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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary 5 Emerging Technical Tools OVERVIEW A trend that has long been recognized is that people who have had influenza may have less severe symptoms when subsequently infected with immunologically distinct viruses. Immunization with the virus of one influenza A subtype has been shown to reduce morbidity and mortality in animals infected with virus of a different subtype, a phenomenon known as heterosubtypic immunity. In the first contribution to this chapter, Suzanne Epstein describes animal studies on the various means of inducing heterosubtypic immunity and explores the possibility of taking advantage of conserved features among influenza viruses to reduce mortality in a pandemic until a matched vaccine became widely available. Routine immunization could potentially be used to induce heterosubtypic immunity in advance of a pandemic, and the vaccine could also be offered early in a pandemic to those who had not received it. An even more ambitious strategy is presented in the next contribution, which describes the engineering of influenza A-resistant chickens that combines (1) RNA interference, (2) genes that block the expression of incoming viral genomes, and (3) RNA decoys, short sequences that mimic the binding sites of RNA proteins and thereby act as competitive inhibitors for transcription. Although researchers pursing this strategy recognize the many logistical and scientific roadblocks in their path, they nonetheless envision the elimination of a major pandemic threat through global repopulation with influenza-resistant transgenic chickens. Rapid detection techniques are critically needed for a quick diagnosis
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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary of the pathogen. The faster the pathogen is detected, the faster the outbreak can be controlled. The chapter continues with a description of several novel approaches for rapid early detection, including the most promising assay, real-time fluorescent polymerase chain reaction, as well as some other techniques: antigen capture/enzyme-linked immunosorbent assay, mass spectrometry, and restriction fragment length polymorphisms. The development of these techniques for detection will enable a quick diagnosis of the agent and faster development of vaccines. The chapter concludes with mathematical modeling of pandemic preparedness plans, showing the consequences on health economic outcomes of possible intervention strategies. This modeling helps to determine the costs and benefits of different strategies and gauges the public health benefits of optimized preparedness. CONTROL OF INFLUENZA VIRUS INFECTION BY IMMUNITY TO CONSERVED VIRAL FEATURES Suzanne L. Epstein1,2 Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration Reprinted with permission, from Epstein (2003), published in Expert Review of Anti-infective Therapy, Copyright 2003 Future Drugs Influenza has circulated among humans for centuries and kills more people than many newly emerging diseases. The present methods for control of influenza are not adequate, especially for dealing with a pandemic. In the face of a rapidly spreading outbreak, a race to isolate the virus and prepare a vaccine would probably not succeed in time to avoid great losses. Thus, additional anti-infection strategies are needed. Broad cross-protection against widely divergent influenza A subtypes is readily achieved in animals by several means of immunization. How does cross-protection work in animals, and can we apply what we have learned about it to induce broad cross-protection in humans? 1 Suzanne L. Epstein, PhD, Chief, Laboratory of Immunology and Developmental Biology, Division of Cellular and Gene Therapies, HFM-730, Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, 301–827–0450, fax: 301–827–0449, e-mail: firstname.lastname@example.org. 2 SLE acknowledges grant support from the National Vaccine Program. I thank Steven Bauer, Ira Berkower, Mark Tompkins, Zi-Shan Zhao and Chia-Yun Lo for critical review of various versions of the manuscript.
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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary Background: Influenza Virus, Immunity, and Vaccination If an influenza pandemic began, emergency efforts to isolate the pandemic virus strain and prepare a vaccine from it would begin, while the pandemic spread. Should we pin our hopes on that race? On antiviral drugs? Or are there vaccines that could be made in advance and offer some degree of protection? Current vaccines focus on variable, strain-specific epitopes of circulating influenza virus strains and new viral strains require new vaccines. Here, a different approach will be considered, vaccination based on shared epitopes as an anti-infective measure that could provide broad protection against even new pandemic strains. This review will draw together relevant observations from animal studies and from human epidemiology. In the venerable influenza field, some of the older literature is highly relevant to current questions in ways that were not considered at the time, so it must be revisited. After providing background on influenza infection and immunity, the review will focus on broad cross-protection against influenza A subtypes. It will explore the mechanisms of cross-protection in animals, the induction of cross-protection by vaccines of different types and their ability to protect against challenge with potential pandemic subtypes, such as H5N1. Finally, it will consider the possibility of broad immune cross-protection in humans and the public health implications for control of epidemics and pandemics. Influenza remains a major public health problem. The World Health Organization (WHO) estimates that in a typical year, 10 to 20 percent of the world’s population is infected with influenza, resulting in 3,000,000 to 5,000,000 severe illnesses and 250,000 to 500,000 deaths (World Health Organization, 1999). In the United States, there are tens of thousands of deaths each year and the problem will increase due to the aging of the population and the susceptibility of the elderly. During pandemics, the losses are even greater. The 1918 influenza pandemic was the most extreme, causing two billion cases, 20 to 40 million deaths worldwide and 500,000 in the United States, and killing with great speed. Young, healthy adults were not spared and approximately 80 percent of the U.S. Army’s World War I deaths were due to influenza (Wright and Webster, 2001). Pandemics in 1957 and 1968 also caused widespread disease and excess deaths. For further historical information, see Kilbourne (1975). Vaccination is a highly successful strategy for controlling infectious diseases. It is cost-effective and population-wide campaigns are feasible. However, the pathogens against which vaccination has been most successful (e.g., smallpox and polio) have viral types that are few in number and genetically stable. With influenza virus, extensive genetic variation leads to the problem that different dominant viral strains circulate in the human population each year (Figure 5-1). The current vaccine system involves
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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary FIGURE 5-1 Periodic outbreaks of influenza in a surveillance study in Texas. Lower panel shows number of persons with acute febrile respiratory illness, upper panel shows number of persons with positive cultures for influenza virus. Strain names are of predominant viruses only. Note that different viral strains dominate in different years. Adapted from Figure 1 in Glezen et al. (1984). Reprinted with permission from Elsevier, Oxford, UK.
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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary worldwide surveillance, predictions of strains likely to circulate during the next season and manufacture of new vaccines. This system is cumbersome, imperfect in effectiveness due to the guesswork involved and rushed in timing. Delays in vaccine derivation and manufacture can lead to shortages, as occurred in 2000 (CDC, 2000). A vaccination strategy that included broad cross-protection in addition to strain-specific protection could have a major public health impact; therefore, the potential of such an approach needs to be thoroughly explored. There are three major influenza virus types, A, B and C. Infection with influenza C virus is relatively mild clinically (Murphy and Webster, 1990) and will not be discussed here. Influenza A and B viruses are distantly related but not cross-reactive or -protective against each other in animals (de St. Groth and Donnelley, 1950), even during mixed simultaneous infection (Liang et al., 1994). The influenza virus A and B genomes each consist of eight separate RNA segments. Point mutations lead to “antigenic drift” (small, incremental changes). Reassortment of entire segments of the genome is an additional source of antigenic variation and, in the case of influenza A, can lead to “antigenic shift” (sudden, large change) corresponding to a change in subtype. Influenza virus and its components are shown diagrammatically in Figure 5-2. Hemagglutinin (HA) and neuraminidase (NA) are the components that vary the most. Subtypes of influenza A virus are defined serologically by their HA and NA antigens. The nomenclature for influenza A reflects this, for example, H3N2 refers to HA of subtype 3 and NA of subtype 2. There are 15 HA subtypes and nine NA subtypes (Wright and Webster, 2001). All these subtypes infect aquatic birds, and human pandemic viruses have arisen from avian viruses by reassortment (Webster, 2002). Emergence in humans of subtypes they have not previously encountered can lead to pandemics, for example, the emergence of H1N1 in 1918, H2N2 in 1957 and H3N2 in 1968 (Kilbourne, 1975). Small outbreaks of novel subtypes in humans occur more often than pandemics, for example, H5N1 in Hong Kong in 1997 (Claas et al., 1998), H9N2 in Hong Kong in 1999 (Saito et al., 2001), or an isolated case of H7N7 in The Netherlands in 2003 (van Kolfschooten, 2003). Immunization with the virus of one influenza A subtype can protect animals against challenge with virus of a different subtype. This cross-protection has long been studied in animal models (Schulman and Kilbourne, 1965). In this review, it will be called heterosubtypic immunity or Het-I, to use the abbreviation of Gerhard (Liang et al., 1994) (it has also been called heterotypic immunity by some authors). This form of immunity does not generally prevent all infection by the heterosubtypic virus but it leads to more rapid viral clearance and to reduction in morbidity and mortality. In this review, the terms ‘protection’ and ‘protective immunity’
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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary FIGURE 5-2 Diagram of influenza virus and its components. The core containing the RNA genome and replication machinery is surrounded by a matrix and then an envelope. HA, NA and M2 extend through the envelope to the outside. Diagram adapted from (www.snm.ch/public/sante/prevention/prevention-sommarie.htm). Reproduced with permission from Dr. Herve Zender, La Societe Neuchateloise de Medecine (SNM).
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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary will not imply complete prevention of viral infection, but instead, a reduction in viral titers and protection of the life and health of the host. Figure 5-3 shows diagrammatically the categories of influenza viruses, their relatedness, the terms for describing immunity to various challenges and the resulting protection. Relatedness of viral core and envelope proteins is shown by similarity of color. The corresponding relationships in protein sequence are shown in Table 5-1 for the HA and NA proteins, as well as for nucleoprotein (NP) as an important conserved protein. A variety of birds and mammals can be infected with influenza A and B viruses, naturally or in the laboratory (Kilbourne, 1987). Serological reagents are often produced in ferrets. Influenza viruses can be adapted to FIGURE 5-3 Categories of influenza viruses and immunity they induce. Colors indicate similarity. For example, influenza virus types A, B and C differ for both internal proteins and the HA and NA external glycoproteins. Within the influenza A type, subtypes have major differences in HA and NA but only subtle differences in internal proteins. Within an influenza A subtype, for example, H1N1, the HA and NA differ in more subtle ways shown by the more similar colors. Note that the term ‘heterologous’ immunity is also used to refer to immunity induced by one virus and reactive with an unrelated virus (Selin et al., 1994) but the term will not be used that way in this review.
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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary TABLE 5-1 Influenza Viruses: Nomenclature and Relatedness Influenza Viruses Percent Amino Acid Homology in Hemagglutinin (HA) Percent Amino Acid Homology in Neuraminidase (NA) Percent Amino Acid Homology in Nucleoprotein (NP) Types Influenza A, B, C 24-40% A vs. B, C unrelateda 26-29% A vs. Ba A vs B, 38% A vs. C, 22%a Subtypes H1-H15, N1-N9 Example: H1N1 25-80%a,b Examples: H1 vs. H3, 25-40% H2vs. H5, 80% 42-57%a Example: H1N1 vs H3N2, 92-97%c Strains within a subtype >90%a >90%d (N2’s) Close to 100% NOTES: aMurphy and Webster, 1990; bScholtissek, 1983; cAltmuller et al., 1989; dXu et al., 1996. mice and in them cause disease with many of the characteristics of human influenza: upper respiratory infection, tracheobronchitis and pneumonia (Yetter et al., 1980; Renegar, 1992). They provide an affordable animal model with a short generation time and many reagents defining surface markers on important cellular populations. In addition, there are numerous recombinant and congenic strains, and more recently transgenic and knockout strains of immunological significance. Thus, much work on immunity to influenza virus infection has been performed in mice. Results in an animal model do not predict in every particular what will happen in humans, but they provide a valuable information base that can help design future studies in humans and novel approaches to vaccine development. Immunity to Influenza Virus Infection How to Analyze Mechanisms of Immunity in Animal Models The complexity and redundancy of the immune system is good for defense against pathogens but hard on those trying to interpret experiments. Any response that is measured was likely accompanied by other concurrent responses that were not. Thus, correlation of a response with protection does not prove that it mediates the protection. Passive transfer of antibody or T-cells helps by showing that an effector is capable of mediating an outcome, but does not mean that it always does. The adoptive
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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary transfer may use unnatural doses and the transferred components may not localize normally. Mice with a targeted gene disruption (‘knockout’) can be used to test whether the corresponding component is required for a certain outcome. Keep in mind however, that a component not required under one set of conditions may still play a role and it may be required under other circumstances. Note also that a knockout animal lacks the component from birth and may compensate for its absence by other biological changes. Another approach to analysis is depletion of certain immune cells in vivo (often CD4+ or CD8+ T-cells). If animals were intact when primed and are depleted only during the period of viral challenge infection, then depletion is informative about effector functions. It is imperfect in that residual cells could lurk at tissue sites not tested or at levels not detectable. However, depletion has the advantage that it can be performed acutely, not leaving much time for compensation by other changes in the animal. Multiple approaches are necessary if we are to accumulate a realistic view of immune responses and their potential under various circumstances. No one approach can describe the multifaceted immune response and all its shifting balances. Immunity to Influenza Virus: B- and T-cell Responses The immune system clears infection the first time a virus is encountered. It also preserves specific memory of viral antigens, so that it can prevent or at least limit reinfection if the same virus is encountered again. Fundamentals of immune responses (B- and T-cell responses, antigen processing, presentation by major histocompatability complex [MHC] class I and II and epitope dominance) are reviewed elsewhere and will not be covered here. Antibodies to influenza virus can protect against reinfection and passively transferred antibody can protect naive animals. However, this form of protection is often subtype-specific or even narrowly specific to certain viral strains (Ada and Jones, 1986), failing to protect against mismatched strains (De Jong et al., 2000). Additional immunity is provided by effector T-cells. They play important roles in clearing influenza virus and protecting against challenge, although they can also cause immunopathology (Wells et al., 1981). Doherty’s and other groups have provided much evidence for a beneficial role of class I MHC-restricted CD8+ cytotoxic T-lymphocytes (CTLs) in clearing primary influenza virus infection (Doherty et al., 1997) and also in protection against challenge with homologous virus (Lu and Askonas, 1980). The conserved NP viral protein is a major target antigen for CTLs in mice (Yewdell et al., 1985). In some studies of immunizations with NP, immune responses were observed but little or no protection
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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary (Webster et al., 1991; Lawson et al., 1994), while in other cases NP regimens were protective against challenge (Ulmer et al., 1993; Fu et al., 1999). MHC class II-restricted CTL activity specific for influenza virus antigens has also been reported (Taylor and Bender, 1995). The role of CD8+ CTLs in protective immunity is virus-specific: CTLs only control the virus they recognize. Bystander viruses coinfecting the same lungs are not controlled (Lukacher et al., 1984), ruling out nonantigen-specific mechanisms based on natural killer (NK) cells or soluble mediators such as interferon (IFN), cytokines, or chemokines released when T-cells recognize virus. Topham and colleagues demonstrated that in vivo protection by CD8+ cells requires lysis mediated by either perforin or Fas (Topham et al., 1997). Tumor necrosis factor (TNF)-α-mediated killing has also been reported in vitro (Liu et al., 1999; Zhao et al., 2001). Mechanisms of Heterosubtypic Immunity Induced by Infection with Live Virus Focus will now be placed on Het-I, that is, cross-protection by prior exposure to one influenza A subtype against challenge with a divergent subtype. Respiratory infection with live wild type virus efficiently induces Het-I and will be discussed initially. Roles of T-cells T-cells are candidates for contributors to Het-I because they participate in clearing virus from infected tissues and many of them cross-react with all influenza A subtypes. In one study of Het-I, in vivo depletion showed that CD4+ and CD8+ T-cells both contributed to control of challenge virus in the nose (Liang et al., 1994). In the lungs, CD4+ cells did not appear to contribute but CD8+ cells did, plus some other mechanism that remained after depletion of both. This study also showed that Het-I against influenza A was immunologically specific in its effector phase; coinfecting influenza B virus replicated unchecked in the same lung tissue (Liang et al., 1994). Thus, like homologous protection by CTLs discussed earlier, Het-I induced by live virus requires specific effector functions of antibodies or T-cells that recognize the virus. Mice with a targeted disruption of the β2-microglobulin (β2m) gene have been studied as a model lacking class I MHC restricted CD8+ T-cells. They can survive primary influenza virus infection and can mount protective immune responses to homologous and heterosubtypic challenge (Bender et al., 1994; Epstein et al., 1997). β2m-/- mice have multiple immune deficiencies besides a lack of CTLs, but one can at least say from these results that CD8+ CTLs are not required for Het-I (Raulet, 1994; Epstein et al.,
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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary 2000). Confirmatory evidence comes from CD8 knockout mice, which also have deficient class I-restricted CTL and retain Het-I (Nguyen et al., 2001). Can T-cell responses alone protect against influenza? Immunoglobulin (Ig)-/- knockout mice lacking antibodies and mature B-cells have been used to study this question, including µMT mice (targeted disruption of the membrane exon of µ heavy chain), JHD mice (disruption of the heavy chain joining segments, thus no Ig gene rearrangement) and DI mice (disruption of JHD segments and also κ light chain constant regions). Several studies have shown that such mice could clear primary influenza virus infection but less effectively than normal mice and immunization protected them at least to some extent against homologous challenge (Bot et al., 1996; Topham and Doherty, 1998; Epstein et al., 1998; Graham and Braciale, 1997). What about Het-I? In one study, no Het-I could be demonstrated in µMT mice but under conditions that showed no protection against homologous challenge, either (Nguyen et al., 2001). Indeed, protective immunity is weaker than normal in these mice. Our group has identified conditions under which Het-I could be demonstrated in mice without antibodies. Immunization with H2N2 or H3N2 viruses partially controlled replication of H1N1 challenge virus. This immunity was dependent upon both CD4+ and CD8+ T-cells (Benton et al., 2001). There is a caveat to interpretation of these results: Ig-/- mice have an immune defect besides absence of antibodies. In a variety of pathogen systems, naive B-cells can restore their ability to clear an infection but not via antibody production (Elkins et al., 1999; Mozdzanowska et al., 2000). These findings suggest a role for B-cells as antigen-presenting cells (APCs). Role of Antibodies Antibodies had been suggested as a mediator of Het-I because foster nursing on immune mothers transferred protection to the pups (Mbawuike et al., 1990) and absence of CD8+ CTLs did not abrogate Het-I. What type of antibodies could be involved? IgG dominates in immune serum and reaches mucosal sites, including the lungs by transudation. IgA is found in the lungs along with IgG, and IgA dominates in the nose where it is thought to be especially important. Since mucosal immunization is highly effective, secretory antibodies have been a focus of study and polymeric IgA has been shown to mediate protection against influenza virus (Renegar and Small, 1991). Polymeric IgA can cross the epithelium of the lung and other organs by transcyrosis dependent upon the poly-Ig receptor and can interfere with viral infection as it crosses the infected cells (Mazanec et al., 1992; Mazanec et al., 1995). Certain IgA monoclonal antibodies (mAbs) to core proteins protect against rotavirus infection, although they do not neutralize virus (Burns et al., 1996; Schwartz-Cornil et al., 2002); these results suggested
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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary annual epidemic vaccine manufacturing period. Given that logistics of egg preparation require ordering about 1 year in advance, availability of sufficient eggs outside the planned period certainly can be questioned. Cell culture-based vaccine manufacture however makes long-term advance planning obsolete, as all starting materials are in stock and readily available whenever required. This advantage however is not illustrated in the assumed “2004 pandemic”, thereby underestimating the advantageous health economics of cell culture-based over egg-based intervention and thus the importance of cell culture-based vaccine manufacturing as tool for increased pandemic preparedness. Although the presented model can lend structure and logic to pandemic preparedness discussions, pandemic planning remains a complex process. The efficacy of interventions, such as vaccines and antivirals, during pandemics needs to be studied and proven beforehand as much as possible in order to make such interventions available in time. Regulatory procedures of such interventions need to be harmonized and adapted to the short-time lines available in pandemic situations and logistical systems need to be set up or streamlined to successfully execute the intervention strategy. Pandemic vaccination might be the most cost-effective approach, but will require the availability of a suitable virus seed and adequate manufacturing facilities to process such a seed. In order to manufacture sufficient amounts for an adequate level of pandemic vaccine, manufacturing capacity needs to be increased. As stated by WHO, policy makers need to keep in mind the several years needed to construct new production facilities and significantly increase production capacity (World Health Organization, 2002). This only has an economical incentive if interpandemic vaccine usage is increased, which—just as pandemic preparedness—is a joint responsibility of the public and private sector. REFERENCES Ada GL, Jones PD. 1986. The immune response to influenza infection. Curr Top Microbiol Immunol 128:1–54. Aebi M, Fah J, Hurt N, Samuel CE, Thomis D, Bazzigher L, Pavlovic J, Haller O, Staeheli P. 1989. cDNA structures and regulation of two interferon-induced human Mx proteins. Mol Cell Biol 9:5062–5072. Alexander DJ. 2003. Report on avian influenza in the Eastern Hemisphere during 1997–2002. Avian Diseases 47:792–797. Altmuller A, Fitch WM, Scholtissek C. 1989. Biological and genetic evolution of the nucleoprotein gene of human influenza A viruses. J Gen Virol 70:2111–2119. American Association of Avian Pathologists. 1992 (August). Proceedings of the Symposium on Biotechnology Applications in Avian Medicine. American Veterinary Medical Association Meeting, Boston, MA. Bender BS, Bell WE, Taylor S, Small PA Jr. 1994. Class I major histocompatibility complex-restricted cytotoxic T lymphocytes are not necessary for heterotypic immunity to influenza. J Infect Dis 170(5):1195-1200.
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The Threat of Pandemic Influenza: Are We Ready? - Workshop Summary Benton KA, Misplon JA, La C-Y, Bruckiewicz RR, Prasad SA, Epstein SL. 2001. Heterosubtypic immunity to influenza A virus in mice lacking either IgA, all Ig, NKT cells, or gd T-cells. J Immunol 166:7437–7445. Bernasconi D, Schultz U, Staeheli P. 1995. The interferon-induced Mx protein of chickens lacks antiviral activity. J Interferon Cytokine Res 15:47–53. Boden D, Pusch O, Lee F, Tucker L, Ramratnam B. 2003. Human immunodeficiency virus type 1 escape from RNA interference. J Virol 77:11531–11535. Bot A, Reichlin A, Isobe H, Bot S, Schulman J, Yokoyama WM, Bona CA. 1996. Cellular mechanisms involved in protection and recovery from influenza virus infection in immunodeficient mice . J Virol 70:5668–5672. Bucher E, Hemmes H, de Haan P, Goldbach R, Prins M. 2004. The influenza A virus NS1 protein binds small interfering RNAs and suppresses RNA silencing in plants. J Gen Virol 85:983–991. Burns JW, Siadat-Pajouh M, Krishnaney AA, Greenberg HB. 1996. Protective effect of rotavirus VP6-specific 19A monoclonal antibodies that lack neutralizing activity. Science 272:104–107. Buxton Bridges C, Katz JM, Seto WH, Chan PK, Tsang D, Ho W, Mak KH, Lim W, Tam JS, Clarke M, Williams SG, Mounts AW, Bresee JS, Conn LA, Rowe T, Hu-Primmer J, Abernathy RA, Lu X, Cox NJ, Fukuda K. 2000. Risk of influenza A (H5N1) infection among health care workers exposed to patients with influenza A (H5N1), Hong Kong. J Infect Dis 181:344–348. Caplen NJ. 2004. Gene therapy progress and prospects. Downregulating gene expression: The impact of RNA interference. Gene Ther 11:1241–1248. CDC (Centers for Disease Control and Prevention). 2000. Updated recommendations from the Advisory Committee on Immunization Practices in response to delays in supply of influenza vaccine for the 2000–01 season. MMWR 49:888–892. Chen HL, Subbarao K, Swayne D, Chen Q, Lu X, Katz J, Cox N, Matsuoka Y. 2003. Generation and evaluation of a high-growth reassortant H9N2 influenza A virus as a pandemic vaccine candidate. Vaccine 21:1974–1979. Cianci C, Tiley L, Krystal M. 1995. Differential activation of the influenza virus polymerase via template RNA binding. J Virol 69:3995–3999. Claas EC, Osterhaus AD. 1998. New clues to the emergence of flu pandemics. Nat Med 4:1122–1123. Claas EC, Osterhaus AD, van Beek R, De Jong JC, Rimmelzwaan GF, Senne DA, Krauss S, Shortridge KF, Webster RG. 1998. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus. Lancet 351:472–477. Couch RB, Keitel WA, Cate TR. 1997. Improvement of inactivated influenza virus vaccines. J Infect Dis 176(Suppl 1):S38–S44. Davies P. 2000. Catching Cold: 1918s Forgotten Tragedy and the Scientific Hunt for the Virus That Caused It. Harmondsworth, UK: Penguin Books. de Jong JC, Beyer WE, Palache AM, Rimmelzwaan GF, Osterhaus AD. 2000. Mismatch between the 1997/1998 influenza vaccine and the major epidemic A(H3N2) virus strain as the cause of an inadequate vaccine-induced antibody response to this strain in the elderly. Med Viral 61:94–99. de St. Groth SF, Donnelley M. 1950. Studies in experimental immunology of influenza. IV. The protective value of active immunization. Aust J Exp Biol Med Sci 28:61–75. Delgadillo MO, Saenz P, Salvador B, Garcia JA, Simon-Mateo C. 2004. Human influenza virus NS1 protein enhances viral pathogenicity and acts as an RNA silencing suppressor in plants. J Gen Virol 85:993–999. Doherty PC, Topham DJ, Tripp RA, Cardin RD, Brooks JW, Stevenson PG. 1997. Effector CD4(+) and CD8(+) T-cell mechanisms in the control of respiratory virus infections. Immunol Rev 159:105–117.
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