Volume 15, Number 3—March 2009
Perspective
Meeting the Challenge of Influenza Pandemic Preparedness in Developing Countries
Figure
![Genetic reassortment and genesis of a new pandemic influenza virus. This study was designed to determine whether the selection and transmission of a new reassortant influenza A virus could occur under experimental conditions in vivo that mimic what might occur in nature. Reassortment between 2 antigenically distinct influenza A viruses was studied in turkeys that had been previously immunized to induce low levels of antibodies to the hemagglutinin (H) of a nonlethal turkey influenza virus (Turke](/eid/images/08-0857-F1.jpg)
Figure. Genetic reassortment and genesis of a new pandemic influenza virus. This study was designed to determine whether the selection and transmission of a new reassortant influenza A virus could occur under experimental conditions in vivo that mimic what might occur in nature. Reassortment between 2 antigenically distinct influenza A viruses was studied in turkeys that had been previously immunized to induce low levels of antibodies to the hemagglutinin (H) of a nonlethal turkey influenza virus (Turkey), and to the neuraminidase (N) of a fowl plague virus (FPV), an avian virus that is highly pathogenic for chickens. Twenty-eight days after immunization, the immunized turkeys were sequentially infected, first with the Turkey virus and 4 h later with FPV. During the first few days, both parent viruses were isolated from the infected turkeys, but by day 4 a reassortant virus containing the FPV hemagglutinin and the Turkey neuraminidase (FPV(H)–Turkey(N)) was also isolated; within 2 days it became the dominant virus. All infected turkeys died, and only the FPV(H)–Turkey(N) reassortant virus could be recovered. In a separate experiment, similarly immunized turkeys were again sequentially infected, but on day 5 a group of nonimmunized or selectively immunized turkeys (Turkey(H) FPV(N)) were placed in the same room. All contact birds soon died of fulminant infection caused by the FPV(H)–Turkey(N) reassortant virus. These experiments demonstrated that under conditions of selective primary immunity, a new virus could be generated through genetic reassortment in vivo and that this reassortant virus could be readily transmitted to contacts. The reassortant virus caused uniformly fatal disease in primary infected and contact birds. Thus, under the conditions of these experiments, genetic reassortment gave rise to a new influenza virus that led to a total population collapse. Adapted from Webster and Campbell (9).
References
- Oshitani H, Kamigaki T, Suzuki A. Major issues and challenges of influenza pandemic preparedness in developing countries. Emerg Infect Dis. 2008;14:875–80. DOIPubMedGoogle Scholar
- Fedson DS, Dunnill P. From scarcity to abundance: pandemic vaccines and other agents for “have not” countries. J Public Health Policy. 2007;28:322–40. DOIPubMedGoogle Scholar
- World Health Organization. Options for the use of human H5N1 influenza vaccines and the WHO H5N1 vaccine stockpile. WHO scientific consultation. 2007 Oct 1–3; Geneva [cited 2008 Dec 10]. Available from http://www.who.int/csr/resources/publications/WHO_HSE_EPR_GIP_2008_1d.pdf
- Higgs ES, Hayden FG, Chotpitayasunondh T, Whitworth J, Farrar J. The Southeast Asian Influenza Clinical Research Network: development and challenges for a new multilateral research endeavor. Antiviral Res. 2008;78:64–8. DOIPubMedGoogle Scholar
- Chen LM, David CT, Zhou H, Cox NJ, Donis RO. Genetic compatibility and virulence of reassortants derived from contemporary avian H5N1 and human H3N2 influenza A viruses. PLoS Pathog. 2008;4:e1000072. DOIPubMedGoogle Scholar
- Belser JA, Blixt O, Chen LM, Pappas C, Maines TR, Van Hoeven N, Contemporary North America influenza H7 viruses possess human receptor specificity: implications for virus transmissibility. Proc Natl Acad Sci U S A. 2008;105:7558–63. DOIPubMedGoogle Scholar
- Reports of increased survival in bird flu patients taking Tamiflu. International Symposium on Respiratory Viral Infections; 2008 Mar 2; Singapore [cited 2008 Dec 10]. Available from http://www.antara.co.id/en/print/?i=1204536377
- Murray CJL, Lopez AD, Chin B, Feehan D, Hill KH. Estimation of potential global influenza mortality on the basis of vital registry data from the 1918–1920 pandemic: a quantitative analysis. Lancet. 2006;368:2211–8. DOIPubMedGoogle Scholar
- Webster RG, Campbell CH. Studies on the origin of pandemic influenza. IV. Selection and transmission of “new” influenza viruses in vivo. Virology. 1974;62:404–13. DOIPubMedGoogle Scholar
- Fidler DP. Influenza virus samples, international law, and global health diplomacy. Emerg Infect Dis. 2008;14:88–94. DOIPubMedGoogle Scholar
- Schnirring L. Indonesia claims wide support for virus-sharing stance. Center for Infectious Disease and Research Policy News. 2008 May 27 [cited 2008 Dec 12]. Available from http://www.cidrap.umn.edu/cidrap/content/influenza/avianflu/news/may2708sharing.html
- Fedson DS. New technologies for meeting the global demand for pandemic influenza vaccines. Biologicals. 2008;36:346–9. DOIPubMedGoogle Scholar
- Fedson DS. Pandemic influenza: a potential role for statins in treatment and prophylaxis. Clin Infect Dis. 2006;43:199–205. DOIPubMedGoogle Scholar
- Fedson DS. Confronting an influenza pandemic with inexpensive generic agents: can it be done? Lancet Infect Dis. 2008;8:571–6. DOIPubMedGoogle Scholar
- Butler D. Cheaper approaches to flu divide flu researchers. Nature. 2007;448:976–7. DOIPubMedGoogle Scholar
- Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus; Abdel-Ghafar AN, Chotpitayasunondh T, Gao Z, Hayden FG, Nguyen DH, de Jong MD, et al. Update on avian influenza A (H5N1) virus infection in humans. N Engl J Med. 2008;358:261–73.
- van de Garde EM, Hak E, Souverein PC, Hoes AW, van den Bosch JM, Leufkens HG. Statin therapy and reduced risk of pneumonia in patients with diabetes. Thorax. 2006;61:957–61. DOIPubMedGoogle Scholar
- Schlienger RG, Fedson DS, Jick S, Jick H, Meier C. Statins and the risk of pneumonia: a population-based nested case-control study. Pharmacotherapy. 2007;27:325–32. DOIPubMedGoogle Scholar
- Mortensen EM, Pugh MJ, Copeland L, Cornell J, Restrepo MI, Anzueto A, Impact of statins and ACE inhibitors on mortality for patients hospitalized with community-acquired pneumonia and influenza. Eur Respir J. 2008;31:611–7. DOIPubMedGoogle Scholar
- Chalmers JD, Singanayagam A, Murray MP, Hill AT. Prior statin use is associated with improved outcomes in community-acquired pneumonia. Am J Med. 2008;121:1002–7. DOIPubMedGoogle Scholar
- Thomsen RW, Riis A, Kornum JB, Christensen S, Johnsen SP, Sorensen HT. Preadmission use of statins and outcomes after hospitalization with pneumonia. Arch Intern Med. 2008;168:2081–7. DOIPubMedGoogle Scholar
- Majumdar SR, McAlister FA, Eurich DT, Padwal RS, Marrie TJ. Statins and outcomes in patients admitted to hospital with community acquired pneumonia: a population based prospective cohort study. BMJ. 2006;333:999–1004. DOIPubMedGoogle Scholar
- Choi HS, Park MJ, Kang HM, Lim IH, Choi CW, You JH. Statin use and mortality in sepsis due to pneumonia. Crit Care Med. 2007;35(Suppl):1362. DOIPubMedGoogle Scholar
- Budd A, Alleva L, Alsharifi M, Koskinen A, Smytha V, Mullbacher A, Increased survival after gemfibrozil treatment of severe mouse influenza. Antimicrob Agents Chemother. 2007;51:2965–8. DOIPubMedGoogle Scholar
- Palamara AT, Nencioni L, Aquilano K, De Chiara G, Hernandez L, Cossolino F, Inhibition of influenza A virus replication by resveratrol. J Infect Dis. 2005;191:1719–29. DOIPubMedGoogle Scholar
- Song JM, Park KD, Lee KH, Byun YH, Park JH, Kim SH, Biological evaluation of anti-influenza viral activity of semi-synthetic catechin derivatives. Antiviral Res. 2007;76:178–85. DOIPubMedGoogle Scholar
- Siddiqui AM, Cui X, Wu R, Dong W, Zhou M, Hu M, The anti-inflammatory effect of curcumin in an experimental model of sepsis is mediated by up-regulation of peroxisome proliferator-activated receptor-gamma. Crit Care Med. 2006;34:1874–82. DOIPubMedGoogle Scholar
- Zheng BJ, Chan KW, Lin YP, Zhao GY, Chan C, Zhang HJ, Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus. Proc Natl Acad Sci U S A. 2008;105:8091–6. DOIPubMedGoogle Scholar
- Simmons C, Farrar JT. Insights into inflammation. N Engl J Med. 2008;359:1621–3. DOIPubMedGoogle Scholar
- McAuley JL, Hornung F, Boyd KL, Smith AM, McKeon R, Bennick J, Expression of the 1918 influenza A virus PB1–F2 enhances the pathogenesis of viral and secondary bacterial pneumonia. Cell Host Microbe. 2007;2:240–9. DOIPubMedGoogle Scholar
- Imai Y, Kuba K, Neely GG, Yaghubian-Malhami R, Perkmann T, van Loo G, Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell. 2008;133:235–49. DOIPubMedGoogle Scholar
- Mizgerd JP, Skerrett SJ. Animal models of human lung disease. Am J Physiol Lung Cell Mol Physiol. 2008;294:L387–98. DOIPubMedGoogle Scholar
- Fukunaga K, Kohli P, Bonnans C, Fredenburgh LE, Levy BD. Cyclooxygenase 2 plays a pivotal role in the resolution of acute lung injury. J Immunol. 2005;174:5033–9.PubMedGoogle Scholar
- Korteweg C, Gu J. Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. Am J Pathol. 2008;172:1155–70. DOIPubMedGoogle Scholar
- van der Poll T, Opal SM. Host-pathogen interactions in sepsis. Lancet Infect Dis. 2008;8:32–43. DOIPubMedGoogle Scholar
- Rittirsch D, Flierl MA, Ward PA. Harmful molecular mechanisms in sepsis. Nat Rev Immunol. 2008;8:776–87. DOIPubMedGoogle Scholar
- Carré JE, Singer M. Cellular energetic metabolism in sepsis: the need for a systems approach. Biochim Biophys Acta 2008;1777:763–71.
- World Health Organization. WHO global conference on severe acute respiratory syndrome (SARS). Where do we go from here? 2003 Jun 17–18 [cited 2008 Dec 10]. Available from http://www.who.int/csr/sars/conference/june_2003/materials/report/en/index.html