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The following is an edited excerpt from and interview with Dr. Jeffrey Taubenberger, conducted in late 2005...
On the issue of human-to-human transmission, how would a human get a virus that they can pass on to another human?
One of the biggest questions facing us is to understand the basis for human-to-human transmission. Influenza viruses are viruses of a wide variety of animals, like wild birds, domestic birds, farm animals. These viruses have the ability to move around between species and adapt to new hosts.
But you know, we don’t actually understand the genetic basis of why this happens. We don’t know what has to change to allow a virus to not only infect a human being, but to acquire all the changes it needs to go from one person to another efficiently. Of course this is the key ultimately to understanding how pandemics form and might actually be the key to preventing a pandemic. Right now we don’t understand it so there’s no way to prevent it.
The last two pandemics, the 1957, and 1968 pandemics were actually mixtures in which a human acquired two or three new genes from a bird flu virus. This mixed virus, or ‘re-assortment virus’ as it’s called, was what led to the pandemic.
But in 1918, we think that something fundamentally different happened. We think that an entirely bird-like virus adapted to humans without mixing with a pre-existing human flu strain. That means that pandemic viruses can certainly do at least two different approaches to how they would become transmissible in humans.
What was known about 1918 when you started your work?
The 1918 flu was clearly one of the worst natural disasters of all recorded history, so there are probably millions of pages of scholarly work on the 1918 flu from physicians and public health officials describing what was happening in 1918 to historical analyses and economic impacts and so on.
But you know, fundamentally we knew very little about this virus. Of course, no virus was isolated in 1918. They didn’t even know influenza virus actually existed. Which meant there was no way to actually directly study this very lethal pathogen. People were not certain as to what kind of influenza virus it was, whether it was human-like, or bird-like, or pig-like. They didn’t understand what changes would be necessary to make this a lethal virus. So, really nothing was really known about the basic biology of the 1918 virus.
Could you describe the tissue samples that you studied?
When we started this project we were using autopsy tissues of U.S. soldiers that died of the flu at the end of World War I in 1918. Small snippets of lung tissue were fixed, and formulated, and embedded in paraffin wax, and stored at the warehouse at the Armed Forces Institute of Pathology for the past 80 years.
We were able to take tiny slivers of that tissue and isolate the genetic material of the flu virus using some molecular biology techniques to actually allow us to fish out very tiny fragments of the virus and characterize them. And we were able to find positive cases.
Then we were able to receive material from another location. A pathologist in San Francisco had been able to go up to Northern Alaska and do and exhumations of a number of bodies of 1918 flu victims that were interred in the permafrost.
He was able to send us frozen lung tissue from one case that still contained fragments of the virus. And that actually made it possible to sequence the entire gene structure of the virus.
Why did the virus disappear? Why was it not more easily accessible than these few samples?
I think it’s a common misconception that the 1918 flu disappeared very suddenly. People very often write that it appeared very suddenly and then disappeared just as suddenly. The 1918 virus actually never disappeared; it is still rotating in humans, just in a highly mutated form.
Here is a virus that emerged in humans sometime around 1918, spread and caused this enormous pandemic whereby practically everybody on Earth was exposed to this virus, something like a third of the world population was made ill, and tens of millions of people died. For this virus to survive inside the human population, it would have to mutate itself into a form that would be different from a pandemic form because everyone who survived the pandemic would actually have protective immunity.
Influenza viruses, in humans especially, do extremely well. They mutate extremely rapidly from one year to the next, which is why the vaccine needs to constantly be reformulated to keep with this really rapid evolution, and that’s exactly what happened in 1918. In the years after, viruses were mutating very rapidly away from the 1918 form and those that lineage of virus is still part of the virus circulation right now.
People are being exposed either with vaccines or through natural infections with influenza viruses today that are direct descendants of the 1918 virus.
What did you learn about the 1918 virus?
Just this year we’ve been able to finish sequencing across the complete genome of the virus. While it’s a great sense of accomplishment to have finished sequencing across the virus, we don’t have really have all the answers that we want.
I think that the most fundamentally important thing that we have learned about the 1918 virus is that its origin is likely to be quite different than the two other pandemics that we know about, the 1957 and the 1968 viruses.
The 1918 virus was not a mixed human-bird virus but was an entirely bird-like virus that adapted ultimately to humans. How this process occurred is something that we are still trying to work out and we don’t fully understand, but I think has tremendous implications for the future and trying to prevent a pandemic like 1918 from happening.
Why was it so lethal?
The lethality of the 1918 virus is still something that is not fully explained. In very recent work that’s been done in conjunction between my laboratory, and collaborators in Mount Sinai School of Medicine in New York City, and the Centers for Disease Control in Atlanta, we found that the entire 1918 virus when rebuilt and put into mice, was extremely virulent. It kills mice in just a couple of days. It kills fertilized chicken embryos.
But one of the biggest mysteries of the 1918 flu was the age group that was severely affected. Influenza viruses, normally when they do kill people, tend to kill people in the extremes of life: newborn infants or the elderly. Populations that have less than optimal immunity.
But in the 1918 virus, while those two populations also had very high mortality, there was this new peak of mortality in young healthy adults: 15 to 35 year olds. People in the prime of their lives were somehow specifically targeted for a lethal outcome with this virus.
I think that it’s very likely that there was a host factor involved -- that people of this age group may have had an extremely odd kind of immune response to this virus, perhaps because of the types of influenza viruses they were exposed to earlier in their lives.
Therefore, even having the complete sequence of the 1918 virus in front of us, we may not actually be able to explain one of the biggest mysteries of the 1918 virus without finding other pieces of information that are currently lost to us.
You don’t buy the argument that the immune system just went into overdrive – that the healthier you were, the more lethal the virus could be?
It’s certainly possible that one of the explanations for high lethality in 1918 was the fact that there was such a robust immune response to the virus that the immune response in itself was damaging.
I still think that any number of possibilities is still open for discussion about what exactly happened in 1918. Until we can understand what influenza viruses circulated before 1918, unless we can analyze serum to look at the kind of antibodies that people had in their blood, of different age groups in 1918, unless that becomes possible by finding collections of serum, for example, from that time point, we may never be able to fully understand exactly what happened.
Could you compare the 1918 virus with the current H5 virus?
The 1918 virus is a different subtype than the current H5 virus. It’s an H1 subtype, which is quite different from the H5. But in general they have a lot of similarities.
They are both avian-like viruses. The 1918 virus has a handful of mutations in each of its genes that distinguish it from bird viruses, that are then maintained in all subsequent human viruses. And we speculate that this small number of changes, maybe around 30 or so in the whole virus, are crucial for this process of how a bird virus becomes a adapted to become a human virus.
The H5 viruses are actually beginning to show adaptations to humans in a way that parallels what happened in 1918. But whereas the 1918 virus may have had 30 changes, the H5 viruses that we see have no more than a small handful of these changes. Luckily, if this is the process that is going on, we are seeing a very early development. We are at a very early stage.
H5N1 is not considered a pandemic virus at this time. There have been no human cases of H5N1 reported in Canada as of January 11, 2006.
How deadly is the H5?
Currently the H5 viruses are quite deadly. We know that right now there have been about 120 documented infections and about 60 deaths, or 50 per cent mortality, which is an extraordinarily high mortality rate for any infectious disease. The 1918 virus had a fatality rate in North America of 2.5 per cent, meaning somewhere around two and a half per cent of the people who became clinically ill in 1918 ultimately ended up dying.
Of course I want you to remember that was at a time when there were no vaccines, no anti-viral drugs, no antibiotics, no respirators, no intensive care units. This was just general supportive care, or no medical care at all. In some parts of the world where there are other medical conditions, starvation, malaria, in the Third World, you saw much higher fatality rates.
I think that if a new pandemic were to emerge, I think it extremely unlikely that it would maintain the high fatality rate that we see now if it were to spread as a pandemic.
Do viruses become less lethal over time, or more lethal?
We don’t yet know the genetic basis of why one influenza virus is inherently more lethal than another, but we can say from general principles of infectious disease that highly lethal agents that kill their host very rapidly and at a very high percentage are unlikely to spread very well.
Ebola is a classic example. It’s an incredibly lethal pathogen with very high fatality rates, that does not spread efficiently at all among humans and is therefore unlikely to cause a widespread outbreak. Influenza viruses are spread very efficiently and I think one of the keys to their success, is that they cause relatively low mortality.
When that first human-to-human case occurs, what would you expect to happen next?
The most important thing for the spread of a pandemic is for it to be able to go person-to-person. And the most important thing for pandemic preparedness would be to recognize that person-to-person spread of a new virus.
The key would be how quickly the surveillance network would actually pick up a new cluster of cases and how quickly an unusual outbreak among humans somewhere in the world would be identified as being unusual.
If it’s a virus that has unusual properties, that causes people to become fairly ill, if it has relatively high fatality rates, it’s likely to be detected fairly early. But this really depends on what part of the world you are in.
I would expect that once a new pandemic virus could get into humans, and could spread person-to-person efficiently, that there would be a small chance that this pandemic could be contained – if it were identified very promptly; if the surveillance network was close to real time; if you can come in and apply anti-viral drugs to try to wipe out the spread of the virus.
I am not so hopeful about that. Influenza is pretty infectious from person to person and the real problem about containing it is that a large number of people that are infected with viruses are shedding viruses before they are even symptomatic. The quarantine and containment strategies that worked with SARS, for example, are very unlikely to work with flu.
That means you would very likely see the rapid distribution of this virus, especially in a global society where tens of thousands of people move between continents every single day in airplanes, that it is likely to spread vary rapidly to other continents. We saw with SARS that within just a few weeks, it has spread from Asia, and to Europe and to North America.
There would likely be a call to shut down travel almost immediately. How effective do you think that would be in slowing the spread?
When a pandemic first emerges, it will be very unlikely that there will be a completely matched vaccine available. The problem with influenza viruses is that because they are so variable, you can’t actually predict what the actual structure of the virus would be that might cause a pandemic. So there is no way to actually make a completely protected vaccine against a future unknown pandemic. Once this pandemic begins to spread, there would not be a vaccine available immediately.
There certainly will be some stockpiles of anti-viral drugs, which will likely be reserved for people who are critically ill, rather than for prophylactic treatment. What we are going to be left with is old-fashioned sort of public health control measures. To limit contact, to avoid crowds, I think there will be calls to close schools, to close public gatherings to limit spread of the virus. It’s likely that borders will close.
All of those things are likely to help a little bit. But ultimately, I think past experience suggests that none of those things will be very effective, and it’s likely that a pandemic virus will be able to spread, to all corners of the globe.
What can we do to protect ourselves once the virus is out in the human population?
People can limit their contact as much as possible with other individuals. If they become ill themselves, they can try to either stay at home or go to hospital if that’s possible. Of course you can just do classic preventative measures: frequently washing your hands, wearing masks is somewhat helpful, for example.
At the public health level, countries are going to implement their pandemic plans which will try to quickly ramp up the availability of vaccines and the distribution of anti-viral drugs, the creation of emergency hospitals for example, so that patients who are critically ill can have beds in hospitals and be appropriately treated.
All of these things are going to have to happen. And of course people are going to have to listen to public health authorities about what is recommended, and follow those guidelines. But ultimately, all of those things that are going to react to a pandemic are not likely to prevent its spread or actually eliminate a pandemic.
The only thing that’s likely to eliminate a pandemic is actually finding a virus, and eliminating its circulation before it becomes transmissible in humans. That is something that might be possible in the future, but is not yet possible. We just don’t know enough to do that.
What worked in 1918?
In 1918 all the things that we just described were done. They recommended people to not gather in public places: they closed theatres, they closed schools. But ultimately, society was not shut down. Despite implications of future risk by public health officials, people did go on with their lives. Commerce occurred, people continued to move around to different parts of the country.
Of course, in 1918, World War I was still on. There was an effort of all the combatant countries to move troops, and personnel and supplies back and forth, between North America and Europe. The needs of the war effort, for example, were in a sense the complete opposite of the needs of public health officials to try to slow the spread of the virus.
Ultimately, none of the containment strategies that were attempted in 1918 worked. And ultimately this virus spread everywhere.
There is a dispute about the numbers of people that died; can you talk about your views on that?
The number of people who are thought to have died directly of the virus, or as a secondary consequence of viral infection and then dying of bacterial pneumonia, or of heart failure, or of or some other medical problem but still directly linked to being infected with the virus has been growing steadily since 1918.
The earliest reports that have been compiled around 1920 or so, suggested that about 20 million people died. I think that that was ignoring much of the world. I think that was looking at North America and Europe, Australia and New Zealand predominantly. I think that scholars have looked at mortality rates around the world and have looked at the evidence that exists. I think that most epidemiologists and scholars would think that that number is much higher.
And a recent conference, in which all these data were pooled together, a best effort was made to come up with a better mortality figure. I think a number of 50 million is much more easily supported, although a number of members of this conference committee suggested that this number might even be double that, at almost 100 million.
What did death look like for people who died from the virus?
There were really two major ways in which people died. The first way was to die very rapidly, probably of the primary viral infection itself. And in those cases, people often basically drowned in their own blood or serum. You would get really severe damage into the lung, and you would actually leak blood into the air spaces of your lung. You would basically drown. And this happened in just a couple of days.
The majority of people however, probably three quarters of the people who died in 1918, actually died of secondary bacterial pneumonias. They had an initial viral infection that caused damage to their lung, and that set them up for infection with a colonizing bacterial agent. And because no anti-biotic were available in 1918, if you got a bacterial pneumonia, even as a young healthy adult, you had a 30 to 50 per cent likelihood of dying.
How personally worried are you about the threat of a pandemic from this H5 virus?
I am certainly concerned what is going on with the H5 virus, but I would not be a person who would say that we are definitely going to see a pandemic or that it’s imminent. I think that it’s a virus that has a number of very concerning properties: it has a very highly pathogenic virus for domestic poultry, like chickens and other bird species, and so is a major agricultural and economic importance. This virus has the ability to completely devastate the farming industry in any country that it gets into. But in addition to that, there are some other features to the H5 virus that are unique and very worrisome.
One is that it has gotten into a small number of people. But it is a growing number. It’s a virus that is very pathogenic in other animals. It’s caused lethal outbreaks in tigers and other large cats in zoos. It has gotten into wild bird populations and gotten into wild birds, which is something that pathogenic chicken viruses have not been known to do in the past.
So this virus is spreading not only by the spread of agriculture and domestic poultry from one area to another, but now actually looks to be spread by wild bird viruses. These features are all really concerning.
But you know, ultimately there is no evidence that this virus has been able to be transmitted efficiently from person-to-person. And we don’t understand why that is.
What I am most concerned about is that we don’t have enough information to make an accurate prediction of what will happen.
The difficulty is trying to deal with something that occurs on a very irregular basis. We know that pandemics happen. Just like tsunamis happen, or earthquakes. But we don’t understand the rules governing the formation of pandemics.
They were certainly no periodicity to the emergency of pandemics, so to say that we are overdue, I think is a bit over-speaking what we actually face. We know, looking back in history, that on average, every 30 or 40 years you see a pandemic. Sometimes that may be as early as nine or ten years between pandemics, sometimes as large as 70 or 80 years between pandemics, but on average about every 30 years or so.
There is certainly no way to say we are due just by timing. It has been 37 years since the last pandemic. We are above the average now, but we could still go for a while. Unfortunately we just can’t predict. The only thing we can do is to say with some confidence that it’s quite likely that at some point in the future there will be a pandemic, and try to do what we can to prepare for it.
Trying to prepare for a very unlikely event, even if it’s one with devastating potential like a pandemic, is difficult. It’s difficult to apply money and planning at a governmental level and a political level to do something and to maintain the public interest in something that only occurs less than once a generation.
When friends and family ask you what they should do to prepare for a pandemic what do you tell them?
I recommend that everyone that is able to get an influenza vaccine every year should do so, that having the vaccine is not only good for individual human health, but reduces the spread of the virus to other people, and to people that would have a very severe outcome with that infection – the elderly, or people with chronic illnesses. Reducing the spread of influenza in humans is quite positive.
People should take standard precautions. In the flu season, people should try to avoid crowds whenever possible. They should wash their hands frequently; they should seek medical attention if they get an influenza-like illness.
I think that it would be a mistake for people to think that they would need to have Tamiflu and any other anti-influenza drugs in their medicine cabinets, and at the first media reports that there might be a new pandemic to immediately take the drugs without any evidence of the virus spreading in their communities. I think that people have to be very cautious about this and people have to listen to what there local, national and public health officials say.
People are saying that this could be one of the greatest risks facing humanity over the next few years. Where would you place that risk?
Pandemic influenza is clearly a very important and very serious public health problem. The sudden emergence of a virus that could make a quarter, or a third, or half of the world’s population ill within a year’s time and lead to millions of deaths and enormous economic impacts is very large. But there are so many risks that we all face, it is hard to know how to stratify an individual risk like a pandemic.
There are other risks of unusual but catastrophic events, earthquakes, tsunamis, hurricanes, at the pandemic level. There are all the chronic problems that are with us everyday that are enormous problems: starvation, chronic illness, malaria, TB, HIV, other things like that. These are all enormous problems, but just because things only happen on an occasional basis is not a reason not to do what we can to be prepared for it.