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6. It is not possible at present to deduce which genes of in uenza govern virulence. It is quite likely that all eight genes contribute to virulence. Additionally, there may need to be an equable t between particular genes of particular in uenza A viruses. Even the virulence of the 1918 pandemic virus is not understood. Therefore, at the present moment, it would not be possible to deliberately construct a hypervirulent in uenza A virus. 7. Recent techniques such as reverse genetics could be applied to the construction of a hypervirulent in uenza A virus should data become available on precise gene structures causing virus virulence within the next 2 3 years. Until this time, a bioterror scienti c program would be restricted to using random gene inserts and subsequent animal passage selection of potentially new hypervirulent viruses. This would entail a large scienti c team and extensive facilities and resources. It is unlikely that any country would be able to initiate such a program without leakage of knowledge into the scienti c community. 8. The old Greek Hippocratic oath may need to be revisited for scientists to discourage their skills being used under any guise which could result in the construction of hypervirulent in uenza or other viruses. 9. The WHO is encouraging every country to produce a pandemic plan dealing with decisions about priority groups for in uenza vaccines, antivirals and vaccine stockpiling, and intensive surveillance. These important documents could double as a counter-bioterrorist plan. 10. New technologies of the use of mammalian (Vero and MDCK) cells for in uenza vaccine production will increase world capacity very signi cantly and allow more rapid vaccine production to cope with production surge during the lead up to a pandemic or a deliberate release. 11. New and existing developments with killed intranasally applied vaccines, live attenuated viruses, new adjuvants, or new virus vectors provide extra security against emergence of a novel in uenza A virus. 12. Each country should now stockpile anti-in uenza A M2 blockers and NIs for one-half of the population for immediate use. Seed vaccine stocks for H1-16 should also be prepared and stockpiled to blunt the rst wave with a vaccine that would, at the very least, provide immunological priming even in the absence of detectable HIA antibody.
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ACKNOWLEDGMENTS The authors were supported by a grant from the Wellcome Trust. Retroscan Virology is part of the EU Network of Excellence for Antiviral Drug Reistance (VIRGIL).
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1. Phillips, H.; Killingray, D. The Spanish in uenza pandemic of 1918 1919: new perspectives. Routledge Social History of Medicine Series, 2002. 2. Churchill, W. S. The Great War, Vols. 1 and 2, George Newnes Ltd., London, 1993. 3. Crosby, A. W. America s Forgotten Pandemic. Cambridge University Press, New York, 1989. 4. Medical Research Committee. Special Report Series No 36. Studies of In uenza in Hospitals of the British Armies in France, 1918, HM Stationary Of ce, London, 1919, p.112. 5. Report on the Pandemic of In uenza 1918 1919. Reports on Public Health and Medical Subjects, No 4. H.M. Stationary Of ce, London, 1920. 6. Lo, K. C.; Geddes, J. F.; Daniels, R. S.; Oxford, J. S. Lack of detection of in uenza genes in archived formalin- xed, paraf n wax-embedded brain samples of encephalitis lethargica patients from 1916 1920. Virchows Arch. 2003, 442, 591 596. 7. Oxford, J. S. In uenza A pandemic of the 20th century with special reference to 1918: virology, pathology and epidemiology. Rev. Med. Virol. 2000, 10, 119 133. 8. Macpherson, W. G.; Herringham, W. P.; Elliott, T. R.; Balfour, A. Medical Services Diseases of the War. Vol 2. Medical Aspects of Aviation and Gas Warfare and Gas Poisoning. MSO, London, 1927. 9. Enserink, M. U.S. monkey pox outbreak traced to a Wisconsin pet dealer. Science 2003, 300, 1639. 10. Collier, L.; Oxford, J. S. Human Virology: A Text for Students of Medicine. Oxford University Press, Oxyford, 2002. 11. Wood, J. M. Developing vaccines against pandemic in uenza. Philos. Trans. R. Soc. London 2001, 356(1416), 1953 1960. 12. Fedson, D. S. Pandemic in uenza and the global vaccine supply. Clin. Infect. Dis. 2003, 36(12), 1552 1561. 13. Stuart-Harris, C. H.; Schild, G. C.; Oxford, J. S. In uenza, the Viruses and the Disease, Edward Arnold, London, 1983. 14. Betts, R. F.; Treanor, J. J. Approaches to improved in uenza vaccination. Vaccine 2000, 18, 1690 1695. 15. Fedson, D. S.; Wajda, A.; Nichol, J. P.; Hammond, G. W.; Kaiser, D. L.; Roos, L. L. Clinical effectiveness of in uenza vaccination in Manitoba. JAMA 1993, 270, 1956 1961. 16. Nichol, K. L.; Nordin, J.; Mullooly, J.; Lask, R.; Fillbrandt, K.; Iwane, M. In uenza vaccination and reduction in hospitalisations for cardiac disease and stroke among the elderly. N. Engl. J. Med. 2003, 348, 1322 1332. 17. Belshe, R. B.; Mendelman, P. M.; Treanor, J.; King, J.; Gruber, W. C.; Piedra, P.; Bernstein, D. I.; Hayden, F. G.; Kotloff, K.; Zangwill, K.; Lacuzio, D.; Wolff, M. The ef cacy of live attenuated, cold-adapted, trivalent, intranasal in uenza virus vaccine in children. N. Engl. J. Med. 1998, 338, 1405 1412. 18. Reichert, T. A.; Sugaya, N., Fedson, D. S.; Glezen, W. P.; Simonsen, L.; Tashiro, M. The Japanese experience with vaccinating school children against in uenza. N. Engl. J. Med. 2001.
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