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With great apprehension, the world is now watching the birth of a novel pandemic already causing tremendous suffering, death, and disruption of normal life. Uncertainty and dread are exacerbated by the belief that what we are experiencing is new and mysterious. However, deadly pandemics and disease emergences are not new phenomena: they have been challenging human existence throughout recorded history. Some have killed sizeable percentages of humanity, but humans have always searched for, and often found, ways of mitigating their deadly effects. With great apprehension, the world is now watching the birth of a novel pandemic already causing tremendous suffering, death, and disruption of normal life. Uncertainty and dread are exacerbated by the belief that what we are experiencing is new and mysterious. However, deadly pandemics and disease emergences are not new phenomena: they have been challenging human existence throughout recorded history. Some have killed sizeable percentages of humanity, but humans have always searched for, and often found, ways of mitigating their deadly effects. We here review the ancient and modern histories of such diseases, discuss factors associated with their emergences, and attempt to identify lessons that will help us meet the current challenge.

Background. Despite the availability of published data on 4 pandemics that have occurred over the past 120 years, there is little modern information on the causes of death associated with influenza pandemics. Methods. We examined relevant information from the most recent influenza pandemic that occurred during the era prior to the use of antibiotics, the 1918–1919 “Spanish flu”; pandemic. We examined lung tissue sections obtained during 58 autopsies and reviewed pathologic and bacteriologic data from 109 published autopsy series that described 8398 individual autopsy investigations. Results. The postmortem samples we examined from people who died of influenza during 1918–1919 uniformly exhibited severe changes indicative of bacterial pneumonia. Bacteriologic and histopathologic results from published autopsy series clearly and consistently implicated secondary bacterial pneumonia caused by common upper respiratory-tract bacteria in most influenza fatalities. Conclusions. The majority of deaths in the 1918–1919 influenza pandemic likely resulted directly from secondary bacterial pneumonia caused by common upper respiratory-tract bacteria. Less substantial data from the subsequent 1957 and 1968 pandemics are consistent with these findings. If severe pandemic influenza is largely a problem of viral-bacterial copathogenesis, pandemic planning needs to go beyond addressing the viral cause alone (e.g., influenza vaccines and antiviral drugs). Prevention, diagnosis, prophylaxis, and treatment of secondary bacterial pneumonia, as well as stockpiling of antibiotics and bacterial vaccines, should also be high priorities for pandemic planning.

Descendants of the H1N1 influenza A virus that caused the catastrophic and historic pandemic of 1918–1919 continue to contribute their genes to new viruses, causing new pandemics, epidemics, and epizootics. Drs. David Morens, Jeffery Taubenberger, and Anthony Fauci discuss the influenza A events of the past 91 years. It is not generally appreciated that descendents of the H1N1 influenza A virus that caused the catastrophic and historic pandemic of 1918–1919 have persisted in humans for more than 90 years and have continued to contribute their genes to new viruses, causing new pandemics, epidemics, and epizootics (see table). The current international pandemic caused by a novel influenza A (H1N1) virus derived from two unrelated swine viruses, one of them a derivative of the 1918 human virus, 3 adds to the complexity surrounding this persistent progenitor virus, its descendants, and its several lineages (see diagram). A useful way to think about . . .

Despite long-term investment, influenza continues to be a significant worldwide problem. The cornerstone of protection remains vaccination, and approved vaccines seek to elicit a hemagglutination inhibition (HAI) titer of ≥1:40 as the primary correlate of protection. However, recent poor vaccine performance raises questions regarding the protection afforded and whether other correlates of protection should be targeted. A healthy volunteer challenge study was performed with a wild-type 2009 A(H1N1)pdm influenza A challenge virus at the NIH Clinical Center to evaluate two groups of participants with HAI titers of ≥1:40 and <1:40. The primary objective was to determine whether participants with HAI titers of ≥1:40 were less likely to develop mild to moderate influenza disease (MMID) after intranasal inoculation. HAI titers of ≥1:40 were protective against MMID but did not reduce the incidence of symptoms alone. Although the baseline HAI titer correlated with some reduction in disease severity measures, overall, the baseline NAI titer correlated more significantly with all disease severity metrics and had a stronger independent effect on outcome. This study demonstrates the importance of examining other immunological correlates of protection rather than solely HAI titers. This challenge study confirms the importance of NAI titer as a correlate and for the first time establishes that it can be an independent predictor of reduction of all aspects of influenza disease. This suggests that NAI titer may play a more significant role than previously thought and that neuraminidase immunity should be considered when studying susceptibility after vaccination and as a critical target in future influenza vaccine platforms. IMPORTANCE This study represents the first time the current gold standard for evaluating influenza vaccines as set by the U.S. Food and Drug Administration and the European Medicines Agency Committee for Medicinal Products for Human Use, a “protective” hemagglutination inhibition (HAI) titer of ≥1:40, has been evaluated in a well-controlled healthy volunteer challenge study since the cutoff was established. We used our established wild-type influenza A healthy volunteer human challenge model to evaluate how well this antibody titer predicts a reduction in influenza virus-induced disease. We demonstrate that although higher HAI titer is predictive of some protection, there is stronger evidence to suggest that neuraminidase inhibition (NAI) titer is more predictive of protection and reduced disease. This is the first time NAI titer has been clearly identified in a controlled trial of this type to be an independent predictor of a reduction in all aspects of influenza. This study represents the first time the current gold standard for evaluating influenza vaccines as set by the U.S. Food and Drug Administration and the European Medicines Agency Committee for Medicinal Products for Human Use, a “protective” hemagglutination inhibition (HAI) titer of ≥1:40, has been evaluated in a well-controlled healthy volunteer challenge study since the cutoff was established. We used our established wild-type influenza A healthy volunteer human challenge model to evaluate how well this antibody titer predicts a reduction in influenza virus-induced disease. We demonstrate that although higher HAI titer is predictive of some protection, there is stronger evidence to suggest that neuraminidase inhibition (NAI) titer is more predictive of protection and reduced disease. This is the first time NAI titer has been clearly identified in a controlled trial of this type to be an independent predictor of a reduction in all aspects of influenza.

Influenza A viruses infect large numbers of warm-blooded animals, including wild birds, domestic birds, pigs, horses, and humans. Influenza viruses can switch hosts to form new lineages in novel hosts. The most significant of these events is the emergence of antigenically novel influenza A viruses in humans, leading to pandemics. Influenza pandemics have been reported for at least 500 years, with inter-pandemic intervals averaging approximately 40 years.

Background. Healthy volunteer wild-type influenza challenge models offer a unique opportunity to evaluate multiple aspects of this important virus. Such studies have not been performed in the United States in more than a decade, limiting our capability to investigate this virus and develop countermeasures. We have completed the first ever wild-type influenza A challenge study under an Investigational New Drug application (IND). This dose-finding study will lead to further development of this model both for A(H1N1)pdm09 and other strains of influenza. Methods. Volunteers were admitted to an isolation unit at the National Institutes of Health Clinical Center for a minimum of 9 days. A reverse genetics, cell-based, Good Manufacturing Practice (GMP)–produced, wild-type A (H1N1)pdm09 virus was administered intranasally. Escalating doses were given until a dose was reached that produced disease in a minimum of 60% of volunteers. Results. An optimal dose of 107 tissue culture infectious dose 50 was reached that caused mild to moderate influenza disease in 69% of individuals with mean viral shedding for 4–5 days and significant rises in convalescent influenza antibody titers. Viral shedding preceded symptoms by 12–24 hours and terminated 2–3 days prior to symptom resolution, indicating that individuals may be infectious before symptom development. As expected, nasal congestion and rhinorrhea were most common, but interestingly, fever was observed in only 10% of individuals. Conclusions. This study represents the first healthy volunteer influenza challenge model using a GMP-produced wild-type virus under an IND. This unique clinical research program will facilitate future studies of influenza pathogenesis, animal model validation, and the rapid, efficient, and cost-effective evaluation of efficacy of novel vaccines and therapeutics.

The evolutionary interaction between influenza A virus and the human immune system, manifest as ‘antigenic drift’ of the viral haemagglutinin, is one of the best described patterns in molecular evolution. However, little is known about the genome-scale evolutionary dynamics of this pathogen. Similarly, how genomic processes relate to global influenza epidemiology, in which the A/H3N2 and A/H1N1 subtypes co-circulate, is poorly understood. Here through an analysis of 1,302 complete viral genomes sampled from temperate populations in both hemispheres, we show that the genomic evolution of influenza A virus is characterized by a complex interplay between frequent reassortment and periodic selective sweeps. The A/H3N2 and A/H1N1 subtypes exhibit different evolutionary dynamics, with diverse lineages circulating in A/H1N1, indicative of weaker antigenic drift. These results suggest a sink–source model of viral ecology in which new lineages are seeded from a persistent influenza reservoir, which we hypothesize to be located in the tropics, to sink populations in temperate regions. A tropical origin for flu virus The current debate in the United States on the selection of strains for the influenza vaccine highlights the need for epidemiological understanding of the influenza virus. An analysis of genome sequences from over 1,300 influenza A virus isolates from around the world shows that its evolution is characterized by a combination of frequent gene reassortment and occasionally strong selection. At the epidemiological level, the H3N2 and H1N1 virus subtypes exhibit dynamics suggestive of an ecological model in which new antigenic variants emerge periodically from a persistent influenza reservoir, perhaps in the tropics, to the sink populations in temperate regions. Current debate on the selection of strains for the influenza vaccine highlights the need for epidemiological understanding of human influenza A virus. This paper analyses genomic sequences from global viral isolates, and hypothesizes that the virus follows a 'sink-source' model, where new lineages keep arising from some areas and dying out in other areas.

Influenza A viruses are important pathogens for humans and for many birds and mammals. Hemagglutinin and neuraminidase are the major surface proteins of this enveloped RNA virus. Influenza A viruses are important pathogens for humans and for many birds and mammals. Hemagglutinin and neuraminidase are the major surface proteins of this enveloped RNA virus. Hemagglutinin requires proteolytic cleavage for activation, but because the viral genome does not encode its own protease, an exogenous serine protease must be provided by host cells. A novel, neuraminidase-dependent mechanism for hemagglutinin activation was described, in which a thrombin-like protease allows an influenza A/H7N6 virus, isolated from a mallard duck, to replicate systemically and induce enhanced disease in avian and mammalian model animals and to replicate in vitro in the absence of trypsin. Thrombin-like protease activation required the N6 neuraminidase, but also required the presence of a thrombin-like cleavage motif in the H7 hemagglutinin. This novel example of neuraminidase-dependent hemagglutinin activation demonstrates the extraordinary evolutionary flexibility of influenza A viruses and is a fascinating example of epistasis between the hemagglutinin and neuraminidase genes.

Pandemic 2009 H1N1 virus isolates containing the neuraminidase inhibitor resistance mutation H275Y have been reported. We describe rapid selection for the H275Y resistance mutation during therapy in 2 immunocompromised individuals at 9 and 14 days of therapy, as well as the first described case of clinically significant resistance to peramivir.

The 1918 influenza pandemic was the deadliest respiratory pandemic of the 20th century and determined the genomic make-up of subsequent human influenza A viruses (IAV). Here, we analyze both the first 1918 IAV genomes from Europe and the first from samples prior to the autumn peak. 1918 IAV genomic diversity is consistent with a combination of local transmission and long-distance dispersal events. Comparison of genomes before and during the pandemic peak shows variation at two sites in the nucleoprotein gene associated with resistance to host antiviral response, pointing at a possible adaptation of 1918 IAV to humans. Finally, local molecular clock modeling suggests a pure pandemic descent of seasonal H1N1 IAV as an alternative to the hypothesis of origination through an intrasubtype reassortment. For archival pathogens, like pH1N1 Influenza A virus the causative agent of 1918/19 pandemic, only few whole genome sequences exist. Here, Patrono et al. provide one complete and two partial genomes from Germany and find variation in two sites in the nucleoprotein gene in pandemic samples compared to pre-pandemic samples, that are associated with resistance to host antiviral response, pointing at a possible viral adaptation to humans.