Having killed some 50 million people worldwide and disappeared in little over a year, the 1918 influenza pandemic is steeped in fear and dread in infectious disease lore. Indeed, a warning of the “return” or emergence of such a virus is often cited as the need for an improved universal flu shot and mass immunization.
Seasonal flu vaccines would likely blunt much of the virulence of the 1918 H1N1 influenza A virus. In addition, antivirals are now available; so are antibiotics to fight bacterial co-infections. On the other hand, there are large populations living now with various underlying conditions that would make them vulnerable to a virulent flu strain. Viruses were not yet discovered in 1918, so public health officials literally did not know what they were facing and certainly had few diagnostics to detect it.
Without these protections, a virus that was both highly virulent and extremely transmissible exacted a horrible price, infecting roughly 500 million people, or one-third of the world’s population then. It killed an estimated 675,000 people in the U.S., lowering life expectancy for men and women by 12 years, according to the CDC.1
As one author described it, the 1918 pandemic “killed more people in a year than the Black Death of the Middle Ages killed in a century; it killed more people in 24 weeks than AIDS has killed in 24 years.”2
Not surprisingly, there was some consternation and concern when the CDC and research partners decided to resurrect and reconstruct the virus in the early 2000s. This concern was certainly not lessened by the ghoulish detail that some of the genetic material was recovered from 1918 flu victims buried in the frozen tundra of an Alaskan village.
With the help of researchers at the Armed Forces Institute of Pathology, Terrence Tumpey, PhD, a microbiologist and chief of the immunology and pathogenesis branch in the CDC’s influenza division, successfully reconstructed the 1918 virus in 2004. He conducted several experiments with the live 1918 virus, which was then destroyed.
Tumpey and colleagues found that two genetic components combined to give the 1918 virus its lethal combination of high virulence and high transmissibility. One of these was the hemagglutinin (HA) surface protein that binds the flu virus to a cell it is infecting. The other, polymerase (PP1), was the genetic component that made high viral replication possible in 1918.
Q&A
Hospital Infection Control & Prevention caught up with Tumpey and asked him to revisit the historic research in the following interview.
HIC: Can you comment on these two genetic components that made the 1918 flu virus so deadly to a susceptible population?
Tumpey: The PP1 — polymerase proteins — are the largest influenza virus genes. You can kind of think of those as the “engine” of the virus. If it is a very efficient engine, then it will make more copies of itself. The polymerase proteins like PP1 were very efficient at allowing the virus to replicate at its high, maximum peak.
We took the reconstructed 1918 virus and used the entire genome sequence, showing it was very virulent in mice and ferrets. We sort of knew that was going to be the result. You can guess that if it was very virulent in people, it will be virulent in mammals. But we thought it was important to show which virus genes were associated with its virulence. We showed that the HA in particular, and to a lesser extent the PP1, were important for high virulence.
HIC: What was it about the HA component that made this virus so lethal?
Tumpey: It is not entirely clear what about the HA is important for its high virulence. Some of the last studies we did with the virus showed that glycosylation was important. Seasonal viruses that are circulating now are heavily glycosylated. They have a lot of sugars in their globular head, and that really attenuates the virus. Whereas the 1918 virus did not have these sugars on the top of the globular head, and we think that contributed to its virulence.
You could take the HA alone of the 1918 virus — just the HA alone — and put it on a number of seasonal flu viruses, and it results in high fatality in animals. It always raises the question of whether you can do it backward. Could we take the 1918 virus and declaw it — can we make it attenuated? We took out the HA and replaced it with a seasonal HA. We showed that the 1918 HA was important for virulence in mammals.
HIC: Is this HA component still circulating in the wild?
Tumpey: The 1918 HA does not exist in nature.
HIC: But if I understand you correctly, the HA component that was used in the vaccine created for the 2009 pandemic virus would cover the 1918 virus even if it remerged?
Tumpey: It was interesting when the 2009 pandemic virus emerged; one of the things we observed by lining up the 2009 HA and the 1918 HA we studied was that there were some similarities. In particular, the globular head and the antigenic sites. When the 2009 pandemic emerged, it was the actual HA from an old ancestor.
Because the antigenic sites were similar, one of the last experiments we did with the 1918 virus here at CDC showed that if you vaccinate ferrets with the human vaccine that we get annually — that has the H1 component — those animals are protected against the 1918 virus.
HIC: There was speculation that a lot of the 1918 deaths were caused by an inflammatory immune response — the so-called “cytokine storm” — particularly for the deaths in the young and healthy.
Tumpey: Whether that contributed to the pathogenesis was a very difficult thing to answer experimentally. So many things get turned on — all these proteins, cytokines, chemokines. There are so many that get turned on [when infection sets in]. Let’s say you have 50 of them that get turned on at a high level — compared to other viruses — well, which one is important? It was difficult to address.
Some people say this is the reason young adults had such a high mortality in 1918. Younger people have a more robust immune response, but I don’t know if I really believe that because the window of the high peak was age 15 to 35. So, does that mean when you are 42 or 45 you no longer have this robust immune response? I didn’t really believe that.
HIC: What about the reports of the overwhelming infection in the lungs?
Tumpey: Certainly, the immune response in the lungs probably contributed to a lot of deaths because the lungs became fluid-filled.
One thing we did notice, that may be underappreciated, is that we saw a lot of neutrophils that are not typically found at high levels in the lung tissue. The lungs would become filled with these neutrophils, which are white blood cells that you generally think of as combating bacteria.
We actually showed that if you knock out the neutrophils, the virus titers were higher. We think that the neutrophils were responding to the virus and that contributed to the overall pathogenesis in our animal response. Immune response probably played a role in the pathogenesis, but whether it was one particular cytokine or a cytokine storm, I’m not sure.
HIC: The general consensus is that the antibiotics we have now would prevent a lot of deaths caused by bacterial co-infections in 1918.
Tumpey: Certainly, a good number of the patients succumbed due to a secondary bacterial infection. Some, not all. There were individuals who died within a very short window of time — in less than five days. It may be safe to say that those individuals died of viral pneumonia.
HIC: The CDC has destroyed the 1918 virus you recreated. Could you still make a vaccine if you needed to?
Tumpey: It wouldn’t be hard to make a vaccine. Now influenza vaccines can be made based on sequencing only. It is commonly done with what we refer to as candidate vaccine viruses. We’ll get a sequence, and with that we can synthesize the HA. Then with the HA, we can rescue a vaccine virus.
With the technology now, you don’t have to have the virus to make a vaccine; you just need the sequence, which we have.
HIC: Why not preserve the 1918 virus as has been done with smallpox virus?
Tumpey: We had set out to rescue it, characterize it, and gain information from it. At that time, we didn’t have any other things we wanted to work on. I was really the only one working with the fully reconstructed 1918 virus.
So, it was the CDC’s decision that they would do this, but I would be the only one working on it. If we ever wanted to work on it again, we could potentially do it. We would have to get approval again, but we could do it. People have 1918 plasmids and are working with it. We just decided we didn’t want it sitting in the freezer in case something happened.
HIC: When these experiments began, there was a lot of concern about it being used as a bioterrorism weapon.
Tumpey: Now that there is immunity to the 1918 virus, I don’t think it would be a very potent BT agent. The 2009 pandemic [strain] is circulating annually, and it has antigenic sites and HA like the 1918 virus.
HIC: There was a plan that you would go into quarantine if you were exposed or became symptomatic. How concerned were you for your personal safety and the risk of introducing the virus in the community?
Tumpey: Based on our BSL-3 laboratories’ safety policies and procedures, we felt it was perfectly safe to work with this virus. It is a really safe environment, and we felt like we could conduct these activities without risk.
I wasn’t worried myself, though we obviously needed policies in place in case something did happen. The idea was I would be quarantined in my house and my family would have to go to a hotel.
REFERENCES
- CDC. History of 1918 Flu Pandemic. March 21, 2108. Available at: https://bit.ly/2LWP2MJ.
- Barry, JM. The Great Influenza: The Story of the Deadliest Pandemic in History. 2004. Viking Books: New York, New York, USA.
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