The Origin and Control of Pandemic Influenza

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Science  07 Sep 2001:
Vol. 293, Issue 5536, pp. 1776-1777
DOI: 10.1126/science.1063817

A worldwide epidemic (pandemic) of type A influenza [HN1] could occur at any time. Such an event will be caused by a “new” virus against which the human population has no immunity, and past experience indicates that this new virus will probably arise in China. With today's crowded conditions and rapid transportation, the epidemic is expected to reach every corner of the globe. Millions of people will become ill, and many will die.

Why was the flu virus that caused the “Spanish influenza” pandemic of 1918 [HN2]—in which more than 20 million people died—so virulent? Fragments of RNA from the 1918 strain have been obtained from lung samples of flu victims preserved in pathology museums or frozen in the Alaskan permafrost. These RNA pieces have yielded the complete sequences of the genes for three crucial flu virus proteins: hemagglutinin, neuraminidase, and nonstructural protein [HN3]. But, so far there are no obvious features in these sequences that hint why the 1918 virus was so virulent. The phylogenetic reanalysis of hemagglutinin gene sequences from humans, birds, and pigs by Gibbs et al. [HN4] (see page 1842 for the report, and page 1773 for the Perspective) suggests that the 1918 virus hemagglutinin gene was a recombinant [HN5], and that the recombination event occurred at about the same time as the Spanish flu pandemic started (1). Whether this recombination in the hemagglutinin gene was the trigger that caused the virus to be so virulent is not yet known.

One mechanism by which influenza viruses with “new” antigens can enter the human population is through genetic reassortment [HN6] between established human viruses and animal or bird viruses with different hemagglutinin and neuraminidase [HN7] antigens. The 1957 (Asian) and 1968 (Hong Kong) strains [HN8] arose in this way. It is clear, however, that new human pandemic viruses may arise in other ways. The avian influenza virus (subtype H5N1) that infected 18 Hong Kong residents in 1997 [HN9], killing 6, was not a reassortant—all of its genes were of avian virus origin. This highly lethal chicken virus had spread from chickens to people but had not learned to spread from person to person, and the epidemic was stopped by killing all the chickens in Hong Kong. Now, in 2001, another H5N1 virus has appeared in the live chicken markets in Hong Kong [HN10]. So far this virus does not appear to have infected anyone, and it differs from the 1997 H5N1 virus in its internal genes. Nevertheless, all of the chickens in Hong Kong have again been slaughtered as a precaution.

With reverse genetics [HN11], Hatta and colleagues [HN12] (see page 1840 for the report, and page 1773 for the Perspective) have reconstructed some of the H5N1 viruses that killed the six people in Hong Kong in 1997 in an attempt to find out why this avian virus was so virulent for humans (2). They were able to divide the H5N1 viruses into two groups with high (HK483) or low (HK486) pathogenicity in mice. Reassortment experiments showed that it was the PB2 gene encoding one of the internal polymerase proteins, together with the high cleavability of the hemagglutinin, that seemed to be responsible for the difference in virulence (for mice) between the two groups of viruses.

What can be done if a new influenza virus suddenly appears and spreads with alarming speed around the world? Slaughter and quarantine of people is not an option and vaccines would take some time to develop. So, antiviral neuraminidase inhibitors [HN13] might provide the first line of defense against a new flu virus. Neuraminidase—one of the glycoprotein “spikes” on the surface of the influenza virus—is an enzyme that cleaves sialic acid residues from receptors for the virus, enabling the virus to spread throughout the body. Inhibition of this enzyme stops this spread and effectively curtails the infection.

Two inhibitors specific for influenza virus neuraminidase are currently being used to control influenza infections, and two others are under development. Relenza (4-guanidino-Neu5Ac2en) was invented in Australia and is marketed by Glaxo-SmithKline [HN14] (see the figure). The other, Tamiflu [4-acetamido-5-amino-3-(1-ethylpropoxyl)-1-cyclohexene-1-carboxylic acid ethyl ester], was invented by Gilead Sciences and is marketed by Hoffman-LaRoche [HN15]. Passage of influenza virus in the presence of these inhibitors, either in vitro or in clinical trials, has led to the selection of drug-resistant viral mutants (3). These are of two kinds: those with sequence changes in the hemagglutinin, and those with sequence changes affecting the catalytic site on the neuraminidase. Drug resistance, however, may not be a problem if and when the drugs are used widely in the community to control influenza (3). Although these compounds are able to stop virus replication, they cannot repair the damage already done by the virus; hence, the drugs must be given very soon after the initial infection in order to be effective. Relenza is a powder inhaled into the lungs; Tamiflu is a pill. These drugs are effective only against the influenza virus, and not against other viruses or bacteria that cause clinical symptoms similar to those of the flu.

Beating the flu.

Crystallographic structure of influenza virus neuraminidase (N9 subtype) showing the rationally designed anti-flu drug, Relenza (4-guanidino-Neu5Ac2en), bound to the active site of the enzyme. The drug is represented as an atom-colored ball-and-stick model (yellow, carbon; blue, nitrogen; red, oxygen). The neuraminidase catalytic site (conserved among all influenza A viruses) is shown with the closer carbon atoms in black and those farther away in gray. (Drawn with MolScript and rendered in Raster3D).

Clearly, rapid, sensitive, simple and cheap diagnostic tests for influenza are needed for the neuraminidase inhibitors to be used effectively in the community. Furthermore, because general practitioners are likely to be swamped with flu patients in the event of an epidemic, it is desirable that these tests be available for use in the local pharmacy or even at home. One such diagnostic test under development by ZymeTx Inc. (Oklahoma, USA) uses a substrate that is specific for influenza neuraminidase and is not cleaved by the neuraminidases of other viruses or bacteria that are likely to be present in the respiratory secretion samples (3). This test, which uses a chemiluminescent reporter group and sensitive Polaroid film, is highly accurate and suitable for use in the local pharmacy. Another diagnostic test under development by Biota Holdings (Melbourne, Australia) and BioStar (Colorado, USA) uses a silicon chip biosensor and optical immunoassay technology (3). The chip has antibodies to flu A and B nucleoproteins attached to its surface, and the refractive index changes if these antigens are present in the test sample, yielding a purple color easy to see by eye. Both of these tests give a result in no more than 20 min [HN16].

It is doubtful whether vaccination would be useful in controlling an influenza pandemic, at least in the early stages. Such an exercise was, in fact, attempted in January 1976, when a swine flu outbreak occurred among army recruits at Fort Dix, New Jersey [HN17] (4). It was thought that the 1918 “Spanish influenza” virus might have returned, prompting President Ford to authorize the expenditure of $350 million to “vaccinate every man, woman, and child in the U.S.A.” This mass vaccination program experienced a number of problems—low antibody titer, vaccine side effects, and litigation tangles—that could happen again if such an exercise were ever to be repeated. (The expected pandemic never materialized.)

The influenza vaccines currently in use are inactivated subunit vaccines containing hemagglutinin and neuraminidase obtained from various strains of cultured flu virus. They are reasonably effective against the strain used to make the vaccine and are cost-effective. However, it would be difficult to make, test, and safety-test enough vaccine in time to protect many people against a new virus. Vaccines currently being developed may show more promise. These include vaccines prepared by reverse genetics, DNA vaccines, vaccines against the conserved regions of the M2 ion channel of the flu virus, and even vaccine “cocktails” containing all known hemagglutinin subtypes [HN18].

But the most promising first line of defense does seem to be antiviral drugs, and of those currently available, the neuraminidase inhibitors, although expensive, appear to be the best. Use of these drugs in the face of an exploding influenza epidemic would, however, be beset with immense social, political, economic, and logistical problems. For the drugs to be of any use, huge quantities would need to be immediately available, and means for their rapid distribution would need to be in place beforehand. Supplies of these drugs at the moment are woefully inadequate. In addition, the companies producing the drugs now seem to have a diminished interest in influenza—possibly because the last flu season was the lightest for many years, and little demand for neuraminidase inhibitors meant few sales and meager profits for the pharmaceutical companies involved. The concept that it is hard to sell umbrellas in a drought seems to have escaped them!

Imagine the following: Somewhere in China, an influenza virus, subtype H9N2, suddenly acquires the ability to infect humans. The virus is highly infectious and highly transmissible, although the disease it causes is fairly mild. Because of this, perhaps, the identity of the new strain is determined only after it has infected a large number of people in China. Some of them carry the new virus into Hong Kong, others into Taiwan, and still others into a number of other countries. There is an explosive pandemic, much social and economic disruption, and a good deal of misery among the victims. Rapidly growing strains of the new virus are created, and vaccine production starts but progresses slowly. The neuraminidase inhibitors Relenza and Tamiflu are eagerly sought but are in very short supply. Who should get these new drugs? Health care workers and those in essential services, obviously, but who will identify them? Even then, there will not be nearly enough of the drugs for all those who need them in the developed world, let alone the rest of the world's population.

The answer seems to be: Stockpile these drugs now, in huge quantities. Their shelf life has not yet been determined, but they are simple chemical compounds and there is no reason to suppose they are not stable. In any case, it would be possible to replace the stockpile every 5 years or so. The cost of making the drugs, as opposed to the prices the pharmaceutical companies charge consumers, would not be exorbitant. Such an expenditure by governments would be a worthwhile investment in their defense against this debilitating and often deadly illness.

HyperNotes Related Resources on the World Wide Web

General Hypernotes

This issue of Science has a related Enhanced Perspective by R. G. Webster titled “A molecular whodunit.”

Dictionaries and Glossaries

The On-line Medical Dictionary is provided by CancerWeb.

The InteliHealth Web site makes available the Merriam-Webster Medical Dictionary.

The Academic Press Dictionary of Science and Technology is made available by the publisher Harcourt.

Web Collections, References, and Resource Lists

The library of the Karolinska Institutet, Stockholm, provides links to biomedical information resources on the Internet. A section on virus diseases is included.

MEDLINEplus, a resource maintained by the U.S. National Library of Medicine, provides reference information and links to Internet biomedical resources.

The Google Web Directory offers collection of virology Internet resources.

The WWW Virtual Library of Microbiology and Virology is maintained by S. Sutton of the Microbiology Network.

All the Virology on the WWW is a resource collection of virology information maintained by D. Sanders.

The National Center for Infectious Diseases (NCID) of the U.S. Centers for Disease Control and Prevention (CDC) offers an influenza information Web page.

The Communicable Disease Surveillance and Response (CSR) division of the World Health Organization (WHO) provides an influenza information page. FluNet is WHO's geographical information system to monitor influenza activity. The WHO Collaborating Centre for Reference and Research on Influenza, Melbourne, provides an introduction to influenza and Internet links.

The Division of Microbiology and Infectious Diseases of the U.S. National Institute of Allergy and Infectious Diseases (NIAID) offers an information page on influenza.

GlaxoSmithKline's Worldwide Vaccines Web site includes an information page on influenza.

Online Texts and Lecture Notes

J. Kimball presents Kimball's Biology Pages, an online biology textbook and glossary. Presentations on viruses and on influenza are included.

Medical Microbiology is an online textbook edited by S. Baron, Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston. A chapter by R. Couch on the orthomyxoviruses and a chapter by W. R. Fleischmann on viral genetics are included.

Microbiology and Immunology On-line from the Department of Microbiology and Immunology, University of South Carolina School of Medicine, offers lecture notes on virology. A presentation by M. Hunt on the influenza virus is included.

The Department of Microbiology and Immunology, University of Leicester, UK, makes available lecture notes and other resources for a virology course; an overview of orthomyxoviruses is included. The Infection & Immunity Web page provides a microbiology glossary and a virology glossary.

The University of Florida Continuing Medical Education Web site makes available a tutorial on influenza by P. Small and B. Bender.

M. Hewlett, Department of Molecular and Cellular Biology, University of Arizona, offers lecture notes for a virology course.

A student project on the influenza virus was prepared for a Brown University course on the development of vaccines to infectious diseases taught by A. De Groot and P. Knopf. A student presentation on antigenic variation with a section on influenza is also available.

General Reports and Articles

The World Congress on Medicine and Health 2000 Web site makes available a conference paper by R. Webster et al. titled “Influenza - Challenges for the new millennium.”

The 1 April 1996 issue of the Annals of Internal Medicine had an editorial by P. Gross titled “Preparing for the next influenza pandemic: A reemerging infection.”

Firepower in the Lab: Automation in the Fight Against Infectious Diseases and Bioterrorism, a 2001 book based on a symposium, edited by S. Layne et al. and available online from the National Academy Press, includes a chapter by J. Taubenberger titled “Sequencing influenza A from the 1918 pandemic, investigating its virulence, and averting future outbreaks.”

The January 1999 issue of Scientific American had an article by W. G. Laver, N. Bischofberger and R. Webster titled “Disarming flu viruses.”

The March-April 1999 issue of the CDC's Emerging Infectious Diseases had an article by R. Snacken et al. titled “The next influenza pandemic: Lessons from Hong Kong, 1997.”

The August 1997 issue of the Journal of Infectious Diseases had a supplement on pandemic influenza.

Numbered Hypernotes

1. Type A influenza and the pandemic threat. Epidemic and pandemic are defined in the dictionary of epidemiology provided by J. Swinton. Kimball's Biology Pages provides an introduction to the influenza A virus. WHO provides a fact sheet on influenza A (H5N1). The Worldwide Vaccines Web site includes presentations on influenza epidemics and influenza pandemics. Epidemic! The World of Infectious Diseases is an online exhibit presented by the American Museum of Natural History. The CDC's National Vaccine Program Office offers a presentation on pandemic influenza. The WHO CSR division makes available an influenza pandemic preparedness plan. offers a 22 February 1999 article titled “The flu pandemic of 1918: Is a repeat performance likely?” and an 8 March 1999 article titled “Eighty years later, threat of influenza pandemic remains large,” both by D. Rekenthaler. The 7 June 2001 issue of the Far Eastern Economic Review had an article by D. Lague titled “A deadly flu ready to strike.” The 3 December 1999 issue of Science had a research article by R. Bush et al. titled “Predicting the evolution of human influenza A.”

2. The “Spanish” influenza pandemic of 1918. R. Bender, Department of Biology, University of Michigan, provides lecture notes on the 1918 influenza pandemic for a course on AIDS and other health crises. R. Siegel makes available a student presentation by M. Billings about the Influenza Pandemic of 1918 on his Human Virology Web page. Influenza 1918 is presented by PBS Online. The P. L. Duffy Resource Centre, Trinity College, Western Australia, provides a collection of links to Internet resources on the 1918 influenza epidemic.

3. Sequencing the genes of influenza virus proteins. The 21 March 1997 issue of Science had a report by J. Taubenberger et al. titled “Initial genetic characterization of the 1918 'Spanish' influenza virus” and a Research News article by E. Pennisi about the research. The 27 February 2001 issue of the Proceedings of the National Academy of Sciences had an article by C. Basler et al. titled “Sequence of the 1918 pandemic influenza virus nonstructural gene (NS) segment and characterization of recombinant viruses bearing the 1918 NS genes” and a commentary by J. Lederberg titled “H1N1-influenza as Lazarus: Genomic resurrection from the tomb of an unknown.” The 6 June 2000 issue had an article by A. Reid et al. titled “Characterization of the 1918 'Spanish' influenza virus neuraminidase gene.” The 16 February 1999 issue had an article by A. Reid, T. Fanning, J. Hulton, and J. Taubenberger titled “Origin and evolution of the 1918 Spanish influenza virus haemagglutinin gene” and a commentary on the research by R. Webster titled “1918 Spanish influenza: The secrets remain elusive.”, provided by the International Influenza Education Panel, makes available an article by J. Oxford titled “Recovery of Spanish 1918 influenza virus genes from formalin-fixed and frozen respiratory tissues.”

4. M. J. Gibbs, J. S. Armstrong, and A. J. Gibbs are in the Division of Botany and Zoology, Australian National University, Canberra.

5. Recombination. PBS's Influenza 1918 includes a section about recombinant viruses. Wong's Virology Web site provides an introduction to recombination and other mechanisms of genetic variation in RNA viruses.

6. Reassortment. Reassortment is defined in the Academic Press Dictionary of Science and Technology. The On-line Medical Dictionary defines reassortant viruses. Flu Season, a presentation of the University of Wisconsin's WhyFiles, includes a section on genetic drift and reassortment.

7. Hemagglutinin and neuraminidase. The Viruses: From Structure to Biology Web site, made available by Washington University School of Medicine, provides introductions to hemagglutinin and neuraminidase in the influenza virus. Student presentations on hemagglutinin and neuraminidase were prepared for a biochemistry course taught by K. Moreman, Department of Biochemistry and Molecular Biology, University of Georgia.

8. The 1957 Asian and 1968 Hong Kong viruses. The CDC's National Vaccine Program Office provides information about the 1957 Asian flu and the 1968 Hong Kong flu pandemics. Kimball's Biology Pages includes a section on the 1957 and 1968 influenza pandemics in the presentation on influenza.

9. The 1997 Hong Kong avian influenza virus subtype H5N1. The CDC's NCID provides information about Influenza A(H5N1) in Hong Kong. A section on the 1997 avian flu outbreak in Hong Kong is included in a presentation by N. Cox titled “Bird flu and influenza updates” prepared for a lecture series on emerging infections of international public health importance offered by the School of Public Health and Community Medicine, University of Washington. Time magazine makes available a 23 February 1998 article by E. Larson about the 1997 Hong Kong flu outbreak titled “The flu hunters.” NIAID Council News had a February 1998 article titled “NIAID in front lines of Hong Kong flu crisis.” The 12 September 1997 issue of Science had a News and Comment article by J. Cohen titled “The flu pandemic that might have been.” The 16 January 1998 issue had a report by K. Subbarao et al. titled “Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness” and a Research News article by G. Vogel titled “Sequence offers clues to deadly flu.” makes available a 28 December 1997 article titled “Hong Kong to kill 1 million chickens to contain 'bird flu'.”

10. Chicken virus H5N1 outbreak in Hong Kong in 2001. CSR's Disease Outbreak News Web site includes 17 May 2001 and 18 May 2001 reports on the 2001 chicken virus in Hong Kong. The Center for Emerging Issues of the U.S. Department of Agriculture provides a 29 May 2001 impact worksheet titled “Avian influenza, Hong Kong.” The Environmental News Network makes available a 28 May 2001 news article titled “1.2 million birds killed to combat Hong Kong's avian flu.”

11. Reverse genetics. The On-line Medical Dictionary defines reverse genetics. Reverse genetics is defined in the genetics glossary provided by the Biology Teaching Organisation, University of Edinburgh, UK. The Human Molecular Genetics On-Line Teaching Site offered by the Department of Biological Sciences, Brunel University, London, provides an introduction to reverse genetics in the section on molecular techniques. The Kawaoka Laboratory Web site provides a research presentation titled “Reverse genetics - Generation of influenza viruses entirely from cloned cDNA.” The 3 August 1999 issue of the Proceedings of the National Academy of Sciences had an article by G. Neumann et al. titled “Generation of influenza A viruses entirely from cloned cDNAs” and a commentary by A. Pekosz, B. He, and R. Lamb titled “Reverse genetics of negative-strand RNA viruses: Closing the circle.”

12. M. Hatta, P. Gao, P. Halfmann, and Y. Kawaoka are at the Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin.

13. Neuraminidase inhibitors. “Influenza: Introduction of the neuraminidase inhibitors” is a research news presentation of the Paul-Ehrlich-Society of Germany. offers a presentation on neuraminidase inhibitors. The 17 December 1999 issue of MMWR (Morbidity and Mortality Weekly Report) had a report titled “Neuraminidase inhibitors for treatment of Influenza A and B infections.” NIAID provides a fact sheet on neuraminidase inhibitors drugs. The November 1999 issue of Influenza, the bulletin of the European Scientific Working Group on Influenza had an article by W. G. Laver titled “Controlling influenza by inhibiting the virus's neuraminidase.” The 25 November 1998 issue of JAMA had a medical news article by J. Stephenson titled “Progress treating, preventing influenza” with a section on neuraminidase inhibitors.

14. Relenza. Biota Holdings Limited, Melbourne, provides information about Relenza. GlaxoSmithKline provides product information (in Adobe Acrobat format) for Relenza. Relenza, a student project by N. Sanderson for the Chemistry Department, Imperial College of Science, Technology and Medicine, London, is available on the Exemplarchem Web site of the Chemical Societies Network. The Physicians' Desk Reference, available on the Health and Age Web site from the Novartis Foundation for Gerontology, provides information about Relenza. The FDA Center for Drug Evaluation and Research provides information on Relenza. NOVA: Science in the News from the Australian Academy of Sciences offers a presentation titled “The end of influenza?” about the development of Zanamivir.

15. Tamiflu. Hoffmann-La Roche Inc. offers a Tamiflu information page with links to Tamiflu product information and a Tamiflu Web site, which includes an introduction to neuraminidase inhibition. Gilead Sciences provides information about Tamiflu. The Physicians' Desk Reference includes information about Tamiflu. The FDA Center for Drug Evaluation and Research provides information on Tamiflu.

16. New diagnostic tests. ZymeTx, Inc. provides information about the ZstatFlu diagnostic test for influenza. ZymeTx's National Flu Surveillance Network makes available a 31 October 2000 press release titled “ZymeTx and Polaroid form strategic alliance for next-generation infectious disease diagnostic platform.” Biota provides information about the Flu OIA diagnostic test kit and its technology. Thermo BioStar provides a product information page about the diagnostic test.

17. The 1976 swine flu scare. The CDC's National Vaccine Program Office provides information about the 1976 swine flu outbreak. The Department of Biology, Haverford College, PA, makes available a student paper by J. Warner titled “The sky is falling: An analysis of the swine flu affair of 1976.” The Capital Century 1900-1999, a history of the Trenton-Princeton, NJ, area, includes an article by P. Mickle about 1976 swine flu scare. The August 1997 supplement issue of the Journal of Infectious Diseases had an article (available in Adobe Acrobat format) by W. Dowdle titled “The 1976 experience.” The Drugs & Devices Information Line provided by the Pharmacoepidemiology Program, Harvard School of Public Health, makes available a presentation by E. Laitin and E. Pelletier titled “The influenza A/New Jersey (swine flu) vaccine and Guillain-Barré syndrome: The arguments for a causal association.”

18. Influenza vaccines. The CDC's NCID provides an information sheet on influenza vaccines. The 20 April 2001 issue of MMWR had a report titled “Prevention and control of influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP).” The February 2001 issue of Scientific American had an article by M. Fischetti on flu vaccines titled “Preparing for battle.” GlaxoSmithKline's Worldwide Vaccines Web site provides information about influenza vaccines and vaccination. Aviron offers a presentation about influenza vaccines. A presentation on vaccines by R. Hunt, Department of Microbiology and Immunology, School of Medicine, University of South Carolina, is made available by the department's Microbiology and Immunology On-line Web site. The Department of Microbiology and Immunology, University of Leicester, UK, makes available lecture notes on viral vaccines for a microbiology course. NIAID provides a 2 March 2000 press release about the Jordan Report: Accelerated Development of Vaccines; a section on influenza vaccines begins on page 49 of the report (which is made available in Adobe Acrobat format). The August 1997 supplement issue of the Journal of Infectious Diseases had an article (in Adobe Acrobat format) by P. Palese et al. titled “Development of novel influenza virus vaccines and vectors.” The July 1999 issue of Scientific American had an article by D. Weiner and R. Kennedy titled “Genetic vaccines.” The Vaccine Page provides access to news about vaccines and an annotated database of vaccine resources on the Internet.

19. Graeme Laver is at the John Curtin School of Medical Research, Australian National University, Canberra.

20. Elspeth Garman is in the Laboratory of Molecular Biophysics, University of Oxford.

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