Influenza

"Sambucus nigra L. products - Sambucol - are based on a standardized black elderberry extract. They are natural remedies with antiviral properties, especially against different strains of influenza virus. Sambucol was shown to be effective in vitro against 10 strains of influenza virus. In a double-blind, placebo-controlled, randomized study, Sambucol reduced the duration of flu symptoms to 3-4 days. Convalescent phase serum showed a higher antibody level to influenza virus in the Sambucol group, than in the control group."

"As we now know, wild birds are the natural reservoir for influenza A viruses. With extensive antigenic and genetic diversity inherent among influenza virus surface proteins, a strain to which humans are immunologically naïve could jump the species barrier at any time. A(H5N1) viruses and, more recently, A(H7N9) viruses, are two such examples. However, swine are also recognized as a “mixing vessel” for influenza viruses, and over the past two decades, there has been an increase in human cases following exposure to infected pigs. There is clearly, and alarmingly, a vast diversity of zoonotic sources of influenza A viruses that could acquire a transmissible phenotype in humans and cause a pandemic."

"Many international health agencies and research laboratories collaborate to track influenza virus evolution, evaluate antigenic drift among circulating and vaccine strains, and sequence viral genes to advance surveillance and preparedness. The production of improved vaccines and diagnostic tools, and better access to therapeutic agents represent resources that were not available a century ago. But influenza viruses are moving targets, and a pandemic virus could nevertheless emerge with as little warning in 2018 as in 1918. As evidenced by this current flu season, influenza viruses can rapidly acquire mutations that evade our most recent vaccine formulations. A universal, broadly protective influenza vaccine for seasonal epidemics—a goal of intense research efforts—would improve our preparedness for subsequent pandemics."

"We are no doubt more prepared in 2018 for an infectious disease threat than in 1918. But it is critical to remember that preparation only stems from a global commitment to share data about viral isolates, support innovative research, and dedicate resources to assess the pandemic risk of new and emerging influenza viruses from zoonotic reservoirs."

"The survival data for TGEV and MHV suggest that enveloped viruses can remain infectious on surfaces long enough for people to come in contact with them, posing a risk for exposure that leads to infection and possible disease transmission. This risk may also occur for other enveloped viruses, such as influenza virus. The potential reemergence of SARS or the emergence of new strains of pandemic influenza virus, including avian and swine influenza viruses, could pose serious risks for nosocomial disease spread via contaminated surfaces. However, this risk is still poorly understood, and more work is needed to quantify the risk of exposure and possible transmission associated with surfaces."

"The small British Crown dependency of Tristan da Cunha is one of the most isolated points on the planet. Over 1700 miles off the coast of South Africa, it is home to fewer than 300 permanent inhabitants. The island’s capital, Edinburgh of the Seven Seas, is commonly considered to be the most remote permanent human settlement. Without suitable ground for a paved airstrip, Tristan da Cunha’s only lifeline to the outside world is by sea. In 1971, the supply ship Tristania brought an unwelcome stowaway to the island: the alphainfluenzavirus H3N2, known as the Hong Kong flu at the time. By winter’s end, 96% of the population would contract influenza, with almost a third experiencing at least two distinct episodes of illness."

"Influenza pandemics are events that have occurred in the past and will undoubtedly occur in the future. There is uncertainty about when the next influenza pandemic will occur, who will be most impacted, and how many will fall victim to this viral disease. These uncertainties make communicating the risk and consequences of pandemic influenza a greater communication challenge than the usual public health threats."

"Waterbirds, to an influenza researcher, are more than majestic swans and charming mallards. They are instead stealthy vectors of novel influenza viruses, some of nature's bioterrorist agents, chauffeuring dangerous microbes from place to place."

"The use of licensed inactivated trivalent influenza vaccine is increasing, but even if all high risk persons currently given priority for this vaccine should be vaccinated each year, influenza epidemics would continue to occur. Healthy school children, preschool children in day care, college students, and working adults would continue to have high morbidity and would continue to spread the virus in the community. Vulnerable high risk patients would be at risk because of repeated challenge to their immunity by contract with infected persons. Recent pandemics illustrate another problem that must be faced with an impending pandemic. The time between recognition of the emergence of a new pandemic virus and the occurrence of the first wave may be short."

"Planning and preparedness efforts are widespread and ongoing, on a scale likely not imagined in 1918. Pandemic plans have been developed by a variety of stakeholders, including nations, states, counties, cities, and businesses. WHO has published essential steps for developing a national pandemic plan, as well as a checklist for pandemic influenza risk and impact management . In the United States, the Department of Health and Human Services published an updated 2017 Pandemic Influenza Plan that highlighted successes since the 2005 Pandemic Influenza Plan and emphasized needed improvements . However, the majority of countries reported by WHO still have no, or no publically available, national plan for pandemic preparedness and risk management."

"Despite improvements since 1918, governments and health care systems remain inadequately prepared for the impact of a 1918-like severe influenza pandemic. A significant focus on improving global preparedness for infectious disease threats has occurred through implementation of the Global Health Security Agenda and associated efforts. Beginning with the revision of the International Health Regulations in 2005, milestones were set for countries to achieve greater response capacity for public health emergencies. However, by 2016, only one-third of countries were in compliance."

"No one really knows, for example, why one nation, such as Australia, can be hit hard by influenza for several years while a neighbouring country, such as New Zealand, sees very low rates, says Webby. Even influenza’s seasonality isn’t entirely understood, nor exactly how it travels around the globe. “We don’t have a real good handle on why it’s a winter disease,” he says."

"Physical activity may lower rates of infection for other types of viral and bacterial diseases, but more data are needed. Several epidemiologic studies suggest that regular physical activity is associated with decreased mortality and incidence rates for influenza and pneumonia. These findings are in accordance with rodent-based studies demonstrating a positive link between chronic exercise and improved host responses to influenza and pneumonia infection. These data must be carefully balanced with published reports of increased infectious disease severity when vigorous exercise was engaged in during active influenza or other viral infections. There is also increasing support for improved antibody responses to influenza immunization in elderly adults who engage in regular exercise training regimens."

"Influenza is able to change itself from one year to the next so the natural infection or immunization the previous year doesn't infect you the following year. HIV does that during a single infection."

"Historical evidence from influenza pandemics which occurred in the past century shows us that pandemics tend to come in waves over the first 2–5 years as the population immunity builds-up (naturally or through vaccination), and then the number of infected cases tends to decrease."

"The impact of the pandemic H1N1 virus was not limited to 1918–1919. The 1918 influenza A virus (Fig. 1) was a new “founder virus” that initiated the current era of circulating influenza A viruses by evolving into progeny pandemic viruses through genetic reassortment. All influenza A pandemics and seasonal epidemics since that time, and almost all cases of human influenza A worldwide, have been caused by descendants of the 1918 influenza virus (Fig. 2). These include not only the antigenically “drifted” descendants of the 1918 H1N1 virus itself but also the genetically reassorted pandemic viruses that appeared in 1957 (H2N2), 1968 (H3N2), and 2009 (H1N1pdm). The exceptions include human infections caused by animal-derived (zoonotic) influenza A viruses, e.g., those from poultry-adapted influenza A viruses such as H5N1 and H7N9. Interestingly, the H1 HA of the 2009 pandemic virus (H1N1pdm) is genetically and antigenically related to the 1918 pandemic virus through its evolution in pigs. This provides not only a fascinating but also a disturbing example of a direct connection between the 1918 founder virus and the currently circulating H1N1pdm influenza virus strain."

"When an influenza A virus switches hosts, as the 1918 pandemic virus did, it must be able to survive in a new infectious ecosystem. It must be able to infect target epithelial cells, replicate, and be transmitted efficiently between members of the new host species. It does not have to be highly pathogenic, given that killing or incapacitating the host would not enhance viral spread. Whereas the 1918 pandemic virus was inherently pathogenic, its subsequent history (e.g., between 1918 and 1946 and after its 1977 reappearance until 2008) was one of apparent viral attenuation over decades of post-pandemic circulation. Regardless of accumulating humoral and cellular immunity in the human population, human seasonal influenza A/H1N1 viruses of the last few decades do not share the pathogenic properties of the 1918 pandemic virus in various animal models."

"Despite our modern arsenal of antibiotics, of viral and bacterial vaccines, of antiviral drugs, advanced intensive care treatment, and nonpharmaceutical interventions (138), we are still doing a poor job of preventing influenza deaths."

"Results of this review point to possible improvements in future studies of the case fatality risk. First, there is a problem in using confirmed cases as the denominator of CFR for influenza, given that most infections are mild and do not present for medical attention. Because it is not feasible to diagnose all suspected cases with laboratory testing except at the very beginning of a pandemic, it is unrealistic that risk estimates based on confirmed cases can be consistently calculated and remain directly comparable over time, age groups, and location. We suggest avoiding entirely the use of case fatality risk based on confirmed cases. The case fatality risk based on symptomatic cases would provide a more reliable early assessment of seriousness for seasonal influenza or the next influenza pandemic. Second, estimation of seriousness in real-time is complicated by delays in reporting and analysis. Estimation of the case fatality risk based on confirmed deaths and symptomatic cases may be possible if relevant models can be prepared in advance and quickly fitted to available data during the pandemic. We have previously discussed real-time estimation of the cumulative incidence of infection based on serologic data. This would form the denominator of the infection fatality risk, but, as noted previously, this is unlikely to be available early in the pandemic. In preparation for the next influenza pandemic, it is essential to reach a consensus on how to define and measure the seriousness of infection (an important indicator of the severity of the pandemic), and whether the analysis can be based entirely on estimates of age-specific risk of death among cases. The consistent estimates of the infection fatality risk at around 1 to 10 deaths per 100,000 infections identified in our review may represent the seriousness of H1N1pdm09 in developed countries where data were available. Similar estimates for seasonal influenza viruses, however, are not available for comparison, and neither are estimates from less developed countries in which the seriousness profile would likely be higher."

"For the past 65 years, the Global Influenza Surveillance and Response System (GISRS), coordinated by the World Health Organization (WHO), has engaged in open and efficient sharing of information, viruses, and responsibilities. The GISRS's extraordinary longevity can be attributed to several generations of dedicated scientists and to the engagement of over 100 countries, often with limited resources. Currently, only two influenza A viruses and two influenza B clades are circulating and causing disease in humans, but 16 additional subtypes of influenza A viruses are circulating in nature (14 in birds and two in bats). Of the latter, six occasionally infect humans, providing an ever-looming pandemic threat. However, there is still a lack of fundamental knowledge to predict if and when a particular viral subtype will acquire pandemic ability. We therefore still fail to predict influenza pandemics, and this must change."

"Problems with sharing influenza samples climaxed in 2007 but then began to be addressed in 2011 following the adoption of the WHO's Pandemic Influenza Preparedness Framework, which places virus sharing and access to benefits on an equal footing. Fair and equitable sharing of benefits arising from the use of genetic resources under the Nagoya protocol should promote further pathogen sharing in a broader context. With respect to the rapid sharing of influenza viruses in particular—the 65-year practice of the GISRS to develop the best possible counter-measures—the Protocol's impact is promising but will need to be thoughtfully managed. Among the needs of the GISRS is the priority to develop better vaccines and antiviral agents to control influenza. Vaccine production has not changed much in decades; it remains a lengthy egg-based process. Furthermore, vaccine efficacy, especially in the elderly, is unsatisfactory and requires annual updates. Universal vaccines that protect against all influenza subtypes are being researched and hold promise for future infection control. Antiviral agents used to treat influenza are limited to antineuraminidase drugs, but polymerase-targeting drugs are in development, suggesting the possibility of future multidrug therapies."

"Three worldwide (pandemic) outbreaks of influenza occurred in the 20th century: in 1918, 1957, and 1968. The latter 2 were in the era of modern virology and most thoroughly characterized. All 3 have been informally identified by their presumed sites of origin as Spanish, Asian, and Hong Kong influenza, respectively. They are now known to represent 3 different antigenic subtypes of influenza A virus: H1N1, H2N2, and H3N2, respectively. Not classified as true pandemics are 3 notable epidemics: a pseudopandemic in 1947 with low death rates, an epidemic in 1977 that was a pandemic in children, and an abortive epidemic of swine influenza in 1976 that was feared to have pandemic potential. Major influenza epidemics show no predictable periodicity or pattern, and all differ from one another. Evidence suggests that true pandemics with changes in hemagglutinin subtypes arise from genetic reassortment with animal influenza A viruses."

"After the influenza pandemic of 1918, influenza went back to its usual pattern of regional epidemics of lesser virulence in the 1930s, 1940s, and early 1950s. With the first isolation of a virus from humans in 1933, speculation began about the possible role of a similar virus in 1918. However, believing that this could have been the case was difficult until the pandemic of 1957. This was the first time the rapid global spread of a modern influenza virus was available for laboratory investigation. With the exception of persons >70 years of age, the public was confronted by a virus with which it had had no experience, and it was shown that the virus alone, without bacterial coinvaders, was lethal."

"The pandemic of 1957 provided the first opportunity to observe vaccination response in that large part of the population that had not previously been primed by novel HA and NA antigens not cross-reactive with earlier influenza A virus antigens. As summarized by Meiklejohn at an international conference on Asian influenza held 3 years after the 1957 onslaught of H2N2, more vaccine was required to initiate a primary antibody response than with the earlier H1 vaccines (almost always observed in heterovariant primed subjects). In 1958, 1959, and 1960 (as recurrent infections occurred), mean initial antibody levels in the population increased (i.e., subjects were primed) and response to vaccination was more readily demonstrated. Divided doses given at intervals of <4 weeks were more beneficial than a single injection. Less benefit was derived from this strategy as years passed. Intradermal administration of vaccine provided no special advantage over the conventional subcutaneous/intramuscular route, even when the same small dose was given. The Asian influenza experience provided the first opportunity to study how the postpandemic infection and disease into an endemic phase subsided. In studies conducted in separate and disparate populations, the populations compared were Navajo school children and New York City medical students. In both groups, subclinical infections occurred each year during the 3-year study period, and clinically manifested infections decreased in conjunction with an increasing level of H2N2-specific hemagglutination inhibition antibody."

"As in 1957, a new influenza pandemic arose in Southeast Asia and acquired the sobriquet Hong Kong influenza on the basis of the site of its emergence to western attention. Once again, the daily press sounded the alarm with a brief report of a large Hong Kong epidemic in the Times of London. A decade after the 1957 pandemic, epidemiologic communication with mainland China was even less efficient than it had been earlier. As this epidemic progressed, initially throughout Asia, important differences in the pattern of illness and death were noted. In Japan, epidemics were small, scattered, and desultory until the end of 1968. Most striking was the high illness and death rates in the United States following introduction of the virus on the West Coast. This experience stood in contrast with the experience in western Europe, including the United Kingdom, in which increased illness occurred in the absence of increased death rates in 1968–1969 and increased death rates were not seen until the following year of the pandemic. Since the Hong Kong virus differed from its antecedent Asian virus by its HA antigen, but had retained the same (N2) NA antigen (16), researchers speculated that its more sporadic and variable impact in different regions of the world were mediated by differences in prior N2 immunity (16–19). Therefore, the 1968 pandemic has been aptly characterized as "smoldering". Further evidence for the capacity of previous N2 experience to moderate the challenge of the Hong Kong virus was provided by Eickhoff and Meiklejohn, who showed that vaccination of Air Force cadets with an H2N2 adjuvant vaccine reduced subsequent influenza from verified H3N2 virus infection by 54%."

"In late 1946, an outbreak of influenza occurred in Japan and Korea in American troops. It spread in 1947 to other military bases in the United States, including Fort Monmouth, New Jersey, where the prototype FM-1 strain was isolated. The epidemic was notable because of the initial difficulty in establishing its cause as an influenza A virus because of its considerable antigenic difference from previous influenza A viruses. Indeed, for a time it was identified as "influenza A prime". The 1947 epidemic has been thought of as a mild pandemic because the disease, although globally distributed, caused relatively few deaths. However, as a medical officer at Fort Monmouth, I can personally attest that there was nothing mild about the illness in young recruits in whom signs and symptoms closely matched those of earlier descriptions of influenza. Most remarkable was the total failure of vaccine containing a 1943 H1N1 strain (effective in the 1943–1944 and 1944–1945 seasons) to protect the large number of US military personnel who were vaccinated. Previously, antigenic variation had been noted, but never had it been of a sufficient degree to compromise vaccine-induced immunity (24). Years later, extensive characterization of HA and NA antigens of the 1943 and 1947 viruses and comparison of their nucleotide and amino acid sequences showed marked differences in the viruses isolated in these 2 years; studies in a mouse model also showed that the 1943 vaccine afforded no protection to the 1947 virus challenge (24). Studies in the Fort Monmouth epidemic also documented, by serial bacterial cultures, for the first time the long suspected relationship of influenza to group A streptococcal carriage and disease."

"In the interest of full disclosure, I predicted the possibility of an imminent pandemic in an op ed piece published in The New York Times on February 13, 1976. On February 13, I was notified that influenza viruses isolated from patients at Fort Dix, New Jersey, a few days earlier and provisionally identified as swine influenza viruses were being mailed to my laboratory in New York City. A high-yield (6:2) genetic reassortant virus (X-53) was produced and later used as a vaccine in a clinical trial in 3,000 people. An even higher yielding HA mutant virus, X-53a, was selected from X-53 and subsequently used in the mass vaccination of 43,000,000 people. (I was a member of a Center for Disease Control advisory committee and an ad hoc advisory committee to President Gerald Ford on actions to be taken to protect the American public against swine influenza.) When no cases were found outside Fort Dix in subsequent months and the neurologic complication of Guillain-Barré syndrome occurred in association with administration of swine influenza vaccine, the National Immunization Program was abandoned, and the entire effort was assailed as a fiasco and disaster."

"Our obsession with geographic eponyms for a disease of worldwide distribution is best illustrated by Russian, or later red influenza or red flu, which first came to attention in November 1977, in the Soviet Union. However, it was later reported as having first occurred in northeastern China in May of that year. It quickly became apparent that this rapidly spreading epidemic was almost entirely restricted to persons <25 years of age and that, in general, the disease was mild, although characterized by typical symptoms of influenza. The age distribution was attributed to the absence of H1N1 viruses in humans after 1957 and the subsequent successive dominance of the H2N2 and then the H3N2 subtypes. When antigenic and molecular characterization of this virus showed that both the HA and NA antigens were remarkably similar to those of the 1950s, this finding had profound implications. Where had the virus been that it was relatively unchanged after 20 years? If serially (and cryptically) transmitted in humans, antigenic drift should have led to many changes after 2 decades. Reactivation of a long dormant infection was a possibility, but the idea conflicts with all we know of the biology of the virus in which a latent phase has not been found. Had the virus been in a deep freeze? This was a disturbing thought because it implied concealed experimentation with live virus, perhaps in a vaccine. Delayed mutation and consequent evolutionary stasis in an animal host are not unreasonable, but in what host? And if a full-blown epidemic did originate, it would be the first to do so in the history of modern virology, and a situation quite unlike the contemporary situation with H5N1 and its protracted epizootic phase. Thus, the final answer to the 1977 epidemic is not yet known."

"All pandemics are different. The minimum requirement seems to be a major change or shift in the HA antigen (1968). In 1957, changes in both HA and NA antigens were associated with higher rates of illness and death. The memorable and probably unique severity of the 1918 pandemic may have depended, at least in part, on wartime conditions and secondary bacterial infections in the absence of antimicrobial drugs. Also, mechanical respirators and supplemental oxygen were not available. Although evidence is strong that recombinational capture of animal influenza HA or NA antigens may be essential for pandemic origins, extreme antigenic drift, such as that which occurred in 1947, can lead to global dissemination and disease by the multiply mutated virus."

"Yes, we can prepare, but with the realization that no amount of hand washing, hand wringing, public education, or gauze masks will do the trick. The keystone of influenza prevention is vaccination. It is unreasonable to believe that we can count on prophylaxis with antiviral agents to protect a large, vulnerable population for more than a few days at a time, and that is not long enough. How long will they be given? To whom? What are the risks in mass administration? All of this is unknown. But vaccination against what? We do not know. Perhaps against H5N1. But do we not already have a vaccine? No, we do not; no vaccine of adequate antigenic potency is available in sufficient supply. The answer lies in an approach first suggested at a World Health Organization meeting in 1969 and repeatedly endorsed since by virtually every pandemic preparedness planning group. This recommendation assumes that the nature of the next pandemic virus cannot be predicted, but that it will arise from 1 of the 16 known HA subtypes in avian or mammalian species. Accordingly, preparation by genetic reassortment of high-yield seed viruses of all HA subtypes should proceed as soon as possible for potential use in vaccine production. Thirty-seven years later, this goal has not yet been achieved."

"Pandemics of influenza have been recognized since earliest recorded history and, because of the mutability of the virus, still represent a formidable threat to the health of the nation. Although much progress has been made in describing the molecular aspects off the virus, in elucidating the epidemiology and modes of spread, and in developing methods for prevention and treatment, a rational strategy for control has not been established."

"Pandemics results from the emergence of an influenza A virus that is novel for the human population. Evidence for recycling of subtypes of influenza A after intervals of 60 years or more has been derived by determining antibody prevalence in elderly populations prior to the emergence of subtypes of H2N2 in 1957 and H3N2 in 1968. A more ominous threat is the reservoir of 14 influenza A subtypes that persist in avian hosts. An avian virus can reassert with a human virus, as occurred in 1957 and 1968, to allow the creation of progeny that possess novel surface antigens with the potential to spread in human populations. Both pandemic viruses, A(H2N2) of 1957 and A(H3N2) of 1968, had evidence of gene reassortment with avian viruses. Swine are considered the most likely “mixing vessel” for this event, but viruses with avian genetic characteristics have also been recovered from horses and aquatic mammals."

"The morbidity and clinical attack rates produced by pandemic influenza have received much less attention than has excess mortality. In other words, the attention has been focused on the groups of persons who are most vulnerable to complications and death as a result of influenza virus infection. For most pandemics, those at greatest risk are the elderly and the very young. These same persons are, for the most part, at the end of the transmission chain; they are not introducers of influenza into the household . Therefore, immunization of these persons may reduce mortality and serious illness but will have little effect on the course of the epidemic. The fires of the epidemic are fed by healthy susceptible school children, college students, and employed persons who have many daily contacts and who are more mobile."

"Two features of the age-specific attack rates are evident. The first feature is that only a finite proportion of the population is infected with each annual epidemic (usually between 25 and 50 percent), and this proportion does not vary between pandemic and interpandemic outbreaks. Even pandemic viruses are not novel for the population do not reduce the pool of susceptibles by more than 50 percent during the first wave. One explanation for this may be that persons naïve for the new virus have more severe illnesses that put them to bed and limit the number of their contacts. On the other hand, during interpandemic outbreaks many persons with partial immunity to the circulating virus have mild illnesses that do not limit activity and reduce contacts. Therefore, the predominance of severe illnesses during pandemic may serve to limit spread, while the mild illnesses observed in interpandemic outbreaks serve to encourage spread even when a portion of persons in the population are immune. This could explain the similarity of attack rates for pandemic and interpandemic periods."

"The second important feature evident from the review of age-specific attack rates is that school children invariably have the highest attack rates during both pandemic and interpandemic periods. Epidemiologic studies during pandemics have demonstrated that children are important for spread of virus in the community. Observations made during the two major pandemics of this century reinforce the thesis that school children are important in the spread of influenza. Even though the populations were universally susceptible to the new influenza viruses that emerged in 1918 and 1957, and even though both viruses had seeded the population in the preceding spring and summer, the first major wave did not occur until schools were in session. Peak activity of both pandemics occurred in late October after school had been in session for 6-8 weeks. For interpandemic periods, observations in Houston have demonstrated that schoolchildren predominate among persons presenting for health care during the early stage of influenza epidemics. The age distribution of culture-positive patients changes during the course of the epidemic, with a shift to preschool children and adults during the latter part of the epidemic (table 4). School absenteeism occurs in the first part of the epidemic and employee absenteeism occurs during the later part. Hospitalizations of persons aged 65 years and older tend to occur during the last half of the epidemic, and pneumonia-influenza deaths are lagged at least 2 weeks after the peak of community morbidity. All of these observations support the thesis that school children are important disseminators of the virus in the community for both pandemic and interpandemic influenza. A series of family studies also have demonstrated that children are the main introducers of influenza into the household, and have found that immunization of school children would be effective for epidemic control."

"Epidemic influenza has been shown to significantly disrupt and adversely effect the delivery of health care. Control of yearly epidemics would not only reduce pain, suffering, and death, but would facilitate planning for efficient delivery of care by reducing the annual stress imposed by the influx of patients during annual influenza epidemics and provide an effective means of combating the threat of the next pandemic."

"The potential for emergence of future pandemic viruses containing such pathogenic HAs is unknown. However, for the purposes of pandemic planning, we must now consider the emergence of pandemics with extreme pathogenicity and high fatality, a concern underscored by the apparent variability in pandemic influenza severity recorded over a period of more than 500 years. As we ponder the possibility of future influenza pandemics caused by viruses with other pathogenic HAs, we must also remember that the pathogenicity of the 1918 pandemic virus seems to have been inherent to an H1 HA subtype that remains in nature today. Thus, if current global population immunity to H1 viruses wanes, another H1 pandemic could arise with the same deadly consequences as those experienced in 1918. All such pathogenic HAs existing in nature therefore represent a fundamental threat and an important target for pre-pandemic vaccine development."

"Influenza was a major public health problem for centuries before 1918, and remains so today, in terms of both sporadic pandemics and annual seasonal epidemic recurrences of variable severity. There will undoubtedly be influenza pandemics in the future, but despite an enormous amount of study, it is not possible to predict when and where they will appear, what viral subtypes they will be caused by, or what pathogenic properties they will display. Enhanced influenza virus surveillance, especially at the animal-human interface, is clearly important, but we lack any real ability to identify pre-pandemic viruses before they become pandemic."

"What variables have so far prevented wild H5N1 and H7N9 waterfowl viruses from becoming efficiently and pandemically transmissible in human populations, as the 1918 virus did? Do all influenza viruses, including poultry-adapted viruses, have the potential to acquire host adaptive mutations that lead to pandemicity, or is such evolution prevented by structural or functional evolutionary constraints associated with adaptation to the previous host? Does influenza A virus poultry adaptation place the virus in a particular evolutionary dead end with respect to subsequent human adaptation? Or can poultry-adapted influenza A viruses acquire mutations like those of the known pandemic viruses? If not, can they adapt to humans through different mechanisms? Again, we have no answers to these important questions."

"Although many thousands of people are continually exposed to a huge array of avian influenza A viruses, few pandemics have emerged over the past millennium; as the global human population has greatly increased, pandemic frequency has not. This suggests that despite a low species barrier for individual zoonotic infection by wild and poultry-adapted influenza A viruses, barriers against productive viral adaptation and onward transmission in humans must be high."

"In the late 1950s and 1960s, Francis and others hypothesized that only a very few naturally occurring influenza A virus subtypes had the ability to cause pandemics. These few virus subtypes reappeared in regular cycles determined by the lifespans of human birth cohorts exposed to them and rendered immune to them. This hypothesis has not yet been refuted by the past century of influenza experience. Extending observations back in time to the century before 1918, epidemiological and archaeserological evidence is consistent with the possibility that pandemics between the 1830s and 1889 may, like those of the past century, have only expressed HA subtypes H1, H2, or H3. Moreover, anecdotal observations going back to the mid-1700s are consistent with such HA recycling. If pandemics are explained by recycling of only a few influenza HA and NA subtypes, our efforts to develop preventive vaccines and our viral surveillance strategies need to be targeted accordingly. We currently do not know whether pandemic influenza threats of the future will be few in number and restricted in severity, or multitudinous and deadly."