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What Can We Learn from Reconstructing the Extinct 1918 Pandemic Influenza Virus?
Abstract
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... The determination of the genomic sequence of the 1918 pandemic virus, and the subsequent reconstruction of the virus, has provided us with the opportunity to decipher the viral-and host-specific properties that contributed to the severity of the 1918-1919 pandemic. It has been demonstrated that in contrast to other influenza viruses, the 1918 pandemic virus is highly virulent and pathogenic in multiple animal species without prior adaptation [45,50]. While obvious knowledge gaps remain, in particular with respect to the origin of the virus and the molecular mechanisms (host and/or viral) underlying differential pathogenesis as compared to other influenza viruses, there have been considerable advances in our understanding of the 1918 pandemic virus. ...
... While resistance to NA inhibitors has been observed in some influenza virus strains, they are still highly effective in the majority of patients [60]. Studies have shown that both adamantane antivirals and NA inhibitors provide protection against the 1918 virus [50]. ...
Background
In the spring of 1918, the “War to End All Wars”, which would ultimately claim more than 37 million lives, had entered into its final year and would change the global political and economic landscape forever. At the same time, a new global threat was emerging and would become one of the most devastating global health crises in recorded history.
Main text
The 1918 H1N1 pandemic virus spread across Europe, North America, and Asia over a 12-month period resulting in an estimated 500 million infections and 50–100 million deaths worldwide, of which ~ 50% of these occurred within the fall of 1918 (Emerg Infect Dis 12:15-22, 2006, Bull Hist Med 76:105-115, 2002). However, the molecular factors that contributed to the emergence of, and subsequent public health catastrophe associated with, the 1918 pandemic virus remained largely unknown until 2005, when the characterization of the reconstructed pandemic virus was announced heralding a new era of advanced molecular investigations (Science 310:77-80, 2005). In the century following the emergence of the 1918 pandemic virus we have landed on the Moon, developed the electronic computer (and a global internet), and have eradicated smallpox. In contrast, we have a largely remedial knowledge and understanding of one of the greatest scourges in recorded history.
Conclusion
Here, we reflect on the 1918 influenza pandemic, including its emergence and subsequent rapid global spread. In addition, we discuss the pathophysiology associated with the 1918 virus and its predilection for the young and healthy, the rise of influenza therapeutic research following the pandemic, and, finally, our level of preparedness for future pandemics.
... Color code: blue is epitope A, red is epitope B, cyan is epitope C, [16]. 2 The Asian flu pandemic in 1956-58 was H2N2, which spread widely in the human population during the time interval 1957-68 [17]. The Hong Kong flu pandemic in 1968-69 was H3N2, which has circulated in the human population as the dominant subtype until recently [17]. ...
... Color code: blue is epitope A, red is epitope B, cyan is epitope C, [16]. 2 The Asian flu pandemic in 1956-58 was H2N2, which spread widely in the human population during the time interval 1957-68 [17]. The Hong Kong flu pandemic in 1968-69 was H3N2, which has circulated in the human population as the dominant subtype until recently [17]. Other subtypes rarely infected humans, although cases of H5N1 and H9N2 have been reported. ...
... From 1957 to 1968, infl uenza viruses of the H2 subtype were prevalent. In 1968, another subtype change occurred when viruses with an H3 HA appeared [24]. While humans experienced two pandemics, viz. ...
... The infl uenza pandemic of 1918–1919 was a unique event in recorded history, costing around 50 million lives in less than a year [69]. Compared to the 1918 pandemic, the pandemics caused by the 1957 (H2N2) and 1968 (H3N2) viruses were relatively mild, with estimates of one million and half a million deaths worldwide, respectively [24]. The current outbreak indicates that the new H1N1 viruses are able to transmit from human to human, and this distinguishes these viruses form other viruses present in nature. ...
The 2009 H1N1 pandemic has slowed down its spread after initial speed of transmission. The conventional swine influenza H1N1 virus (SIV) in pig populations worldwide needs to be differentiated from pandemic H1N1 influenza virus, however it is also essential to know about the exact role of pigs in the spread and mutations taking place in pig-to-pig transmission. The present paper reviews epidemiological features of classical SIV and its differentiation with pandemic influenza.
... H1N1 reappeared in 1977 and persists today (Nakajima et al., 1978). The Asian flu pandemic in 1956 -58 was H2N2, which spread widely in the human population during the time interval 1957-68 (Palese et al., 2006). The Hong Kong flu pandemic in 1968 -69 was H3N2, which has circulated in the human population as the dominant subtype until recently (Palese et al., 2006). ...
... The Asian flu pandemic in 1956 -58 was H2N2, which spread widely in the human population during the time interval 1957-68 (Palese et al., 2006). The Hong Kong flu pandemic in 1968 -69 was H3N2, which has circulated in the human population as the dominant subtype until recently (Palese et al., 2006). Other subtypes rarely infected humans, although cases of H5N1 and H9N2 have been reported. ...
The recent emergence of H1N1 (swine flu) illustrates the ability of the influenza virus to create antigens new to the human immune system, even within a given hemagglutinin and neuraminidase subtype. This new H1N1 strain is sufficiently distinct, for example, from the A/Brisbane/59/2007 (H1N1)-like virus strain of influenza in the 2008/09 Northern hemisphere vaccine that protection is not expected to be substantial. The human immune system responds primarily to the five epitope regions of the hemagglutinin protein. By determining the fraction of amino acids that differ between a vaccine strain and a viral challenge strain in the dominant epitope regions, a measure of antigenic distance that correlates with epidemiological studies of H3 influenza A vaccine efficacy in humans with R(2) = 0.81 is derived. This measure of antigenic distance is called p(epitope). The relation between vaccine efficacy and p(epitope) is given by E = 0.47 - 2.47 x p(epitope). We here identify the epitope regions of H1 hemagglutinin, so that vaccine efficacy may be reliably estimated for H1N1 influenza A.
... This pattern challenges the classically described W-shaped agespecific mortality curve, which was based on crude annual mortality data rather than monthly excess mortality [36]. In addition, for the 1918 pandemic, the curious age pattern of young adults having the highest mortality risk may be further explained by an unusual immune pathology that affected young adults [37]. Because the contributions of the 2 possibilities—recycling and immune pathology—cannot be resolved for the 1918 pandemic [37], projections of a future pandemic impact cannot unequivocally evaluate the full range of possible age patterns. ...
... In addition, for the 1918 pandemic, the curious age pattern of young adults having the highest mortality risk may be further explained by an unusual immune pathology that affected young adults [37]. Because the contributions of the 2 possibilities—recycling and immune pathology—cannot be resolved for the 1918 pandemic [37], projections of a future pandemic impact cannot unequivocally evaluate the full range of possible age patterns. We note that recycling is not an issue for a contemporary pandemic threat such as A/H5N1, yet the age distribution of human cases and deaths so far is reminiscent of that of the 1918 pandemic, with the highest impact being among the young [38]. ...
How to allocate limited vaccine supplies in the event of an influenza pandemic is currently under debate. Conventional vaccination strategies focus on those at highest risk for severe outcomes, including seniors, but do not consider (1) the signature pandemic pattern in which mortality risk is shifted to younger ages, (2) likely reduced vaccine response in seniors, and (3) differences in remaining years of life with age.
We integrated these factors to project the age-specific years of life lost (YLL) and saved in a future pandemic, on the basis of mortality patterns from 3 historical pandemics, age-specific vaccine efficacy, and the 2000 US population structure.
For a 1918-like scenario, the absolute mortality risk is highest in people <45 years old; in contrast, seniors (those >or=65 years old) have the highest mortality risk in the 1957 and 1968 scenarios. The greatest YLL savings would be achieved by targeting different age groups in each scenario; people <45 years old in the 1918 scenario, people 45-64 years old in the 1968 scenario, and people >45 years old in the 1957 scenario.
Our findings shift the focus of pandemic vaccination strategies onto younger populations and illustrate the need for real-time surveillance of mortality patterns in a future pandemic. Flexible setting of vaccination priority is essential to minimize mortality.
... Influenza A virus (IAV) can cause very severe pandemic outbreaks. For example, the 1918 pandemic caused by influenza A H1N1 resulted in over 40 million deaths worldwide [3]. However, influenza B virus (IBV) has only caused seasonal epidemics, and symptoms are usually less severe than those caused by IAV [4]. ...
Introduction
Vaccination is the most effective method to control the prevalence of seasonal influenza and the most widely used influenza vaccine is the inactivated influenza vaccine (IIV). Each season, the influenza vaccine must be updated to be most effective against current circulating variants. Therefore, developing a universal influenza vaccine (UIV) that can elicit both broad and durable protection is of the utmost importance.
Area covered
This review summarizes and compares the available influenza vaccines in the market and inactivation methods used for manufacturing IIVs. Then, we discuss the latest progress of the UIV development in the IIV format and the challenges to address for moving these vaccine candidates to clinical trials and commercialization. The literature search was based on the Centers for Disease Control and Prevention (CDC) and the PubMed databases.
Expert opinion
The unmet need for UIV is the primary aim of developing the next generation of influenza vaccines. The IIV has high antigenicity and a refined manufacturing process compared to most other formats. Developing the UIV in IIV format is a promising direction with advanced biomolecular technologies and next-generation adjuvant. It also inspires the development of universal vaccines for other infectious diseases.
... Tal ha sido así, que, en los últimos 110 años, se han reportado cuatro episodios de pandemias de influenza humana. En 1918, se registró la más devastadora, causada por influenza A H1N1, provocando entre 40-50 millones de fallecidos de acuerdo con los reportes de la época 4,7 . En 1957 fue causada por A H2N2 y en 1968 por A H3N2. En 2009, la primera pandemia de este siglo fue causada por una nueva variedad de virus influenza A H1N1 que anteriormente circulaba en los cerdos 8 . ...
Since the second half of 2022, an increase in influenza cases in migratory birds has been reported in Latin America. Influenza A and B viruses are the main agents associated with seasonal epidemic influenza in humans. Influenza A viruses circulate not only in humans but also in animals, including migratory birds. The exchange of genomic RNA segments among two viruses increases the diversity of circulating subtypes and may even facilitate the generation of potentially pandemic viral progeny. The zoonotic nature of influenza A virus can generate infections in humans with animal-origin viruses. Avian-origin influenza A virus has caused transmissions in humans, including severe cases and deaths, with influenza A H5N1 being the most prominent. It is important to take preventive and control measures in case of an increase in influenza cases in migratory birds to prevent possible pandemics in Chile and the world.
... On the other hand, pandemic influenza is characterized by a fast spread of the influenza A virus from the virus origin to the rest of the world in several waves over a short period, as witnessed in the first influenza pandemic of 1918 by the influenza A H1N1 virus strain, and subsequent pandemics of 1957, 1968, and 2009, caused by the Influenza A H2N2, H3N2, and H1N1 virus strains, respectively [97,99]. ...
Essential oils (EOs) are chemical substances, mostly produced by aromatic plants in response to stress, that have a history of medicinal use for many diseases. In the last few decades, EOs have continued to gain more attention because of their proven therapeutic applications against the flu and other infectious diseases. Influenza (flu) is an infectious zoonotic disease that affects the lungs and their associated organs. It is a public health problem with a huge health burden, causing a seasonal outbreak every year. Occasionally, it comes as a disease pandemic with unprecedentedly high hospitalization and mortality. Currently, influenza is managed by vaccination and antiviral drugs such as Amantadine, Rimantadine, Oseltamivir, Peramivir, Zanamivir, and Baloxavir. However, the adverse side effects of these drugs, the rapid and unlimited variabilities of influenza viruses, and the emerging resistance of new virus strains to the currently used vaccines and drugs have necessitated the need to obtain more effective anti-influenza agents. In this review, essential oils are discussed in terms of their chemistry, ethnomedicinal values against flu-related illnesses, biological potential as anti-influenza agents, and mechanisms of action. In addition, the structure-activity relationships of lead anti-influenza EO compounds are also examined. This is all to identify leading agents that can be optimized as drug candidates for the management of influenza. Eucalyptol, germacrone, caryophyllene derivatives, eugenol, terpin-4-ol, bisabolene derivatives, and camphecene are among the promising EO compounds identified, based on their reported anti-influenza activities and plausible molecular actions, while nanotechnology may be a new strategy to achieve the efficient delivery of these therapeutically active EOs to the active virus site.
... In the past 100 years, there have been four influenza pandemics, two of which were caused by the H1N1 subtype. The Spanish flu of 1918 caused nearly 50 million deaths [3]. Currently, vaccination is the primary and most effective method of fighting against IAV infection. ...
Influenza A virus (IAV) can cause high morbidity and mortality globally every year. Myriad host kinases and their related signaling pathways are involved in IAV infection, and the important role of the c-Jun N-terminal kinase signaling pathway during infection has been demonstrated. SP600125, an inhibitor of c-Jun N-terminal kinase, was found in our previous study to suppress IAV replication in vitro. In this study, we established a mouse model of H1N1 IAV infection and treated the mice with SP600125 to study its protective effect. The results showed that SP600125 treatment reduced the pulmonary inflammatory response, lung injury, and pulmonary viral load and increased the survival rate of H1N1-infected mice. Our data confirm the crucial role of c-Jun N terminal kinase in H1N1 virus replication and inflammatory responses in vivo. Hence, we speculate that SP600125 has a potential antiviral therapeutic benefit against IAV infection.
... On the other hand, the middle and left-most (youngest) modes of the W are part of the 1918 pandemic. A prior-immunity argument suggests that the diminution of mortality among older cohorts (that is, the rightmost trough of the W) was due to acquired immunity in these cohorts from the 1890 pandemic (Palese 2004;Palese, Tumpey, and Garcia-Sastre 2006); this is also consistent with the available data. ...
... 18 Kobasa et al. (2007). 19 Palese et al. (2006). 20 Kennedy (2005). ...
Despite rapid advance in the prevention, diagnosis, and treatment, infectious diseases remain a central challenge for global health policy. In the twenty-first century, the life sciences—including microbiology, virology, and immunology—have been marshalled as key tools in the fight against infectious disease, and the promotion of global health. Rapid advance in these fields, however, has given rise to the “dual-use dilemma,” when one and the same piece of scientific research or technology has the capacity to help or harm humanity. While not unique to fields that address infectious disease, contemporary cases of dual-use research are largely identified in the context of the life sciences. In this chapter I outline the debate about dual-use research in the life sciences, in particular the ethics of dual-use research. After a historical overview of the dual-use dilemma in the twenty-first century, I examine ethical issues in attempting to trade off the risks and benefits of dual-use research. I address how we select alternative, less risky experiments; translational issues arising for dual-use research; and political commitments to realise the benefits and mitigate the risks arising from such research. I then discuss the governance of dual-use research, before concluding with a brief discussion on priority setting in infectious disease research as a path forward for policymakers.
... These sequence data suggest that the 1918 pandemic was almost identical genetically in its near-simultaneous appearances around the globe, and that it shared many genetic features with, and was likely derived from, a wild waterfowl influenza A virus that had somehow directly or indirectly switched hosts to become a human-adapted virus. Reverse genetics for influenza viruses, developed in 1999developed in (Fodor et al. 1999Neumann et al. 1999), allowed production of infectious influenza A virions containing one or more 1918 virus genes for in vitro and in vivo studies, which provided initial characterization of 1918 viral pathogenesis (Basler et al. 2001;Geiss et al. 2002;Tumpey et al. 2002Tumpey et al. , 2004Tumpey et al. , 2005aTumpey et al. ,b, 2007Stevens et al. 2004Stevens et al. , 2006Glaser et al. 2005;Kash et al. 2006;Palese et al. 2006), addressing questions of host adaptation, pathogenesis, the role of the host inflammatory response, and factors associated with transmission in mammals. ...
Just over a century ago in 1918-1919, the "Spanish" influenza pandemic appeared nearly simultaneously around the world and caused extraordinary mortality-estimated at 50-100 million fatalities-associated with unexpected clinical and epidemiological features. The pandemic's sudden appearance and high fatality rate were unprecedented, and 100 years later still serve as a stark reminder of the continual threat influenza poses. Sequencing and reconstruction of the 1918 virus have allowed scientists to answer many questions about its origin and pathogenicity, although many questions remain. Several of the unusual features of the 1918-1919 pandemic, including age-specific mortality patterns and the high frequency of severe pneumonias, are still not fully understood. The 1918 pandemic virus initiated a pandemic era still ongoing. The descendants of the 1918 virus remain today as annually circulating and evolving influenza viruses causing significant mortality each year. This review summarizes key findings and unanswered questions about this deadliest of human events.
... Reverse genetics technology for influenza viruses, developed in 1999 (40,41), also allowed production of infectious influenza A virions containing one or more 1918 virus genes for in vitro and in vivo study. A multicenter collaborative project involving (32,37,(42)(43)(44)(45)(46)(47)(48)(49)(50)(51). These initial 1918 virus studies evaluated key questions of host adaptation, pathogenesis, and the role of the host inflammatory response in disease control and pathogenesis, as well as factors associated with transmission among mammals. ...
The 2018–2019 period marks the centennial of the “Spanish” influenza pandemic, which caused at least 50 million deaths worldwide. The unprecedented nature of the pandemic’s sudden appearance and high fatality rate serve as a stark reminder of the threat influenza poses. Unusual features of the 1918–1919 pandemic, including age-specific mortality and the high frequency of severe pneumonias, are still not fully understood. Sequencing and reconstruction of the 1918 virus has allowed scientists to answer many questions about its origin and pathogenicity, although many questions remain. This Review summarizes key findings and still-to-be answered questions about this deadliest of human events.
... During the past century humans have experienced five influenza pandemics by three subtypes of IAVs: H1N1 in 1918 (Spanish flu), H2N2 in 1957 (Asian flu), H3N2 in 1968 (Hong Kong flu), H1N1 in 1977 (Russian flu), and again H1N1 in 2009 (swine flu). Collectively these pandemics led to the death of tens of millions of people (1)(2)(3)(4). ...
In spite of the enormous amount of research, influenza virus is still one of the major challenges for medical virology due to its capacity to generate new variants, which potentially lead to severe epidemics and pandemics. We demonstrated here that a swarm of small interfering RNA (siRNA) molecules, including more than 100 different antiviral RNA molecules targeting the most conserved regions of the influenza A virus genome, could efficiently inhibit the replication of all tested avian and seasonal influenza A variants in human primary monocyte-derived macrophages and dendritic cells. The wide antiviral spectrum makes the virus-specific siRNA swarm a potentially efficient treatment modality against both avian and seasonal influenza viruses.
... Notable is that pandemic influenza particularly targets otherwise healthy youths as well as the immune-compromised. During the 1918 H1N1 pandemic, local mortalities of 30% and more were recorded, and an overall mortality of approximately 2.6% with up to 50 million lives lost [2] [3]. The epizoonotic expansion over the past decade of highly pathogenic H5N1 avian-influenza (HPAI) has so far resulted in a 61.8% mortality of the confirmed 348 human infections (WHO) identified up till the beginning of 2008 and continues to pose a realistic risk of also developing into a human pandemic [4]. ...
It is necessary to understand whether some humans possess natural humoral-immune protection for avian-H5N1 influenza. To broadly assess an exposure naïve cohort we have examined intravenous immunoglobulins (IVIGs) isolated from pools of many thousands of normal Australian blood donations. In studies of the anti-H5N1 antibody poten-tial of these highly purified IVIG therapeutics and of individual donor sera we have identified antibodies that bind to both H5N1 surface envelope and internal viral proteins and neutralize in vitro MDCK and Vero cell infections by highly pathogenic avian influenza clade I and II and human-derived H5N1 isolates. As this reactivity is removed by adsorption with purified H3N2 and H1N1 strains, anti-H5N1 cross-reacting hetero-typic antibodies are implicated. These findings support that some individuals do contain low levels of specific and neutralizing anti-H5N1 antibodies. The protective relevance of this in vivo remains yet to be determined.
... However, adaptation to humans may occur and cause an influenza pandemic followed by the establishment of a new lineage of human influenza viruses. This may be what occurred in the 1918 virus, though the origin of this virus is still controversial [3]. Reassortment is an important mechanism of viral gene segment rearrangement in a host cell infected with 2 or more different viruses [2]. ...
The 2009 influenza A pandemic virus (H1N1(pdm)) may reassort with old seasonal influenza A virus (H1N1₁₄₁) in humans and potentially change their pathogenicity.
This study focuses on the reassortment of ribonucleoproteins (RNPs) among H1N1(pdm) and seasonal influenza A viruses. A single RNP gene reassortment altered reporter gene expression levels driven by polymerase complex in transfection system. The growth rates of recombinant viruses with different RNP recombinations were changed in A549 cells. Mice were infected with recombinant viruses containing single RNP gene reassortment, and pathogenicity was examined. The results demonstrated that the median lethal dose (LD₅₀) of the PB2₁₄₁/PB1₁₄₁/PA(pdm)/NP₁₄₁ recombinant virus was lower than that of the seasonal H1N1 virus. Viral titers of this reassorted virus in the lung and spleen were significantly higher than that in seasonal H1N1 virus-challenged mice.
Although the changes of RNP activity did not exactly reflect to mice virulence, we consistently observed that the PA gene of H1N1(pdm) results in increased polymerase activity, better replication in mice, and lower LD₅₀. Our findings suggest that monitoring of gene reassortment for the 2009 pandemic influenza and seasonal human viruses is also important, which would help to constrain the potential emergence of a more virulent influenza A variant.
... We began by asking whether unexposed humans really are antibodydefenceless against a pandemic influenza. Although the lethality of the 1918 pandemic is frequently reported, 22,23 what is seldom appreciated is the fact that the majority (497%) of those infected survived. Given that strain-specific 'seasonal' neutralizing antibodies to highly variable but dominant antigenic sites can take weeks to months to develop, 24 what major immune mechanisms were immediately capable and available to protect such a large proportion of the population? ...
Fundamentally new approaches are required for the development of vaccines to pre-empt and protect against emerging and pandemic influenzas. Current strategies involve post-emergent homotypic vaccines that are modelled upon select circulating 'seasonal' influenzas, but cannot induce cross-strain protection against newly evolved or zoonotically introduced highly pathogenic influenza (HPI). Avian H5N1 and the less-lethal 2009 H1N1 and their reassortants loom as candidates to seed a future HPI pandemic. Therefore, more universal 'seasoned' vaccine approaches are urgently needed for heterotypic protection ahead of time. Pivotal to this is the need to understand mechanisms that can deliver broad strain protection. Heterotypic and heterosubtypic humoral immunities have largely been overlooked for influenza cross-protection, with most 'seasoned' vaccine efforts for humans focussed on heterotypic cellular immunity. However, 5 years ago we began to identify direct and indirect indicators of humoral-herd immunity to protein sites preserved among H1N1, H3N2 and H5N1 influenzas. Since then the evidence for cross-protective antibodies in humans has been accumulating. Now proposed is a rationale to stimulate and enhance pre-existing heterotypic humoral responses that, together with cell-mediated initiatives, will deliver pre-emptive and universal human protection against emerging epidemic and pandemic influenzas.
... The currently circulating 2009 strain is caused by an H1N1 subtype virus and is a triple reassortant, containing segments from avian, swine, and human influenza strains [181][182]. H1N1 and H3N2 subtype viruses are still circulating in humans today, while the H2N2 strain appears to have been displaced by the H3N2 strain's emergence in 1968 [183]. Whether the current pandemic strain will eventually displace the H3N2 strain remains to be seen. ...
The use of viral vectors as vaccine candidates has shown promise against a number of pathogens. However, preexisting immunity to these vectors is a concern that must be addressed when deciding which viruses are suitable for use. A number of properties, including the existence of antigenically distinct subtypes, make influenza viruses attractive candidates for use as viral vectors. Here, we evaluate the ability of influenza viral vectors containing inserts of foreign pathogens to elicit antibody and CD8(+) T cell responses against these foreign antigens in the presence of preexisting immunity to influenza virus in mice. Specifically, responses to an H3N1-based vector expressing a 90 amino acid polypeptide derived from the protective antigen (PA) of Bacillus anthracis or an H1N1-based vector containing a CD8(+) T cell epitope from the glycoprotein (GP) of lymphocytic choriomeningitis virus were evaluated following infections with either homosubtypic or heterosubtypic influenza viruses. We found that mice previously infected with influenza viruses, even those expressing HA and NA proteins of completely different subtypes, were severely compromised in their ability to mount an immune response against the inserted epitopes. This inhibition was demonstrated to be mediated by CD8(+) T cells, which recognize multiple strains of influenza viruses. These CD8(+) T cells were further shown to protect mice from a lethal challenge by a heterologous influenza subtype. The implication of these data for the use of influenza virus vectors and influenza vaccination in general are discussed.
... With a mortality up to 250 times greater than strains that cause epidemics the lethality of the 1918 avian H1N1 influenza pandemic is frequently reported (Palese et al, 2006; Taubenberger and Morens, 2006), but seldom appreciated is the fact that the majority (>97%) of those infected survived, amounting to 0.8-2 billion lives recovered. The most profound defence against influenza is provided by adaptive immunity that is mediated by neutralizing strain-specific " seasonal " antibodies directed against highly variable naïve antigens of an infecting influenza. ...
Well understood are the adaptive and dramatic neutralizing homosubtypic antibody responses to hypervariable, immunodominant sites of the hemagglutinin (HA) and neuraminidase (NA) of individual influenza strains. These define influenza subtypes and vaccines modelled upon their HA and NA antigens provide seasonal neutralizing antibody protection against subsequent exposure to the strain and its close relatives, but give little if any protection against antigenically drifted or shifted strains. Contrasting to this is a different form of acquired antibody response, called heterosubtypic immunity. This provides a more seasoned adaptive antibody response to immune-recessive epitopes that are highly-conserved amongst strains. Although, such responses are of lower individual amplitudes than seasonal mechanisms they are active across influenza subtypes, and may give pre-emptive protection against new strains yet to emerge. Heterosubtypic immunities have been well studied in animals, but surprisingly there is minimal evidence for this type of antibody immunity in humans. Thus championed is the notion that seasoned humoral responses can through repeated exposure to sites widely conserved across different strains, cumulatively provide humans with a level of broad protection against emergent novel strains, such as H5N1, that is not afforded by seasonal humoral responses.
... We also postulate that the human population, having experienced infections with currently circulating H1N1 viruses, is partially immune to a 1918 or 1918-like virus. Finally, we have recently developed a guinea pig transmission model for influenza which will help us to better understand the molecular basis of virulence and the mechanisms by which pandemic influenza viruses are transmitted.123. ...
... The 1918 'Spanish Flu' killed more than 500 000 people in the U.S.A. and a total of 20–50 million people worldwide [2]. Vaccination remains the primary method for prevention of influenza, but vaccine strains must be continually updated and their protective efficacy is limited in patients over 65 years of age, who are the major target group [3]. An alternative lies in antiviral drugs. ...
Influenza NA (neuraminidase) is an antiviral target of high pharmaceutical interest because of its essential role in cleaving sialic acid residues from cell surface glycoproteins and facilitating release of virions from infected cells. The present paper describes the use of structural information in the progressive design from a lead binding ion (a sulfate) to a potent submicromolor inhibitor (K(i) 0.13 microM). Structural information derived from the X-ray structure of an NA complexed with several sulfate ions, in combination with results derived from affinity labelling and molecular modelling studies, was used to guide design of potent sulfonic acid-based inhibitors. These inhibitors are structural fragments of the polysulfonate triazine dye Cibacron Blue 3GA and represent novel lead scaffolds for designing non-carbohydrate inhibitors for influenza neuraminidases.
... The multifunctional NS1 protein of influenza virus Influenza A and B viruses cause a highly contagious respiratory disease in humans and are responsible for periodic worldwide pandemics that cause high human mortality (Garcia-Sastre, 2004;Noah and Krug, 2005). The most devastating pandemic occurred in 1918, resulting in 30 million deaths worldwide (Tumpey et al., 2005;Palese et al., 2006). The current recommended trivalent influenza vaccine includes antigens from recently circulating strains of influenza A and B viruses. ...
Viral and microbial constituents contain specific motifs or pathogen-associated molecular patterns (PAMPs) that are recognized by cell surface- and endosome-associated Toll-like receptors (TLRs). In addition, intracellular viral double-stranded RNA is detected by two recently characterized DExD/H box RNA helicases, RIG-I and Mda-5. Both TLR-dependent and -independent pathways engage the IkappaB kinase (IKK) complex and related kinases TBK-1 and IKKvarepsilon. Activation of the nuclear factor kappaB (NF-kappaB) and interferon regulatory factor (IRF) transcription factor pathways are essential immediate early steps of immune activation; as a result, both pathways represent prime candidates for viral interference. Many viruses have developed strategies to manipulate NF-kappaB signaling through the use of multifunctional viral proteins that target the host innate immune response pathways. This review discusses three rapidly evolving areas of research on viral pathogenesis: the recognition and signaling in response to virus infection through TLR-dependent and -independent mechanisms, the involvement of NF-kappaB in the host innate immune response and the multitude of strategies used by different viruses to short circuit the NF-kappaB pathway.
... Several groups have analyzed the potential for cross-reactive epitopes, both at the Ab level (between different types of N1) and in the highly conserved internal gene segments. This work constitutes the basis for the recent sugges-tion that one of the potential strategies to develop universal influenza vaccines relies on the identification of protective and cross-reactive antibodies, followed by the mapping of the epitopes recognized by such antibodies (30). ...
The Immune Epitope Database and Analysis Resources (IEDB) (www.immuneepitope.org) was recently developed to capture epitope related data. IEDB also hosts various bioinformatics tools that can be used to identify novel epitopes as well as to analyze and visualize existing epitope data. Herein, a comprehensive analysis was undertaken (i) to compile and inventory existing knowledge regarding influenza A epitopes and (ii) to determine possible cross-reactivities of identified epitopes among avian H5N1 and human influenza strains. At present, IEDB contains >600 different epitopes derived from 58 different strains and 10 influenza A proteins. By using the IEDB analysis resources, conservancy analyses were performed, and several conserved and possibly cross-reactive epitopes were identified. Significant gaps in the current knowledge were also revealed, including paucity of Ab epitopes in comparison with T cell epitopes, limited number of epitopes reported for avian influenza strains/subtypes, and limited number of epitopes reported from proteins other than hemagglutinin and nucleoprotein. This analysis provides a resource for researchers to access existing influenza epitope data. At the same time, the analysis illustrates gaps in our collective knowledge that should inspire directions for further study of immunity against the influenza A virus.
• B lymphocytes
• T lymphocytes
• conservancy
• pandemic cross-reactivity
... Most transmissions of whole avian influenza viruses from birds to humans do not result in sustained circulation in the human population. However, adaptation to humans may occur and result in an influenza pandemic followed by the establishment of a new lineage of human viruses, as was the case in 1918 (Palese et al., 2006). Since 1997, highly pathogenic avian influenza A viruses of the H5N1 subtype that have been circulating in South-East Asia, and spread more recently to the Middle-East, Eastern ...
The transcription/replication activity of ribonucleoproteins derived from influenza A primary isolates of human (A/Paris/908/97) or avian origin (A/Mallard/Marquenterre/MZ237/83, A/Hong Kong/156/97) was compared upon reconstitution in mammalian or avian cells, using viral-like reporter RNAs synthesized under the control of the human and chicken RNA polymerase I promoters, respectively. In avian cells, transcription/replication activities were in the same range with all ribonucleoproteins tested. In human cells, ribonucleoproteins derived from A/Mallard/Marquenterre/MZ237/83 showed reduced transcription/replication activity and reduced NP binding to the PB1-PB2-PA complex (P) or to the isolated PB2 subunit, as compared to the ribonucleoproteins derived from A/Paris/908/97. Both defects were restored when PB2 residue Glu-627 was changed to a Lys. Ribonucleoproteins derived from the human A/Hong Kong/156/97 H5N1 isolate showed efficient NP-P interaction in human cells, and high levels of activity which were determined mostly by the PB2 and PA proteins. Our data suggest that PB2 might play a pivotal role in molecular interactions involving both the viral nucleoprotein and cellular proteins.
Animal models are essential for studying disease pathogenesis and to test the efficacy and safety of new vaccines and therapeutics. For most diseases, there is no single model that can recapitulate all features of the human condition, so it is vital to understand the advantages and disadvantages of each. The purpose of this review is to describe popular comparative animal models, including mice, ferrets, hamsters, and non-human primates (NHPs), that are being used to study clinical and pathological changes caused by influenza A virus infection with the aim to aid in appropriate model selection for disease modeling.
Influenza infections continue to be a global threat. This chapter provides a current overall view of the influenza infection pathogenesis, historical landmarks with pandemic events, features of the viral particle – the virion – and treatment regimes with neuraminidase inhibitors. In addition, treatment optimization schemes are introduced integrating host infection modeling, drug dynamics under the PK/PD approach, and control-based methods. Combining inverse optimal and impulsive control, the chapter hypothesizes schemes of dose tailoring towards personalized treatment, where the dose dynamically adapts according to the viral load evolution. The proposed control-based treatment is compared with the current fixed-dose framework in terms of treatment efficacy and reduction of the total amount of drug. The chapter closes by highlighting the implications of the control-based schemes not only to tackle influenza infections but also to combat similar acute infectious diseases such as COVID-19.
Several mathematical models in SARS-CoV-2 have shown how the target cell model can help to understand the spread of the virus in the host and how potential antiviral treatments can help to control the virus. Concepts as equilibrium and stability have shown to be crucial to qualitatively determine the best alternatives to schedule drugs, based on their effectiveness in reducing the viral infection and replication rates. Important biological events such as rebounds of the infections (when antivirals are incorrectly interrupted) can also be explained by means of a dynamic study of the target cell model. In this work a full characterization of the dynamical behavior of the target cell models under control actions is given and, based on this characterization, the optimal fixed-dose antiviral schedule that produces the smallest amount of dead cells (without viral load rebounds) is computed. The results of several simulations – performed by considering real patient data – show the potential benefits of both the model characterization and the control strategy.
The influenza virus mutates and spreads rapidly, making it suitable for studying evolutionary and ecological processes. The ecological factors and processes by which different lineages of influenza compete or coexist within hosts through time and across geographical space are poorly known. We hypothesized that competition would be stronger for influenza viruses infecting the same host compared to different hosts (the Host Barrier Hypothesis), and for those with a higher cross-region transmission intensity (the Geographic Barrier Hypothesis). Using available sequences of the influenza A (H1N1) virus in GenBank, we identified six lineages, twelve clades, and several replacement events. We found that human-hosted lineages had a higher cross-region transmission intensity than swine-hosted lineages. Co-occurrence probabilities of lineages infecting the same host were lower than those infecting different hosts, and human-hosted lineages had lower co-occurrence probabilities and genetic diversity than swine-hosted lineages. These results show that H1N1 lineages infecting the same host or with high cross-region transmission rates experienced stronger competition and extinction pressures than those infecting different hosts or with low cross-region transmission. Our study highlights how host and geographic barriers shape the competition, extinction, and coexistence patterns of H1N1 lineages and clades. K E Y W O R D S coexistence, competition, geographic barrier, host barrier, influenza A virus, interspecific transmission
Influenza is an infectious respiratory disease that, in humans, is caused by influenza A and influenza B viruses. Typically characterized by annual seasonal epidemics, sporadic pandemic outbreaks involve influenza A virus strains of zoonotic origin. The WHO estimates that annual epidemics of influenza result in 1 billion infections, 3-5 million cases of severe illness and 300,000-500,000 deaths. The severity of pandemic influenza depends on multiple factors, including the virulence of the pandemic virus strain and the level of pre-existing immunity. The most severe influenza pandemic, in 1918, resulted in >40 million deaths worldwide. Influenza vaccines are formulated every year to match the circulating strains, as they evolve antigenically owing to antigenic drift. Nevertheless, vaccine efficacy is not optimal and is dramatically low in the case of an antigenic mismatch between the vaccine and the circulating virus strain. Antiviral agents that target the influenza virus enzyme neuraminidase have been developed for prophylaxis and therapy. However, the use of these antivirals is still limited. Emerging approaches to combat influenza include the development of universal influenza virus vaccines that provide protection against antigenically distant influenza viruses, but these vaccines need to be tested in clinical trials to ascertain their effectiveness.
Influenza viruses are among the most common causes of human respiratory infections [1], and among the most significant because they cause high morbidity and mortality. Influenza outbreaks have apparently occurred since at least the Middle Ages, if not since ancient times [2]. In the elderly, in infants, and in people with chronic diseases, influenza is associated with especially high mortality. In the United States, influenza results in approximately 200,000 hospitalizations and 36,000 deaths in a typical endemic season [3]. In addition to annual winter outbreaks, pandemic influenza viruses occasionally emerge [4,5], as they have every eight to 41 years, for at least several centuries. Up to 50% of the population can be infected in a single pandemic year, and the number of deaths caused by influenza can dramatically exceed what is normally expected [6].
The ’Spanish’ influenza pandemic of 1918-1919 was the most severe in recorded history, affecting approximately 25% of the world’s population and killing in the order of 50 million people. Subsequent influenza pandemics of the 20th century have been less severe. An understanding of the mechanisms underlying the severity of the 1918 pandemic could potentially help to reduce the extent of future pandemics. To this end, the entire 1918 virus and viruses bearing combinations of 1918 genes have been reconstructed through reverse genetics techniques. The availability of a viable 1918 strain has enabled researchers to investigate the viral and host factors underlying the extreme pathogenicity of the 1918 virus. These studies and others have revealed many features regarding the unusual epidemiology, pathogenicity, replication and transmission of the 1918 virus, and aid us in predicting the severity of future pandemic outbreaks.
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Viral diseases are important threats to public health worldwide. With the number of emerging viral diseases increasing the last decades, there is a growing need for appropriate animal models for virus studies. The relevance of animal models can be limited in terms of mimicking human pathophysiology. In this review, we discuss the utility of animal models for studies of influenza A viruses, HIV and SARS-CoV in light of viral emergence, assessment of infection and transmission risks, and regulatory decision making. We address their relevance and limitations. The susceptibility, immune responses, pathogenesis, and pharmacokinetics may differ between the various animal models. These complexities may thwart translating results from animal experiments to the humans. Within these constraints, animal models are very informative for studying virus immunopathology and transmission modes and for translation of virus research into clinical benefit. Insight in the limitations of the various models may facilitate further improvements of the models.
Bionanocomposites resulting from the assembly of negatively charged polysaccharides (xanthan gum) and sepiolite at the nanometer scale are able to associate efficiently to influenza-virus particles. This produces stable dispersions suitable as effective intranasal or intramuscular flu vaccines, as confirmed from experiments carried out in mice.
Inuit children in Nunavut, Canada, have high rates of lower respiratory tract infection (LRTI) early in life. Whether this commonly results in chronic respiratory symptoms later in life is unknown.
A cross-sectional survey of 3- to 5-years-old Inuit children was conducted in all three regions of Nunavut, as part of the "Qanuippitali, what about us, how are we?" survey.
Reported chronic cough and wheezing were common in preschool Inuit children, although reported asthma diagnosed by a healthcare professional was uncommon. The presence of smokers in the home tended to be associated with severe LRTI in the first 2 years of life. Reported wheezing as well as reported bronchitis or pneumonia in the previous 12 months was significantly associated with severe LRTI in the first 2 years of life. Reported wheezing was also strongly associated with reported bronchitis or pneumonia in the past 12 months. The prevalence of chronic moist cough could not be clearly assessed, due to limitations in the questionnaire.
Severe LRTI in the first 2 years of life was associated with ongoing respiratory morbidity in preschool Inuit children, although symptoms appeared to lessen in severity over time.
Humoral virus neutralizing activity is crucial in preventing influenza virus infection. However, the influenza neutralizing activity in the general population remains unclear.
In this study we performed a serological survey of 200 blood donors from Guangzhou, China. Using a microneutralization (MN) assay, neutralizing activities against influenza A 2009 H1N1, H3N2 and H5N1 were measured. Anti-haemagglutinin antibody was assayed by haemagglutination inhibition (HI) test. Also, antibodies against M1 and M2 matrix proteins were measured using an enzyme-linked immunosorbent assay (ELISA).
By MN assay, 86% of the individuals showed neutralizing activity against H3N2, 11% against 2009 H1N1, and none against H5N1. The positive rate for H3N2 increased as the age of individuals increased. Interestingly, males displayed a 4 times higher positive rate against 2009 H1N1 than females. The results of ELISA revealed that 97.5% of the individuals had positive M1 titres and 21% had positive M2 titres. Furthermore, anti-haemagglutinin antibody had a much higher correlation with the neutralization activity than anti-M1 and anti-M2 antibodies.
Neutralizing activities against H5N1 and 2009 H1N1 were low in the general population. Therefore, public health agencies should design strategies for preventing potential H5N1 and 2009 H1N1 pandemics.
Drugs with relatively short elimination half-lives typically require more-frequent daily dosing to avoid large peak-to-trough concentration variation. Conversely, drugs with long elimination half-lives generally require less-frequent dosing because plasma concentration variations between doses are smaller. The pharmacokinetic comparison of memantine 20 mg one daily and 10 mg twice daily demonstrates that peak-to-trough fluctuations with once-daily dosing regimens is similar to twice-daily dosing. Therefore, it is expected that the efficacy and adverse effect profile would be comparable between these dosing schemes. Recent clinical studies in which the safety and tolerability of once-daily dosing has been shown to be comparable with that of twice daily dosing support the results of the analysis. 4–7 Recent clinical trials also suggest that an extended-release once-daily formulation is well tolerated and effective for the treatment of moderate to severe Alzheimer's disease. 8–10 Based on the current pharmacokinetic analysis, a single conventional-release 20-mg dose (two 10-mg tablets) may offer the same daily convenience as a single extended-release formulation and with similar tolerability as 10 mg taken twice daily.
In Anbetracht des Potenzials von Influenza-A-Viren, saisonale Epidemien und verheerende Pandemien in der menschlichen Bevölkerung auszulösen, besteht großes Interesse, die Virulenz vermittelnden Mechanismen dieser Viren zu verstehen. In dieser Arbeit wurden wichtige Virulenzfaktoren von Influenza-A-Viren untersucht, das Hämagglutinin (HA) und die virale Polymerase. Diese waren in vorherigen Studien als entscheidende Virulenz bestimmende Faktoren des Influenza A/Puerto Rico/8/34 H1N1-Virus (hvPR8) identifiziert worden, welches eine außergewöhnlich hohe Virulenz in Mäusen besitzt. Es wurde angenommen, dass das Oberflächenprotein HA von hvPR8 für ein effizientes Eindringen des Virus in die Zelle essentiell ist, und dass daraufhin die virale Polymerase bestehend aus den Untereinheiten PB2, PB1 und PA ihren Virulenz fördernden Effekt ausüben kann. In dieser Arbeit wurde gezeigt, dass Valin an Position 504 in PB2 und Leucin an Position 550 in PA die entscheidenden Aminosäuren darstellen, welche die Virulenz und Polymeraseaktivität erhöhen. Die Herstellung neuer, hochvirulenter PR8-Viren in der Maus bewies, dass auch andere Aminosäuren der Polymerase, wie Glycin an Position 349 in PA und Arginin an Position 208 in PB1, hohe Virulenz und eine gesteigerte Polymeraseaktivität vermitteln können.
Es wurden weitere Hinweise gewonnen, dass HA für ein effizientes Eindringen von hvPR8 in Wirtszellen verantwortlich ist. Da die Rezeptorbindung und Fusionsaktivität von HA hierbei eine Rolle spielen könnten, wurde hvPR8 diesbezüglich im Vergleich zu einem niedrigvirulenten Standard-PR8-Virus (lvPR8) untersucht. Hinsichtlich der Rezeptorbindung zeigte sich, dass HA von hvPR8 eine höhere Affinität für alpha 2,6-verknüpfte Sialinsäure (SA) und eine geringere Affinität für alpha 2,3-verknüpfte SA als HA von lvPR8 besitzt. Aufgrund dieser Eigenschaften könnte hvPR8 seine Zielzellen besonders effizient infizieren und/oder einen von lvPR8 verschiedenen Zelltropsimus besitzen. Letzteres scheint im Alveolargewebe der Mauslunge nicht der Fall zu sein, da für beide Viren ein Tropismus für Typ II-Pneumozyten festgestellt wurde. Weiterhin zeigte sich, dass HA von hvPR8 bei höheren pH-Werten fusionsaktiv ist als HA von lvPR8. Dies könnte hvPR8 ermöglichen, während des Absinkens des pH-Wertes im zellulären Endosom schneller ins Zytoplasma zu gelangen und einem lysosomalen Abbau zu entgehen. Durch die Analyse von Viren mit mutiertem HA wurden für die Virulenz sowie Rezeptorbindung oder Fusion kritische Aminosäuren im HA von hvPR8 identifiziert. Diese Analyse deutet darauf hin, dass eine günstige Rezeptorbindung in Kombination mit der Fusionsaktivität bei höheren pH-Werten im Endosom das effiziente Eindringen von hvPR8 vermitteln und damit dem Virus einen Replikationsvorteil verschaffen.
Ten years ago, somewhere during January 1999, half of a bucket of transformer mineral oil found its way into the Belgian food chain. A couple of months later, the ingestion of off-odor soft drinks landed a dozen school children in a hospital. Against the background of major police and judicial dysfunction in a highly mediatized pedophile case, both of these incidents triggered the famous “Dioxin and Coca-Cola Crisis ” which turned the tiny kingdom of Belgium upside down. There was a nationwide recall of all Coca-Cola products. Worldwide, imports of Belgian meat and dairy products were suspended, with a direct economic cost of 800 million euro. Ministers resigned, careers were broken, the “eternal ” Christian-Democratic governemental parties were removed from power—all of this without a single medical casualty. Thus, we learned that when there is a widespread perception of a major health risk for a community, minor incidents or major non-events can turn into a public health crisis.This is true, especially when there is inadequate information or scientific uncertainty about the causes, nature, or dimensions of (unusual)
Authors who examine the Influenza Pandemic of 1918-19 fail to grasp its full context. Placing it alongside the Great War or other diseases only provides a partial construction, dramatically altering the narrative. With these limitations authors make it an exceptional example and model for future influenza pandemics. A full context involves incorporating the Great War and the Influenza Pandemic of 1889-92. Solely examining England demonstrates the unique experience of one country. Presenting the entire context is vital to comprehending how the public, medical professionals, and government officials perceived and reacted to the flu in the entire period 1889-1919. This examination shows that the pandemic of 1918-19 was the extreme, and that there are other courses for flu pandemics. It argues that, despite increased mortality, in 1918-19 the general public were not dramatically altered by the event. This illuminates it in an entirely different manner for all involved.
The recent incidence and spread in humans of the 'swine flu' influenza A virus has raised global concerns regarding its virulence and pandemic potential. The main cause of the so-called swine flu has been identified as human infection by influenza A viruses of a new H1N1 (hemagglutinin 1, neuraminidase 1) subtype, or '2009 H1N1 strain'.
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.
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.
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.
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.
The Impact of Event Scale Revised (IES-R) has been used in various epidemiological studies to assess the prevalence of post-traumatic stress disorder (PTSD). Previous studies using the IES-R Japanese version to assess the mental health of firefighters were based on the premise that firefighters had experienced a traumatic event(s) as a matter of course. However, use of the IES-R-J does not indicate whether or not a traumatic event was experienced. The purpose of this study is to clarify the differences between: (1) IES-R-J high and low score groups; and (2) those who report symptoms similar to those of PTSD with and without having been being exposed to a traumatic event.
Questionnaire packets distributed to all 157 workers in a Japanese fire station included the IES-R, the Japan Brief Job Stress Questionnaire, a questionnaire regarding traumatic event experiences, and demographic questions. Participants who scored > or = 25 points on the IES-R-J scale were defined as the PTSD high risk (HR) group; those with scores < 25 points as the PTSD low risk (LR) group.
One hundred thirty-one of the 157 subjects (83.4%) responded to the questionnaire; three were excluded from the analysis because of missing data. The mean total IES-R-J score was 14.9 +/- 15.2. Twenty-eight subjects scored in the PTSD HR group (> or = 25); 100 scored in the LR group (< 25). A total of 54 (42.2%) participants had experienced a traumatic event; 57.8% had not. In the HR group, 14 subjects had experienced a traumatic event and 14 had not. Participants who had experienced a traumatic event reported a higher incidence of intrusion/re-experience symptoms than did those who had not experienced a traumatic event. The level of social support significantly affected the risk for PTSD. Firefighters who scored > or = 25 on the IES-R-J and, thus, considered to be at high risk for the development of PTSD, were less confident about their health, experienced more job stressors and had less social support than did those whose IES-R-J scores were < 25. Having experienced a traumatic event was reported by only 42% of all the participants and by only 50% of those in the high risk PTSD group.
Although the IES-R is an easily-administered tool useful in epidemiological studies evaluating psychological stress, it is recommended that the questionnaire be amended to include a question regarding the existence of a threatened experience or event and to analyze the data using positive and negative predictive value methodology.
The influenza pandemic of 1918 killed nearly 50 million people worldwide and was characterized by an atypical W-shaped mortality curve, where adults between the ages of 30-60 years fared better than younger adults aged 18-30 years. In this review, we will discuss why this influenza virus strain was so virulent and how immunological memory to the 1918 virus may have shaped the W mortality curve. We will end on the topic of the 'honeymoon' period of infectious diseases--the clinically documented period between the ages of 4-13 years during which children demonstrate less morbidity and/or mortality to infectious diseases, in general, compared with young adults.
Recent and ongoing zoonotic infections of humans with avian influenza viruses have highlighted the importance of transmission in the development of an influenza pandemic. Despite the ability of H5N1 influenza viruses to grow to high titers and cause severe disease in human hosts, these viruses do not spread efficiently from human-to-human. The question of what viral, host and environmental factors are required to render an influenza virus transmissible has therefore become very topical. Recent work in the ferret model has suggested that receptor binding specificity is an important factor, but that the trait of human-like receptor recognition alone is not sufficient to confer a transmissible phenotype. In addition to the ferret, the guinea pig has been identified as a useful model host for transmission studies. Further research using these models is needed, toward understanding the molecular circumstances under which transmission can occur. A crucial role of antiviral drugs in mitigating an influenza pandemic will be to slow the spread of infection while an appropriate vaccine is in production. The efficacy of antivirals in preventing transmission is therefore of great importance. While the adamantanes, amantadine and rimantadine, have been found to fail in this respect due to the high transmissibility of drug resistant variants, the neuraminidase inhibitors, oseltamivir and zanamivir, show more promise. Anti-influenza drugs in development which show efficacy in terms of mitigating disease or viral growth should also be tested for their potential to block transmission.
The influenza A virus pandemic of 1918–1919 resulted in an
estimated 20–40 million deaths worldwide. The hemagglutinin and
neuraminidase sequences of the 1918 virus were previously determined.
We here report the sequence of the A/Brevig Mission/1/18 (H1N1)
virus nonstructural (NS) segment encoding two proteins, NS1 and nuclear
export protein. Phylogenetically, these genes appear to be close to the
common ancestor of subsequent human and classical swine strain NS
genes. Recently, the influenza A virus NS1 protein was shown to be a
type I IFN antagonist that plays an important role in viral
pathogenesis. By using the recently developed technique of generating
influenza A viruses entirely from cloned cDNAs, the hypothesis that the
1918 virus NS1 gene played a role in virulence was tested in a mouse
model. In a BSL3+ laboratory, viruses were generated that possessed
either the 1918 NS1 gene alone or the entire 1918 NS segment in a
background of influenza A/WSN/33 (H1N1), a mouse-adapted virus
derived from a human influenza strain first isolated in 1933. These
1918 NS viruses replicated well in tissue culture but were attenuated
in mice as compared with the isogenic control viruses. This attenuation
in mice may be related to the human origin of the 1918 NS1 gene. These
results suggest that interaction of the NS1 protein with host-cell
factors plays a significant role in viral pathogenesis.
The NS1 protein is the only nonstructural protein encoded by influenza A virus. It has been proposed that the NS1 performs several regulatory functions during the viral replication cycle, including the regulation of synthesis, transport, splicing, and translation of mRNAs. Through the use of reverse genetics, a viable transfectant influenza A virus (delNS1) which lacks the NS1 gene has been generated. Our results indicate that the NS1 of influenza A virus is an auxiliary (virulence) factor which plays a crucial role in inhibiting interferon-mediated antiviral responses of the host.
We describe a new reverse-genetics system that allows one to efficiently generate influenza A viruses entirely from cloned cDNAs. Human embryonic kidney cells (293T) were transfected with eight plasmids, each encoding a viral RNA of the A/WSN/33 (H1N1) or A/PR/8/34 (H1N1) virus, flanked by the human RNA polymerase I promoter and the mouse RNA polymerase I terminator-together with plasmids encoding viral nucleoprotein and the PB2, PB1, and PA viral polymerases. This strategy yielded >1 x 10(3) plaque-forming units (pfu) of virus per ml of supernatant at 48 hr posttransfection. The addition of plasmids expressing all of the remaining viral structural proteins led to a substantial increase in virus production, 3 x 10(4)-5 x 10(7) pfu/ml. We also used reverse genetics to generate a reassortant virus containing the PB1 gene of the A/PR/8/34 virus, with all other genes representing A/WSN/33. Additional viruses produced by this method had mutations in the PA gene or possessed a foreign epitope in the head of the neuraminidase protein. This efficient system, which does not require helper virus infection, should be useful in viral mutagenesis studies and in the production of vaccines and gene therapy vectors.
The influenza pandemic of 1918-20 is recognized as having generally taken place in three waves, starting in the northern spring and summer of 1918. This pattern of three waves, however, was not universal: in some locations influenza seems to have persisted into or returned in 1920. The recorded statistics of influenza morbidity and mortality are likely to be a significant understatement. Limitations of these data can include nonregistration, missing records, misdiagnosis, and nonmedical certification, and may also vary greatly between locations. Further research has seen the consistent upward revision of the estimated global mortality of the pandemic, which a 1920s calculation put in the vicinity of 21.5 million. A 1991 paper revised the mortality as being in the range 24.7-39.3 million. This paper suggests that it was of the order of 50 million. However, it must be acknowledged that even this vast figure may be substantially lower than the real toll, perhaps as much as 100 percent understated.
The 1918 influenza pandemic caused more than 20 million deaths worldwide. Thus, the potential impact of a re-emergent 1918 or 1918-like influenza virus, whether through natural means or as a result of bioterrorism, is of significant concern. The genetic determinants of the virulence of the 1918 virus have not been defined yet, nor have specific clinical prophylaxis and/or treatment interventions that would be effective against a re-emergent 1918 or 1918-like virus been identified. Based on the reported nucleotide sequences, we have reconstructed the hemagglutinin (HA), neuraminidase (NA), and matrix (M) genes of the 1918 virus. Under biosafety level 3 (agricultural) conditions, we have generated recombinant influenza viruses bearing the 1918 HA, NA, or M segments. Strikingly, recombinant viruses possessing both the 1918 HA and 1918 NA were virulent in mice. In contrast, a control virus with the HA and NA from a more recent human isolate was unable to kill mice at any dose tested. The recombinant viruses were also tested for their sensitivity to U.S. Food and Drug Administration-approved antiinfluenza virus drugs in vitro and in vivo. Recombinant viruses possessing the 1918 NA or both the 1918 HA and 1918 NA were inhibited effectively in both tissue culture and mice by the NA inhibitors, zanamivir and oseltamivir. A recombinant virus possessing the 1918 M segment was inhibited effectively both in tissue culture and in vivo by the M2 ion-channel inhibitors amantadine and rimantadine. These data suggest that current antiviral strategies would be effective in curbing the dangers of a re-emergent 1918 or 1918-like virus.
The 'Spanish' influenza pandemic of 1918-19 was the most devastating outbreak of infectious disease in recorded history. At least 20 million people died from their illness, which was characterized by an unusually severe and rapid clinical course. The complete sequencing of several genes of the 1918 influenza virus has made it possible to study the functions of the proteins encoded by these genes in viruses generated by reverse genetics, a technique that permits the generation of infectious viruses entirely from cloned complementary DNA. Thus, to identify properties of the 1918 pandemic influenza A strain that might be related to its extraordinary virulence, viruses were produced containing the viral haemagglutinin (HA) and neuraminidase (NA) genes of the 1918 strain. The HA of this strain supports the pathogenicity of a mouse-adapted virus in this animal. Here we demonstrate that the HA of the 1918 virus confers enhanced pathogenicity in mice to recent human viruses that are otherwise non-pathogenic in this host. Moreover, these highly virulent recombinant viruses expressing the 1918 viral HA could infect the entire lung and induce high levels of macrophage-derived chemokines and cytokines, which resulted in infiltration of inflammatory cells and severe haemorrhage, hallmarks of the illness produced during the original pandemic.
In wild aquatic birds and poultry around the world, influenza A viruses carrying 15 antigenic subtypes of hemagglutinin (HA) and 9 antigenic subtypes of neuraminidase (NA) have been described. Here we describe a previously unidentified antigenic subtype of HA (H16), detected in viruses circulating in black-headed gulls in Sweden. In agreement with established criteria for the definition of antigenic subtypes, hemagglutination inhibition assays and immunodiffusion assays failed to detect specific reactivity between H16 and the previously described subtypes H1 to H15. Genetically, H16 HA was found to be distantly related to H13 HA, a subtype also detected exclusively in shorebirds, and the amino acid composition of the putative receptor-binding site of H13 and H16 HAs was found to be distinct from that in HA subtypes circulating in ducks and geese. The H16 viruses contained NA genes that were similar to those of other Eurasian shorebirds but genetically distinct from N3 genes detected in other birds and geographical locations. The European gull viruses were further distinguishable from other influenza A viruses based on their PB2, NP, and NS genes. Gaining information on the full spectrum of avian influenza A viruses and creating reagents for their detection and identification will remain an important task for influenza surveillance, outbreak control, and animal and public health. We propose that sequence analyses of HA and NA genes of influenza A viruses be used for the rapid identification of existing and novel HA and NA subtypes.
The influenza A viral heterotrimeric polymerase complex (PA, PB1, PB2) is known to be involved in many aspects of viral replication and to interact with host factors, thereby having a role in host specificity. The polymerase protein sequences from the 1918 human influenza virus differ from avian consensus sequences at only a small number of amino acids, consistent with the hypothesis that they were derived from an avian source shortly before the pandemic. However, when compared to avian sequences, the nucleotide sequences of the 1918 polymerase genes have more synonymous differences than expected, suggesting evolutionary distance from known avian strains. Here we present sequence and phylogenetic analyses of the complete genome of the 1918 influenza virus, and propose that the 1918 virus was not a reassortant virus (like those of the 1957 and 1968 pandemics), but more likely an entirely avian-like virus that adapted to humans. These data support prior phylogenetic studies suggesting that the 1918 virus was derived from an avian source. A total of ten amino acid changes in the polymerase proteins consistently differentiate the 1918 and subsequent human influenza virus sequences from avian virus sequences. Notably, a number of the same changes have been found in recently circulating, highly pathogenic H5N1 viruses that have caused illness and death in humans and are feared to be the precursors of a new influenza pandemic. The sequence changes identified here may be important in the adaptation of influenza viruses to humans.
The pandemic influenza virus of 1918–1919 killed an estimated 20 to 50 million people worldwide. With the recent availability
of the complete 1918 influenza virus coding sequence, we used reverse genetics to generate an influenza virus bearing all
eight gene segments of the pandemic virus to study the properties associated with its extraordinary virulence. In stark contrast
to contemporary human influenza H1N1 viruses, the 1918 pandemic virus had the ability to replicate in the absence of trypsin,
caused death in mice and embryonated chicken eggs, and displayed a high-growth phenotype in human bronchial epithelial cells.
Moreover, the coordinated expression of the 1918 virus genes most certainly confers the unique high-virulence phenotype observed
with this pandemic virus.
The persistence of H5N1 avian influenza viruses in many Asian countries and their ability to cause fatal infections in humans have raised serious concerns about a global flu pandemic. Here we report the isolation of an H5N1 virus from a Vietnamese girl that is resistant to the drug oseltamivir, which is an inhibitor of the viral enzyme neuraminidase and is currently used for protection against and treatment of influenza. Further investigation is necessary to determine the prevalence of oseltamivir-resistant H5N1 viruses among patients treated with this drug.
We sequenced 28 million base pairs of DNA in a metagenomics approach, using a woolly mammoth (Mammuthus primigenius) sample
from Siberia. As a result of exceptional sample preservation and the use of a recently developed emulsion polymerase chain
reaction and pyrosequencing technique, 13 million base pairs (45.4%) of the sequencing reads were identified as mammoth DNA.
Sequence identity between our data and African elephant (Loxodonta africana) was 98.55%, consistent with a paleontologically
based divergence date of 5 to 6 million years. The sample includes a surprisingly small diversity of environmental DNAs. The
high percentage of endogenous DNA recoverable from this single mammoth would allow for completion of its genome, unleashing
the field of paleogenomics.
Influenza A (H5N1) virus with an amino acid substitution in neuraminidase conferring high-level resistance to oseltamivir was isolated from two of eight Vietnamese patients during oseltamivir treatment. Both patients died of influenza A (H5N1) virus infection, despite early initiation of treatment in one patient. Surviving patients had rapid declines in the viral load to undetectable levels during treatment. These observations suggest that resistance can emerge during the currently recommended regimen of oseltamivir therapy and may be associated with clinical deterioration and that the strategy for the treatment of influenza A (H5N1) virus infection should include additional antiviral agents.
The threat of a human influenza pandemic has greatly increased over the past several years with the emergence of highly virulent avian influenza viruses, notably H5N1 viruses, which have infected humans in several Asian and European countries. Previous influenza pandemics have arrived with little or no warning, but the current widespread circulation of H5N1 viruses among avian populations and their potential for increased transmission to humans and other mammalian species may afford us an unprecedented opportunity to prepare for the next pandemic threat. The US Department of Health and Human Services is coordinating a national strategy to respond to an influenza pandemic that involves multiple agencies, including the Centers for Disease Control and Prevention, the Food and Drug Administration, and the National Institutes of Health (NIH). Within NIH, the National Institute of Allergy and Infectious Diseases (NIAID) conducts basic and clinical research to develop new vaccine technologies and antiviral drugs against influenza viruses. We describe recent research progress in preparing for pandemic influenza.
The 1918 influenza A H1N1 virus caused the worst pandemic of influenza ever recorded. To better understand the pathogenesis and immunity to the 1918 pandemic virus, we generated recombinant influenza viruses possessing two to five genes of the 1918 influenza virus. Recombinant influenza viruses possessing the hemagglutinin (HA), neuraminidase (NA), matrix (M), nonstructural (NS), and nucleoprotein (NP) genes or any recombinant virus possessing both the HA and NA genes of the 1918 influenza virus were highly lethal for mice. Antigenic analysis by hemagglutination inhibition (HI) tests with ferret and chicken H1N1 antisera demonstrated that the 1918 recombinant viruses antigenically most resembled A/Swine/Iowa/30 (Sw/Iowa/30) virus but differed from H1N1 viruses isolated since 1930. HI and virus neutralizing (VN) antibodies to 1918 recombinant and Sw/Iowa/30 viruses in human sera were present among individuals born before or shortly after the 1918 pandemic. Mice that received an intramuscular immunization of the homologous or Sw/Iowa/30-inactivated vaccine developed HI and VN antibodies to the 1918 recombinant virus and were completely protected against lethal challenge. Mice that received A/PR/8/34, A/Texas/36/91, or A/New Caledonia/20/99 H1N1 vaccines displayed partial protection from lethal challenge. In contrast, control-vaccinated mice were not protected against lethal challenge and displayed high virus titers in respiratory tissues. Partial vaccine protection mediated by baculovirus-expressed recombinant HA vaccines suggest common cross-reactive epitopes on the H1 HA. These data suggest a strategy of vaccination that would be effective against a reemergent 1918 or 1918-like virus.
Comparison of the oligonucleotide maps of the RNAs of current human influenza (H1N1) virus isolates shows these strains to be much more closely related to viruses isolated in 1950 than to strains which circulated before or after that period.
A system is described that allows use of recombinant DNA technology to modify the genome of influenza virus, a negative-strand RNA virus, and to engineer vectors for the expression of foreign genes. Recombinant RNA is expressed from plasmid DNA in which the coding sequence of the influenza A virus NS gene is replaced with that of the chloramphenicol acetyltransferase gene. When transfected with purified influenza A virus polymerase proteins--in the presence of helper virus--the recombinant RNA is amplified, expressed, and packaged into virus particles, which can be passaged several times. The data indicate that the 22 5' terminal and the 26 3' terminal bases of the influenza A virus RNA are sufficient to provide the signals for RNA transcription, RNA replication, packaging of RNA into influenza virus particles.
Analyses of the complex regulatory networks leading to T cell survival, death, and immune deficiency have been aided in the past year by the dramatic development of new technologies to identify T cells and assess T cell function. These new techniques have shown that functional inactivation and apoptotic elimination of both virus-specific and non-virus-specific T cell populations mold T cell responses to viral infections.
We have rescued influenza A virus by transfection of 12 plasmids into Vero cells. The eight individual negative-sense genomic viral RNAs were transcribed from plasmids containing human RNA polymerase I promoter and hepatitis delta virus ribozyme sequences. The three influenza virus polymerase proteins and the nucleoprotein were expressed from protein expression plasmids. This plasmid-based reverse genetics technique facilitates the generation of recombinant influenza viruses containing specific mutations in their genes.
Current textbooks link influenza pandemics to influenza A virus subtypes H2 (1889-91), H3 (1990), H1 (1918-20), H2 (1957-58) and H3 (1968), a pattern suggesting subtype recycling in humans. Since H1 reappeared in 1977, whatever its origin, some workers feel that H2 is the next pandemic candidate. This report reviews the publications on which the concept of influenza A virus subtype recycling is based and concludes that the data are inconsistent with the purported sequence of events. The three influenza pandemics prior to 1957-58 were linked with subtypes through retrospective studies of sera from the elderly, or through seroarchaeology. The pandemic seroarchaeological model for subtype H1 has been validated by the recent recovery of swine virus RNA fragments from persons who died from influenza in 1918. Application of the model to pre-existing H3 antibody among the elderly links the H3 subtype to the pandemic of 1889-91, not that of 1900 as popularly quoted. Application of the model to pre-existing H2 antibody among the elderly fails to confirm that this subtype caused a pandemic in the late 1800's, a finding which is consistent with age-related excess mortality patterns during the pandemics of 1957 (H2) and 1968 (H3). H2 variants should be included in pandemic planning for a number of reasons, but not because of evidence of recycling. It is not known when the next pandemic will occur or which of the 15 (or more) haemagglutinin subtypes will be involved. Effective global surveillance remains the key to influenza preparedness.
Advances in immunology and molecular genetics have accelerated our understanding of the genetic and cellular basis of many diseases. At the same time, remarkable progress in recombinant DNA technology has enabled the development of molecular and cellular treatments for infectious diseases, inherited disorders and cancer. This Perspective is intended to give a sample of the progress over the past ten years in cellular, genetic and immune therapy of disease. During this time, monoclonal antibody technology and cellular transplantation have begun to come of age in biomedicine. Innovations in gene delivery have not only catalyzed the nascent field of human gene therapy, but may also ultimately impact human health by advancing recombinant vaccine technology.
Influenza remains an important disease in humans and animals. In contrast to measles, smallpox and poliomyelitis, influenza is caused by viruses that undergo continuous antigenic change and that possess an animal reservoir. Thus, new epidemics and pandemics are likely to occur in the future, and eradication of the disease will be difficult to achieve. Although it is not clear whether a new pandemic is imminent, it would be prudent to take into account the lessons we have learned from studying different human and animal influenza viruses. Specifically, reconstruction of the genes of the 1918 pandemic virus and studies on their contribution to virulence will be important steps toward understanding the biological capabilities of this lethal virus. Increasing the availability of new antiviral drugs and developing superior vaccines will provide us with better approaches to control influenza and to have a positive impact on disease load. A concern is that the imposition of new rules for working with infectious influenza viruses under high security and high containment conditions will stifle scientific progress. The complex questions of what makes an influenza virus transmissible from one human to another and from one species to another, as well as how the immune system interacts with the virus, will require the active collaboration and unencumbered work of many scientific groups.
There is still uncertainty on the correlates of protection by influenza vaccine. To determine the relationship between hemagglutination-inhibition (HI) titer and the specificity and avidity of serum antibodies, we analyzed serum from a longitudinal trial (1983-1987) of influenza vaccine efficacy [Keitel WA, Cate TR, Couch RB, Huggins LL, Hess KR. Efficacy of repeated annual immunization with inactivated influenza virus vaccines over a five year period. Vaccine 1997;15(10):1114-22 ]. We captured native virus particles with fetuin and separately measured relative antibody levels and avidities of antibodies against native glycoproteins and antibodies against denatured viral proteins. Most subjects had pre-existing antibodies against A/Victoria/75 and, although 70% had >two-fold increased antibodies against A/Philippines/82 after vaccination, only 30% showed increased antibodies to A/Victoria/75 indicating no dominance of original antigenic sin. There was variation in the levels of antibodies to unfolded antigens compared to native, but antibodies against denatured proteins never exceeded those against native virus. In some cases, the avidity increased without a significant increase in antibody concentration, which might explain why some vaccinees with low HI titer demonstrate adequate protection. We found that the negative correlation between pre-vaccination HI titer and the increase after vaccination is also seen when antibodies are measured directly, but that there is little relationship between HI titer and antibodies against native glycoproteins, either in amount or avidity. Our assay, which has also been adapted for recent influenza viruses that do not bind to fetuin, may be useful for vaccine evaluation.
Recent studies suggest that memory T-cell differentiation continues for weeks or months following antigen clearance, although commitment to the memory lineage occurs during the effector stage of development. Several variables associated with priming, such as the duration of antigenic stimulation, degree of co-stimulation, cytokine environment, and CD4(+) T-cell help, may program epigenetic qualitative differences into the ensuing effector and memory populations. Defining what memory qualities best protect the organism from re-infection, as well as how commitment to the memory lineage is specified following T-cell activation remains an important goal.
Influenza virus: lessons learned
- Zamarin
Zamarin, D., and Palese, P. (2003). Influenza virus: lessons learned. In Eighth International Kilmer Memorial Conference, Osaka, Japan, J.B. Kowalski and R.F. Morissey, eds. (Laval, Canada: Polyscience Publications, Inc.), pp. 308–319.
Influenza: old and new threats
- Palese
Palese, P. (2004). Influenza: old and new threats. Nat. Med. 10, S82–
S87.
Recent human influenza A (H1N1) viruses are closely related genetically to strains isolated in 1950.
- Nakajima K.
- Desselberger U.
- Palese P.
Recent human influenza A (H1N1) viruses are closely related genetically to strains isolated in 1950
- Nakajima