Historical background

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The influenza pandemic of 1918 was exceptional in both breadth and depth. Outbreaks of the disease swept not only North America and Europe but also spread as far as the Alaskan wilderness and the most remote islands of the Pacific. It has been estimated that one-third of the world's population (500 million people) may have become infected and ill during the pandemic [6, 16]. The disease was also exceptionally severe, with mortality rates among the infected of more than 2.5%, compared to less than 0.1% in other influenza epidemics [44, 60]. Total mortality attributable to the 1918 pandemic was probably around 40 million [12, 27, 52].

Unlike most subsequent influenza virus strains that have developed in Asia, the 'first wave' or 'spring wave' of the 1918 pandemic seemingly arose in the United States in March, 1918 [1, 12, 28]. However, the near simultaneous appearance of influenza in March-April, 1918 in North America, Europe, and Asia makes definitive assignment of a geographic point of origin difficult [28]. It is possible that a mutation or reassortment occurred in the late summer of 1918, resulting in significantly enhanced virulence. The main wave of the global pandemic, the 'fall wave' or 'second wave,' occurred in September-November, 1918. In many places, there was yet another severe wave of influenza in early 1919 [28].

Three extensive outbreaks of influenza within one year is unusual, and may point to unique features of the 1918 virus that could be revealed in its sequence. Interpandemic influenza outbreaks generally occur in a single annual wave in the late winter. The severity of annual outbreaks is affected by antigenic drift, with an antigenic variant virus strain emerging every two to three years. Even in pandemic influenza, when the normal late winter seasonality pattern may be violated, the successive occurrence of distinct waves within a year is unusual. The 1890 pandemic began in the late spring of 1889 and took several months to spread throughout the world, peaking in northern Europe and the United States late in 1889 or early 1890. The second wave peaked in spring 1891 (more than a year after the first wave) and the third wave in early 1892 [28]. As in 1918, subsequent waves seemed to produce more severe illness, so that the peak mortality rate was reached in the third wave of the pandemic. The three waves, however, were spread over more than three years, in contrast to less than one year in 1918. It is unclear

70 65 60

70 65 60

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1900 1906 1912 1918 1924 1930 1936 1942 1948 1954 1960


Fig. 1. Life expectancy in the United States, 1900-1960 showing the impact of the 1918

influenza pandemic [24, 42, 78]

what gave the 1918 virus this unusual ability to generate repeated waves of illness. Perhaps the surface proteins of the virus drifted more rapidly than they did in other influenza virus strains, or perhaps the virus had an unusually effective mechanism for evading the human immune system.

It has been estimated that the influenza epidemic of 1918 killed 675,000 Americans, including 43,000 servicemen mobilized for World War I [12]. The impact was so profound as to depress average life expectancy in the U.S. by more than 12 years, Fig. 1 [24], and may have played a significant role in ending the World War I conflict [12, 43].

The majority of individuals who died during the pandemic succumbed to secondary bacterial pneumonia [28, 39, 84], since no antibiotics were available in 1918. However, a subset died rapidly after the onset of symptoms, often with either massive acute pulmonary hemorrhage or pulmonary edema, and often in fewer than 5 days [39, 83, 84]. In the hundreds of autopsies performed in 1918, the primary pathologic findings were confined to the respiratory tree and death was due to pneumonia and respiratory failure [83]. These findings are consistent with infection by a well-adapted influenza virus capable of rapid replication throughout the entire respiratory tree [54, 72]. There was no clinical or pathological evidence for systemic circulation of the virus [83].

Furthermore, in the 1918 pandemic most deaths occurred among young adults, a group in which there usually is a very low death rate from influenza. Influenza and pneumonia death rates for 15-34 year olds were more than 20 times higher in 1918 than in previous years, Fig. 2 [42, 67]. The 1918 pandemic is also unique among influenza pandemics in that absolute risk of influenza mortality was higher in those less than 65 years of age than in those greater than 65. Strikingly, persons less than 65 years old accounted for greater than 99% of all excess influenza-related deaths in 1918-19 [67]. In contrast, the less-than-65 age group accounted for only 36% of all excess influenza-related mortality in the 1957 H2N2 pandemic and 48% in the 1968 H3N2 pandemic. Overall, nearly half of the influenza-related deaths in the 1918 influenza pandemic were young adults, age 20-40, Fig. 2 [67]. Why this




<1 1-4 5-14 15-24 25-34 35-44 45-54 55-64 65-74 75-84 >85 Age Divisions

Fig. 2. Influenza and pneumonia mortality by age, United States. Influenza and pneumonia specific mortality by age, including an average of the inter-pandemic years 1911-1915 (dashed line), and the pandemic year 1918 (solid line). Specific death rate is per 100,000 of the population in each age division [24, 42, 78]

particular age group suffered such extreme mortality is not fully understood (see below).

The 1918 influenza had as another unique feature the simultaneous infection of both humans and swine. Interestingly, swine influenza was first recognized as a clinical entity in that species in the fall of 1918 [32] concurrent with the spread of the second wave of the pandemic in humans [14]. Investigators were impressed by clinical and pathological similarities of human and swine influenza in 1918 [32, 48]. 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 [13]. 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 [66].

Thereafter the disease became widespread among swine herds in the U.S. midwest. The epizootic of 1919-1920 was as extensive as the one in 1918-1919. The disease then appeared among swine in the midwest every year, leading to Richard Shope's isolation of the first influenza virus in 1930, A/swine/Iowa/30 [65], three years before the isolation of the first human influenza virus, A/WS/33 by Smith, Andrewes, and Laidlaw [69]. Classical swine viruses have continued to circulate not only in North American pigs, but also in swine in Europe and Asia [4, 35,49].

During the fall and winter of 1918-19, severe influenza-like outbreaks were noted not only in swine in the United States, but also in Europe and China [3,9,32]. Since 1918 there have been many examples of both H1N1 and H3N2 human influenza A virus strains becoming established in swine [5, 7, 86], while swine

<1 1-4 5-14 15-24 25-34 35-44 45-54 55-64 65-74 75-84 >85 Age Divisions

Fig. 2. Influenza and pneumonia mortality by age, United States. Influenza and pneumonia specific mortality by age, including an average of the inter-pandemic years 1911-1915 (dashed line), and the pandemic year 1918 (solid line). Specific death rate is per 100,000 of the population in each age division [24, 42, 78]

influenza A virus strains have been isolated only sporadically from humans [21, 85].

The unusual severity of the 1918 pandemic and the exceptionally high mortality it caused among young adults have stimulated great interest in the influenza virus strain responsible for the 1918 outbreak [12, 33, 47]. Since the first human and swine influenza A viruses were not isolated until the early 1930's [65, 69], characterization of the 1918 virus strain has had previously to rely on indirect evidence [29, 64].

Epidemiological data on influenza prevalence by age in the population, collected between 1900 and 1918, provide good evidence for the emergence of an antigenically novel influenza virus in 1918 [28]. Jordan showed that from 1900-1917, the 5-15 age group accounted for 11% of total influenza cases in this series while the >65 age group similarly accounted for 6% of influenza cases. In 1918 the 5-15 year old group jumped to 25% of influenza cases, compatible with exposure to an antigenically novel virus strain but the > 65 age group only accounted for 0.6% of the influenza cases in 1918. It is likely that the latter age group accounted for a significantly lower percentage of influenza cases because younger people were so susceptible to the novel virus strain (as seen in the 1957 pandemic [46, 67]) but it is also possible that these older people had pre-existing H1 antibodies. Further evidence for pre-existing H1 immunity can be derived from the age adjusted mortality data in Fig. 2. Those individuals >75 years had a lower influenza and pneumonia case mortality rate in 1918 than they had for the pre-pandemic period of 1911-1917.

When 1918 influenza case rates by age [28] are superimposed on the familiar 'W' shaped mortality curve (seen in Fig. 2), a different perspective emerges (Fig. 3). As shown, those <35 years of age in 1918 accounted for a disproportionately high influenza incidence by age. Interestingly, the 5-14 age group accounted for a large fraction of 1918 influenza cases, but had an extremely low case mortality rate compared to other age groups (Fig. 3). Why this age group had such a low case fatality rate cannot yet be fully explained. Conversely, why the 25-34 age group had such a high influenza and pneumonia mortality rate in 1918 remains enigmatic but it is one of the truly unique features of the 1918 influenza pandemic.

One theory that may explain these data concerns the possibility that the virus had an intrinsically high virulence that was tempered only in those patients who had been born before 1889. It can be speculated that the virus circulating prior to 1889 was an H1-like virus strain that provided partial protection against the 1918 virus strain [46, 67, 74].

Thus, it seems clear that the H1N1 virus of the 1918 pandemic contained an antigenically novel hemagglutinin and most humans and swine were susceptible to this virus in 1918. Given the severity of the pandemic, it is also reasonable to suggest that the other dominant surface protein, neuraminidase, would also have been replaced by antigenic shift before the start of the pandemic [54, 72]. In fact, sequence and phylogenetic analyses suggest that the genes encoding these two surface proteins were derived from an avian-like influenza virus shortly before the start of the 1918 pandemic and that the precursor virus did not circulate widely in

Age Divisions

Fig. 3. Influenza and pneumonia mortality by age (solid line), with influenza morbidity by age (dashed line) superimposed. Influenza and pneumonia mortality by age as in Fig. 2. Specific death rate per age group, left ordinal axis. Influenza morbidity presented as ratio of incidence in persons of each group to incidence in persons of all ages (=100), right ordinal axis. Horizontal line at 100 (right ordinal axis) represents average influenza incidence in the total population [74] (Adapted from [28])

Age Divisions

Fig. 3. Influenza and pneumonia mortality by age (solid line), with influenza morbidity by age (dashed line) superimposed. Influenza and pneumonia mortality by age as in Fig. 2. Specific death rate per age group, left ordinal axis. Influenza morbidity presented as ratio of incidence in persons of each group to incidence in persons of all ages (=100), right ordinal axis. Horizontal line at 100 (right ordinal axis) represents average influenza incidence in the total population [74] (Adapted from [28])

either humans or swine before 1918 [15, 53, 55]. It is currently unclear what other influenza gene segments were novel in the 1918 pandemic virus in comparison to the previously circulating virus strain. It is possible that on-going sequence and phylogenetic analyses of the gene segments of the 1918 virus may help elucidate this question.

Genetic characterization of the 1918 virus

Sequence and functional analysis of the hemagglutinin and neuraminidase gene segments

Frozen and fixed lung tissue from five fall wave 1918 influenza victims has been used to examine directly the genetic structure of the 1918 influenza virus. Two of the cases analyzed were U.S. Army soldiers who died in September, 1918, one in Camp Upton, New York and the other in Fort Jackson, South Carolina. The available material consists of formalin-fixed, paraffin-embedded (FFPE) autopsy tissue, hematoxylin and eosin-stained microscopic sections, and the clinical histories of these patients. A third sample was obtained from an Alaskan Inuit woman who had been interred in permafrost in Brevig Mission, Alaska, since her death from influenza in November 1918. The influenza virus sequences derived from these three cases have been called A/South Carolina/1/18 (H1N1), A/New York/1/18 (H1N1), and A/Brevig Mission/1/18 (H1N1), respectively. More recently, partial hemagglutinin (HA) sequence of two additional fixed autopsy cases of 1918 influenza victims from the Royal London Hospital were determined [57]. The HA sequences from these five cases show >99% sequence identity, but differ at amino acid residue 225 (see below). To date, five 1918 influenza gene segment sequences have been published [2, 53, 55, 56, 59]. The sequences of the three polymerase genes are nearing completion.

The sequence of the 1918 HA is most closely related to that of the A/swine/ Iowa/30 virus. However, despite this similarity the sequence has many avian-like structural 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 sequence consensus, suggesting that there was little immunologic pressure on the HA protein before the fall of 1918 [53]. Another mechanism by which influenza viruses evade the human immune system is the acquisition of glycosylation sites to mask antigenic epitopes. The HAs from modern H1N1 viruses have up to five glycosylation sites in addition to the four found in all avian HAs. The HA of the 1918 virus has only the four conserved avian sites [53].

Influenza virus infection requires binding of the HA protein to sialic acid receptors on the host cell surface. The HA receptor binding site consists of a subset of amino acids that are invariant in all avian HAs but vary in mammalian-adapted HAs. Human-adapted influenza viruses preferentially bind sialic acid receptors with a(2-6) linkages. Those viral strains adapted to birds preferentially bind a(2-3) linked sugars [17, 45, 81]. To shift from the proposed avian-adapted receptor binding site configuration (with a preference for a(2-3) sialic acids) to that of swine H1s (which can bind both a(2-3) and a(2-6)) requires only one amino acid change, E190D. The HA sequences of all five 1918 cases have the E190D change [57]. In fact, the critical amino acids in the receptor-binding site of two of the 1918 cases are identical to that of the A/swine/Iowa/30 HA. The other three 1918 cases have an additional change from the avian consensus, G225D. Since swine viruses with the same receptor site as A/swine/Iowa/30 bind both avian and mammalian-type receptors [17], A/New York/1/18 virus probably also had the capacity to bind both. The change at residue 190 may represent the minimal change necessary to allow an avian H1-subtype HA to bind mammalian-type receptors [18, 23, 53, 57, 70], a critical step in host adaptation.

The crystal structure analysis of the 1918 HA [18,70] suggests that the overall structure of the receptor binding site is akin to that of an avian H5 HA in terms of its having a narrower pocket than that identified for the human H3 HA [82]. This provides an additional clue for an avian-like derivation of the 1918 HA. The four antigenic sites that have been identified for another H1 HA, the A/PR/8/34 virus HA [8], also appear to be the major antigenic determinants on the 1918 HA. X-ray analyses suggest that these sites are exposed on the 1918 HA and thus they could be readily recognized by the human immune system.

The principal biological role of neuraminidase (NA) is the cleavage of the terminal sialic acid residues that are receptors for the virus' HA protein [51]. The active site of the enzyme consists of 15 invariant amino acids that are conserved in the 1918 NA. The functional NA protein is configured as a homotetramer in which the active sites are found on a terminal knob carried on a thin stalk [10].

Some early human virus strains have short (11-16 amino acids) deletions in the stalk region, as do many virus strains isolated from chickens. The 1918 NA has a full-length stalk and has only the glycosylation sites shared by avian N1 virus strains [62]. Although the antigenic sites on human-adapted N1 neuraminidases have not been definitively mapped, it is possible to align the N1 sequences with N2 subtype NAs and examine the N2 antigenic sites for evidence of drift in N1. There are 22 amino acids on the N2 protein that may function in antigenic epitopes [10]. The 1918 NA matches the avian consensus at 21 of these sites [55]. This finding suggests that the 1918 NA, like the 1918 HA, had not circulated long in humans before the pandemic and very possibly had an avian-like origin [58].

Neither the 1918 HA nor NA genes have obvious genetic features that can be related directly to virulence. Two known mutations that can dramatically affect the virulence of influenza virus strains have been described. For viral activation HA must be cleaved into two pieces, HA1 and HA2 by a host protease [38, 61]. Some avian H5 and H7 subtype viruses acquire a mutation that involves the addition of one or more basic amino acids to the cleavage site, allowing HA activation by ubiquitous proteases [31,80]. Infection with such a pantropic virus strain can cause systemic disease with high mortality in birds. This mutation was not observed in the 1918 virus [53, 73].

The second mutation with a significant effect on virulence through pantropism has been identified in the NA gene of two mouse-adapted influenza virus strains, A/WSN/33 and A/NWS/33. Mutations at a single codon (N146R or N146Y, leading to the loss of a glycosylation site) appear, like the HA cleavage site mutation, to allow the virus to replicate in many tissues outside the respiratory tract [40]. This mutation was also not observed in the NA of the 1918 virus [55].

Therefore, neither surface protein-encoding gene has known mutations that would allow the 1918 virus to become pantropic. Since clinical and pathological findings in 1918 showed no evidence of replication outside the respiratory system [83, 84], mutations allowing the 1918 virus to replicate systemically would not have been expected. However, the relationship of other structural features of these proteins (aside from their presumed antigenic novelty) to virulence remains unknown. In their overall structural and functional characteristics, the 1918 HA and NA are avian-like but they also have mammalian-adapted characteristics.

Interestingly, recombinant influenza viruses containing the 1918 HA and NA and up to three additional genes derived from the 1918 virus (the other genes being derived from the A/WSN/33 virus) were all highly virulent in mice [77]. Furthermore, expression microarray analysis performed on whole lung tissue of mice infected with the 1918 HA/NA recombinant showed increased upregulation of genes involved in apoptosis, tissue injury and oxidative damage [30]. These findings were unusual because the viruses with the 1918 genes had not been adapted to mice. One explanation is that the combination of the genes/proteins of the 1918 virus was "optimal" because the 1918 genes possibly work synergistically in terms of virulence. The completion of the sequence of the entire genome of the 1918 virus and the reconstruction and characterization of viruses with 1918 genes under appropriate biocontainment conditions will shed more light on this hypothesis and should allow a definitive examination of this explanation.

Antigenic analysis of recombinant viruses possessing the 1918 HA and NA by hemagglutination inhibition tests using ferret and chicken antisera suggested a close relationship with the A/swine/Iowa/30 virus and H1N1 viruses isolated in the 1930s [77], further supporting data of Shope from the 1930's [66]. Interestingly, when mice were immunized with different H1N1 virus strains, challenge studies using the 1918-like viruses revealed partial protection by this treatment suggesting that current vaccination strategies are adequate against a 1918-like virus [77]. In fact, the data may even allow us to suggest that the human population, having experienced a long period of exposure to H1N1 viruses, may be partially protected against a 1918-like virus [77].

Sequence and functional analysis of the non-structural gene segment

The complete coding sequence of the 1918 non-structural (NS) segment was completed [2]. The functions of the two proteins, NS1 and NS2 (NEP), encoded by overlapping reading frames [37] of the NS segment are still being elucidated [19, 20, 34, 41, 50]. The NS1 protein has been shown to prevent type I interferon (IFN) production, by preventing activation of the latent transcription factors IRF-3 [71] and NF-kB [79]. One of the distinctive clinical characteristics of the 1918 influenza was its ability to produce rapid and extensive damage to both the upper and lower respiratory epithelium [83]. Such a clinical course suggests a virus that replicated to a high titer and spread quickly from cell to cell. Thus, an NS1 protein that was especially effective at blocking the type I IFN system might have contributed to the exceptional virulence of the 1918 virus strain [19, 71, 79]. To address this possibility, transfectant A/WSN/33 influenza viruses were constructed with the 1918 NS1 gene or with the entire 1918 NS segment (coding for both NS1 and NS2 (NEP) proteins) [2]. In both cases, viruses containing 1918 NS genes were attenuated in mice compared to wild-type A/WSN/33 controls. The attenuation demonstrates that NS1 is critical for the virulence of A/WSN/33 in mice and suggests that NS1-related interferon antagonism is host specific. This is supported by transcriptional profiling (microarray analysis) of infected human lung epithelial cells that showed that a virus with the 1918 NS1 gene was more effective at blocking the expression of IFN-regulated genes than the isogenic parental mouse-adapted A/WSN/33 virus [22] suggesting that the 1918 NS1 contributes virulence characteristics in human cells but not murine ones. The 1918 NS1 protein varies from that of the WSN virus at 10 amino acid positions. The amino acid differences between the 1918 and A/WSN/33 NS segments may be important in the adaptation of the latter virus strain to mice and likely account for the observed differences in virulence in these experiments. Recently, a single amino acid change (D92E) in the NS1 protein was associated with increased virulence of the 1997 Hong Kong H5N1 viruses in a swine model [63]. This amino acid change was not found in the 1918 NS1 protein.

Sequence and functional analysis of the matrix gene segment

The coding region of influenza A RNA segment 7 from the 1918 pandemic virus, consisting of the open reading frames of the two matrix genes, M1 and M2, has been sequenced [56]. While this segment is highly conserved among influenza virus strains, the 1918 sequence does not match any previously sequenced influenza virus strains. The 1918 sequence matches the consensus over the M1 RNA-binding domains and nuclear localization signal and the highly conserved transmembrane domain of M2. Amino acid changes that correlate with high yield and pathogenicity in animal models were not found in the 1918 virus strain.

The M1 mRNA is colinear with the viral RNA, while the M2 mRNA is encoded by a spliced transcript [36]. The proteins encoded by these mRNAs share their initial nine amino acids and also have a stretch of 14 amino acids in overlapping reading frames. The M1 protein is a highly conserved 252 amino acid protein. It is the most abundant protein in the viral particle, lining the inner layer of the viral membrane and contacting the ribonucleoprotein core. M1 has been shown to have several functions [36] including regulation of nuclear export of vRNPs, both permitting the transport of vRNP particles into the nucleus upon infection and preventing newly exported vRNP particles from re-entering the nucleus. The 97 amino acid M2 protein is a homotetrameric integral membrane protein that exhibits ion channel activity and is the target of the drug amantadine [25]. The ion channel activity of M2 is important both during virion uncoating and during viral budding [36].

Five amino acid sites have been identified in the transmembrane region of the M2 protein that are involved in resistance to the antiviral drug, amantadine: sites 26, 27, 30, 31 and 34 [26]. The 1918 influenza M2 sequence is identical at these positions to that of the amantadine sensitive influenza virus strains. Thus, it was predicted that the M2 protein of the 1918 influenza virus would be sensitive to amantadine. This was recently demonstrated experimentally. A recombinant virus possessing the 1918 matrix segment was inhibited effectively both in tissue culture and in vivo by the M2 ion-channel inhibitors amantadine and rimantadine [76].

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