Most of those deaths are in people 65 and older. H3N2 viruses circulating today are descendants of the H3N2 virus that emerges in Cases of Guillain-Barre syndrome, a neurologic condition that in rare instances has been associated with vaccination, among vaccine recipients appeared to be in excess of what was expected, so officials determine the vaccination program should be halted.
The program increases the likelihood of children getting recommended vaccinations on schedule. It is a critical tool for tracking the movement of flu viruses globally.
Country data is updated weekly and is publically available. A virus that is a hybrid of human, bird and swine flu viruses is detected in pigs. This virus becomes the dominant flu virus in U. June The first nasal spray flu vaccine is licensed. Government National Strategy for Pandemic Influenza is published The entire genome of the H1N1 pandemic influenza virus is sequenced CDC stops recommending adamantanes during the season after high levels of resistance among influenza A viruses.
In the US, resistance increased from 1. The document outlines U. These tests can detect influenza with high specificity that enhances diagnosis and treatment options. But during the pandemic, pathologists failed to consistently find the bacillus. This undermined claims about its primary role and jeopardised the prospect of producing a vaccine.
Walter Morley Fletcher , Secretary of the MRC, suggested to the War Office and Army Medical Services that attention should be turned to the possible role of a so-called 'filter-passing virus', and in November the search for the virus began. The first British investigations into the role of a virus in influenza were carried out by two teams in France and within weeks both claimed they had identified a filterable agent from sick servicemen.
These findings were controversial - there was no test for a virus, so its presence had to be inferred: it could not be seen with light microscopes, retained by bacterial filters or studied using culture methods. Only the presence of symptoms, and traces in serological tests suggested any 'thing' was present in infected people and animals. Canine distemper was selected as the model for influenza, and for over a decade Laidlaw and the resident veterinary pathologist, G.
Dunkin , used distemper to build virus research at the Institute. The research attracted some powerful patrons. The Field , a country and field sports magazine, already had a Distemper fund to finance work on the disease, and in October The Field 's editor, Sir Theodore Crooke, proposed to Fletcher that the fund should be devoted to supporting Laidlaw and Dunkin.
Until , Laidlaw and Dunkin used puppies bred at Mill Hill to experiment on distemper, but dogs were not ideal experimental animals. Dogs presented an awkwardly variable clinical picture, they were expensive and slow to breed, sometimes hard to handle, and attracted vociferous antivivisection protests. So in late , they introduced the ferret as a new experimental animal, marking the start of a long scientific career.
Laidlaw and Dunkin attributed much of their success on distemper to their work with the ferret; they developed an experimental vaccine for ferret distemper in , then modified for dogs in Burroughs-Wellcome started commercial production in , and by the vaccine was protecting the nation's dogs. This scientific and commercial success legitimised the NIMR's approach to virus diseases. Its primary goal became virus identification and control through the production of serological assays, therapeutic sera, and vaccines.
New interest in applying this approach to influenza was sparked in , when the American researcher, Richard E. Shope announced that a combination of a bacillus and a filterable virus produced a disease in pigs — 'hog flu' — analogous to human influenza.
Virtually every expert on influenza believes another pandemic is nearly inevitable, that it will kill millions of people, and that it could kill tens of millions—and a virus like , or H5N1, might kill a hundred million or more—and that it could cause economic and social disruption on a massive scale. This disruption itself could kill as well.
Given those facts, every laboratory investigator and every public health official involved with the disease has two tasks: first, to do his or her work, and second, to make political leaders aware of the risk.
The preparedness effort needs resources. Only the political process can allocate them. They continually circulate in humans in yearly epidemics mainly in the winter in temperate climates and antigenically novel virus strains emerge sporadically as pandemic viruses Cox and Subbarao, In the United States, influenza is estimated to kill 30, people in an average year Simonsen et al. Every few years, a more severe influenza epidemic occurs, causing a boost in the annual number of deaths past the average, with 10, to 15, additional deaths.
Occasionally, and unpredictably, influenza sweeps the world, infecting 20 to 40 percent of the population in a single year. In these pandemic years, the numbers of deaths can be dramatically above average. In —, a pandemic was estimated to cause 66, excess deaths in the United States Simonsen et al.
In , the worst pandemic in recorded history was associated with approximately , total deaths in the United States U. Department of Commerce, and killed at least 40 million people worldwide Crosby, ; Patterson and Pyle, ; Johnson and Mueller, Influenza A viruses constantly evolve by the mechanisms of antigenic drift and shift Webster et al.
The importance of predicting the emergence of new circulating influenza virus strains for subsequent annual vaccine development cannot be underestimated Gensheimer et al. Recent circulation of highly pathogenic avian H5N1 viruses in Asia from to has caused a small number of human deaths Claas et al. How and when novel influenza viruses emerge as pandemic virus strains and how they cause disease is still not understood.
Studying the extent to which the influenza was like other pandemics may help us to understand how pandemic influenzas emerge and cause disease in general. On the other hand, if we determine what made the influenza different from other pandemics, we may use the lessons of to predict the magnitude of public health risks a new pandemic virus might pose.
The predominant natural reservoir of influenza viruses is thought to be wild waterfowl Webster et al. Periodically, genetic material from avian virus strains is transferred to virus strains infectious to humans by a process called reassortment. Human influenza virus strains with recently acquired avian surface and internal protein-encoding RNA segments were responsible for the pandemic influenza outbreaks in and Scholtissek et al. The change in the hemagglutinin subtype or the hemagglutinin HA and the neuraminidase NA subtype is referred to as antigenic shift.
Because pigs can be infected with both avian and human virus strains, and various reassortants have been isolated from pigs, they have been proposed as an intermediary in this process Scholtissek, ; Ludwig et al. Until recently there was only limited evidence that a wholly avian influenza virus could directly infect humans, but in 18 people were infected with avian H5N1 influenza viruses in Hong Kong, and 6 died of complications after infection Claas et al. Although these viruses were very poorly transmissible or non-transmissible Claas et al.
In —, H5N1 outbreaks in poultry have become widespread in Asia Tran et al. In , a highly pathogenic H7N7 outbreak occurred in poultry farms in The Netherlands.
This virus caused infections predominantly conjunctivitis in 86 poultry handlers and 3 secondary contacts. One of the infected individuals died of pneumonia Fouchier et al.
In , an H7N3 influenza outbreak in poultry in Canada also resulted in the infection of a single individual World Health Organization, , and a patient in New York was reported to be sick following infection with an H7N2 virus Lipsman, Therefore, it may not be necessary to invoke swine as the intermediary in the formation of a pandemic virus strain because reassortment between an avian and a human influenza virus could take place directly in humans. While reassortment involving genes encoding surface proteins 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.
Among other features, there must be functional HA receptor binding and interaction between viral and host proteins Weis et al. Defining the minimal adaptive changes needed to allow a reassortant virus to function in humans is essential to understanding how pandemic viruses emerge. This was the case in and and was almost certainly the case in While immunological novelty may explain much of the virulence of the influenza, it is likely that additional genetic features contributed to its exceptional lethality.
Unfortunately not enough is known about how genetic features of influenza viruses affect virulence. The degree of illness caused by a particular virus strain, or virulence, is complex and involves host factors like immune status, and viral factors like host adaptation, transmissibility, tissue tropism, or viral replication efficiency.
The genetic basis for each of these features is not yet fully characterized, but is most likely polygenic in nature Kilbourne, Prior to the analyses on the virus described in this review, only two pandemic influenza virus strains were available for molecular analysis: the H2N2 virus strain from and the H3N2 virus strain from The pandemic resulted from the emergence of a reassortant influenza virus in which both HA and NA had been replaced by gene segment closely related to those in avian virus strains Scholtissek et al.
More recently it has been shown that the PB1 gene was replaced in both the and the pandemic virus strains, also with a likely avian derivation in both cases Kawaoka et al. The remaining five RNA segments encoding the PA, PB2, nucleoprotein, matrix and non-structural proteins, all were preserved from the H1N1 virus strains circulating before These segments were likely the direct descendants of the genes present in the virus.
Because only the and influenza pandemic virus strains have been available for sequence analysis, it is not clear what changes are necessary for the emergence of a virus strain with pandemic potential. Sequence analysis of the influenza virus allows us potentially to address the genetic basis of virulence and human adaptation.
The influenza pandemic of 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 may have been clinically infected during the pandemic Frost, ; Burnet and Clark, The disease was also exceptionally severe, with mortality rates among the infected of more than 2. Total mortality attributable to the pandemic was probably around 40 million Crosby, ; Johnson and Mueller, ; Patterson and Pyle, However, the near simultaneous appearance of influenza in March—April in North America, Europe, and Asia makes definitive assignment of a geographic point of origin difficult Jordan, It is possible that a mutation or reassortment occurred in the late summer of , resulting in significantly enhanced virulence.
In many places, there was yet another severe wave of influenza in early Jordan, Three extensive outbreaks of influenza within 1 year is unusual, and may point to unique features of the 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 antigenically modified virus strain emerging every 2 to 3 years. Even in pandemic influenza, while the normal late winter seasonality may be violated, the successive occurrence of distinct waves within a year is unusual.
The pandemic began in the late spring of and took several months to spread throughout the world, peaking in northern Europe and the United States late in or early The second wave peaked in spring over a year after the first wave and the third wave in early Jordan, As in , subsequent waves seemed to produce more severe illness so that the peak mortality was reached in the third wave of the pandemic.
The three waves, however, were spread over more than 3 years, in contrast to less than 1 year in It is unclear what gave the virus this unusual ability to generate repeated waves of illness. Perhaps the surface proteins of the virus drifted more rapidly than other influenza virus strains, or perhaps the virus had an unusually effective mechanism for evading the human immune system. The influenza epidemic of killed an estimated , Americans, including 43, servicemen mobilized for World War I Crosby, The impact was so profound as to depress average life expectancy in the United States by more than 10 years Grove and Hetzel, Figure and may have played a significant role in ending the World War I conflict Crosby, ; Ludendorff, Life expectancy in the United States, —, showing the impact of the influenza pandemic.
Many individuals who died during the pandemic succumbed to secondary bacterial pneumonia Jordan, ; LeCount, ; Wolbach, because no antibiotics were available in However, a subset died rapidly after the onset of symptoms often with either massive acute pulmonary hemorrhage or pulmonary edema, often in less than 5 days LeCount, ; Winternitz et al. In the hundreds of autopsies performed in , the primary pathologic findings were confined to the respiratory tree and death was due to pneumonia and respiratory failure Winternitz et al.
These findings are consistent with infection by a well-adapted influenza virus capable of rapid replication throughout the entire respiratory tree Reid and Taubenberger, ; Taubenberger et al.
There was no clinical or pathological evidence for systemic circulation of the virus Winternitz et al. Furthermore, in the pandemic most deaths occurred among young adults, a group that usually has a very low death rate from influenza. Influenza and pneumonia death rates for to year-olds were more than 20 times higher in than in previous years Linder and Grove, ; Simonsen et al.
The pandemic is also unique among influenza pandemics in that absolute risk of influenza mortality was higher in those younger than age 65 than in those older than Strikingly, persons less than 65 years old accounted for more than 99 percent of all excess influenza-related deaths in — Simonsen et al. In contrast, the less-than age group accounted for only 36 percent of all excess influenza-related mortality in the H2N2 pandemic and 48 percent in the H3N2 pandemic. Overall, nearly half of the influenza-related deaths in the influenza pandemic were young adults aged 20 to 40 Simonsen et al.
Why this particular age group suffered such extreme mortality is not fully understood see below. Influenza and pneumonia mortality by age, United States.
Influenza and pneumonia specific mortality by age, including an average of the interpandemic years — dashed line , and the pandemic year solid line. Specific death rate is more The influenza had 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 Koen, concurrently with the spread of the second wave of the pandemic in humans Dorset et al. Investigators were impressed by clinical and pathological similarities of human and swine influenza in Koen, ; Murray and Biester, An extensive review by the veterinarian W.
Dimoch of the diseases of swine published in August makes no mention of any swine disease resembling influenza Dimoch, — Thus, contemporary investigators were convinced that influenza virus had not circulated as an epizootic disease in swine before and that the virus spread from humans to pigs because of the appearance of illness in pigs after the first wave of the influenza in humans Shope and Lewis, Thereafter the disease became widespread among swine herds in the U.
The epizootic of — was as extensive as in — Classical swine viruses have continued to circulate not only in North American pigs, but also in swine populations in Europe and Asia Brown et al. During the fall and winter of —, severe influenza-like outbreaks were noted not only in swine in the United States, but also in Europe and China Beveridge, ; Chun, ; Koen, Since there have been many examples of both H1N1 and H3N2 human influenza A virus strains becoming established in swine Brown et al.
The unusual severity of the pandemic and the exceptionally high mortality it caused among young adults have stimulated great interest in the influenza virus strain responsible for the outbreak Crosby, ; Kolata, ; Monto et al. Because the first human and swine influenza A viruses were not isolated until the early s Shope and Lewis, ; Smith et al. The relationship to swine influenza is also reflected in the simultaneous influenza outbreaks in humans and pigs around the world Beveridge, ; Chun, ; Koen, Although historical accounts described above suggest that the virus spread from humans to pigs in the fall of , the relationship of these two species in the development of the influenza has not been resolved.
Which influenza A subtype s circulated before the pandemic is not known for certain. In a recent review of the existing archaeoserologic and epidemiologic data, Walter Dowdle concluded that an H3-subtype influenza A virus strain circulated from the — pandemic to , when it was replaced by the novel H1N1 virus strain of the pandemic Dowdle, It is reasonable to conclude that the virus strain must have contained a hemagglutinin gene encoding a novel subtype such that large portions of the population did not have protective immunity Kilbourne, ; Reid and Taubenberger, In fact, epidemiological data collected between and on influenza prevalence by age in the population provide good evidence for the emergence of an antigenically novel influenza virus in Jordan, In the 5- to year-old group jumped to 25 percent of influenza cases, compatible with exposure to an antigenically novel virus strain.
It is likely that this 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 pandemic [ Ministry of Health, ; Simonsen et al.
Further evidence for pre-existing H1 immunity can be derived from the age-adjusted mortality data in Figure Interestingly, the 5 to 14 age group accounted for a large fraction of influenza cases, but had an extremely low case mortality rate compared to other age groups Figure Why this age group had such a low case fatality rate cannot yet be fully explained.
Conversely, why the 25 to 34 age group had such a high influenza and pneumonia mortality rate in remains enigmatic, but it is one of the truly unique features of the influenza pandemic. Influenza and pneumonia mortality by age solid line , with influenza morbidity by age dashed line superimposed. Influenza and pneumonia mortality by age as in Figure Specific death rate per age group, left ordinal axis.
Influenza morbidity presented more One theory that may explain these data concerns the possibility that the virus had an intrinsically high virulence that was only tempered in those patients who had been born before It can be speculated that the virus circulating prior to was an H1-like virus strain that provided partial protection against the virus strain Ministry of Health, ; Simonsen et al.
Short of this cross-protection in patients older than 29 years of age, the pandemic of might have been even more devastating Zamarin and Palese, A second possibility remains that the high mortality of young adults in the 20 to 40 age group may have been a consequence of immune enhancement in this age group. Currently, however, the absence of pre human influenza samples and the lack of pre sera samples for analysis makes it impossible to test this hypothesis. Thus, it seems clear that the H1N1 virus of the pandemic contained an antigenically novel hemagglutinin to which most humans and swine were susceptible in Given the severity of the pandemic, it is also reasonable to suggest that the other dominant surface protein, NA, also would have been replaced by antigenic shift before the start of the pandemic Reid and Taubenberger, ; Taubenberger et al.
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 pandemic and that the precursor virus did not circulate widely in either humans or swine before Fanning et al. It is currently unclear what other influenza gene segments were novel in the pandemic virus in comparison to the previously circulating virus strain.
It is possible that sequence and phylogenetic analyses of the gene segments of the virus may help elucidate this question. Phylogenetic tree of the influenza virus hemagglutinin gene segment. Amino acid changes in three lineages of the influenza virus hemagglutinin protein segment, HA1. The tree shows the numbers of unambiguous changes between these sequences, with branch more Samples of frozen and fixed lung tissue from five second-wave influenza victims dating from September to February have been used to examine directly the genetic structure of the influenza virus.
Two of the cases analyzed were U. The available material consists of formalin-fixed, paraffin-embedded 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 To date, five RNA segment sequences have been published Basler et al.
More recently, the HA sequences of two additional fixed autopsy cases of influenza victims from the Royal London Hospital were determined Reid et al. However, despite this similarity the sequence 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 sequence consensus, suggesting there was little immunologic pressure on the HA protein before the fall of Reid et al.
Another mechanism by which influenza viruses evade the human immune system is the acquisition of glycosylation sites to mask antigenic epitopes. The HA of the virus has only the four conserved avian sites Reid et al.
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. The other three cases have an additional change from the avian consensus, GD.
The change at residue may represent the minimal change necessary to allow an avian H1-subtype HA to bind mammalian-type receptors Reid et al. The crystal structure analysis of the HA Stevens et al. This provides an additional clue for the avian derivation of the HA. The X-ray analyses suggest that these sites are exposed on the HA and thus they could be readily recognized by the human immune system.
The principal biological role of NA is the cleavage of the terminal sialic acid residues that are receptors for the virus's HA protein Palese and Compans, The active site of the enzyme consists of 15 invariant amino acids that are conserved in the 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 Colman et al.
Some early human virus strains have short amino acids deletions in the stalk region, as do many virus strains isolated from chickens. The NA has a full-length stalk and has only the glycosylation sites shared by avian N1 virus strains Schulze, 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 Colman et al. The NA matches the avian consensus at 21 of these sites Reid et al. This finding suggests that the NA, like the HA, had not circulated long in humans before the pandemic and very possibly had an avian origin Reid and Taubenberger, Neither the 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. 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 Kawaoka and Webster, ; Webster and Rott, Infection with such a pantropic virus strain can cause systemic disease in birds with high mortality.
This mutation was not observed in the virus Reid et al. Mutations at a single codon NR or NY, 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 Li et al.
This mutation was also not observed in the NA of the virus Reid et al. Therefore, neither surface protein-encoding gene has known mutations that would allow the virus to become pantropic.
Because clinical and pathological findings in showed no evidence of replication outside the respiratory system Winternitz et al. 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 HA and NA are avian-like, but they also have mammalian-adapted characteristics. These findings were unusual because the viruses with the genes had not been adapted to mice. The completion of the sequence of the entire genome of the virus and the reconstruction and characterization of viruses with genes under appropriate biosafety conditions will shed more light on these findings and should allow a definitive examination of this explanation.
Interestingly, when mice were immunized with different H1N1 virus strains, challenge studies using the like viruses revealed partial protection by this treatment, suggesting that current vaccination strategies are adequate against a like virus Tumpey et al. 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 like virus Tumpey et al. The best approach to analyzing the relationships among influenza viruses is phylogenetics, whereby hypothetical family trees are constructed that take available sequence data and use them to make assumptions about the ancestral relationships between current and historical influenza virus strains Fitch et al.
Because influenza viruses possess eight discrete RNA segments that can move independently between virus strains by the process of reassortment, these evolutionary studies must be performed independently for each gene segment. Change in hemagglutinin HA and neuraminidase NA proteins over time. The number of amino acid changes from a hypothetical ancestor was plotted versus the date of viral isolation for viruses isolated from to Open circles, human HA; closed more A comparison of the complete HA Figure and NA genes with those of numerous human, swine, and avian sequences demonstrates the following: Phylogenetic analyses based on HA nucleotide changes either total or synonymous or HA amino acid changes always place the HA with the mammalian viruses, not with the avian viruses Reid et al.
In fact, both synonymous and nonsynonymous changes place the HA in the human clade. Phylogenetic analyses of total or synonymous NA nucleotide changes also place the NA sequence with the mammalian viruses, but analysis of nonsynonymous changes or amino acid changes places the NA with the avian viruses Reid et al. Because the HA and NA have avian features and most analyses place HA and NA near the root of the mammalian clade close to an ancestor of the avian genes , it is likely that both genes emerged from an avian-like influenza reservoir just prior to Reid et al.
Clearly, by the virus had acquired enough mammalian-adaptive changes to function as a human pandemic virus and to form a stable lineage in swine. The complete coding sequence of the non-structural NS segment was completed Basler et al.
One of the distinctive clinical characteristics of the influenza was its ability to produce rapid and extensive damage to both the upper and lower respiratory epithelium Winternitz et al. 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 virus strain Garcia-Sastre et al.
This amino acid change was not found in the NS1 protein. The coding region of influenza A RNA segment 7 from the pandemic virus, consisting of the open reading frames of the two matrix genes, M1 and M2, has been sequenced Reid et al. Although this segment is highly conserved among influenza virus strains, the sequence does not match any previously sequenced influenza virus strains. The 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 virus strain. The proteins encoded by these mRNAs share their initial 9 amino acids and also have a stretch of 14 amino acids in overlapping reading frames.
The M1 protein is a highly conserved 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 RNP core. M1 has been shown to have several functions Lamb and Krug, , 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 reentering the nucleus.
The amino-acid M2 protein is a homotetrameric integral membrane protein that exhibits ion-channel activity and is the target of the drug amantadine Hay et al. The ion-channel activity of M2 is important both during virion uncoating and during viral budding Lamb and Krug, 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 Holsinger et al. The 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 influenza virus would be sensitive to amantadine. This was recently demonstrated experimentally. A recombinant virus possessing the matrix segment was inhibited effectively both in tissue culture and in vivo by the M2 ion-channel inhibitors amantadine and rimantadine Tumpey et al.
The phylogenetic analyses suggest that the matrix genes, while more avian-like than those of other mammalian influenza viruses, were mammalian adapted Reid et al. For example, the extracellular domain of the M2 protein contains four amino acids that differ consistently between the avian and mammalian clades M2 residues 14, 16, 18, and The sequence matches the mammalian sequence at all four of these residues Reid et al.
The nucleoprotein gene NP of the pandemic influenza A virus has been amplified and sequenced from archival material Reid et al. The NP gene is known to be involved in many aspects of viral function and to interact with host proteins, thereby playing a role in host specificity Portela and Digard, NP is highly conserved, with a maximum amino acid difference of 11 percent among virus strains, probably because it must bind to multiple proteins, both viral and cellular.
Numerous studies suggest that NP is a major determinant of host specificity Scholtissek et al. The NP amino acid sequence differs at only six amino acids from avian consensus sequences, consistent with reassortment from an avian source shortly before However, the NP nucleotide sequence has more than differences from avian consensus sequences, suggesting substantial evolutionary distance from known avian sequences.
Both the NP gene and protein sequences fall within the mammalian clade upon phylogenetic analysis. Phylogenetic analyses of NP sequences from many virus strains result in trees with two main branches, one consisting of mammalian-adapted virus strains and one of avian-adapted virus strains Gammelin et al.
The NP gene segment was not replaced in the pandemics of and , so it is likely that the sequences in the mammalian clade are descended from the NP segment. The mammalian branches, unlike the avian branch, show a slow but steady accumulation of changes over time. Extrapolation of the rate of change along the human branch back to a putative common ancestor suggests that this NP entered the mammalian lineage sometime after Gammelin et al.
Separate analyses of synonymous and nonsynonymous substitutions also placed the virus NP gene in the mammalian clade Reid et al.
When synonymous substitutions were analyzed, the virus gene was placed within and near the root of swine viruses. When nonsynonymous viruses were analyzed, the virus gene was placed within and near the root of the human viruses.
The evolutionary distance of the NP from avian and mammalian sequences was examined using several different parameters. There are at least three possibilities for the origin of the NP gene segment Reid et al. First, it could have been retained from the previously circulating human virus, as was the case with the and pandemic virus strains, whose NP segments are descendants of the NP.
The large number of nucleotide changes from the avian consensus and the placement of the sequence in the mammalian clade are consistent with this hypothesis. Neighbor-joining analyses of nonsynonymous nucleotide sequences or of amino acid sequences place the sequence within and near the root of the human clade. The NP has only a few amino acid differences from most bird virus strains, but this consistent group of amino acid changes is shared by the NP and its subsequent mammalian descendants and is not found in any birds, resulting in the sequence being placed outside the avian clade Reid et al.
One or more of these amino acid substitutions may be important for adaptation of the protein to humans. However, the very small number of amino acid differences from the avian consensus argues for recent introduction from birds—80 years after , the NP genes of human influenza virus strains have accumulated more than 30 additional amino acid differences from the avian consensus a rate of 2.
Thus it seems unlikely that the NP, with only six amino acid differences from the avian consensus, could have been in humans for many years before This conclusion is supported by the regression analysis that suggests that the progenitor of the virus probably entered the human population around Reid et al.
A second possible origin for the NP segment is direct reassortment from an avian virus. The small number of amino acid differences between and the avian consensus supports this hypothesis. While varies at many nucleotides from the nearest avian virus strain, avian virus strains are quite diverse at the nucleotide level.
The great evolutionary distance between the sequence and the avian consensus suggests that no avian virus strain similar to those in the currently identified clades could have provided the virus strain with its NP segment. A final possibility is that the gene segment was acquired shortly before from a source not currently represented in the database of influenza sequences.
There may be a currently unknown influenza host that, while similar to currently characterized avian virus strains at the amino acid level, is quite different at the nucleotide level. It is possible that such a host was the source of the NP segment Reid et al. Five of the eight RNA segments of the influenza virus have been sequenced and analyzed.
Their characterization has shed light on the origin of the virus and strongly supports the hypothesis that the virus was the common ancestor of both subsequent human and swine H1N1 lineages. Sequence analysis of the genes to date offers no definitive clue as to the exceptional virulence of the virus strain.
Thus, experiments testing models of virulence using reverse genetics approaches with influenza genes have begun. In future work it is hoped that the pandemic virus strain can be placed in the context of influenza virus strains that preceded it and followed it.
Identification of an influenza RNA-positive case from the first wave would have tremendous value in deciphering the genetic basis for virulence by allowing differences in the sequences to be highlighted.
Identification of pre human influenza RNA samples would clarify which gene segments were novel in the virus. In many respects, the influenza pandemic was similar to other influenza pandemics. In its epidemiology, disease course, and pathology, the pandemic generally was different in degree but not in kind from previous and subsequent pandemics.
Furthermore, laboratory experiments using recombinant influenza viruses containing genes from the virus suggest that the and like viruses would be as sensitive to the Food and Drug Administration-approved anti-influenza drugs rimantadine and oseltamivir as other virus strains Tumpey et al. However, there are some characteristics of the pandemic that appear to be unique: Mortality was exceptionally high, ranging from 5 to 20 times higher than normal.
Clinically and pathologically, the high mortality appears to be the result of a higher proportion of severe and complicated infections of the respiratory tract, not with systemic infection or involvement of organ systems outside the influenza virus's normal targets. The mortality was concentrated in an unusually young age group. Finally, the waves of influenza activity followed each other unusually rapidly, resulting in three major outbreaks within a year's time.
Each of these unique characteristics may find their explanation in genetic features of the virus. The challenge will be in determining the links between the biological capabilities of the virus and the known history of the pandemic.
The work on the influenza virus, especially its origin, has led to the support of more comprehensive influenza virus surveillance and genomics initiatives for both human and animal influenza A viruses. We believe significant advancement in the understanding of influenza biology and ecology can be made by the generation of full genomic sequences of a large number of influenza viruses from different hosts.
In conclusion, some of the questions that need to be addressed in pandemic influenza include the following:. Unless we make progress in understanding these and other issues involving the complex ecology and biology of influenza viruses, we will face the risk of revisiting the past in our future.
Simonsen, 6 D. Olson, 7 C. Viboud, 8 E. Heiman, 6 R. Taylor, 9 M. Miller, 8 and T. Reichert Pandemic influenza is often thought of as a tornado—a sudden disaster that arrives with little warning and does its worst in a relatively short time.
Only three of these calamities occurred in the twentieth century. For the Spanish influenza pandemic, a new study by Olson et al. For the pandemic, a classic study documented that the emerging H2N2 influenza virus caused substantial excess mortality during the first three seasons it was in circulation. Although mortality caused by the pandemic virus was unimpressive relative to surrounding severe epidemics, the age shift signature sets it apart.
Furthermore, antibodies to H3-like antigens—the result of exposure to these antigens in childhood prior to —relatively protected people aged 77 years and older. The good news from epidemiological studies for pandemic preparedness planning is that past pandemics gave significant warning signs of their arrival.
In , a pandemic herald wave occurred 6 months or more before the majority of mortality impact the following fall. The Asian H2N2 influenza virus was characterized by early summer, , but significant mortality in the United States did not occur until October. In , the pandemic wave of mortality in Europe crested a full year after the pandemic strain first arrived.
Finally, the pandemic age shift documented for all pandemics studied begs the crucial question of who should be given first priority for vaccine and antivirals, should these be in short supply in the early phase of a pandemic. The lesson of the history of pandemics appears to be that at least the initial attack may sometimes occur with gentleness and thus may afford a substantial breathing space for the preparation and use of specific vaccine Stuart-Harris, Why worry about pandemics of the past?
Three influenza pandemics occurred in the twentieth century, and the patterns and magnitude of pandemic mortality are the only impact data available for all three of these events Table We believe, therefore, that continued epidemiological analyses of historic mortality data and sero-archaeology—the study of stored serum samples to uncover when specific influenza antigens were circulating—can expand our understanding of pandemic mortality patterns and severity, and that such studies will greatly aid public health planning for pandemic influenza.
In this review, we present the story of pandemic influenza as seen through the lens of epidemiology. We revisit a classic study of the pandemic that analyzes age-specific mortality data from the United States, which shows that most of the mortality was spread over three seasons; we also compare the age-specific mortality impact in the United States to that in Japan.
For the pandemic, we present a study of newly uncovered mortality data from New York City that tells a fetching story about a herald wave and the sparing of the elderly Olson et al. These efforts to study the epidemiology of past pandemic impact on mortality are akin to the efforts by virologists who, in the interest of predicting the future, are hard at work identifying and studying preserved human and animal virus specimens from the Spanish flu pandemic Reid and Taubenberger, But instead of molecular clues to viral pathogenicity and recombination, mortality data provides some important insights into how the pandemic evolves over time, and which age groups are at highest risk for severe outcomes.
It is certainly true that, like a tornado, no one can predict precisely when a new pandemic strain might emerge. However, studies of past pandemics show that the next pandemic may well not do its worst in the first season.
Instead, historical evidence shows that there can be herald waves or smoldering activity during the first season in which the pandemic influenza virus emerges, suggesting that the preparation time for pandemic vaccines and antivirals might be longer than a few months. Second, pandemic impact cannot be discussed without speaking of age. During a pandemic, the younger population is at substantially increased risk relative to non-pandemic influenza seasons; in some pandemics, this sparing of the elderly may occur as a consequence of antigen recycling.
The pandemic age shift has important consequences for thinking about how best to protect the population and minimize years of life lost to future pandemic influenza. It has previously been demonstrated that all three pandemics of this century were characterized by a shift in the age distribution of deaths Simonsen et al.
The younger population in that study, persons under 65 years of age experienced a sharply elevated mortality risk and accounted for a markedly increased fraction of all influenza-related deaths.
As we will discuss below, the pandemic age shift pattern was exacerbated by the protection of the very elderly by virtue of their experience with H3 antigens as children Simonsen et al.
For the pandemic, then, the observed age shift was due to a combination of increased risk among the young and decreased risk among the elderly Simonsen et al. During the A H2N2 Asian pandemic in the United States, nearly 40 percent of all influenza-related deaths occurred in the younger population under 65 years of age.
The proportion of deaths among people under age 65 that occurred during A H2N2 epidemics dropped to 5 percent by , when circulation of this virus ceased. In the A H3N2 pandemic, this proportion was approximately 50 percent, but declined to less than 10 percent over the next decade Figure Simonsen et al.
The age shift in mortality was even more pronounced in the A H1N1 Spanish influenza pandemic Collins, ; Simonsen, ; Olson et al. The pandemic is the only one known in which a shift in the hemagglutinin antigen was not accompanied by a shift in the neuraminidase antigen.
Perhaps for that reason, the pandemic mortality impact was not particularly severe compared to the severe epidemic in — the last A H2N2 epidemic , as well as two severe H3N2 epidemics in — and — Table People aged 75 years and older were far less likely to die of influenza during the pandemic than during these three surrounding epidemics, whereas people aged 45—64 years were at nearly three-fold elevated risk.
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