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Influenza Epidemics and Pandemics

Origin of influenza pandemics

Antigenic shift

Currently available information suggests that the natural reservoir of influenza A viruses is among aquatic birds.11, 12, and 13 x RG Webster, M Peiris, H Chen, et al.. H5N1 outbreaks and enzootic influenza. Emerg Inf Dis 12 (2006) (3 - 8) x RG Webster, WJ Bean, OT Gorman, et al.. Evolution and ecology of influenza A viruses. Microbiol Rev 56 (1992) (152 - 179) x DJ Alexander. A review of avian influenza viruses in different bird species. Vet Microbiol 74 (2000) (3 - 13) All 16 HA and nine NA subtypes have been identified in birds (see Chapter 2). Occasionally, a new influenza virus subtype is introduced into the human population, in a process referred to as antigenic shift. 14 x RG Webster, WG Laver. Pandemic variation of influenza viruses. ED Kilbourne (Ed.) The Influenza Viruses and Influenza (Academic Press, 1975) (269 - 314) As indicated above, there are several ways by which such new human virus subtypes may arise ( Figure 12 ), and it is likely that each has played a role in the influenza pandemics of the 20th century. First, an avian virus may be transmitted directly to humans and subsequently adapt to the new host by mutation. Second, a human influenza virus may acquire a number of gene segments from an avian virus in a process of genetic reassortment. Third, it is possible that an “old” human virus, which has circulated before, is reintroduced into the human population.

Figure 12 Origin of antigenic shift and pandemic influenza. The natural reservoir of influenza A viruses is among migratory aquatic birds. A virus with a new HA subtype may be introduced into the human population by direct transmission of an avian virus to humans or by genetic reassortment between an avian and a human virus. source: Adapted from Nicholson KG et al. Influenza. Lancet 2003; 362: 1733–1745 7 x KG Nicholson, JM Wood, M Zambon. Influenza. Lancet 362 (2003) (1733 - 1745) with permission from Elsevier.

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References in context

  • Occasionally, a new influenza virus subtype is introduced into the human population, in a process referred to as antigenic shift.14 As indicated above, there are several ways by which such new human virus subtypes may arise (Figure 12), and it is likely that each has played a role in the influenza pandemics of the 20th century.
    Go to context

Direct transmission of avian viruses to humans

Rarely, a highly pathogenic avian influenza (HPAI; see also Chapter 2) virus is transmitted directly from birds to humans. 3, x JK Taubenberger, DM Morens. 1918 influenza: the mother of all pandemics. Emerg Inf Dis 12 (2006) (15 - 22) 11, x RG Webster, M Peiris, H Chen, et al.. H5N1 outbreaks and enzootic influenza. Emerg Inf Dis 12 (2006) (3 - 8) 15, 16, 17, and 18 x KF Shortridge. Pandemic influenza: a zoonosis?. Semin Respir Infect 7 (1992) (11 - 25) x RG Webster. Influenza virus: transmission between species and relevance to emergence of the next human pandemic. Arch Virol Suppl 13 (1997) (105 - 113) x T Horimoto, Y Kawaoka. Pandemic threat posed by avian influenza A viruses. Clin Microbiol Rev 14 (2001) (129 - 149) x JC De Jong, ECJ Claas, ADME Osterhaus, RG Webster, WL Lim. A pandemic warning?. Nature 389 (1997) (554) It was not until the 1997 H5N1 bird flu outbreak in Hong Kong that it was appreciated that such direct transmission could occur. During this outbreak, 18 people were reportedly infected with the H5N1 virus, six of whom died.18, 19, and 20 x JC De Jong, ECJ Claas, ADME Osterhaus, RG Webster, WL Lim. A pandemic warning?. Nature 389 (1997) (554) x EC Claas, AD Osterhaus, R van Beek, et al.. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus. Lancet 351 (1998) (472 - 477) x K Subbarao, A Klimov, J Katz, et al.. Characterisation of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory disease. Science 279 (1998) (393 - 396) The virus isolated from the victims had the same genetic make-up as the virus causing the epidemic among chickens in Hong Kong at the time, indicating that it was transmitted directly from chickens to humans. The 1997 H5N1 bird flu virus was in fact a “multiple avian reassortant”, which originated from an H5N1 reservoir in geese, reassorted before crossing to terrestrial poultry (especially chickens), and then probably acquired the internal protein genes and the NA gene through further reassortment with H9N2 and H6N1 viruses originating from quails. 21 x Y Guan, KF Shortridge, S Krauss, RG Webster. Molecular characterization of H9N2 influenza viruses: were they the donors of the “internal” genes of H5N1 viruses in Hong Kong?. Proc Natl Acad Sci USA 96 (1999) (9363 - 9367)

While the bird flu outbreak in 1997 was the first documented example of a purely avian virus causing respiratory disease and deaths among humans,18, 19, and 20 x JC De Jong, ECJ Claas, ADME Osterhaus, RG Webster, WL Lim. A pandemic warning?. Nature 389 (1997) (554) x EC Claas, AD Osterhaus, R van Beek, et al.. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus. Lancet 351 (1998) (472 - 477) x K Subbarao, A Klimov, J Katz, et al.. Characterisation of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory disease. Science 279 (1998) (393 - 396) it has since become apparent that the 1918 Spanish flu virus was also an avian virus. 3, x JK Taubenberger, DM Morens. 1918 influenza: the mother of all pandemics. Emerg Inf Dis 12 (2006) (15 - 22) 22, 23, 24, and 25 x RG Webster. 1918 Spanish influenza: the secrets remain elusive. Proc Natl Acad Sci 96 (1999) (1164 - 1166) x AH Reid, TG Fanning, JV Hultin, et al.. Origin and evolution of the 1918 “Spanish” influenza virus hemagglutinin gene. Proc Natl Acad Sci 96 (1999) (1651 - 1656) x SJ Gamblin, LF Haire, RJ Russell, et al.. The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science 303 (2004) (1838 - 1842) x JK Taubenberger, AH Reid, RM Lourens, et al.. Characterization of the 1918 influenza virus polymerase genes. Nature 437 (2005) (889 - 893) Even though the precise origin of the 1918 virus remains enigmatic, 3, x JK Taubenberger, DM Morens. 1918 influenza: the mother of all pandemics. Emerg Inf Dis 12 (2006) (15 - 22) 11, x RG Webster, M Peiris, H Chen, et al.. H5N1 outbreaks and enzootic influenza. Emerg Inf Dis 12 (2006) (3 - 8) 22 x RG Webster. 1918 Spanish influenza: the secrets remain elusive. Proc Natl Acad Sci 96 (1999) (1164 - 1166) based on characterization of genetic material isolated from victims of the 1918 pandemic, it is clear now that the virus was not a human–avian reassortant, but rather an avian-like virus that was introduced in its entirety into the human population and subsequently adapted to the new host. The adaptation involved a combination of mutations in different genes of the virus, including the HA and polymerase genes. 3, x JK Taubenberger, DM Morens. 1918 influenza: the mother of all pandemics. Emerg Inf Dis 12 (2006) (15 - 22) 23, 24, and 25 x AH Reid, TG Fanning, JV Hultin, et al.. Origin and evolution of the 1918 “Spanish” influenza virus hemagglutinin gene. Proc Natl Acad Sci 96 (1999) (1651 - 1656) x SJ Gamblin, LF Haire, RJ Russell, et al.. The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science 303 (2004) (1838 - 1842) x JK Taubenberger, AH Reid, RM Lourens, et al.. Characterization of the 1918 influenza virus polymerase genes. Nature 437 (2005) (889 - 893) Adaptation of an avian virus to the human host might thus give rise to a virus capable of human-to-human transmission. Determination of the structure and receptor-binding properties of the 1918 HA 24 x SJ Gamblin, LF Haire, RJ Russell, et al.. The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science 303 (2004) (1838 - 1842) has suggested that, indeed, by mutation of the receptor-binding site, the HA acquired the ability to interact with human α2,6-linked sialic acid receptors (see Chapter 2). This may explain how the virus evolved the ability to spread efficiently in the human population, although other viral genes were likely involved in human-to-human transmission as well. Since adaptation to the new host requires the accumulation of a number of mutations, it may involve a considerable period of time. Indeed, there is some circumstantial evidence that the 1918 virus entered the human population several years before the pandemic. 3, x JK Taubenberger, DM Morens. 1918 influenza: the mother of all pandemics. Emerg Inf Dis 12 (2006) (15 - 22) 22 x RG Webster. 1918 Spanish influenza: the secrets remain elusive. Proc Natl Acad Sci 96 (1999) (1164 - 1166) There is a close genetic relationship between the 1918 virus and the porcine A/Swine/Iowa/30 (H1N1) virus. However, this does not necessarily imply that the human virus originated in pigs. Rather, the 1918 virus or its precursor may have been transmitted from humans to pigs. 4, x ED Kilbourne. Influenza pandemics of the 20th century. Emerg Inf Dis 12 (2006) (9 - 14) 22 x RG Webster. 1918 Spanish influenza: the secrets remain elusive. Proc Natl Acad Sci 96 (1999) (1164 - 1166)

Remarkably, the H5N1 virus isolated from victims of the recent outbreaks in Asia have acquired a number of mutations in the polymerase complex that are also present in the 1918 virus. 25 x JK Taubenberger, AH Reid, RM Lourens, et al.. Characterization of the 1918 influenza virus polymerase genes. Nature 437 (2005) (889 - 893) These mutations are likely important for efficient replication of the virus in humans. Indeed, once having crossed the species barrier to humans, the H5N1 evidently replicates very efficiently and is highly pathogenic (see Chapter 5), killing about half of the people with a confirmed H5N1 infection. Fortunately, there is no evidence yet for human-to-human transmission of the virus, all reported cases of human infection being directly linked to exposure of the victims to infected poultry. Clearly, additional mutations or reassortment events are required to permit efficient human-to-human spread. If, however, the H5N1 virus would acquire the ability to efficiently spread in the human population, while maintaining its current level of pathogenicity, the scale of the ensuing global catastrophe would be beyond comprehension. 11 x RG Webster, M Peiris, H Chen, et al.. H5N1 outbreaks and enzootic influenza. Emerg Inf Dis 12 (2006) (3 - 8)

Genetic reassortment

Genetic reassortment may occur when a host cell is simultaneously infected with two influenza A viruses. The RNA segments from both viruses are replicated in the nucleus of the cell. During the reassembly of new virus particles (see Chapter 2), the RNA segments from the two strains can get mixed together and a third “new” viral strain can be produced with a unique combination of genes.

As illustrated in Figure 13 , the 1957 Asian H2N2 virus subtype obtained its HA, NA, and PB1 genes from an avian virus and the other fives genes from the circulating H1N1 human strain, 1, x PF Wright, RG Webster. Orthomyxoviruses. DM Knipe, PM Howley, DE Griffin (Eds.) et al. Fields Virology 4th edn. (Lippincott Williams & Wilkins, 2001) (1533 - 1579) 4, x ED Kilbourne. Influenza pandemics of the 20th century. Emerg Inf Dis 12 (2006) (9 - 14) 7, x KG Nicholson, JM Wood, M Zambon. Influenza. Lancet 362 (2003) (1733 - 1745) 14, 15, 16, and 17 x RG Webster, WG Laver. Pandemic variation of influenza viruses. ED Kilbourne (Ed.) The Influenza Viruses and Influenza (Academic Press, 1975) (269 - 314) x KF Shortridge. Pandemic influenza: a zoonosis?. Semin Respir Infect 7 (1992) (11 - 25) x RG Webster. Influenza virus: transmission between species and relevance to emergence of the next human pandemic. Arch Virol Suppl 13 (1997) (105 - 113) x T Horimoto, Y Kawaoka. Pandemic threat posed by avian influenza A viruses. Clin Microbiol Rev 14 (2001) (129 - 149) the human H1N1 virus in turn being a distant descendent of the 1918 Spanish flu virus. 3 x JK Taubenberger, DM Morens. 1918 influenza: the mother of all pandemics. Emerg Inf Dis 12 (2006) (15 - 22) Likewise, the 1968 Hong Kong H3N2 virus acquired its HA and PB1 genes from an avian virus, but retained the NA and remaining five other genes from the then circulating H2N2 human virus. It is remarkable that the H3 of the Hong Kong virus differed in only seven amino acid residues from its hypothetical avian ancestor virus, providing very strong support for the concept that the Hong Kong virus indeed arose as a result of genetic reassortment. 26 x WJ Bean, M Schell, J Katz, et al.. Evolution of the H3 influenza virus hemagglutinin from human and nonhuman hosts. J Virol 66 (1992) (1129 - 1138)

Figure 13 Genetic reassortment between human and avian influenza A viruses as the origin of the pandemic 1957 Asian flu and 1968 Hong Kong flu viruses. The segmented nature of the influenza virus genome facilitates reassortment. Pigs – which support the replication of both avian and human influenza A viruses – possibly serve as a “mixing vessel”. The Asian H2N2 virus subtype obtained its HA, NA and PB1 genes from an avian virus. Likewise, the HA and PB1 genes of the Hong Kong H3N2 virus are of avian origin – the Hong Kong virus retained the NA gene plus five other genes from the circulating human virus. source: Adapted from Potter CW, editor. Influenza (Perspectives in Medical Virology), 2003 with permission from Elsevier.

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References in context

  • The 1957 Asian (H2N2) and 1968 Hong Kong (H3N2) viruses were reassortants of avian and circulating human viruses (see Figure 13).
    Go to context

  • As illustrated in Figure 13, the 1957 Asian H2N2 virus subtype obtained its HA, NA, and PB1 genes from an avian virus and the other fives genes from the circulating H1N1 human strain,1,4,7,14–17 the human H1N1 virus in turn being a distant descendent of the 1918 Spanish flu virus.3 Likewise, the 1968 Hong Kong H3N2 virus acquired its HA and PB1 genes from an avian virus, but retained the NA and remaining five other genes from the then circulating H2N2 human virus.
    Go to context

It has long been thought that genetic reassortment would occur exclusively in pigs. The pig provides an ideal “mixing vessel”, since pigs are readily infectable by both human and avian influenza viruses due to the molecular nature of their sialic acid receptors 27 x T Ito, JN Couceiro, S Kelm, et al.. Molecular basis for the generation in pigs of influenza A viruses with pandemic potential. J Virol 72 (1998) (7367 - 7373) (see Chapter 2). However, there is increasing evidence now that other species, including man, might also serve as mixing vessels. Indeed, since HPAI viruses do have the ability to occasionally cross the species barrier to humans, coinfection of cells with an avian and a human virus may well occur within a human host.

Reintroduction of an old strain

A third way by which an antigenic shift may occur and a pandemic arise is reintroduction of an “old” strain into the human population. A virus could remain hidden, for example in a frozen state such that little change would occur, and re-emerge as a pandemic virus when the immunity in the population to that virus has waned. The appearance of the Russian flu (H1N1) in 1977 supports the idea of reintroduction of a previous strain. The virus turned out to be identical in all of its genes to the H1N1 virus that circulated before 1957 and caused a major epidemic in 1950. 4, x ED Kilbourne. Influenza pandemics of the 20th century. Emerg Inf Dis 12 (2006) (9 - 14) 28 x K Nakajima, U Desselberger, P Palese. Recent human influenza A (H1N1) viruses are closely related genetically to strains isolated in 1950. Nature 274 (1978) (334 - 339)

 
x

Figure 12 Origin of antigenic shift and pandemic influenza. The natural reservoir of influenza A viruses is among migratory aquatic birds. A virus with a new HA subtype may be introduced into the human population by direct transmission of an avian virus to humans or by genetic reassortment between an avian and a human virus. source: Adapted from Nicholson KG et al. Influenza. Lancet 2003; 362: 1733–1745 7 x KG Nicholson, JM Wood, M Zambon. Influenza. Lancet 362 (2003) (1733 - 1745) with permission from Elsevier.

f03-12-9780723434337

References in context

  • Occasionally, a new influenza virus subtype is introduced into the human population, in a process referred to as antigenic shift.14 As indicated above, there are several ways by which such new human virus subtypes may arise (Figure 12), and it is likely that each has played a role in the influenza pandemics of the 20th century.
    Go to context

Figure 13 Genetic reassortment between human and avian influenza A viruses as the origin of the pandemic 1957 Asian flu and 1968 Hong Kong flu viruses. The segmented nature of the influenza virus genome facilitates reassortment. Pigs – which support the replication of both avian and human influenza A viruses – possibly serve as a “mixing vessel”. The Asian H2N2 virus subtype obtained its HA, NA and PB1 genes from an avian virus. Likewise, the HA and PB1 genes of the Hong Kong H3N2 virus are of avian origin – the Hong Kong virus retained the NA gene plus five other genes from the circulating human virus. source: Adapted from Potter CW, editor. Influenza (Perspectives in Medical Virology), 2003 with permission from Elsevier.

f03-13-9780723434337

References in context

  • The 1957 Asian (H2N2) and 1968 Hong Kong (H3N2) viruses were reassortants of avian and circulating human viruses (see Figure 13).
    Go to context

  • As illustrated in Figure 13, the 1957 Asian H2N2 virus subtype obtained its HA, NA, and PB1 genes from an avian virus and the other fives genes from the circulating H1N1 human strain,1,4,7,14–17 the human H1N1 virus in turn being a distant descendent of the 1918 Spanish flu virus.3 Likewise, the 1968 Hong Kong H3N2 virus acquired its HA and PB1 genes from an avian virus, but retained the NA and remaining five other genes from the then circulating H2N2 human virus.
    Go to context

References

Label Authors Title Source Year
1

References in context


  • Go to context

  • Influenza viruses continuously undergo antigenic evolution.1 It is this quality that allows them to evade the pre-existing immunity of the host, which implies that immune responses mounted against earlier forms of the virus are less effective or completely ineffective against newer variants.
    Go to context

  • These are commonly referred to as “antigenic drift” and “antigenic shift”.1 Antigenic drift occurs through continuous mutation of the RNA genome of the virus.
    Go to context

  • Occasionally, an entirely new influenza A virus subtype of avian origin emerges in the human population.
    Go to context

  • Antigenic drift is a gradual process.
    Go to context

  • As illustrated in Figure 13, the 1957 Asian H2N2 virus subtype obtained its HA, NA, and PB1 genes from an avian virus and the other fives genes from the circulating H1N1 human strain,1,4,7,14–17 the human H1N1 virus in turn being a distant descendent of the 1918 Spanish flu virus.3 Likewise, the 1968 Hong Kong H3N2 virus acquired its HA and PB1 genes from an avian virus, but retained the NA and remaining five other genes from the then circulating H2N2 human virus.
    Go to context

PF Wright, RG Webster. Orthomyxoviruses. DM Knipe, PM Howley, DE Griffin (Eds.) et al. Fields Virology 4th edn. (Lippincott Williams & Wilkins, 2001) (1533 - 1579) 2001
3

References in context

  • By far the most devastating pandemic was the Spanish flu outbreak, which hit at the end of the First World War.3,4 It spread across the globe in three consecutive waves in 1918–19, killing at least 50 million people.5 The subsequent pandemics in 1957 and 1968 were milder,4 but nonetheless also caused a total of approximately 2 million deaths.
    Go to context

  • Rarely, a highly pathogenic avian influenza (HPAI; see also Chapter 2) virus is transmitted directly from birds to humans.3,11,15–18 It was not until the 1997 H5N1 bird flu outbreak in Hong Kong that it was appreciated that such direct transmission could occur.
    Go to context

  • Indeed, there is some circumstantial evidence that the 1918 virus entered the human population several years before the pandemic.3,22 There is a close genetic relationship between the 1918 virus and the porcine A/Swine/Iowa/30 (H1N1) virus.
    Go to context

  • Indeed, there is some circumstantial evidence that the 1918 virus entered the human population several years before the pandemic.3,22 There is a close genetic relationship between the 1918 virus and the porcine A/Swine/Iowa/30 (H1N1) virus.
    Go to context

  • Indeed, there is some circumstantial evidence that the 1918 virus entered the human population several years before the pandemic.3,22 There is a close genetic relationship between the 1918 virus and the porcine A/Swine/Iowa/30 (H1N1) virus.
    Go to context

  • Indeed, there is some circumstantial evidence that the 1918 virus entered the human population several years before the pandemic.3,22 There is a close genetic relationship between the 1918 virus and the porcine A/Swine/Iowa/30 (H1N1) virus.
    Go to context

  • As illustrated in Figure 13, the 1957 Asian H2N2 virus subtype obtained its HA, NA, and PB1 genes from an avian virus and the other fives genes from the circulating H1N1 human strain,1,4,7,14–17 the human H1N1 virus in turn being a distant descendent of the 1918 Spanish flu virus.3 Likewise, the 1968 Hong Kong H3N2 virus acquired its HA and PB1 genes from an avian virus, but retained the NA and remaining five other genes from the then circulating H2N2 human virus.
    Go to context

JK Taubenberger, DM Morens. 1918 influenza: the mother of all pandemics. Emerg Inf Dis 12 (2006) (15 - 22) 2006
4

References in context

  • By far the most devastating pandemic was the Spanish flu outbreak, which hit at the end of the First World War.3,4 It spread across the globe in three consecutive waves in 1918–19, killing at least 50 million people.5 The subsequent pandemics in 1957 and 1968 were milder,4 but nonetheless also caused a total of approximately 2 million deaths.
    Go to context

  • By far the most devastating pandemic was the Spanish flu outbreak, which hit at the end of the First World War.3,4 It spread across the globe in three consecutive waves in 1918–19, killing at least 50 million people.5 The subsequent pandemics in 1957 and 1968 were milder,4 but nonetheless also caused a total of approximately 2 million deaths.
    Go to context

  • Despite their annual seasonal character, influenza epidemics are unpredictable.4,7 When precisely they will start and how long they will last are questions that are difficult to answer in advance. Figure 11 illustrates the variation in the onset and duration of influenza epidemics recorded in the Netherlands in the last three decades of the previous century.
    Go to context

  • While the bird flu outbreak in 1997 was the first documented example of a purely avian virus causing respiratory disease and deaths among humans,18–20 it has since become apparent that the 1918 Spanish flu virus was also an avian virus.3,22–25 Even though the precise origin of the 1918 virus remains enigmatic,3,11,22 based on characterization of genetic material isolated from victims of the 1918 pandemic, it is clear now that the virus was not a human–avian reassortant, but rather an avian-like virus that was introduced in its entirety into the human population and subsequently adapted to the new host.
    Go to context

  • As illustrated in Figure 13, the 1957 Asian H2N2 virus subtype obtained its HA, NA, and PB1 genes from an avian virus and the other fives genes from the circulating H1N1 human strain,1,4,7,14–17 the human H1N1 virus in turn being a distant descendent of the 1918 Spanish flu virus.3 Likewise, the 1968 Hong Kong H3N2 virus acquired its HA and PB1 genes from an avian virus, but retained the NA and remaining five other genes from the then circulating H2N2 human virus.
    Go to context

  • A third way by which an antigenic shift may occur and a pandemic arise is reintroduction of an “old” strain into the human population.
    Go to context

  • Figure 14 gives an overview of the influenza pandemics that occurred in the past century.4,29,30 The most terrible outbreak was the Spanish flu in 1918, with an estimated 50 million deaths,5 justifying its description as “the last great plague of mankind”.
    Go to context

ED Kilbourne. Influenza pandemics of the 20th century. Emerg Inf Dis 12 (2006) (9 - 14) 2006
7

References in context


  • Go to context

  • There is no doubt that there will be other pandemics in the future.6,7 Having its reservoir among migratory waterfowl, the influenza virus is non-eradicable and will continue to affect humans.
    Go to context

  • Despite their annual seasonal character, influenza epidemics are unpredictable.4,7 When precisely they will start and how long they will last are questions that are difficult to answer in advance. Figure 11 illustrates the variation in the onset and duration of influenza epidemics recorded in the Netherlands in the last three decades of the previous century.
    Go to context

  • As illustrated in Figure 13, the 1957 Asian H2N2 virus subtype obtained its HA, NA, and PB1 genes from an avian virus and the other fives genes from the circulating H1N1 human strain,1,4,7,14–17 the human H1N1 virus in turn being a distant descendent of the 1918 Spanish flu virus.3 Likewise, the 1968 Hong Kong H3N2 virus acquired its HA and PB1 genes from an avian virus, but retained the NA and remaining five other genes from the then circulating H2N2 human virus.
    Go to context

  • There is no doubt that there will be influenza pandemics in the future.7,11,22 It is not so much a matter of whether they will occur but rather when they will occur.
    Go to context

  • In May 2001, and in February and April 2002, the H5N1 virus subtype was once again detected in Hong Kong's poultry markets,7,33 the specific virus strain differing significantly from the 1997 H5N1 bird flu virus.
    Go to context

KG Nicholson, JM Wood, M Zambon. Influenza. Lancet 362 (2003) (1733 - 1745) 2003
11

References in context

  • Currently available information suggests that the natural reservoir of influenza A viruses is among aquatic birds.11–13 All 16 HA and nine NA subtypes have been identified in birds (see Chapter 2).
    Go to context

  • Rarely, a highly pathogenic avian influenza (HPAI; see also Chapter 2) virus is transmitted directly from birds to humans.3,11,15–18 It was not until the 1997 H5N1 bird flu outbreak in Hong Kong that it was appreciated that such direct transmission could occur.
    Go to context

  • While the bird flu outbreak in 1997 was the first documented example of a purely avian virus causing respiratory disease and deaths among humans,18–20 it has since become apparent that the 1918 Spanish flu virus was also an avian virus.3,22–25 Even though the precise origin of the 1918 virus remains enigmatic,3,11,22 based on characterization of genetic material isolated from victims of the 1918 pandemic, it is clear now that the virus was not a human–avian reassortant, but rather an avian-like virus that was introduced in its entirety into the human population and subsequently adapted to the new host.
    Go to context

  • Remarkably, the H5N1 virus isolated from victims of the recent outbreaks in Asia have acquired a number of mutations in the polymerase complex that are also present in the 1918 virus.25 These mutations are likely important for efficient replication of the virus in humans.
    Go to context

  • There is no doubt that there will be influenza pandemics in the future.7,11,22 It is not so much a matter of whether they will occur but rather when they will occur.
    Go to context

RG Webster, M Peiris, H Chen, et al.. H5N1 outbreaks and enzootic influenza. Emerg Inf Dis 12 (2006) (3 - 8) 2006
12

References in context

  • Currently available information suggests that the natural reservoir of influenza A viruses is among aquatic birds.11–13 All 16 HA and nine NA subtypes have been identified in birds (see Chapter 2).
    Go to context

RG Webster, WJ Bean, OT Gorman, et al.. Evolution and ecology of influenza A viruses. Microbiol Rev 56 (1992) (152 - 179) 1992
13

References in context

  • Currently available information suggests that the natural reservoir of influenza A viruses is among aquatic birds.11–13 All 16 HA and nine NA subtypes have been identified in birds (see Chapter 2).
    Go to context

DJ Alexander. A review of avian influenza viruses in different bird species. Vet Microbiol 74 (2000) (3 - 13) 2000
14

References in context

  • Occasionally, a new influenza virus subtype is introduced into the human population, in a process referred to as antigenic shift.14 As indicated above, there are several ways by which such new human virus subtypes may arise (Figure 12), and it is likely that each has played a role in the influenza pandemics of the 20th century.
    Go to context

  • As illustrated in Figure 13, the 1957 Asian H2N2 virus subtype obtained its HA, NA, and PB1 genes from an avian virus and the other fives genes from the circulating H1N1 human strain,1,4,7,14–17 the human H1N1 virus in turn being a distant descendent of the 1918 Spanish flu virus.3 Likewise, the 1968 Hong Kong H3N2 virus acquired its HA and PB1 genes from an avian virus, but retained the NA and remaining five other genes from the then circulating H2N2 human virus.
    Go to context

  • Clearly, a number of conditions must be satisfied in order for an outbreak of influenza to be classified as a “pandemic”.14 These include: (i) the emergence of a new influenza A virus subtype in the human population, unrelated to the virus subtypes that circulated immediately before the outbreak; (ii) a total lack of immunity to the new virus among the population; (iii) capacity of the virus to spread by person-to-person transmission; and (iv) rapid dissemination of the infection beyond its site of origin.
    Go to context

RG Webster, WG Laver. Pandemic variation of influenza viruses. ED Kilbourne (Ed.) The Influenza Viruses and Influenza (Academic Press, 1975) (269 - 314) 1975
15

References in context

  • Rarely, a highly pathogenic avian influenza (HPAI; see also Chapter 2) virus is transmitted directly from birds to humans.3,11,15–18 It was not until the 1997 H5N1 bird flu outbreak in Hong Kong that it was appreciated that such direct transmission could occur.
    Go to context

  • As illustrated in Figure 13, the 1957 Asian H2N2 virus subtype obtained its HA, NA, and PB1 genes from an avian virus and the other fives genes from the circulating H1N1 human strain,1,4,7,14–17 the human H1N1 virus in turn being a distant descendent of the 1918 Spanish flu virus.3 Likewise, the 1968 Hong Kong H3N2 virus acquired its HA and PB1 genes from an avian virus, but retained the NA and remaining five other genes from the then circulating H2N2 human virus.
    Go to context

KF Shortridge. Pandemic influenza: a zoonosis?. Semin Respir Infect 7 (1992) (11 - 25) 1992
16

References in context

  • Rarely, a highly pathogenic avian influenza (HPAI; see also Chapter 2) virus is transmitted directly from birds to humans.3,11,15–18 It was not until the 1997 H5N1 bird flu outbreak in Hong Kong that it was appreciated that such direct transmission could occur.
    Go to context

  • As illustrated in Figure 13, the 1957 Asian H2N2 virus subtype obtained its HA, NA, and PB1 genes from an avian virus and the other fives genes from the circulating H1N1 human strain,1,4,7,14–17 the human H1N1 virus in turn being a distant descendent of the 1918 Spanish flu virus.3 Likewise, the 1968 Hong Kong H3N2 virus acquired its HA and PB1 genes from an avian virus, but retained the NA and remaining five other genes from the then circulating H2N2 human virus.
    Go to context

RG Webster. Influenza virus: transmission between species and relevance to emergence of the next human pandemic. Arch Virol Suppl 13 (1997) (105 - 113) 1997
17

References in context

  • Rarely, a highly pathogenic avian influenza (HPAI; see also Chapter 2) virus is transmitted directly from birds to humans.3,11,15–18 It was not until the 1997 H5N1 bird flu outbreak in Hong Kong that it was appreciated that such direct transmission could occur.
    Go to context

  • As illustrated in Figure 13, the 1957 Asian H2N2 virus subtype obtained its HA, NA, and PB1 genes from an avian virus and the other fives genes from the circulating H1N1 human strain,1,4,7,14–17 the human H1N1 virus in turn being a distant descendent of the 1918 Spanish flu virus.3 Likewise, the 1968 Hong Kong H3N2 virus acquired its HA and PB1 genes from an avian virus, but retained the NA and remaining five other genes from the then circulating H2N2 human virus.
    Go to context

T Horimoto, Y Kawaoka. Pandemic threat posed by avian influenza A viruses. Clin Microbiol Rev 14 (2001) (129 - 149) 2001
18

References in context

  • Rarely, a highly pathogenic avian influenza (HPAI; see also Chapter 2) virus is transmitted directly from birds to humans.3,11,15–18 It was not until the 1997 H5N1 bird flu outbreak in Hong Kong that it was appreciated that such direct transmission could occur.
    Go to context

  • During this outbreak, 18 people were reportedly infected with the H5N1 virus, six of whom died.18–20 The virus isolated from the victims had the same genetic make-up as the virus causing the epidemic among chickens in Hong Kong at the time, indicating that it was transmitted directly from chickens to humans.
    Go to context

  • While the bird flu outbreak in 1997 was the first documented example of a purely avian virus causing respiratory disease and deaths among humans,18–20 it has since become apparent that the 1918 Spanish flu virus was also an avian virus.3,22–25 Even though the precise origin of the 1918 virus remains enigmatic,3,11,22 based on characterization of genetic material isolated from victims of the 1918 pandemic, it is clear now that the virus was not a human–avian reassortant, but rather an avian-like virus that was introduced in its entirety into the human population and subsequently adapted to the new host.
    Go to context

JC De Jong, ECJ Claas, ADME Osterhaus, RG Webster, WL Lim. A pandemic warning?. Nature 389 (1997) (554) 1997
19

References in context

  • During this outbreak, 18 people were reportedly infected with the H5N1 virus, six of whom died.18–20 The virus isolated from the victims had the same genetic make-up as the virus causing the epidemic among chickens in Hong Kong at the time, indicating that it was transmitted directly from chickens to humans.
    Go to context

  • While the bird flu outbreak in 1997 was the first documented example of a purely avian virus causing respiratory disease and deaths among humans,18–20 it has since become apparent that the 1918 Spanish flu virus was also an avian virus.3,22–25 Even though the precise origin of the 1918 virus remains enigmatic,3,11,22 based on characterization of genetic material isolated from victims of the 1918 pandemic, it is clear now that the virus was not a human–avian reassortant, but rather an avian-like virus that was introduced in its entirety into the human population and subsequently adapted to the new host.
    Go to context

EC Claas, AD Osterhaus, R van Beek, et al.. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus. Lancet 351 (1998) (472 - 477) 1998
20

References in context

  • During this outbreak, 18 people were reportedly infected with the H5N1 virus, six of whom died.18–20 The virus isolated from the victims had the same genetic make-up as the virus causing the epidemic among chickens in Hong Kong at the time, indicating that it was transmitted directly from chickens to humans.
    Go to context

  • While the bird flu outbreak in 1997 was the first documented example of a purely avian virus causing respiratory disease and deaths among humans,18–20 it has since become apparent that the 1918 Spanish flu virus was also an avian virus.3,22–25 Even though the precise origin of the 1918 virus remains enigmatic,3,11,22 based on characterization of genetic material isolated from victims of the 1918 pandemic, it is clear now that the virus was not a human–avian reassortant, but rather an avian-like virus that was introduced in its entirety into the human population and subsequently adapted to the new host.
    Go to context

K Subbarao, A Klimov, J Katz, et al.. Characterisation of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory disease. Science 279 (1998) (393 - 396) 1998
21

References in context

  • Rarely, a highly pathogenic avian influenza (HPAI; see also Chapter 2) virus is transmitted directly from birds to humans.3,11,15–18 It was not until the 1997 H5N1 bird flu outbreak in Hong Kong that it was appreciated that such direct transmission could occur.
    Go to context

Y Guan, KF Shortridge, S Krauss, RG Webster. Molecular characterization of H9N2 influenza viruses: were they the donors of the “internal” genes of H5N1 viruses in Hong Kong?. Proc Natl Acad Sci USA 96 (1999) (9363 - 9367) 1999
22

References in context

  • While the bird flu outbreak in 1997 was the first documented example of a purely avian virus causing respiratory disease and deaths among humans,18–20 it has since become apparent that the 1918 Spanish flu virus was also an avian virus.3,22–25 Even though the precise origin of the 1918 virus remains enigmatic,3,11,22 based on characterization of genetic material isolated from victims of the 1918 pandemic, it is clear now that the virus was not a human–avian reassortant, but rather an avian-like virus that was introduced in its entirety into the human population and subsequently adapted to the new host.
    Go to context

  • Indeed, there is some circumstantial evidence that the 1918 virus entered the human population several years before the pandemic.3,22 There is a close genetic relationship between the 1918 virus and the porcine A/Swine/Iowa/30 (H1N1) virus.
    Go to context

  • Indeed, there is some circumstantial evidence that the 1918 virus entered the human population several years before the pandemic.3,22 There is a close genetic relationship between the 1918 virus and the porcine A/Swine/Iowa/30 (H1N1) virus.
    Go to context

  • Indeed, there is some circumstantial evidence that the 1918 virus entered the human population several years before the pandemic.3,22 There is a close genetic relationship between the 1918 virus and the porcine A/Swine/Iowa/30 (H1N1) virus.
    Go to context

  • There is no doubt that there will be influenza pandemics in the future.7,11,22 It is not so much a matter of whether they will occur but rather when they will occur.
    Go to context

RG Webster. 1918 Spanish influenza: the secrets remain elusive. Proc Natl Acad Sci 96 (1999) (1164 - 1166) 1999
23

References in context

  • While the bird flu outbreak in 1997 was the first documented example of a purely avian virus causing respiratory disease and deaths among humans,18–20 it has since become apparent that the 1918 Spanish flu virus was also an avian virus.3,22–25 Even though the precise origin of the 1918 virus remains enigmatic,3,11,22 based on characterization of genetic material isolated from victims of the 1918 pandemic, it is clear now that the virus was not a human–avian reassortant, but rather an avian-like virus that was introduced in its entirety into the human population and subsequently adapted to the new host.
    Go to context

  • The adaptation involved a combination of mutations in different genes of the virus, including the HA and polymerase genes.3,23–25 Adaptation of an avian virus to the human host might thus give rise to a virus capable of human-to-human transmission.
    Go to context

AH Reid, TG Fanning, JV Hultin, et al.. Origin and evolution of the 1918 “Spanish” influenza virus hemagglutinin gene. Proc Natl Acad Sci 96 (1999) (1651 - 1656) 1999
24

References in context

  • While the bird flu outbreak in 1997 was the first documented example of a purely avian virus causing respiratory disease and deaths among humans,18–20 it has since become apparent that the 1918 Spanish flu virus was also an avian virus.3,22–25 Even though the precise origin of the 1918 virus remains enigmatic,3,11,22 based on characterization of genetic material isolated from victims of the 1918 pandemic, it is clear now that the virus was not a human–avian reassortant, but rather an avian-like virus that was introduced in its entirety into the human population and subsequently adapted to the new host.
    Go to context

  • The adaptation involved a combination of mutations in different genes of the virus, including the HA and polymerase genes.3,23–25 Adaptation of an avian virus to the human host might thus give rise to a virus capable of human-to-human transmission.
    Go to context

  • Determination of the structure and receptor-binding properties of the 1918 HA24 has suggested that, indeed, by mutation of the receptor-binding site, the HA acquired the ability to interact with human α2,6-linked sialic acid receptors (see Chapter 2).
    Go to context

SJ Gamblin, LF Haire, RJ Russell, et al.. The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science 303 (2004) (1838 - 1842) 2004
25

References in context

  • While the bird flu outbreak in 1997 was the first documented example of a purely avian virus causing respiratory disease and deaths among humans,18–20 it has since become apparent that the 1918 Spanish flu virus was also an avian virus.3,22–25 Even though the precise origin of the 1918 virus remains enigmatic,3,11,22 based on characterization of genetic material isolated from victims of the 1918 pandemic, it is clear now that the virus was not a human–avian reassortant, but rather an avian-like virus that was introduced in its entirety into the human population and subsequently adapted to the new host.
    Go to context

  • The adaptation involved a combination of mutations in different genes of the virus, including the HA and polymerase genes.3,23–25 Adaptation of an avian virus to the human host might thus give rise to a virus capable of human-to-human transmission.
    Go to context

  • Remarkably, the H5N1 virus isolated from victims of the recent outbreaks in Asia have acquired a number of mutations in the polymerase complex that are also present in the 1918 virus.25 These mutations are likely important for efficient replication of the virus in humans.
    Go to context

JK Taubenberger, AH Reid, RM Lourens, et al.. Characterization of the 1918 influenza virus polymerase genes. Nature 437 (2005) (889 - 893) 2005
26

References in context

  • As illustrated in Figure 13, the 1957 Asian H2N2 virus subtype obtained its HA, NA, and PB1 genes from an avian virus and the other fives genes from the circulating H1N1 human strain,1,4,7,14–17 the human H1N1 virus in turn being a distant descendent of the 1918 Spanish flu virus.3 Likewise, the 1968 Hong Kong H3N2 virus acquired its HA and PB1 genes from an avian virus, but retained the NA and remaining five other genes from the then circulating H2N2 human virus.
    Go to context

  • The first convincing report of an influenza pandemic describes an outbreak in 1580, which started in Asia in the summer, and then spread via Africa to Europe and finally to America.26 In Britain it came in two waves, a pattern that was also seen in subsequent influenza pandemics.
    Go to context

WJ Bean, M Schell, J Katz, et al.. Evolution of the H3 influenza virus hemagglutinin from human and nonhuman hosts. J Virol 66 (1992) (1129 - 1138) 1992
27

References in context

  • The pig provides an ideal “mixing vessel”, since pigs are readily infectable by both human and avian influenza viruses due to the molecular nature of their sialic acid receptors27 (see Chapter 2).
    Go to context

T Ito, JN Couceiro, S Kelm, et al.. Molecular basis for the generation in pigs of influenza A viruses with pandemic potential. J Virol 72 (1998) (7367 - 7373) 1998
28

References in context

  • A third way by which an antigenic shift may occur and a pandemic arise is reintroduction of an “old” strain into the human population.
    Go to context

  • As mentioned above, the virus was subsequently found to be virtually identical to one that had caused a human epidemic in 1950.28 Consequently, most people over 23 years old possessed antibody to it.
    Go to context

  • A cyclic theory has been proposed suggesting that pandemics may appear in a specific recurring pattern.28 The interval between the 1889 (H2) and 1900 pandemics (H3) matches that between the 1957 (H2) and 1968 (H3) pandemics.
    Go to context

K Nakajima, U Desselberger, P Palese. Recent human influenza A (H1N1) viruses are closely related genetically to strains isolated in 1950. Nature 274 (1978) (334 - 339) 1978

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