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Re-creation of the 1918 influenza virus: The work is beginning to pay off
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The re-creation of the 1918 influenza virus is arguably perhaps the most dramatic and astonishing biological achievement so far in the 21st century. Building upon the groundbreaking work of Taubenberger et al, (Nature, 2005;437:889) who established the molecular structure of the 1918 virus, Terry Tumpey and a team of scientists from the CDC, National Institute of Allergy and Infectious Disease and Mount Sinai School of Medicine in New York City (Science, 2005;310:77) re-created the whole virus using the techniques of reverse genetics. The work was carried out entirely in the biosafety level 3 enhanced (BSL3) laboratory at CDC.
The term “groundbreaking” is doubly appropriate in describing the work of Taubenberger and his colleagues, since some of the virus sequences were derived from exhuming the bodies of several Alaskan natives who were believed to have been killed by the 1918 pandemic, and whose bodies were permanently preserved in the Alaskan permafrost. The entire virus sequence has now been published in a series of about eight papers published sequentially beginning in the late 1990s.
The virus generated in the CDC laboratories by Tumpey et al, was extremely “hot” by any measure. It was extraordinarily virulent. In contrast to contemporary H1N1 viruses, it caused death in mice and embryonated chicken eggs, and grew very well in human bronchial epithelial cells. Virus titers in mice four days after infection with the 1918 virus were 39,000 times higher than titers following inoculation with a recent H1N1 strain.
Interestingly, all eight gene segments of the virus had to be present to achieve maximum virulence. Substitution of any gene segment with one from a contemporary H1N1 virus resulted in somewhat decreased virulence. The whole virus generates a level of virulence never previously observed for any influenza virus.
Why was this work done? It’s really very simple. We are assuredly going to face an influenza pandemic sometime in the future, whether due to an H5, H7 or H9 virus or perhaps some other hemagglutinin. Anything that we can possibly learn about the virulence determinants of this extraordinary 1918 virus will surely put us in a better position to deal with the next pandemic.
This work has been criticized for one of two reasons. First, some argue that once such a virulent virus is generated, it is quite likely that somewhere, sometime, it will escape containment and get out into a population that may be highly susceptible. The several laboratory escapes of the SARS virus have been cited as examples. Terrence Tumpey argues that, should such an event occur in spite of all containment efforts, the population at large has some N1 antibody as a result of either natural infection by H1N1 virus or immunization with current vaccines that contain N1 antigen and that such neuraminidase antibody might confer some level of protection against life-threatening illness or death.
Whether that is indeed true is obviously not known at this time.
The second criticism derives from the fact that the virus sequences are published and are therefore public information. Thus, it may be argued that any madman with several hundred million dollars to spend could theoretically build and equip the necessary laboratories and perhaps recruit enough unethical scientists to recreate this virus and perhaps transfer some of its virulence determinants into other viruses to create an entirely new agent of biological warfare.
It is a given, of course, that there are no absolute guarantees of safety. Responsible authorities believe, however, that the benefits to be realized by this work more than outweigh the risks. Both Tony Fauci from NIAID and Julie Gerberding from CDC jointly approved this work before it was undertaken.
The payoff, in terms of new information we are learning, is already starting to occur, albeit slowly. Wing-pui Kong, et al (PNAS, 2006;103: 15987) from the same group of investigators at CDC, NIAID, and the Mount Sinai University School of Medicine, created short strands of DNA from the 1918 virus and used it as a naked DNA vaccine in mice. It induced both cellular and humoral immunity; injected mice showed complete protection against lethal challenge. T-cell depletion had no effect on protection, suggesting that protection was mediated entirely by humoral HAI antibody. This was subsequently confirmed by passive transfer of purified IgG and subsequent rechallenge.
Most recently, Tumpey et al, again from the same group (Science, 2007; 315: 655), reported that only a modest 2-amino acid change in the hemagglutinin receptor binding site of the 1918 virus changed the receptor binding preference from the human (alpha) 2,6 to the avian (alpha) 2,3 sialic acid and created a virus that would not transmit from ferret to ferret. This suggested that a predominant human (alpha) 2,6 binding site preference is necessary for optimal transmission of this virus. Could a similar set of mutations change the H5N1 avian virus into a human pandemic disaster?
Thus, slowly but surely, we are beginning to learn more about the inner workings of the 1918 virus, and it isn’t all encouraging. What is encouraging is that eventually, as we learn more, we will inevitably acquire some ability to interdict, control or modify a putative pandemic virus or to create better immunologic defenses against it. There is much, much more yet to learn about the reasons for the extraordinary events of 1918-19.
For more information:
- Theodore C. Eickhoff, MD, is an Emeritus Professor in the Division of Infectious Diseases for the Department of Medicine at the University of Colorado Health Sciences Center in Denver. He is the Chief Medical Editor for Infectious Diseases in Children’s sister publication, Infectious Disease News.