Division of Molecular Pathology, Department of Cellular Pathology and Genetics, Armed Forces Institute of Pathology, 1413 Research Blvd, Building 101, Room 1057, Rockville, MD 20850-3125, USA
Correspondence
Jeffery Taubenberger
taubenbe{at}afip.osd.mil
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ABSTRACT |
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Published ahead of print on 6 June 2003 as DOI 10.1099/vir.0.19302-0
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INTRODUCTION |
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The 1918 influenza pandemic fits the classic pattern of influenza epidemiology in many ways. It occurred 28 years after the previous pandemic of 1890 and emerged globally with explosive suddenness in September 1918 after a limited wave earlier in the year. Most communities experienced morbidity of 2540 % and the vast majority of cases were self-limiting. Age-specific morbidity was also similar to other pandemics, with children under 15 years of age experiencing the highest rates of infection (Jordan, 1927). Clinically, the 1918 pandemic presented the same symptoms and course as influenza of other years and, pathologically, the disease was similar to other pandemics in that damage was confined largely to the respiratory tract (Wolbach, 1919
; Winternitz et al., 1920
). However, the 1918 pandemic differed from other pandemics in a few key respects. First, while the clinical course in the majority of cases was mild, a substantially higher percentage of cases developed severe pneumonic complications. As a result, the case mortality rate in the USA averaged 2·5 %, several times higher than the contemporary average. Also, mortality during the 1918 pandemic was concentrated in an unusually young age group (Linder & Grove, 1943
; Marks & Beatty, 1976
; Rosenau & Last, 1980
). People under the age of 65 accounted for more than 99 % of excess influenza-related deaths in 1918. In 1957 and 1968, people under 65 accounted for only 36 and 48 % of excess deaths due to influenza (Simonsen et al., 1998
). The age group affected most severely by the 1918 pandemic was between 20 and 40 years and this group accounted for almost half of influenza deaths during the pandemic.
Until recently, the 1918 pandemic strain was not available for study, since influenza viruses were not isolated and cultured until the 1930s. By then, 15 years of circulation in humans had altered significantly the antigenicity of the circulating H1 haemagglutinin (HA), as assessed serologically (Shope, 1936; Taubenberger et al., 2001
), and only indirect analyses of the 1918 strain could be performed. Recently, extraction of RNA from fixed and frozen lung tissues from victims of the 1918 pandemic has allowed the sequencing of the 1918 influenza virus genome (Taubenberger et al., 1997
). Four of eight gene segments have been sequenced (Reid et al., 1999
, 2000
, 2002
; Basler et al., 2001
). This work has two principal goals: to determine the genetic contribution to the virulence of the 1918 influenza and to determine the origin of the pandemic virus. Understanding the basis of the virulence of the 1918 strain could help in the development of influenza treatment and prevention, while knowing where and how the strain developed could help direct surveillance and prevention efforts.
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Influenza A virus biology and ecology |
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Pandemic influenza results when an influenza virus strain emerges with an HA protein to which few people have prior immunity (Kilbourne, 1977). It is thought that the source of HA genes new to humans is the extensive pool of influenza viruses that infect wild birds (Wright & Webster, 2001
). Periodically, genetic material from avian strains is transferred to strains infectious to humans by reassortment. Of the 15 HA subtypes found in birds (H1H15), only three (H1, H2 and H3) are known to have caused pandemics in man (Kilbourne, 1997
). Recently, wholly avian H5N1 and H9N2 viruses (without reassortment) caused illness in a limited number of people in China (Lin et al., 2000
; Hatta & Kawaoka, 2002
). Avian and human HAs differ in their ability to bind to different forms of sialic acids and avian HAs bind poorly to the sialic acid receptors prevalent in the human respiratory tract. These different receptor affinities act as a barrier to cross-species infection. Before a virus with an avian HA can replicate and spread efficiently in humans, some adaptation of the HA binding affinity is necessary. It is not known currently whether the HA subtypes that have become established in human strains were able to adapt more easily than other subtypes or whether all 15 avian subtypes pose a similar risk of reassortment.
Since pigs can be infected with both avian and human strains, and various reassortants have been isolated from pigs, they have been proposed as an intermediary in the generation of reassortant pandemic strains (Ludwig et al., 1995). In 1979, an avian influenza A virus began infecting swine in Northern Europe, thereby establishing a stable virus lineage (Ludwig et al., 1995
). Since that time, there has been evidence of reassortment between the new swine lineage and human strains circulating currently. Viruses have been detected in swine in which the avian-derived H1 and N1 have been replaced by reassortment with the H3 and N2 HA and NA segments circulating concurrently in humans (Castrucci et al., 1993
; Claas et al., 1994
; Marozin et al., 2002
). However, reassortant strains with the avian-derived H1 and N1 along with human-adapted core protein segments have not been found. Such reassortant strains would be antigentically novel and probably capable of effective replication in humans and, therefore, would have substantial pandemic potential. Similarly, a number of triple reassortant strains, which include gene segments of swine, human and avian origin, have been isolated recently from pigs in the USA. Several reassortant viruses bearing human HA and NA segments have been isolated from swine but, as yet, no viruses with swine or avian surface proteins and human internal protein segments have been detected (Zhou et al., 2000
; Marozin et al., 2002
; Olsen, 2002
).
Until recently, it was thought that reassortment between avian and human strains would be unlikely to take place in humans because there was no evidence that humans could be infected by a wholly avian influenza virus. However, in 1997, 18 people were infected with avian H5N1 influenza viruses in Hong Kong and six died of complications after infection (Claas et al., 1998; Subbarao et al., 1998
). Although these viruses were very poorly transmissible, if at all (Katz et al., 1999
), their detection indicates that humans can be infected with wholly avian influenza virus strains. Therefore, it may not be necessary to invoke swine as the intermediary in the formation of a pandemic strain (Scholtissek, 1995
), since reassortment could take place directly in humans (Young & Palese, 1979
; Palese & Young, 1982
).
While reassortment appears to be a critical event for the production of a pandemic virus, a significant amount of data exists to suggest that influenza viruses must also acquire specific adaptations to spread and replicate efficiently in a new host. In addition to the adaptation of the HA protein to host cell receptors, other viral proteins must be able to interact with each other and various host cell proteins. Unfortunately, little is known about which specific genetic features of influenza viruses contribute to the emergence of a virulent pandemic strain. Virulence is complex and involves a number of features, including host adaptation, transmissibility, tissue tropism and virus replication efficiency. The genetic basis for each of these features is not characterized fully yet but is most likely polygenic in nature (Kilbourne, 1977).
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The 1957 and 1968 influenza virus pandemic strains |
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A pandemic virus faces the twin challenges of being antigenically new to its host, while being supremely well adapted to it. This challenge was met in 1957 and 1968 by reassortment: combining surface proteins novel to humans with human-adapted internal proteins (with the intriguing exception of PB1). The 1968 viral HA appears to have had an avian origin (Fang et al., 1981; Bean et al., 1992
). Sequencing of an avian H3 HA gene (A/duck/Ukraine/1/63) isolated in 1963 demonstrated its close molecular similarity to the HA gene of A/Aichi/2/68, the latter being an example of the 1968 pandemic virus. For example, 1605 of 1765 nucleotides (90·9 %) are identical between the two viruses, while 542 of 566 amino acids (95·8 %) are identical (Fang et al., 1981
). In addition, of the approximately 40 amino acid residues involved in antigenic recognition, only four residues differ between A/duck/Ukraine/1/63 and A/Aichi/2/68. For comparison, there are 14 amino acid differences in antigenic residues between A/duck/Ukraine/1/63 and A/Victoria/3/75, a human virus isolated only 7 years after the A/Aichi/2/68 virus (Fang et al., 1981
). Also, phylogenetic analyses support strongly the avian origin of the 1968 pandemic HA gene (Bean et al., 1992
).
Like the 1968 H3 pandemic strain, the HA of the 1957 pandemic is closely related also to avian H2 sequences. When the 1957 H2 sequences are compared as a group to avian HA sequences, only four amino acids differ consistently between the human and avian groups [N92D, T114
K, K156
E and I214
T; H3 subtype sequence numbering (Winter et al., 1981
)]. Residue 226, which is Q in all avian sequences and L in most human sequences, is likely also to reflect a consistent difference between human and avian strains, since it is critical to improving the H2 binding affinity for receptors on human cells. Approximately 40 amino acids have been identified as being involved in antibody binding in the H3 molecule (Wiley et al., 1981
) and studies indicate that the H2 subtype has a similar antigenic structure (Tsuchiya et al., 2001
). Only one of the five amino acids differing between avian and early human isolates is in an antigenic site, suggesting that there had been little or no antigenic drift pressure on the H2 molecule before it emerged in a pandemic strain. Phylogenetic analyses (Schafer et al., 1993
) indicate that the gene was acquired from an avian source shortly before 1957. It appears that the avian source was Eurasian, since the pandemic viral sequences resembled Eurasian avian sequences much more closely than they resembled North American avian sequences.
The 1957 pandemic strain also acquired a novel N2-subtype NA, replacing the N1 of the previous strain. The sequence of the new NA was related very closely to avian N2 sequences, with only six amino acids differing consistently from avian sequences. Thirty-four amino acids have been identified as potentially antigenic residues on the N2 protein (Martinez et al., 1983); none of the six differences are in these antigenic sites, suggesting that the protein had not been under selective antigenic pressure in humans before the pandemic. The avian sequence related most closely to the 1957 sequences is A/chicken/Korea/MS96/96, which differs at over 20 amino acids. There are no full-length N2 sequences from wild birds in the published databases but it seems likely that the recent avian origin of the 1957 N2 will be confirmed by further sequencing of wild avian strains.
The hypothesis that reassortment between avian and human strains is the likely mechanism for the generation of new pandemic strains has become well accepted. During a recent outbreak of highly pathogenic avian influenza in The Netherlands, efforts were made to minimize the possibility of simultaneous infection with human and avian influenza, especially when the virus began by causing conjunctivitis in humans. Those involved in the culling process were vaccinated against circulating human strains and discouraged from contact with sick birds when suffering flu-like symptoms in an effort to minimize the possibility of an individual being infected simultaneously with human and avian strains (ProMED Mail, 2003). Given that the 1957 and 1968 pandemic strains may well have originated in just such a dual infection, these precautions seem appropriate. It is possible, though, that reassortment is not the only route to a pandemic. In 1947, drift in the prevailing H1 strain resulted in vaccine failure and outbreaks of influenza on a pandemic scale (Kilbourne, 1997
). In 1977, an H1N1 virus re-emerged, having been absent since 1957, but failed either to cause a pandemic or to replace the prevailing H3N2 subtype (Nakajima et al., 1978
).
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Origin of the 1918 HA gene |
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There is reason to question whether the 1918 pandemic strain originated in a simple reassortment immediately before the pandemic. Extensive phylogenetic analyses of the HA gene segment, in particular, are difficult to reconcile with the hypothesis of direct avian origin (Reid et al., 1999). The sequence of the 1918 HA, although it is related more closely to avian strains than subsequent mammalian H1 sequences, has many more differences from avian sequences than the 1957 and 1968 HA sequences. If it should prove true that the 1918 pandemic strain acquired a novel HA via a different mechanism than subsequent pandemics, this could have important public health implications. An alternate origin could even have contributed to the exceptional virulence of the 1918 pandemic strain. Despite the current lack of influenza virus samples from before 1918, several indirect experimental approaches have been explored to test the hypothesis of an alternative origin of the 1918 influenza virus strain.
The sequence of the 1918 HA is related most closely to A/sw/Iowa/30, the first influenza virus isolated from swine (Reid et al., 1999). The similarity suggests that the human pandemic influenza virus became established in swine, in which it changed very slowly over the next 12 years. Unlike the 1957 and 1968 pandemic HAs, phylogenetic analyses do not place the 1918 sequence in the avian clade. However, the 1918 pandemic sequence is related more closely to avian H1s than to any other mammalian H1s and has many avian features. Of the 41 amino acids that have been shown to be targets of the immune system and subject to antigenic drift pressure in humans, 37 match the avian consensus sequence, suggesting that there was little immunologic pressure on the HA protein before the autumn of 1918 (Reid et al., 1999
; Brownlee & Fodor, 2001
). Another mechanism by which influenza viruses evade the human immune system is the acquisition of glycosylation sites to mask antigenic epitopes. Modern human H1N1s have up to five glycosylation sites in addition to the four found in all avian strains. The 1918 virus has only the four conserved avian sites.
The H1 receptor-binding site apparently required little change from the avian-adapted receptor-binding site configuration [with a preference for (2,3) sialic acids] to that of swine H1s [which can bind both
(2,3) and
(2,6) sialic acids] (Matrosovich et al., 1997
). The receptor-binding residues of the 1918 HA differs by as little as one amino acid (E190
D) from the avian consensus.
In spite of the many ways in which the 1918 HA resembles avian viruses, phylogenetic analyses always place the 1918 HA with the mammalian viruses and not with the avian viruses (Reid et al., 1999). Both the 1957 and 1968 pandemic strains appear to have resulted from reassortments of a human-adapted influenza virus strain with HA genes from a Eurasian avian lineage strain (Scholtissek et al., 1978b
; Bean et al., 1992
; Schafer et al., 1993
). In contrast, the 1918 HA is much less avian-like and, while probably novel to humans in 1918, does not appear to have been derived directly from an avian strain (Taubenberger et al., 2001
). Table 1
presents the number of amino acid differences between pandemic viruses and the consensus HA sequences of both North American and Eurasian birds. The numbers demonstrate that the HA genes of the pandemic viruses of 1968 and 1957 are more Eurasian avian-like (seven and five differences) than North American avian-like (13 and 19 differences). In contrast, the 1918 pandemic virus HA gene appears much less avian than either the 1968 or 1957 viruses and has no clear affinity with either North American or Eurasian avian viruses (Table 1
). A similar situation can be demonstrated with the NA genes of the 1918 and 1957 strains.
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Involvement of an intermediate host in 1918? |
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Indeed, during the 1918 pandemic, simultaneous outbreaks of influenza were seen in humans and swine. Interestingly, swine influenza was first recognized as a clinical entity in that species in the autumn of 1918 (Koen, 1919) concurrently with the spread of the second wave of the pandemic in humans (Dorset et al., 1922
). Investigators were impressed by the clinical and pathological similarities between human and swine influenza in 1918 (Koen, 1919
; Murray & Biester, 1930
). An extensive review by the veterinarian W. W. Dimoch of the diseases of swine published in August 1918 makes no mention of any swine disease resembling influenza (Dimoch, 1918
). Thus, contemporary investigators were convinced that influenza virus had not circulated as an epizootic disease in swine before 1918 and that the virus spread from humans to pigs because of the appearance of illness in pigs after the first wave of the 1918 influenza in humans (Shope, 1936
).
Thereafter, the disease became widespread among swine herds in the Midwest USA. The epizootic of 19191920 was as extensive as that in 19181919. The disease then appeared among swine in the Midwest every year, leading to R. E. Shope's isolation of the first influenza virus in 1930, A/swine/Iowa/30 (Shope & Lewis, 1931), 3 years before the isolation of the first human influenza virus, A/WS/33, by W. Smith, C. Andrewes and P. Laidlaw (Smith et al., 1933
). Classical swine viruses have continued to circulate not only in North American pigs but also in swine populations in Europe and Asia (Nerome et al., 1982
; Kupradinun et al., 1991
; Brown et al., 1997
).
During the fall and winter of 19181919, severe influenza-like disease outbreaks were noted not only in swine in the USA but also in Europe and China (Koen, 1919; Chun, 1919
; Beveridge, 1977
). The classical swine H1N1 lineage became endemic in swine herds in the USA and there are good data to support the global circulation of the 1918 influenza virus in pigs concurrently with its circulation in humans. Since 1918, there have been many examples of both H1N1 and H3N2 human influenza A virus strains becoming established in swine (Castrucci et al., 1993
; Brown et al., 1998
; Zhou et al., 2000
). Unfortunately for the argument that swine might have served as the intermediate between avian and humans in 1918, swine influenza virus strains have been isolated only sporadically from humans (Gaydos et al., 1977
; Woods et al., 1981
; Rimmelzwaan et al., 2001
). It seems probable that at least during the height of the 1918 pandemic, the direction of transmission was from humans to pigs. However, is it possible that before the pandemic, the originally avian HA was gradually adapting into a swine influenza virus strain?
Interestingly, an avian H1N1 lineage has become established in European swine in the last 20 years, providing a model for the evolution of avian viruses in pigs. As noted earlier, the 1918 HA1 sequence had many more amino acid differences from avian sequences than did the 1957 and 1968 pandemic strains but very few of these change were in antigenic sites, suggesting that the 1918 HA had not been subjected to significant selective pressure before emerging as a pandemic. In phylogenetic analyses, the 1918 HA is always placed in the mammalian clade. It would be interesting to note whether, at some point in the evolution of an avian H1N1 lineage in European pigs, a similar degree of divergence from the avian clade would be found. The earliest avian-like H1N1 strains were isolated from swine in Northern Europe in 1979 and 1980. A/swine/Arnsberg/6554/79 has 12 amino acid differences from the avian consensus sequence and A/Swine/Netherlands/3/80 has seven differences. In both cases, three of the differences are in antigenic sites. In contrast, the 1918 HA has 28 amino acid differences from the avian consensus sequence, of which four are in antigenic sites. The latest avian-like H1N1 isolated from swine in Europe from which sequence is available, A/swine/Belgium/117/96, has 17 differences from the avian consensus sequence, of which five are in antigenic sites. Furthermore, phylogenetic analyses place even A/swine/Belgium/117/96 in the avian clade. Thus, it appears that even 20 years of evolution in swine has not resulted in the number of changes from the avian consensus sequence exhibited by the 1918 pandemic strain.
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CONCLUSION |
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ACKNOWLEDGEMENTS |
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