genes from a human virus through this process of reassortment that happened in nature. And, so we’re assessing that approach as a more sudden approach and something that could happen to cause H5N1 virus to become a pandemic strain more suddenly. That’s not to say that there aren’t additional mutations that the virus may acquire in the same way that the 1918 virus had to acquire mutations from the originating ancestral virus which have been an avian virus.

Tom Skinner: Next question, please?

Operator: Yes, our next question comes from John Lauerman with Bloomberg News.

John Lauerman: Hi, thanks for doing this. Were you working, the process that you were doing in the laboratory, could you have created, potentially, a pandemic virus? And what kind of protection did you have in the laboratory to make sure that if you did create a transmissible form of H5N1, to make sure that that did not escape the laboratory?

Dr. Katz: Yes, of course the possibility was there that we would generate a strain that had the property of transmissibility, that’s what the question of the study was. But the study was conducted using most stringent safety precautions that protected both laboratory workers and the public from the potential release of this virus. The work was done in BSL3 containment with the appropriate enhancements that, as I said would protect both the laboratory worker and the environment. And we always use these precautions when we do any work with H5N1 virus and in fact, this level of bio-safety that we used is the standard level that is accepted for work with H5N1 viruses.

Tom Skinner: Next question, please?

Operator: Our next question comes from Richard Knox with National Public Radio.

Richard Knox: Yes, thanks very much. A couple of things. One is I assume that what you did in recording this work does not cover all of the bases of possible reassortants between H3N2 and H5N1, so if that’s the case, I’m wondering how many more bases do you need to cover to make sure that there isn’t one combination out there that would do the transmissibility trick? And secondly, how reassuring do you think this is? Does it suggest that we may have more time than we feared we might before this virus might become a pandemic?

Dr. Katz: Okay, to answer the first part of your question, yes you’re right that we only did use a relatively small number of reassortants and there are many more combinations that are possible, over 50 combinations are out there so that would take years of work to go through all of those reassortants. We chose to use some that had what we believed the greatest likelihood of being viable, a good virus that grew well and was viable, and therefore had the potential for transmission. But yes, there are many other combinations that we could investigate in the future.

Dr. Gerberding: I would just maybe add, this is Julie Gerberding, that I’m cautious about using the word “reassuring.” I think this is very important work, and it’s reassuring to know that we have a laboratory tool that will help us understand transmission dynamics with much more precision than we’ve ever been able to do before. But I’m not reassured from the public health perspective because, as I said, this virus is still out there, it’s still evolving, flu is always unpredictable, and though we weren’t able to do this through some simple gene exchanges, as you pointed out, there are many other combinations and subtle changes that the virus itself could make; and we’ve got strains emerging probably as we speak. So, lets not use the word “reassuring” in terms of what might happen with H5N1.

Tom Skinner: Next question, please?

Operator: Our next question comes from Erika Checks with Nature, please go ahead.

Erika Checks: Hi, I guess I just have two quick questions, the first is, you passaged the virus five times in ferrets, and I wonder how applicable that is to the situation in nature that we have where there’s actually lots and lots of livestock and lots and lots of people that the virus could passage through? And then the second is, there’s definitely, you can use this model to look at how transmissible this particular strain might be, but does it tell you anything else about the determinants of transmissibility and package (unintelligible), if you could go out and make predications without constructing the actual virus itself?

Dr. Katz: Okay, to answer the first part, yes, we only did do five serial passages from ferret to ferret, that’s more than has occurred in nature, in humans at that time. We could have kept passaging indefinitely, again, it’s within the realms of timing and what’s reasonable to do in the laboratory. We thought that was a reasonable number and rounds of replication of the virus to allow it to acquire changes. And if there was some portion of the genome that really needed to adapt to the ferrets we thought that we would see it in that period of passages. And so, can you just tell me the second part of your question again?

Erika Checks: Determine the (unintelligible) of H5N1 or reassorted viruses. In other words, do you have to construct every single reassorted virus from scratch and test it now, or is there, have you learned something more that you can take out to the field and say “Okay, we can tell that this, or this, or this might be what is making this virus dangerous”?

Dr. Katz: Well, there are two approaches, and one is the approach that we’ve taken where we make genetic changes to a virus in the laboratory, and see if those genetic changes confer enhanced transmissibility. So far the genetic changes we’ve made haven’t enhanced the virus’s ability to transmit. And that tells us that it’s a more complex process that probably requires multiple different genetic changes. We can also use our model in another way, and that is to look at the viruses out there in the field that are naturally acquiring genetic changes all the time and see, in certain situations whether any of those viruses now have enhanced their ability in our animal model to transmit. And so, using either approach, we should be able to, in the future, identify genetic changes that are important in enhancing this essential property for a pandemic strain.

Tom Skinner: Next question, please?

Operator: Yes, our next question comes from Betsy McKay with Wall Street Journal.

Betsy McKay: (unintelligible) colleagues, looking at future experiments, could you tell us again, where do you take it from here? What lab experiments are you doing now or planning to do to follow up on this work? You mention the guinea pig model, are you working with other strains and so forth? Thanks.

Dr. Katz: Most of this work is still going to be in the ferret model. We haven’t established the guinea pig model for transmissibility at this time. In considering the ferret model, we plan to use more recent H5N1 strains and more recent H3N2 strains and again, generate reassortants in the laboratory and see if these different reassortants now have the properties of transmissibility in this model that we’ve established.

Tom Skinner: Next question, please?

Operator: Our next question comes from Denise Grady with New York Times.

Denise Grady: Thank you very much. I’d like to ask a couple of questions. One is, you both seem to be emphasizing the importance here of having shown that this model is a good one, and what I’m wondering then is, would you say that that is more important than this finding, (unintelligible) about this reassortant at this point? Just in terms of trying to understand the importance of this particular finding since it’s only one of many reassortants that you could have made? And then, two more, if you don’t mind. I’m wondering if there are any other viruses beside H3N2 that you would try this experiments with? And then, is there any way to explain why, exactly the reassortant was not transmissible? What happened in here – H3N2 has the ability, and yet now it’s not transmissible? Is it not in the drop list, or what? If that’s possible. Thank-you.

Dr. Katz: Okay, good questions. I think to answer your first question, the model is important, the results with that reassortant is important, but most importantly, it’s the knowledge of knowing that this process isn’t simple. And there is a complex procedure for a virus to acquire the properties of transmissibility. Secondly, there is another human influenza A virus that does circulate from season to season, it’s not as common in causing wide outbreaks of seasonal influenza, but it has been circulating in recent years and that’s the H1N1 virus, and it is possible in the future that we should conduct some studies using a similar approach with this strain. And the question of why it is not transmissible, of course that is the question that we are very interested in asking. We dissected out the H3N2 virus and found that even if you just had the surface glycoproteins of the H3N2 virus and then the avian internal virus genes, that that was not sufficient to transmissibility either, so again, that points to the fact that it’s a complex interaction between both the surface proteins and the internal genes. And on the biological level, we know these viruses are infectious. When we infect the first ferret, we know that these viruses are replicating well, so there’s something in addition to just being able to replicate to relatively high levels that is important for transmissibility.

Tom Skinner: Melissa, we’ll take a few more questions, please.

Operator: Thank you, our next question comes from Jia-Rui Chong with LA Times.

Jai-Rui Chong: Hi, thanks for taking the question. I have two questions. The first is, how do we interpret the results of this research in the context of some of the other recent research about the genetic mutation? Like, there was a report in Science, I think in March, about how maybe there are only two mutations needed for H5N1 to become really dangerous. And then, there was also this thing in Nature about how that cluster of viruses bounced in (unintelligible) in Indonesia had 21 mutations? And the other question I had was, were there any new things that the reassorted viruses did? Like, did they become any more virulent? Or anything like that?

Dr. Katz: Okay, to answer the last question first, the reassorted viruses actually became less virulent in the ferret model. To go back to the studies that have been reported in scientific journals and recent months, there’s one article that looks at particular changes in the key surface glycoprotein, the hemagglutinin and in the receptor binding properties of this virus and we’re aware of changes in that area. Our important (unintelligible) when viruses become pandemic, of a pandemic nature and move away from being an avian virus and so, actually, in the work that we present in this report, we looked at one virus, an H5N1 virus that was isolated from an individual in 2003 that had one mutation in that area, that had not completely changed its receptor specificity, but causing the virus to head in the direction of having the binding abilities that are more like a human virus. And in that situation, even that virus didn’t transmit effectively. So I think, again the picture is more complex, and it requires probably some of those changes, but then also, other changes, such as acquiring genes from human influenza viruses.

Tom Skinner: Melissa, we’ll take one more question, please.

Operator: Thank you, our last question comes from Daniel DeNoon with WebMD. Please go ahead.

Daniel DeNoon: Hello, thank you. I’m just wondering, since publishing this, where your work is taking you and what specifically you’re working on right now?

Dr. Katz: As I said before, we are continuing now to do similar types of experiments using this model, but working with more recent H5N1 viruses, because as we all know, these viruses have changed genetically since 1997 and are continuing to change. So we can create new reassortants with more recent H5N1 and H3N2 viruses.

Tom Skinner: Thank you Melissa, and thank you all for joining us and please be reminded once again of the embargo of 5 p.m. on Monday, July 31st for the release of this information. Thanks again and we’ll definitely keep you posted as new developments come about.

Operator: Thank you. That concludes today’s conference, you may disconnect at this time.




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