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Protective Immunity and Susceptibility to Infectious Diseases: Lessons From the 1918 Influenza Pandemic
Abstract
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.
... The one age grouping that does very well against flu is people aged four through 13 years. Children of this age tend to stand up tough against most infections, the period in human growth when the immune system is the most robust (Ahmed et al., 2007(Ahmed et al., , p. 1188. ...
... In 1918, there was exceptional senior sparing, and the first effects of the sparing kicked in right about at age 30. This is clear in data for the USA, and it shows up wherever age-specific data is available, everywhere in the world (Ahmed et al., 2007(Ahmed et al., , pp. 1188(Ahmed et al., -1893Chowell et al., 2010, p. 571;Gagnon et al., 2013, pp. 1-2). ...
... Undaunted, others have suggested that the "Russian" flu was H3N8 or possibly H2N8, replacing the H2N2 or H3N2 (or both) that had been circulating before 1889. Others offer H3N2 as the best candidate for the 1889 pandemic (Ahmed et al., 2007(Ahmed et al., , p. 1188Dowdle, 2006, p. 37;Eyler, 2010, p. 28;Garmaroudi, 2007;Márquez Morfín & Molina del Villar, 2010, p.132;Morens & Taubenberger, 2018b, p. 1451Nguyen-Van-Tam & Hampson, 2003, p. 1762Saunders-Hastings & Krewski, 2016, p. 7;Tognotti, 2009, p. 331;Wang & Palese, 2013, p. 218;Valleron et al., 2010, p. 8778). ...
This article explores the history of influenza, focusing on the four major flu pandemics in the last century and a half, outbreaks starting in 1889, 1918, 1957, and 1968. The article looks closely at flu etiology and the historical puzzles over which flu subtype was responsible for each major outbreak. Some mysteries regarding pandemic influenza remain, with core questions stubbornly refusing to yield answers. This article seeks to explore the history of flu in the hope that we can take away some lessons learned as we try to get ready for potential future flu pandemics.
... One of the earliest examples of an infectious disease whose epidemiology suggested a protective effect of immune immaturity was the 1918 H1N1 influenza pandemic. 3,4 In most years, influenza virus infections pose the highest risk of death to the very young and the elderly. 5,6 For the very young, the increased risk has been attributed to an underdeveloped immune system that fails to control virus replication, as well as physiological differences such as smaller airways more easily compromised during respiratory infections. ...
... One explanation is that older adults had protective antibodies from previous exposures to related H1 influenza viruses that were circulating before 1889, and that these were missing in the younger adults. 3 However, this explanation cannot account for the increased mortality in younger adults, especially in males. Their participation in World War I efforts increased their exposure to the virus because of travel and contact with large numbers of infected persons. ...
... For example, the reason(s) for the decreased mortality in school-aged children even in geographically isolated, infectionnaïve populations, as occurred in Alaska during the 1918 H1N1 influenza pandemic, are unknown. 3 Similar unexplained phenomena have also been observed for other viruses, including measles, VZV (causing chickenpox), and EBV. One can speculate that these observations reflect differences in innate immunity, which are most robust in this age group and deteriorate with age. ...
Maturation of the adaptive immune response is typically thought to improve outcome to virus infections. However, long-standing observations of natural infections with old viruses such as Epstein-Barr virus and newer observations of emerging viruses such as severe acute respiratory syndrome coronavirus 2 responsible for COVID-19 suggest that immune immaturity may be beneficial for outcome. Mechanistic studies and studies of patients with inborn errors of immunity have revealed that immune dysregulation reflecting inappropriate antibody and T-cell responses plays a crucial role in causing bystander inflammation and more severe disease. Further evidence supports a role for innate immunity in normally regulating adaptive immune responses. Thus, changes in immune responses that normally occur with age may help explain an apparent protective role of immune immaturity during virus infections.
... Speci c age-related Spanish u mortality followed, instead, a W-shaped curve characterized by high mortality in infants and young children, as well as in older people, with a third peak of mortality in individuals aged 15 to 30 years. Those over the age of thirty could have been protected by pre-existing cross-immunity likely due to an H1 u virus that was in circulation in 1889 [1,5]. Regarding infant mortality, a so-called honeymoon period was recognized, as mortality rates decreased after the rst two years of life in 4-12 years old children, only to increase again in later childhood. ...
... Regarding infant mortality, a so-called honeymoon period was recognized, as mortality rates decreased after the rst two years of life in 4-12 years old children, only to increase again in later childhood. This epidemiological pattern is consistent with host-pathogen coadaptation [5,6]. ...
Background
Although it is well known that the older people have been the most susceptible to COVID-19, there areconfl icting data on the susceptibility of centenarians. Two epidemiological study have shown that oldercentenarians (> 101 years old at the time of the 2020 pandemic peak) are more resilient than the remainingcentenarians, suggesting that this resilience might be linked to the 1918 Spanish Flu pandemic. To gaininsight into this matter, specifi cally whether the resilience of older centenarians to SARS-CoV-2 infection islinked to the Spanish Flu they had been affected by, we conducted a retrospective serological study. Thisstudy examined serum samples from 33 centenarians, encompassing semi- (aged > 104 < 110 years, N = 7)and supercentenarians (aged > 109 years, N = 4), born between 1905 and 1922, against both SARS-CoV-2 and1918 H1N1 pseudotype virus.
Results
Anamnestic and laboratory data indicate that SARS-CoV-2 infection occurred in 8 centenarians. The infectionappeared to have been asymptomatic or mild, and hospitalization was not required, despite 3 out of 8 beingbetween 109 and 110 years old. The levels of anti-spike antibodies in centenarians infected and/or vaccinatedwere higher, although not signifi cantly, than those produced by a random sample of seventy-year-oldindividuals used as controls. All centenarians had antibody levels against the 1918 H1N1 virus signifi cantlyhigher (almost 50 times) than those observed in the quoted group of seventy-year-old subjects, confi rming thekey role in maintaining immunological memory from a priming that occurred over 100 years ago.Centenarians whose blood was collected prior to the pandemic outbreak demonstrated neutralisingantibodies against the 1918 H1N1 virus, but all these subjects tested negative for SARS-CoV-2.
Conclusion
This retrospective study clearly demonstrates that older centenarians are quite resilient to COVID-19, as theyare capable of producing good levels of neutralising antibodies and experiencing mild or asymptomaticdisease. This could be attributed to the 1918 Spanish fl u pandemic through mechanisms other than thepresence of cross-reactive antibodies between the 1918 H1N1 virus and SARS-CoV-2.
... The ideal age to implement a new therapy and stop ART is uncertain, but optimally it should happen before late childhood and adolescence when the struggle with adherence hits hardest. Interestingly, this exact period between 4 and 12 years is called the "honeymoon period of infectious diseases" by immunologists (18), during which outcome from many infections is superior to that observed in younger and older age groups. Although equally susceptible to infection, children at this stage have lower mortality and morbidity from several other infections, including tuberculosis, influenza, mumps, measles, and Varicella-Zoster (18,19). ...
... Interestingly, this exact period between 4 and 12 years is called the "honeymoon period of infectious diseases" by immunologists (18), during which outcome from many infections is superior to that observed in younger and older age groups. Although equally susceptible to infection, children at this stage have lower mortality and morbidity from several other infections, including tuberculosis, influenza, mumps, measles, and Varicella-Zoster (18,19). Partly for this reason, it has not been surprising that children have, with rare exceptions, suffered little in the way of severe disease during the SARS-CoV-2 pandemic (20)(21)(22). ...
Only three well-characterised cases of functional cure have been described in paediatric HIV infection over the past decade. This underlines the fact that early initiation of combination antiretroviral therapy (cART), whilst minimising the size of the viral reservoir, is insufficient to achieve cure, unless other factors contribute. In this review, we consider these additional factors that may facilitate functional cure in paediatric infection. Among the early life immune activity, these include HIV-specific cytotoxic T-lymphocyte (CTL) and natural killer (NK) cell responses. The former have less potent antiviral efficacy in paediatric compared with adult infection, and indeed, in early life, NK responses have greater impact in suppressing viral replication than CTL. This fact may contribute to a greater potential for functional cure to be achieved in paediatric versus adult infection, since post-treatment control in adults is associated less with highly potent CTL activity, and more with effective antiviral NK cell responses. Nonetheless, antiviral CTL responses can play an increasingly effective role through childhood, especially in individuals expressing then ‘protective’ HLA-I molecules HLA-B*27/57/58:01/8101. The role of the innate system on preventing infection, in shaping the particular viruses transmitted, and influencing outcome is discussed. The susceptibility of female fetuses to in utero mother-to-child transmission, especially in the setting of recent maternal infection, is a curiosity that also provides clues to mechanisms by which cure may be achieved, since initial findings are that viral rebound is less frequent among males who interrupt cART. The potential of broadly neutralising antibody therapy to facilitate cure in children who have received early cART is discussed. Finally, we draw attention to the impact of the changing face of the paediatric HIV epidemic on cure potential. The effect of cART is not limited to preventing AIDS and reducing the risk of transmission. cART also affects which mothers transmit. No longer are mothers who transmit those who carry genes associated with poor immune control of HIV. In the cART era, a high proportion (>70% in our South African study) of transmitting mothers are those who seroconvert in pregnancy or who for social reasons are diagnosed late in pregnancy. As a result, now, genes associated with poor immune control of HIV are not enriched in mothers who transmit HIV to their child. These changes will likely influence the effectiveness of HLA-associated immune responses and therefore cure potential among children.
... Sex differences between individuals of reproductive age are explained by different levels of sex steroids 18 . The literature mostly provides information on sex differences in the frequency of development, severity, and mortality rates from sepsis in children during neonatal and puberty compared with adults 19 . However, there is a lack of data about sex differences in the morphofunctional state of the immune system in prepubertal period as well as the features of immune and inflammatory responses in SIRS both at prepubertal males and females. ...
... In our study, the mortality rate from LPS in 10-dayold males was 56% (13 rats out of 23) and it was higher than in females (17%, 2 rats out of 12). Our results are consistent with literature data that revealed high mortality rates from infectious and inflammatory diseases in prepubertal boys 19 . Probably, high mortality rates in males are associated with the more pronounced inflammatory reactions in the target organs that we had identified: the area of necrosis in the liver and the number of neutrophils in the lungs were higher in males. ...
It is a common fact, that the content of sex hormones in humans and animals varies in different age periods. The functional state of the immune system also changes with age. However, sex differences studies of inflammatory and immune responses during puberty prevail in literature. Investigation of immune responses to LPS peculiarities in prepubertal females and males may contribute to the development of more effective immunotherapy and minimize side effects of children vaccination. Therefore, the aim of this work was to investigate the LPS-induced SIRS sex differences in prepubertal Wistar rats. Despite the absence of sex differences in estradiol and testosterone levels, LPS-induced inflammatory changes in liver and lungs are more pronounced among males. Males demonstrate the increasing neopterin, corticosterone levels and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity. Not less important is that in females, demonstrating less morphological changes in liver and lungs, endotoxin level is tenfold higher, and corticosterone level decreases. Thus, endotoxin cannot be used as a marker of the severity of multiple organ failure in prepubertal period. The LPS-induced immune reactions in females and males are similar and are characterized by immunosuppression. Both females and males have decreased production of cytokines (IL-2, IL-4, TNF-α, TGF-β) and the absolute number of CD3 + and CD3 + CD8 + lymphocytes in blood. The acute atrophy of thymus and apoptosis of thymic cells are revealed in animals of both sexes. However, the number of CD3 + CD4 + T-helpers and CD4 + CD25 + Foxp3 + T-cells decreases only in females with SIRS, and in males there was a decrease of CD45R + B-cells. The least expressed sex differences in immune responses in the prepubertal period can be determined by the low levels of sex steroids and the absence of their immunomodulatory effect. Further studies require the identification of mechanisms, determining the sex differences in the inflammatory and immune responses in prepubertal animals.
... Besides, the lack of pre-existing antibodies (virusspecific or cross-reactive) as well as the shortage of the preexisting influenza virus specific CD8 ? T cells among the young population was another prime factor for the viral pathogenecity [9,21]. This is to be noted that the protective influenza virus-specific antibody responses may be longlived [9,21,22]. ...
... T cells among the young population was another prime factor for the viral pathogenecity [9,21]. This is to be noted that the protective influenza virus-specific antibody responses may be longlived [9,21,22]. However, pointing out the virally infected persons as well applying the proper anti-viral therapy is always essential to limit the dreadful propagation of the disease. ...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently causing the respiratory illness termed as the coronavirus disease 2019 or the COVID-19 pandemic. Indeed, the significant increase in deaths in the current days due to influenza around the world started in 1889 is a continued public health threat because of its intermittent style of pandemic outbreaks. An array of research on the influenza viruses has been conducted especially pointing on (1) the development of the anti-viral drugs and the design of probable vaccines on trial basis, (2) the biochemical and genetic aspects underlying the viral pathogenicity, (3) the viral epidemiology, and on (4) the protective immunity against the influenza viruses. Current review briefly discussed the epidemic/ pandemic history of influenza and correlated with the current epidemiology, the possible preventive measures that may be taken by the public health professionals as well as to increase the protective awareness among the general people. The viral reassortments during the initiation of pandemics have also been focused based on the previous literatures.
... There is a high mortality rate of non-adults who were 5 years old or under (50% [60/120]) in the circum-contact cemetery in Huanchaco. Infants and young children (<5 years) have developing immune systems and therefore may have an increased susceptibility to infectious diseases (Ahmed et al., 2007;Learmonth, 1988;Roberts and Buikstra, 2003;Roberts et al., 1992). Diseases that do not typically manifest in the skeleton, like smallpox, may be inferred by identifying an increase in the child mortality rate through time (Cook, 1992;Dixon, 1962;Wood et al., 1992). ...
... Perhaps the best-known example of an influenza pandemic is the 1918 pandemic, which is often erroneously referred to as the "Spanish flu" despite evidence that the virus responsible for the pandemic did not originate in Spain nor did Spain suffer the highest death rate, globally (Barry 2004). One of the most remarkable features of the 1918 influenza pandemic was the relatively high mortality rate among young adults, which is unusual given that mortality during seasonal influenza outbreaks is typically highest among infants, young children, and older adults (Ahmed, Oldstone, and Palese 2007). Instead, studies by paleoepidemiologists and historical demographers have confirmed that mortality rates were high among individuals between the ages of 15 and 34 (Taubenberger and Morens 2006), with a peak among adults who were 28 years of age when the pandemic struck (Gagnon et al. 2013;Hallman and Gagnon 2014;Wilson et al. 2014). ...
The field of paleoepidemiology utilizes epidemiological and bioarchaeological methods and theoretical frameworks to examine aggregate patterns of disease and other health outcomes in past populations. Paleoepidemiological studies most often use data gathered from the skeletal remains of deceased individuals to investigate the origin and antiquity of specific diseases in the past; explore the coevolutionary history of particular pathogens and their human hosts; and assess patterns of intra- and interpopulation variation in susceptibility to disease, risks of mortality (frailty), and the various health outcomes produced by diseases and other conditions in past human populations.
Paleoepidemiological scholarship benefits from an interdisciplinary approach to the study of health and disease in the past, applying analytical techniques common in epidemiological studies of living populations, such as hazards analysis and survival analysis, while also drawing on the theories and methods traditionally employed in bioarchaeological research. However, unlike contemporary epidemiological studies, paleoepidemiological work is also constrained by the biases and limitations of skeletal data, including issues of preservation, hidden heterogeneity in frailty, selective mortality, and the potential for skeletal indicators of stress and disease to simultaneously signal “good” and “poor” health. In spite of these limitations, the field of paleoepidemiology provides valuable insights into past pandemics of diseases like tuberculosis and plague, major epidemiologic transitions in antiquity, and the developmental origins of health and disease in past human populations. Importantly, the results and conclusions of paleoepidemiological research hold value not only for scholars interested in life and health in the past but also researchers and public health experts concerned with understanding and mitigating global health crises in the present and future.
... For the pandemic SARS-CoV-2, in contrast, individuals of all age classes were initially immuno-na€ ıve. Interestingly, in the absence of adaptive immune responses, also RSV and influenza virus infections very likely cause more severe disease in adults as compared to children, as described for immunocompromised patients (Whitley & Monto, 2006;Chatzis et al, 2018) or in viral pandemics such as the 1918 "Spanish Flu," during which large parts of the population initially were immuno-na€ ıve (Ahmed et al, 2007). While this general age trend is consistent with our proposed model, the clinically observed higher morbidity of RSV (and influenza) as compared to COVID-19, particularly in neonates and infants, likely owes this to a complex combination of virological, anatomical, and immunological reasons. ...
The risk of developing severe COVID-19 rises dramatically with age. Schoolchildren are significantly less likely than older people to die from SARS-CoV-2 infection, but the molecular mechanisms underlying this age-dependence are unknown. In primary infections, innate immunity is critical due to the lack of immune memory. Children, in particular, have a significantly stronger interferon response due to a primed state of their airway epithelium. In single-cell transcriptomes of nasal turbinates, we find increased frequencies of immune cells and stronger cytokine-mediated interactions with epithelial cells, resulting in increased epithelial expression of viral sensors (RIG-I, MDA5) via IRF1. In vitro, adolescent peripheral blood mononuclear cells produce more cytokines, priming A549 cells for stronger interferon responses to SARS-CoV-2. Taken together, our findings suggest that increased numbers of immune cells in the airways of children and enhanced cytokine-based interactions with epithelial cells tune the setpoint of the epithelial antiviral system. Our findings shed light on the molecular basis of children's remarkable resistance to COVID-19 and may suggest a novel concept for immunoprophylactic treatments.
... Several considerations point to the independent value of T-cell responses as a complement to antibodies in the assessment of anti-viral immunity. In general, the relative contribution of antibody and T-cell effector functions in viral immunity is characteristic for each pathogen [2,3]. 2 ...
Quantitative metrics for vaccine-induced T-cell responses are an important need for developing correlates of protection and their use in vaccine-based medical management and population health. Molecular TCR analysis is an appealing strategy but currently requires a targeted methodology involving complex integration of ex vivo data (antigen-specific functional T-cell cytokine responses and TCR molecular responses) that uncover only public antigen-specific metrics. Here, we describe an untargeted private TCR method that measures breadth and depth metrics of the T-cell response to vaccine challenge using a simple pre- and post-vaccine subject sampling, TCR immunoseq analysis, and a bioinformatic approach using self-organizing maps and GLIPH2. Among 515 subjects undergoing SARS-CoV-2 mRNA vaccination, we found that breadth and depth metrics were moderately correlated between the targeted public TCR response and untargeted private TCR response methods. The untargeted private TCR method was sufficiently sensitive to distinguish subgroups of potential clinical significance also observed using public TCR methods (the reduced T-cell vaccine response with age and the paradoxically elevated T-cell vaccine response of patients on anti-TNF immunotherapy). These observations suggest the promise of this untargeted private TCR method to produce T-cell vaccine-response metrics in an antigen-agnostic and individual-autonomous context.
... This lack of exposure may have led to a weaker immune response in the young. Alongside this, it was proposed that the honeymoon period of infectious diseases typically protects children (414 y of age) from morbidity and mortality (7). Despite these assumptions, the theory does not truly justify the spike in the increase in fatality among young adults. ...
Respiratory viruses such as influenza are encountered multiple times through infection and/or vaccination and thus have the potential to shape immune cell phenotypes over time. In particular, memory T cell compartments may be affected, as both CD4+ and CD8+ T cell responses likely contribute to viral control. In this study, we assessed immune phenotypes using cytometry by time of flight in the peripheral blood of 22 humans with acute respiratory illness and 22 age-matched noninfected controls. In younger infected individuals (1–19 y of age), we found decreased B and NK cell frequencies and a shift toward more effector-like CD4+ and CD8+ T cell phenotypes, compared with young healthy controls. Significant differences between noninfected and infected older individuals (30–74 y of age) were not seen. We also observed a decrease in naive CD4+ T cells and CD27+CD8+ T cells as well as an increase in effector memory CD8+ T cells and NKT cells in noninfected individuals with age. When cell frequencies were regressed against age for infected versus noninfected subjects, significant differences in trends with age were observed for multiple cell types. These included B cells and various subsets of CD4+ and CD8+ T cells. We conclude that acute respiratory illness drives T cell differentiation and decreases circulating B cell frequencies preferentially in young compared with older individuals.
... One peculiar characteristic of "Spanish flu" was the epidemiological curve of deaths, being W-instead of U-shaped, as usually observed in the seasonal epidemics and in other flu pandemics. The fact that older adults fared better than younger adults in influenza severity might be due to the presence among older adults of an immunological memory to an H1 influenza A virus that was circulating in 1889, thus causing a lower case-fatality rate among subjects aged 30-60 years than among those aged 18-30 years [38]. In fact, generally the extreme ages of life are particularly burdened by mortality, whereas the middle, productive, age of young adults is spared. ...
In 1918 many countries, but not Spain, were fighting World War I. Spanish press could report about the diffusion and severity of a new infection without censorship for the first-time, so that this pandemic is commonly defined as “Spanish flu”, even though Spain was not its place of origin. “Spanish flu” was one of the deadliest pandemics in history and has been frequently compared with the coronavirus disease (COVID)-19 pandemic. These pandemics share similarities, being both caused by highly variable and transmissible respiratory RNA viruses, and diversity, represented by diagnostics, therapies, and especially vaccines, which were made rapidly available for COVID-19, but not for “Spanish flu”. Most comparison studies have been carried out in the first period of COVID-19, when these resources were either not yet available or their use had not long started. Conversely, we wanted to analyze the role that the advanced diagnostics, anti-viral agents, including monoclonal antibodies, and innovative COVID-19 vaccines, may have had in the pandemic containment. Early diagnosis, therapies, and anti-COVID-19 vaccines have markedly reduced the pandemic severity and mortality, thus preventing the collapse of the public health services. However, their influence on the reduction of infections and re-infections, thus on the transition from pandemic to endemic condition, appears to be of minor relevance. The high viral variability of influenza and coronavirus may probably be contained by the development of universal vaccines, which are not easy to be obtained. The only effective weapon still remains the disease prevention, to be achieved with the reduction of promiscuity between the animal reservoirs of these zoonotic diseases and humans.
... L'âge figure assurément parmi les principaux paramètres individuels contribuant au risque de mortalité consécutive à une infection. Ce constat n'est pas récent, et des études précédentes ont montré que la fonction reliant âge et mortalité induite par les maladies infectieuses n'est pas linéaire [6]. En effet, la mortalité diminue souvent avec l'âge au cours des premières années de vie et augmente ensuite avec le vieillissement (forme en J de la courbe de mortalité en fonction de l'âge). ...
... Population studies examining the HLA-associated influenza pathogenesis provide critical information regarding disease protection or susceptibility. Global indigenous population studies have reported higher incidences of morbidity and mortality during both seasonal and pandemic influenza virus infections than in non-indigenous populations [125][126][127][128][129][130][131][132][133][134][135][136]. The lesser degree of HLA diversity exhibited by indigenous communities is likely to have arisen from an evolutionary bottleneck that established a small ancestral pool with little HLA diversity. ...
Influenza A virus is a respiratory pathogen that is responsible for regular epidemics and occasional pandemics that result in substantial damage to life and the economy. The yearly reformulation of trivalent or quadrivalent flu vaccines encompassing surface glycoproteins derived from the current circulating strains of the virus does not provide sufficient cross-protection against mismatched strains. Unlike the current vaccines that elicit a predominant humoral response, vaccines that induce CD8+ T cells have demonstrated a capacity to provide cross-protection against different influenza strains, including novel influenza viruses. Immunopeptidomics, the mass spectrometric identification of human-leukocyte-antigen (HLA)-bound peptides isolated from infected cells, has recently provided key insights into viral peptides that can serve as potential T cell epitopes. The critical elements required for a strong and long-living CD8+ T cell response are related to both HLA restriction and the immunogenicity of the viral peptide. This review examines the importance of HLA and the viral immunopeptidome for the design of a universal influenza T-cell-based vaccine.
... Cela peut se produire soit en raison d'une diversité génétique individuelle, soit en raison de variations de notre état de santé, résultant de maladies bactériennes ou virales, d'immunosuppression iatrogène, de déficits vitaminiques ou de malnutrition [9][10][11][12][13]. Il faut également noter que les changements de notre état immunitaire entraînent souvent des infections plus symptomatiques ou plus graves après la puberté que lorsqu'elles surviennent pendant l'enfance où elles sont souvent peu symptomatiques [14][15][16]. ...
... are most common in the lungs and the mouth [87]. Comparable to middleaged adults, children and older adults are most susceptible to infections initiated from the URT, such as pneumonia [88] and influenza [89]. Towards the stage of middle-aged adults, the susceptibility rate decreases, with an increase in the immune responses of the mature URT [90,91]. ...
The nasal region is one of the distinct environments for the survival of various microbiota.
The human microbial niche begins to inhabit the human body right from birth, and the microbiota survive as commensals or opportunistic pathogens throughout the life of humans in their bodies in various habitats. These microbial communities help to maintain a healthy microenvironment by preventing the attack of pathogens and being involved in immune regulation. Any dysbiosis of microbiota residing in the mucosal surfaces, such as the nasal passages, guts, and genital regions, causes immune modulation and severe infections. The coexistence of microorganisms in the mucosal layers of respiratory passage, resulting in infections due to their co-abundance and interactions, and
the background molecular mechanisms responsible for such interactions, need to be considered for investigation. Additional clinical evaluations can explain the interactions among the nasal microbiota, nasal dysbiosis and neurodegenerative diseases (NDs). The respiratory airways usually act as a substratum place for the microbes and can act as the base for respiratory tract infections. The microbial metabolites and the microbes can cross the blood–brain barrier and may cause NDs, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and multiple sclerosis (MS). The scientific investigations on the potential role of the nasal microbiota in olfactory functions and the relationship
between their dysfunction and neurological diseases are limited. Recently, the consequences of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) in patients with neurological diseases are under exploration. The crosstalk between the gut and the nasal microbiota is highly influential, because their mucosal regions are the prominent microbial niche and are connected to the olfaction, immune regulation, and homeostasis of the central nervous system. Diet is one of the major factors, which strongly influences the mucosal membranes of the airways, gut, and lung. Unhealthy diet
practices cause dysbiosis in gut microbiota and the mucosal barrier. The current review summarizes the interrelationship between the nasal microbiota dysbiosis, resulting olfactory dysfunctions, and the progression of NDs during aging and the involvement of coronavirus disease 2019 in provoking the NDs.
... Coronaviruses belong to a family of viruses that inspire respiratory illness in people, including the primary cold and progressively severe diseases [1], for example, Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). This gathering of infectious viruses can cause zoonotic transfer to human, as was shown during the situation for MERS and SARS outbreaks. ...
In recent times, coronavirus (SARS-CoV-2) becomes a pandemic disease across the globe. This virus affects the severe acute respiratory system that causes a type of pneumonia, which results in an outbreak in Wuhan, China, and then in whole global countries. The virus possesses a complex structure and varied in composition along with its geometrical shape and size. Contributions of the lipid and protein components of a virus to the influenza viral envelope’s mechanical properties are still unknown. In this work, the virus is modeled like the SARS-CoV-2 and surrounded with spikes made up of S glycoproteins, and numerical analysis was made to predict its mechanical behavior while resting on the substrate. The static and viscoelastic response of the virus was carried out in a finite element (FE) commercial software Ansys. The impact of changing viral envelope thickness on SARS-CoV-2 and bald virus stiffness was investigated. The viscoelastic analysis shows the increase in the deformation and stress with an increase in the pressure. The static analysis predicts the lower stiffness for SARS-CoV-2 compared to bald virion and increases with the increase in the envelop thickness. This study is useful for analyzing the effect of geometry and mechanical properties on the mechanical response of SARS-CoV-2.
... Indigenous populations worldwide are disproportionately affected by greater infection rates, disease severity and mortality when novel pandemic virus strains enter human circulation. During the 1918-1919 H1N1 influenza pandemic, higher rates of mortality were reported amongst the Maōri people of New Zealand (7-fold higher than the European population (6)), First Nations people of Canada (8-fold higher than non-First Nations (7)), Alaskan Natives (100% of adults in some populations (8)), Indigenous Australians (10-20% compared to <1% of other Australians (9)) and Western Samoans (19-22% of total population (10)). Although less severe, the 2009 H1N1 pandemic virus also caused higher hospitalisation and mortality rates for Indigenous Australians (6.6-fold higher hospitalisation and 5.2fold higher mortality than Non-Indigenous Australians (11)), New Zealand Maōri (5-fold higher hospitalization (12)), Pacific Islanders (7-fold higher hospitalization (12,13)), American Indians and Alaskan Natives (4-fold higher mortality (14)) and First Nations people of Canada (3-fold higher hospitalisation (15)). ...
CD8⁺ T cells are a pivotal part of the immune response to viruses, playing a key role in disease outcome and providing long-lasting immunity to conserved pathogen epitopes. Understanding CD8⁺ T cell immunity in humans is complex due to CD8⁺ T cell restriction by highly polymorphic Human Leukocyte Antigen (HLA) proteins, requiring T cell epitopes to be defined for different HLA allotypes across different ethnicities. Here we evaluate strategies that have been developed to facilitate epitope identification and study immunogenic T cell responses. We describe an immunopeptidomics approach to sequence HLA-bound peptides presented on virus-infected cells by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Using antigen presenting cell lines that stably express the HLA alleles characteristic of Indigenous Australians, this approach has been successfully used to comprehensively identify influenza-specific CD8⁺ T cell epitopes restricted by HLA allotypes predominant in Indigenous Australians, including HLA-A*24:02 and HLA-A*11:01. This is an essential step in ensuring high vaccine coverage and efficacy in Indigenous populations globally, known to be at high risk from influenza disease and other respiratory infections.
... This claim of Ewald's can be also correlated with the hypothesis of the other scientists who believe that the Russian influenza (1889-1892) was caused by the H3Nx strain which circulated until 1918 and then with favorable conditions and reassortment events caused 1918 Spanish flu outbreak 17 . The another reason identified for the increased pathogenicity of the influenza virus during the 1918 pandemic was the absence of pre-existing cross-reactive antibodies for the influenza virus in the young population 17,18 . Thus we can say that the virulence of the strain may depend on the transmission mode as argued by Ewald but is not limited to that alone. ...
The ongoing COVID-19 pandemic has brought the entire world to a near lockdown. Having infected more than 6,54,08,787 people and claiming more than 15,09,743 lives as on 4th December 2020 it has made mankind to rethink over its claim of being highly advanced. Although we have come a long way both in terms of technology and medical advancements from 1918’s Spanish flu to latest novel coronavirus outbreak, still somehow we feel ourselves somewhat as helpless as we were back in 1918. There still remains a gap in understanding the full mechanism of the infection cycle of zoonotic diseases and their intensive relationships with their reservoir hosts. In this review we will be discussing why it’s still a challenge for us to fight these viral diseases and also how out of nowhere these diseases appear claiming millions of life every now and then. Also, we will try to understand how the reservoir ‘bats’ escape virulence.
... Entre las situaciones de emergencias sanitarias y pandemias, la gripe es probablemente la mayor preocupación financiera, debido a su capacidad para alcanzar proporciones pandémicas a nivel mundial (Ahmed et al., 2007), prueba de ello son la influenza A, H1N1 o gripe porcina (2009)(2010), que causó 200 mil decesos y cientos de millones de personas contagiadas en más de 200 países (Verikios et al., 2015), como el COVID-19, con efectos globales. ...
Este artículo analizó los efectos financieros de la pandemia COVID-19 en las empresas farmacéuticas listadas en el índice de The New York Stock Exchange (NYSE). Se utilizó la metodología de estudio de eventos aplicada a una muestra de cincuenta empresas que conforman el sector farmacéutico del NYSE. Los resultados mostraron evidencia a favor de la eficiencia de este mercado financiero, lo que confirmó que detrás de todo gran fenómeno histórico radica un efecto financiero. Asimismo, pudo demostrarse que los rendimientos bursátiles de las empresas del sector farmacéutico presentaron resultados positivos ante los comunicados de la OMS, relativos al COVID-19.
... At individual level humans have their own genetic and immune systems which are the rst biological contention barrier against viruses [173]. However, our systems are not necessarily prepared for ghting against quickly evolving viruses [4]. Decreasing nongenetic risk factors is an important way to be prepared, as having a more healthy system always improve our defenses [29,90]. ...
... The 1918 Spanish influenza pandemic resulted in over 50 million deaths worldwide and remains one of the deadliest plagues ever experienced in human history [1]. Annually, influenza infection continues to cause epidemics and is responsible for 3-5 million severe infections and 500,000 deaths worldwide https://www.who.int/en/news-room/ ...
Syngeneic murine systems have pre-fixed MHC, making them an imperfect model for investigating the impact of MHC polymorphism on immunodominance in influenza A virus (IAV) infections. To date, there are few studies focusing on MHC allelic differences and its impact on immunodominance even though it is well documented that an individual’s HLA plays a significant role in determining immunodominance hierarchy. Here, we describe a broad-based CD8+ T cell response in a healthy individual to IAV infection rather than a typical immunodominance hierarchy. We used a systematic antigen screen approach combined with epitope prediction to study such a broad CD8+ T cell response to IAV infection. We show CD8+ T cell responses to nine IAV proteins and identify their minimal epitope sequences. These epitopes are restricted to HLA-B*44:03, HLA-A*24:02 and HLA-A*33:03 and seven out of the nine epitopes are novel (NP319–330#, M1124–134, M27–15, NA337–346, PB239–49, HA445–453 and NS1195–203). Additionally, most of these novel epitopes are highly conserved among H1N1 and H3N2 strains that circulated in Australia and other parts of the world.
... This is most evident when unpredicted seasonal or pandemic viruses emerge in human circulation. During the 1918-1919 influenza pandemic, 100% of Alaskan adults died in some isolated villages, while only school-aged children survived 4 . Western Samoa was the hardest hit with a total population loss of 19-22% 5 . ...
Indigenous people worldwide are at high risk of developing severe influenza disease. HLA-A*24:02 allele, highly prevalent in Indigenous populations, is associated with influenza-induced mortality, although the basis for this association is unclear. Here, we define CD8 ⁺ T-cell immune landscapes against influenza A (IAV) and B (IBV) viruses in HLA-A*24:02-expressing Indigenous and non-Indigenous individuals, human tissues, influenza-infected patients and HLA-A*24:02-transgenic mice. We identify immunodominant protective CD8 ⁺ T-cell epitopes, one towards IAV and six towards IBV, with A24/PB2 550–558 -specific CD8 ⁺ T cells being cross-reactive between IAV and IBV. Memory CD8 ⁺ T cells towards these specificities are present in blood (CD27 ⁺ CD45RA ⁻ phenotype) and tissues (CD103 ⁺ CD69 ⁺ phenotype) of healthy individuals, and effector CD27 ⁻ CD45RA ⁻ PD-1 ⁺ CD38 ⁺ CD8 ⁺ T cells in IAV/IBV patients. Our data show influenza-specific CD8 ⁺ T-cell responses in Indigenous Australians, and advocate for T-cell-mediated vaccines that target and boost the breadth of IAV/IBV-specific CD8 ⁺ T cells to protect high-risk HLA-A*24:02-expressing Indigenous and non-Indigenous populations from severe influenza disease.
... Other recent outbreaks that occurred in the last decade include influenza A (H1N1 subtype) in 2009 and Ebola in 2014 (Muyembe-Tamfum et al., 2012). In the past century, there were some other notable viral pandemics recorded which caused deaths of millions of people worldwide including -flu pandemic (H1N1 virus) in 1918, flu (H2N2 virus) (Ahmed et al., 2007;Glinsky, 2010;Song et al., 2012). ...
Infectious diseases caused by viruses can elevate up to undesired pandemic conditions affecting the global population and normal life function. These in turn impact the established world economy, create jobless situations, physical, mental, emotional stress, and challenge the human survival. Therefore, timely detection, treatment, isolation and prevention of spreading the pandemic infectious diseases not beyond the originated town is critical to avoid global impairment of life (e.g., Corona virus disease - 2019, COVID-19). The objective of this review article is to emphasize the recent advancements in the electrochemical diagnostics of twelve life-threatening viruses namely - COVID-19, Middle east respiratory syndrome (MERS), Severe acute respiratory syndrome (SARS), Influenza, Hepatitis, Human immunodeficiency virus (HIV), Human papilloma virus (HPV), Zika virus, Herpes simplex virus, Chikungunya, Dengue, and Rotavirus. This review describes the design, principle, underlying rationale, receptor, and mechanistic aspects of sensor systems reported for such viruses. Electrochemical sensor systems which comprised either antibody or aptamers or direct/mediated electron transfer in the recognition matrix were explicitly segregated into separate sub-sections for critical comparison. This review emphasizes the current challenges involved in translating laboratory research to real-world device applications, future prospects and commercialization aspects of electrochemical diagnostic devices for virus detection. The background and overall progress provided in this review are expected to be insightful to the researchers in sensor field and facilitate the design and fabrication of electrochemical sensors for life-threatening viruses with broader applicability to any desired pathogens.
... 25 In typical uncomplicated infections, viral replication apparently remains limited to the mucosal lining of the pharynx and upper tracheobronchial tree. Determinants of progression of a predominantly upper respiratory tract infection to fatal pulmonary disease are poorly understood but likely include a number of different factors such as age, immune and underlying health status, preexisting immunity to viral antigens (principally hemagglutinin), 29 and pharyngeal bacterial flora. The findings in this and other studies 24 suggest that severe disease is associated with the development of influenza viral pneumonia, 23,25,30 with or without secondary bacterial pneumonia. ...
Context
In March 2009, a novel swine-origin influenza A/H1N1 virus was identified. After global spread, the World Health Organization in June declared the first influenza pandemic in 41 years.
Objective
To describe the clinicopathologic characteristics of 34 people who died following confirmed A/H1N1 infection with emphasis on the pulmonary pathology findings.
Design
We reviewed medical records, autopsy reports, microbiologic studies, and microscopic slides of 34 people who died between May 15 and July 9, 2009, and were investigated either by the New York City Office of Chief Medical Examiner (32 deaths) or through the consultation service of a coauthor (2 deaths).
Results
Most of the 34 decedents (62%) were between 25 and 49 years old (median, 41.5 years). Tracheitis, bronchiolitis, and diffuse alveolar damage were noted in most cases. Influenza viral antigen was observed most commonly in the epithelium of the tracheobronchial tree but also in alveolar epithelial cells and macrophages. Most cases were reverse transcription–polymerase chain reaction positive for influenza. Histologic and microbiologic autopsy evidence of bacterial pneumonia was detected in 55% of cases. Underlying medical conditions including cardiorespiratory diseases and immunosuppression were present in 91% of cases. Obesity (body mass index, >30) was noted in 72% of adult and adolescent cases.
Conclusions
The pulmonary pathologic findings in fatal disease caused by the novel pandemic influenza virus are similar to findings identified in past pandemics. Superimposed bacterial infections of the respiratory tract were common. Preexisting obesity, cardiorespiratory diseases, and other comorbidities also were prominent findings among the decedents.
... In 1918 influenza pandemic, subjects born before 1889 {aged 30-60 years) showed a better outcome when compared to younger people [11]. This intriguing response may be probably explained by the fact that older subjects had acquired cross-protective antibodies having met in their life an H1 and/or N1 influenza virus and surely, in the period of time from 1889 to 1892, the H3 influenza virus which sustained the Russian Influenza pandemic [12]. In contrast, younger people born after 1889 were more immunologically naïve to influenza viruses. ...
Background
In 1918 an unknown infectious agent spread around the world infecting over one-third of the general population and killing almost 50 million people. Many countries were at war, the First World War. Since Spain was a neutral country and Spanish press could report about the infection without censorship, this condition is commonly remembered as “Spanish influenza”. This review examines several aspects during the 1918 influenza pandemic to bring out evidences which might be useful to imagine the possible magnitude of the present coronavirus disease 2019 (COVID-19).
Methods
In the first part of this review we will examine the origin of the SARS-Coronavirus-2 and 1918 Spanish Influenza Virus and the role played by host and environment in its diffusion. We will also include in our analysis an evaluation of different approaches utilized to restrain the spread of pandemic and to treat infected patients. In the second part, we will try to imagine the magnitude of the present COVID-19 pandemic and the possible measures able to restrain in the present environment its spread.
Results
Several factors characterize the outcome in a viral pandemic infection. They include the complete knowledge of the virus, the complete knowledge of the host and of the environment where the host lives and the pandemic develops.
Conclusion
By comparing the situation seen in 1918 with the current one, we are now in a more favourable position. The experience of the past teaches us that their success is linked to a rapid, constant and lasting application. Then, rather than coercion, awareness of the need to observe such prevention measures works better.
... Western Samoa was the hardest hit with a total population loss of 19-22% 5 . As many as 10-20% of Indigenous Australians died from pandemic influenza in 1919 6 in comparison to <1% of other Australians, with some reports showing up to 50% mortality in Indigenous Australian communities 7 . ...
Indigenous people worldwide are at high-risk of developing severe influenza disease. HLA-A*24:02 allele, highly prevalent in Indigenous populations, is associated with influenza-induced mortality, although the basis for this association is unclear. We defined CD8 ⁺ T-cell immune landscapes against influenza A (IAV) and B (IBV) viruses in HLA-A*24:02-expressing Indigenous and non-Indigenous individuals, human tissues, influenza-infected patients and HLA-A*24:02-transgenic mice. We identified immunodominant protective CD8 ⁺ T-cell epitopes, one towards IAV and six towards IBV, with A24/PB2 550-558 -specific CD8 ⁺ T-cells cells being cross-reactive between IAV and IBV. Memory CD8 ⁺ T-cells towards these specificities were present in blood (CD27 ⁺ CD45RA ⁻ phenotype) and tissues (CD103 ⁺ CD69 ⁺ phenotype) of healthy subjects, and effector CD27 ⁻ CD45RA ⁻ PD-1 ⁺ CD38 ⁺ CD8 ⁺ T-cells in IAV/IBV patients. Our data present the first evidence of influenza-specific CD8 ⁺ T-cell responses in Indigenous Australians, and advocate for T-cell-mediated vaccines that target and boost the breadth of IAV/IBV-specific CD8 ⁺ T-cells to protect high-risk HLA-A*24:02-expressing Indigenous and non-Indigenous populations from severe influenza disease.
One Sentence Summary
Influenza-specific CD8 ⁺ T-cell specificities restricted by HLA-A*24:02.
... Infections which have been noted to increase in severity in young adults, such as Spanish influenza and tuberculosis, are typically discussed as outliers, and explanations sought. However the medical literature a century ago noted that the case fatality rate (deaths/cases) by age is J-shaped for a number of infections, with a 'honeymoon period' in school-age children and rising fatality throughout adulthood 3,4 . This pattern, which has never been systematically examined, appears to have been largely forgotten, and the explanation for it is unknown. ...
The COVID-19 pandemic has ignited interest in age-specific manifestations of infection but surprisingly little is known about relative severity of infectious disease between the extremes of age. In a systematic analysis we identified 142 datasets with information on severity of disease by age for 32 different infectious diseases, 19 viral and 13 bacterial. For almost all infections, school-age children have the least severe disease, and severity starts to rise long before old age. Indeed, for many infections even young adults have more severe disease than children, and dengue was the only infection that was most severe in school-age children. Together with data on vaccine response in children and young adults, the findings suggest peak immune function is reached around 5–14 years of age. Relative immune senescence may begin much earlier than assumed, before accelerating in older age groups. This has major implications for understanding resilience to infection, optimal vaccine scheduling, and appropriate health protection policies across the life course.
... The term "cytokine storm" was first used when observing the massive cytokine releases related to cancer or to cancer-related therapies (16,17). The term has come to be used in a host of clinical conditions, mostly related to cancer treatment responses or to infectious disease states (18,19). ...
Older adults are far more vulnerable to adverse health outcomes and mortality after contracting COVID-19. There are likely multiple age-related biological, clinical and environmental reasons for this increased risk, all of which are exacerbated by underlying age-associated changes to the immune system as well as increased prevalence of chronic disease states in older adults. Innate immune system overactivity, termed the cytokine storm, appears to be critical in the development of the worst consequences of COVID-19 infection. Pathophysiology suggests that viral stimulation of the innate immune system, augmented by inflammatory signals sent from dying cells, ramps up into a poorly controlled outpouring of inflammatory mediators. Other aging related changes in cells such as senescence as well as higher prevalence of chronic disease states also likely ramp up inflammatory signaling. This in turn drives downstream pathophysiological changes to pulmonary, cardiovascular, skeletal muscle, and brain tissues that drive many of the adverse health outcomes observed in older adults. This article provides an overview of the underlying etiologies of innate immune system activation and adaptive immune system dysregulation in older adults and how they potentiate the consequences of the COVID-19 related cytokine storm, and possible uses of this knowledge to develop better risk assessment and treatment monitoring strategies.
... Older adults born prior to 1889 fared significantly better against the pandemic influenza virus than those born after; it is theorized that this was the result of an H1 and/or N1 influenza virus that circulated within the population prior to 1889, when it was replaced by an H3 influenza virus (the "Russian" influenza pandemic of 1889-1892). Therefore, individuals born before 1889 would have had cross-reactive antibodies and immunity that protected them from the 1918 H1N1 influenza virus while younger populations would have been immunologically naïve [37,38]. Again in 2009, studies showed a role for existing Ab and T cells in protection against the pandemic virus as those born in 1900-1920 had high Ab titers against the 2009 pandemic virus [39]. ...
Influenza virus infections represent a serious public health threat and account for significant morbidity and mortality worldwide due to seasonal epidemics and periodic pandemics. Despite being an important countermeasure to combat influenza virus and being highly efficacious when matched to circulating influenza viruses, current preventative strategies of vaccination against influenza virus often provide incomplete protection due the continuous antigenic drift/shift of circulating strains of influenza virus. Prevention and control of influenza virus infection with vaccines is dependent on the host immune response induced by vaccination and the various vaccine platforms induce different components of the local and systemic immune response. This review focuses on the immune basis of current (inactivated influenza vaccines (IIV) and live attenuated influenza vaccines (LAIV)) as well as novel vaccine platforms against influenza virus. Particular emphasis will be placed on how each platform induces cross-protection against heterologous influenza viruses, as well as how this immunity compares to and contrasts from the “gold standard” of immunity generated by natural influenza virus infection.
... These sensing strategies are further complemented by the aforementioned surface visualization/characterization tools (AFM, EM, XRD) presenting a complete package of technologies that can potentially be used for diagnosis, prognosis, drug discovery, drug analysis, and disease spread surveillance, all of which are vital for ensuring good community health. 14,15 A general overview of these groups including their mechanisms is discussed in Table 1. It is also obvious that for quick technology development, such as for the development of biosensors for COVID-19, it is essential to build on the existing scientific evidence for the use of technology in similar applications. ...
Biosensors and nanoscale analytical tools have seen unprecedented growth in literature in the past 20 years, with a large number of reports on the topic of ’ultra-sensitive’, ’cost-effective’ and ’early-detection’ tools with a potential of ’mass- production’ cited on the web of science. Yet none of these tools are commercially available in the market or practically viable for mass production and use in pandemic diseases such as COVID-19. In this context, we review the technological challenges and opportunities that bio/chemical sensors and characterization tools present us by critically analyzing the bottlenecks which have hindered the implementation of advanced sensing technologies in pandemic diseases. We also describe in brief COVID- 19 by comparing it with other pandemic strains such as SARS and MERS for the identification of features that enable biosensing. Moreover, we discuss visualization and characterization tools that can potentially be used not only for sensing applications but also assist in speeding up the drug discovery and vaccine development process. Furthermore, we discuss the emerging mechanism with wastewater analysis for early warning of the outbreak, focusing on sensors for rapid and on-site analysis of SARS-COV-2 in sewage. To conclude, we provide holistic insights into challenges associated with the quick translation of sensing technologies, policies, ethical issues, technology adoption, and an overall outlook of the role of the sensing technologies in pandemics.
... This fact is related to the deteriorations of living conditions associated with the historical turbulence caused by the Second World War and the subsequent Greek Civil War (Close 2013;Magoulis & Miniadis 2017). Secondly, within this general context, there were significant regional differences: those born in the north-western prefecture of Chania were found to be significantly taller compared to those in the other three prefectures with homogenous mean values of height, which might reflect the protective action of isolation against the introduction of infectious diseases related to trade flows which were more consistent in the other lowland prefectures of Crete (Ahmed et al. 2007;Wolfe et al. 2007;Malina et al. 2018). ...
This paper aimed to validate the hypothesis that at the beginning of the 20th century, the island of Crete maintained better living conditions in comparison with the rest of Greece. We analysed trends in adult height in both sexes following two steps. In the first, height was considered by sex and birth cohorts for the island as a whole. In the second, the same approach was applied to study the phenomenon in the four prefectures of the island. Average heights were 155.4±6.2 cm and 168.7±6.4 cm in females and males, respectively, and the trend in time constantly increases in the latter. The distribution of stature in the four prefectures of the island highlighted the significantly taller stature of the males in Chania, compared to the other three. Our findings report higher average statures compared to those of Cretan conscripts born between 1927 and 1945. Our results confirm that the Cretans were wealthier at the turn of the 20th century, before being annexed to Greece. Moreover, they suggest that the taller statures of the males in the prefecture of Chania may reflect protection action of isolation to the introduction of infectious diseases related to trade flows.
Influenza B viruses (IBVs) cause substantive morbidity and mortality, and yet immunity towards IBVs remains understudied. CD8⁺ T-cells provide broadly cross-reactive immunity and alleviate disease severity by recognizing conserved epitopes. Despite the IBV burden, only 18 IBV-specific T-cell epitopes restricted by 5 HLAs have been identified currently. A broader array of conserved IBV T-cell epitopes is needed to develop effective cross-reactive T-cell based IBV vaccines. Here we identify 9 highly conserved IBV CD8⁺ T-cell epitopes restricted to HLA-B*07:02, HLA-B*08:01 and HLA-B*35:01. Memory IBV-specific tetramer⁺CD8⁺ T-cells are present within blood and tissues. Frequencies of IBV-specific CD8⁺ T-cells decline with age, but maintain a central memory phenotype. HLA-B*07:02 and HLA-B*08:01-restricted NP30-38 epitope-specific T-cells have distinct T-cell receptor repertoires. We provide structural basis for the IBV HLA-B*07:02-restricted NS1196-206 (11-mer) and HLA-B*07:02-restricted NP30-38 epitope presentation. Our study increases the number of IBV CD8⁺ T-cell epitopes, and defines IBV-specific CD8⁺ T-cells at cellular and molecular levels, across tissues and age.
Background
“Herd immunity” became a contested term during the COVID‐19 pandemic. Although the term “herd immunity” is often used to refer to thresholds at which some diseases can be eliminated (e.g., due to mass vaccination), the term has multiple referents. Different concepts of herd immunity have been relevant throughout the history of immunology and infectious disease epidemiology. For some diseases, herd immunity plays a role in the development of an endemic equilibrium, rather than elimination via threshold effects.
Methods
We reviewed academic literature from 1920 to 2022, using historical and philosophical analysis to identify and develop relevant concepts of herd immunity.
Results
This paper analyses the ambiguity surrounding the concept of herd immunity during the pandemic. We argue for the need to recapture a long‐standing interpretation of this concept as one of the factors that leads to a dynamic endemic equilibrium between a host population and a mutating respiratory pathogen.
Conclusions
Informed by the history of infectious disease epidemiology, we argue that understanding the concept in this way will help us manage both SARS‐CoV‐2 and hundreds of other seasonal respiratory pathogens with which we live but which have been disrupted due to sustained public health measures/non‐pharmaceutical interventions targeting SARS‐CoV‐2.
There are eerie similarities between the 1918 Spanish influenza and 2019 COVID-19 pandemics that are somewhat surprising and disheartening, given that the time interval between the 2 pandemics is more than 100 years. This article covers the national response, etiology and pathophysiology, disease course and treatments, nursing shortages, healthcare responses, sequelae following infections, and economic and social impacts of both pandemics. Understanding the development and course of both pandemics will inform clinical nurse specialists about the changes that need to be made to be better prepared to recognize the changes that need to be made to prepare for the next pandemic.
In 1955, René Dubos famously expressed his "second thoughts on the germ theory", attributing infectious diseases to various "changing circumstances" that weaken the host by unknown mechanisms. He rightly stressed that only a small minority of individuals infected by almost any microbe develop clinical disease. Intriguingly, though, he did not mention the abundant and elegant findings reported from 1905 onward that unambiguously pointed to host genetic determinants of infection outcome in plants and animals, including human inborn errors of immunity. Diverse findings over the next 50 y corroborated and extended these earlier genetic and immunological observations that René Dubos had neglected. Meanwhile, the sequential advent of immunosuppression- and HIV-driven immunodeficiencies unexpectedly provided a mechanistic basis for his own views. Collectively, these two lines of evidence support a host theory of infectious diseases, with inherited and acquired immunodeficiencies as the key determinants of severe infection outcome, relegating the germ to an environmental trigger that reveals an underlying and preexisting cause of disease and death.
To cope with novel virus infections to which no prior adaptive immunity exists, the body strongly relies on the innate immune system. In such cases, including infections with SARS-CoV-2, children tend to fair better than adults. In the context of COVID-19, it became evident that a rapid interferon response at the site of primary infection is key for successful control of the virus and prevention of severe disease. The airway epithelium of children was shown to exhibit a primed state already at homeostasis and to respond particularly well to SARS-CoV-2 infection. However, the underlying mechanism for this priming remained elusive. Here we show that interactions between airway mucosal immune cells and epithelial cells are stronger in children, and via cytokine-mediated signaling lead to IRF-1-dependent upregulation of the viral sensors RIG-I and MDA5. Based on a cellular in vitro model we show that stimulated human peripheral blood mononuclear cells (PBMC) can induce a robust interferon-beta response towards SARS-CoV-2 in a lung epithelial cell line otherwise unresponsive to this virus. This is mediated by type I interferon, interferon-gamma and TNF, and requires induction of both, RIG-I and MDA5. In single cell-analysis of nasal swab samples the same cytokines are found to be elevated in mucosal immune cells of children, correlating with elevated epithelial expression of viral sensors. In vitro analysis of PBMC derived from healthy adolescents and adults confirm that immune cells of younger individuals show increased cytokine production and potential to prime epithelial cells. In co-culture with SARS-CoV-2-infected A549 cells, PBMC from adolescents significantly enhance the antiviral response. Taken together, our study suggests that higher numbers and a more vigorous activity of innate immune cells in the airway mucosa of children tune the set-point of the epithelial antiviral system. This likely is a major contributor to the robust immune response to SARS-CoV-2 in children. Our findings shed light on the molecular underpinnings of the stunning resilience of children towards severe COVID-19, and may propose a novel concept for immunoprophylactic treatments.
Host age is often evoked as an intrinsic factor aggravating the outcome of host-pathogen interactions. However, the shape of the relationship between age and infection-induced mortality might differ among pathogens, with specific clinical and ecological traits making some pathogens more likely to exert higher mortality in older hosts. Here, we used a large dataset on age-specific case fatality rate (CFR) of 28 human infectious diseases to investigate i) whether age is consistently associated to increased CFR, ii) whether pathogen characteristics might explain higher CFR in older adults. We found that, for most of the infectious diseases considered here, CFR slightly decreased during the first years of life and then steeply increased in older adults. Pathogens inducing diseases with long-lasting symptoms had the steepest increase of age-dependent CFR. Similarly, bacterial diseases and emerging viruses were associated with increasing mortality risk in the oldest age classes. On the contrary, we did not find evidence suggesting that systemic infections have steeper slopes between CFR and age; similarly, the relationship between age and CFR did not differ according to the pathogen transmission mode. Overall, our analysis shows that age is a key trait affecting infection-induced mortality rate in humans, and that the extent of the aggravating effect on older adults depends on some key traits, such as the duration of illness.
Infectious pathogens cause severe human illnesses and great deaths per year worldwide. Rapid, sensitive, and accurate detection of pathogens is of great importance for preventing infectious diseases caused by pathogens and optimizing medical healthcare systems. Inspired by a microbial defense system (i.e., CRISPR/ CRISPR‐associated proteins (Cas) system, an adaptive immune system for protecting microorganisms from being attacked by invading species), a great many new biosensors have been successfully developed and widely applied in the detection of infectious viruses and pathogenic bacteria. Moreover, advanced nanotechnologies have also been integrated into these biosensors to improve their detection stability, sensitivity, and accuracy. In this review, the recent advance in CRISPR/Cas systems‐based nano/biosensors and their applications in the detection of infectious viruses and pathogenic bacteria are comprehensively reviewed. First of all, the categories and working principles of CRISPR/Cas systems for establishing the nano/biosensors are simply introduced. Then, the design and construction of CRISPR/Cas systems‐based nano/biosensors are comprehensively discussed. In the end, attentions are focused on the applications of CRISPR/Cas systems‐based nano/biosensors in the detection of infectious viruses and pathogenic bacteria. Impressively, the remaining opportunities and challenges for the further design and development of CRISPR/Cas system‐based nano/biosensors and their promising applications are proposed.
Für Sportlerinnen und Sportler mit Atemwegserkrankungen gab es schon immer unterschiedliche Empfehlungen – die Coronapandemie hat die Sachlage nicht gerade vereinfacht. Unsere Autoren helfen Ihnen, die richtigen Entscheidungen zu treffen, wenn Sie Sportlerinnen und Sportler mit Atemwegserkrankungen betreuen.
Biological anthropologists are ideally suited for the study of pandemics given their strengths in human biology, health, culture, and behavior, yet pandemics have historically not been a major focus of research. The COVID-19 pandemic has reinforced the need to understand pandemic causes and unequal consequences at multiple levels. Insights from past pandemics can strengthen the knowledge base and inform the study of current and future pandemics through an anthropological lens. In this paper, we discuss the distinctive social and epidemiological features of pandemics, as well as the ways in which biological anthropologists have previously studied infectious diseases, epidemics, and pandemics. We then review interdisciplinary research on three pandemics–1918 influenza, 2009 influenza, and COVID-19–focusing on persistent social inequalities in morbidity and mortality related to sex and gender; race, ethnicity, and Indigeneity; and pre-existing health and disability. Following this review of the current state of pandemic research on these topics, we conclude with a discussion of ways biological anthropologists can contribute to this field moving forward. Biological anthropologists can add rich historical and cross-cultural depth to the study of pandemics, provide insights into the biosocial complexities of pandemics using the theory of syndemics, investigate the social and health impacts of stress and stigma, and address important methodological and ethical issues. As COVID-19 is unlikely to be the last global pandemic, stronger involvement of biological anthropology in pandemic studies and public health policy and research is vital.
This conclusion chapter to the volume Pandemic Re-Awakenings: The Forgotten and Unforgotten 'Spanish' Flu of 1918-1919 Oxford University Press, 2022) critically investigates when the so-called ‘forgetting’ of the Great Flu began and when it supposedly ended. The dialectical relationship between remembering and forgetting of the 1918-1919 influenza pandemic was initially shaped by the ‘prememory’ of earlier epidemics (including the ‘Russian’ flu pandemic of 1889-90), which also instilled a subtle dynamic of ‘pre-forgetting’. The tension between public oblivion and private recollections continued even after the generation of survivors gradually passed away and was repeatedly regenerated by moments of rediscovery. Ultimately, the revival of interest in the build-up of the centenary prepared the ground for the popular reception of the Coronavirus pandemic and enabled a surge of rediscovery of the ‘Spanish’ Flu.
Rationale:
The importance of the adaptative T cell response in the control and resolution of viral infection has been well-established. However, the nature of T cell-mediated viral control mechanisms in life-threatening stages of COVID-19 has yet to be determined.
Objective:
The aim of the present study was to determine the function and phenotype of T cell populations associated with survival or death of COVID-19 patients under intensive care as a result of phenotypic and functional profiling by mass cytometry.
Findings:
Increased frequencies of circulating, polyfunctional, CD4+CXCR5+HLA-DR+ stem cell memory T cells (TSCM) and decreased proportions of Granzyme-B and Perforin-expressing effector memory T cells (TEM) were detected in recovered and deceased patients, respectively. The higher abundance of polyfunctional CD8+PD-L1+CXCR3+ T effector cells, CXCR5+HLA-DR+ TSCM, as well as anti-nucleocapsid (NC) cytokine-producing T cells permitted to differentiate between recovered and deceased patients. The results from a principal component analysis showed an imbalance in the T cell compartment allowed for the separation of recovered and deceased patients. The paucity of circulating CD8+PD-L1+CXCR3+ Teff-cells and NC-specific CD8+ T-cells accurately forecasts fatal disease outcome.
Conclusion:
This study provides insight into the nature of the T cell populations involved in the control of COVID-19 and therefor might impact T cell-based vaccine designs for this infectious disease.
This article is a detailed study of tuberculosis mortality in Tromsø town, in a period of considerable population growth and dwelling density increase. From 1878 we have access to an almost complete list of individual causes of death from the local burial registers, combined with the population censuses of 1875, 1885, 1900, 1910 and 1920; we have reconstructed Tromsø’s population by sex and age in order to estimate the mortality rates of the total population at risk of dying from 1878 to 1920. Our findings show that women aged 15 to 49 were at highest risk for most of this period, but that this gradually changed over time. What caused these tuberculosis deaths is a complex multifaceted topic, but we have chosen to highlight three aspects which can contribute to increased understanding of both age and gender differences: the lack of pasteurization of milk, inherited resistance and migration.
Keywords: Tuberculosis, epidemiology, mortality, gender differences
Among the four genera of influenza viruses (IVs) and the four genera of coronaviruses (CoVs), zoonotic αIV and βCoV have occasionally caused airborne epidemic outbreaks in humans, who are immunologically naïve, and the outbreaks have resulted in high fatality rates as well as social and economic disruption and losses. The most devasting influenza A virus (IAV) in αIV, pandemic H1N1 in 1918, which caused at least 40 million deaths from about 500 million cases of infection, was the first recorded emergence of IAVs in humans. Usually, a novel human-adapted virus replaces the preexisting human-adapted virus. Interestingly, two IAV subtypes, A/H3N2/1968 and A/H1N1/2009 variants, and two lineages of influenza B viruses (IBV) in βIV, B/Yamagata and B/Victoria lineage-like viruses, remain seasonally detectable in humans. Both influenza C viruses (ICVs) in γIV and four human CoVs, HCoV-229E and HCoV-NL63 in αCoV and HCoV-OC43 and HCoV-HKU1 in βCoV, usually cause mild respiratory infections. Much attention has been given to CoVs since the global epidemic outbreaks of βSARS-CoV in 2002–2004 and βMERS-CoV from 2012 to present. βSARS-CoV-2, which is causing the ongoing COVID-19 pandemic that has resulted in 890,392 deaths from about 27 million cases of infection as of 8 September 2020, has provoked worldwide investigations of CoVs. With the aim of developing efficient strategies for controlling virus outbreaks and recurrences of seasonal virus variants, here we overview the structures, diversities, host ranges and host receptors of all IVs and CoVs and critically review current knowledge of receptor binding specificity of spike glycoproteins, which mediates infection, of IVs and of zoonotic, pandemic and seasonal CoVs.
Numerous epidemiological and clinical studies have noted differences in the incidence and severity of parasitic diseases between males and females. Although in some instances this may be due to gender-associated differences in behavior, there is overwhelming evidence that sex-associated hormones can also modulate immune responses and consequently directly influence the outcome of parasitic infection. Animal models of disease can often recreate the gender-dependent differences observed in humans, and the role of sex-associated hormones can be confirmed by experimentally altering their levels. Under normal circumstances, levels of sex hormones not only differ between males and females but vary according to age. Furthermore, not only are females of reproductive age subject to the regular hormonal cycles which control ovulation, they are also exposed to dramatically altered levels during pregnancy. It is thus not surprising that the severity of many diseases, including those caused by parasites, has been shown to be affected by one or more of these circumstances. In addition, infection with many pathogens has been shown to have an adverse influence on pregnancy. In this article we review the impact of sex-associated hormones on the immune system and the development and maintenance of immunity to the intracellular protozoan parasites Toxoplasma gondii, Plasmodium spp., and Leishmania spp.
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.
Long-lived plasma cells and memory B cells are the primary cellular components of long-term humoral immunity and as such are vitally important for the protection afforded by most vaccines. The SAP gene has been identified as the genetic locus responsible for X-linked lymphoproliferative disease, a fatal immunodeficiency. Mutations in SAP have also been identified in some cases of severe common variable immunodeficiency disease. The underlying cellular basis of this genetic disorder remains unclear. We have used a SAP knockout mouse model system to explore the role of SAP in immune responses. Here we report that mice lacking expression of SAP generate strong acute IgG antibody responses after viral infection, but show a near complete absence of virus-specific long-lived plasma cells and memory B cells, despite the presence of virus-specific memory CD4+ T cells. Adoptive transfer experiments show that SAP-deficient B cells are normal and the defect is in CD4+ T cells. Thus, SAP has a crucial role in CD4+ T-cell function: it is essential for late B-cell help and the development of long-term humoral immunity but is not required for early B-cell help and class switching.
Although naturally occurring smallpox was eliminated through the efforts of the World Health Organization Global Eradication Program, it remains possible that smallpox could be intentionally released. Here we examine the magnitude and duration of antiviral immunity induced by one or more smallpox vaccinations. We found that more than 90% of volunteers vaccinated 25-75 years ago still maintain substantial humoral or cellular immunity (or both) against vaccinia, the virus used to vaccinate against smallpox. Antiviral antibody responses remained stable between 1-75 years after vaccination, whereas antiviral T-cell responses declined slowly, with a half-life of 8-15 years. If these levels of immunity are considered to be at least partially protective, then the morbidity and mortality associated with an intentional smallpox outbreak would be substantially reduced because of pre-existing immunity in a large number of previously vaccinated individuals.
Memory B cells are a central component of humoral immunity, and yet little is known about their longevity in humans. Immune memory after smallpox vaccination (DryVax) is a valuable benchmark for understanding the longevity of B cell memory in the absence of re-exposure to Ag. In this study, we demonstrate that smallpox vaccine-specific memory B cells last for >50 years in immunized individuals. Virus-specific memory B cells initially declined postimmunization, but then reached a plateau approximately 10-fold lower than peak and were stably maintained for >50 years after vaccination at a frequency of approximately 0.1% of total circulating IgG(+) B cells. These persisting memory B cells were functional and able to mount a robust anamnestic Ab response upon revaccination. Additionally, virus-specific CD4(+) T cells were detected decades after vaccination. These data show that immunological memory to DryVax vaccine is long-lived and may contribute to protection against smallpox.
The 114-day epidemic of the severe acute respiratory syndrome (SARS) swept 29 countries, affected a reported 8,098 people, left 774 patients dead and almost paralyzed the Asian economy. Aggressive quarantine measures, possibly aided by rising summer temperatures, successfully terminated the first eruption of SARS and provided at least a temporal break, which allows us to consolidate what we have learned so far and plan for the future. Here, we review the genomics of the SARS coronavirus (SARS-CoV), its phylogeny, antigenic structure, immune response and potential therapeutic interventions should the SARS epidemic flare up again.
New and emerging infectious diseases continue to plague the world, and there is significant concern that recombinant infectious agents can be used as bioterrorism threats. Microbiologists are increasingly being asked to apply their scientific knowledge to respond to these threats. The recent pandemic caused by the severe acute respiratory syndrome (SARS) coronavirus illustrated not only how a newly evolved pathogen can rapidly spread throughout the world but also how the global community can unite to identify the causative agent and control its spread. Rapid response research mechanisms, such as those used by the SARS Accelerated Vaccine Initiative (SAVI), have shown that the application of emergency management techniques, together with rapid response research, can be highly effective when applied appropriately to new infectious diseases.
Recent outbreaks of highly pathogenic avian influenza A virus infections (H5 and H7 subtypes) in poultry and in humans (through direct contact with infected birds) have had important economic repercussions and have raised concerns that a new influenza pandemic will occur in the near future. The eradication of pathogenic avian influenza viruses seems to be the most effective way to prevent influenza pandemics, although this strategy has not proven successful so far. Here, we review the molecular factors that contribute to the emergence of pandemic strains.
T cell expansion and memory formation are generally more effective when elicited by live organisms than by inactivated vaccines. Elucidation of the underlying mechanisms is important for vaccination and therapeutic strategies. We show that the massive expansion of antigen-specific CD8 T cells that occurs in response to viral infection is critically dependent on the direct action of type I interferons (IFN-Is) on CD8 T cells. By examining the response to infection with lymphocytic choriomeningitis virus using IFN-I receptor-deficient (IFN-IR(0)) and -sufficient CD8 T cells adoptively transferred into normal IFN-IR wild-type hosts, we show that the lack of direct CD8 T cell contact with IFN-I causes >99% reduction in their capacity to expand and generate memory cells. The diminished expansion of IFN-IR(0) CD8 T cells was not caused by a defect in proliferation but by poor survival during the antigen-driven proliferation phase. Thus, IFN-IR signaling in CD8 T cells is critical for the generation of effector and memory cells in response to viral infection.
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 Spanish influenza pandemic of 1918 to 1919 swept the globe and resulted in the deaths of at least 20 million people. The basis of the pulmonary damage and high lethality caused by the 1918 H1N1 influenza virus remains largely unknown. Recombinant influenza viruses bearing the 1918 influenza virus hemagglutinin (HA) and neuraminidase (NA) glycoproteins were rescued in the genetic background of the human A/Texas/36/91 (H1N1) (1918 HA/NA:Tx/91) virus. Pathogenesis experiments revealed that the 1918 HA/NA:Tx/91 virus was lethal for BALB/c mice without the prior adaptation that is usually required for human influenza A H1N1 viruses. The increased mortality of 1918 HA/NA:Tx/91-infected mice was accompanied by (i) increased (>200-fold) viral replication, (ii) greater influx of neutrophils into the lung, (iii) increased numbers of alveolar macrophages (AMs), and (iv) increased protein expression of cytokines and chemokines in lung tissues compared with the levels seen for control Tx/91 virus-infected mice. Because pathological changes in AMs and neutrophil migration correlated with lung inflammation, we assessed the role of these cells in the pathogenesis associated with 1918 HA/NA:Tx/91 virus infection. Neutrophil and/or AM depletion initiated 3 or 5 days after infection did not have a significant effect on the disease outcome following a lethal 1918 HA/NA:Tx/91 virus infection. By contrast, depletion of these cells before a sublethal infection with 1918 HA/NA:Tx/91 virus resulted in uncontrolled virus growth and mortality in mice. In addition, neutrophil and/or AM depletion was associated with decreased expression of cytokines and chemokines. These results indicate that a human influenza H1N1 virus possessing the 1918 HA and NA glycoproteins can induce severe lung inflammation consisting of AMs and neutrophils, which play a role in controlling the replication and spread of 1918 HA/NA:Tx/91 virus after intranasal infection of mice.
Functional impairment of antigen-specific T cells is a defining characteristic of many chronic infections, but the underlying mechanisms of T-cell dysfunction are not well understood. To address this question, we analysed genes expressed in functionally impaired virus-specific CD8 T cells present in mice chronically infected with lymphocytic choriomeningitis virus (LCMV), and compared these with the gene profile of functional memory CD8 T cells. Here we report that PD-1 (programmed death 1; also known as Pdcd1) was selectively upregulated by the exhausted T cells, and that in vivo administration of antibodies that blocked the interaction of this inhibitory receptor with its ligand, PD-L1 (also known as B7-H1), enhanced T-cell responses. Notably, we found that even in persistently infected mice that were lacking CD4 T-cell help, blockade of the PD-1/PD-L1 inhibitory pathway had a beneficial effect on the 'helpless' CD8 T cells, restoring their ability to undergo proliferation, secrete cytokines, kill infected cells and decrease viral load. Blockade of the CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitory pathway had no effect on either T-cell function or viral control. These studies identify a specific mechanism of T-cell exhaustion and define a potentially effective immunological strategy for the treatment of chronic viral infections.
The continued westward dissemination of H5N1 influenza A viruses in avian populations and the nearly 50% mortality rate of humans infected with H5N1 are a source of great international concern. A mutant H5N1 virus with the capability to spread rapidly between humans could cause a global catastrophe. Governments have reacted by developing national response plans, stockpiling antiviral drugs and speeding up the development and approval of vaccines. Here we summarize what is known about the interaction between influenza A viruses and the mammalian host response, specifically emphasizing issues that might be of interest to the broader immunology community.
Numerous studies over the past 10 years have demonstrated the importance of naturally occurring CD4+ CD25+ Foxp3+ regulatory T cells (nTregs) in immune regulation. We analyzed the mechanism of action of nTregs in a well-characterized model of autoimmune gastritis and demonstrated that nTregs act at an early stage of disease progression to inhibit the differentiation of naïve T cells to pathogenic T-helper 1 effectors. The effects of nTregs in this model are not antigen-specific but are mediated by activation of the nTregs by ubiquitous self-peptide major histocompatibility complex class II complexes together with cytokines released by activated effector cells. Studies in vitro confirmed that some nTregs exist in an activated state in vivo and can be activated to exert non-specific suppressor effector function by stimulation with interleukin-2 in the absence of engagement of their T-cell receptor. Natural Tregs can differentiate in vitro to exhibit potent granzyme B-dependent, partially perforin-independent cytotoxic cells that are capable of specifically killing antigen-presenting B cells. Natural Treg-mediated killing of antigen-presenting cells may represent one pathway by which they can induce long-lasting suppression of autoimmune disease.
The influenza pandemic of 1918-19 was responsible for about 50 million deaths worldwide. Modern histopathological analysis of autopsy samples from human influenza cases from 1918 revealed significant damage to the lungs with acute, focal bronchitis and alveolitis associated with massive pulmonary oedema, haemorrhage and rapid destruction of the respiratory epithelium. The contribution of the host immune response leading to this severe pathology remains largely unknown. Here we show, in a comprehensive analysis of the global host response induced by the 1918 influenza virus, that mice infected with the reconstructed 1918 influenza virus displayed an increased and accelerated activation of host immune response genes associated with severe pulmonary pathology. We found that mice infected with a virus containing all eight genes from the pandemic virus showed marked activation of pro-inflammatory and cell-death pathways by 24 h after infection that remained unabated until death on day 5. This was in contrast with smaller host immune responses as measured at the genomic level, accompanied by less severe disease pathology and delays in death in mice infected with influenza viruses containing only subsets of 1918 genes. The results indicate a cooperative interaction between the 1918 influenza genes and show that study of the virulence of the 1918 influenza virus requires the use of the fully reconstructed virus. With recent concerns about the introduction of highly pathogenic avian influenza viruses into humans and their potential to cause a worldwide pandemic with disastrous health and economic consequences, a comprehensive understanding of the global host response to the 1918 virus is crucial. Moreover, understanding the contribution of host immune responses to virulent influenza virus infections is an important starting point for the identification of prognostic indicators and the development of novel antiviral therapies.
A defining characteristic of persistent viral infections is the loss and functional inactivation of antiviral effector T cells, which prevents viral clearance. Interleukin-10 (IL-10) suppresses cellular immune responses by modulating the function of T cells and antigen-presenting cells. In this paper, we report that IL-10 production is drastically increased in mice persistently infected with lymphocytic choriomeningitis virus. In vivo blockade of the IL-10 receptor (IL-10R) with a neutralizing antibody resulted in rapid resolution of the persistent infection. IL-10 secretion was diminished and interferon gamma production by antiviral CD8+ T cells was enhanced. In persistently infected mice, CD8alpha+ dendritic cell (DC) numbers declined early after infection, whereas CD8alpha- DC numbers were not affected. CD8alpha- DCs supported IL-10 production and subsequent dampening of antiviral T cell responses. Therapeutic IL-10R blockade broke the cycle of IL-10-mediated immune suppression, preventing IL-10 priming by CD8alpha- DCs and enhancing antiviral responses and thereby resolving infection without causing immunopathology.
Persistent viral infections are a major health concern. One obstacle inhibiting the clearance of persistent infections is functional inactivation of antiviral T cells. Although such immunosuppression occurs rapidly after infection, the mechanisms that induce the loss of T-cell activity and promote viral persistence are unknown. Herein we document that persistent viral infection in mice results in a significant upregulation of interleukin (IL)-10 by antigen-presenting cells, leading to impaired T-cell responses. Genetic removal of Il10 resulted in the maintenance of robust effector T-cell responses, the rapid elimination of virus and the development of antiviral memory T-cell responses. Therapeutic administration of an antibody that blocks the IL-10 receptor restored T-cell function and eliminated viral infection. Thus, we identify a single molecule that directly induces immunosuppression leading to viral persistence and demonstrate that a therapy to neutralize IL-10 results in T-cell recovery and the prevention of viral persistence.
The 1918 influenza pandemic was unusually severe, resulting in about 50 million deaths worldwide. The 1918 virus is also highly pathogenic in mice, and studies have identified a multigenic origin of this virulent phenotype in mice. However, these initial characterizations of the 1918 virus did not address the question of its pathogenic potential in primates. Here we demonstrate that the 1918 virus caused a highly pathogenic respiratory infection in a cynomolgus macaque model that culminated in acute respiratory distress and a fatal outcome. Furthermore, infected animals mounted an immune response, characterized by dysregulation of the antiviral response, that was insufficient for protection, indicating that atypical host innate immune responses may contribute to lethality. The ability of influenza viruses to modulate host immune responses, such as that demonstrated for the avian H5N1 influenza viruses, may be a feature shared by the virulent influenza viruses.
A pandemic H5N1 influenza outbreak would be facilitated by an absence of immunity to the avian-derived virus in the human population. Although this condition is likely in regard to hemagglutinin-mediated immunity, the neuraminidase (NA) of H5N1 viruses (avN1) and of endemic human H1N1 viruses (huN1) are classified in the same serotype. We hypothesized that an immune response to huN1 could mediate cross-protection against H5N1 influenza virus infection.
Mice were immunized against the NA of a contemporary human H1N1 strain by DNA vaccination. They were challenged with recombinant A/Puerto Rico/8/34 (PR8) viruses bearing huN1 (PR8-huN1) or avN1 (PR8-avN1) or with H5N1 virus A/Vietnam/1203/04. Additional naïve mice were injected with sera from vaccinated mice prior to H5N1 challenge. Also, serum specimens from humans were analyzed for reactivity with avN1. Immunization elicited a serum IgG response to huN1 and robust protection against the homologous challenge virus. Immunized mice were partially protected from lethal challenge with H5N1 virus or recombinant PR8-avN1. Sera transferred from immunized mice to naïve animals conferred similar protection against H5N1 mortality. Analysis of human sera showed that antibodies able to inhibit the sialidase activity of avN1 exist in some individuals.
These data reveal that humoral immunity elicited by huN1 can partially protect against H5N1 infection in a mammalian host. Our results suggest that a portion of the human population could have some degree of resistance to H5N1 influenza, with the possibility that this could be induced or enhanced through immunization with seasonal influenza vaccines.
The programmed cell death 1 (PD-1) surface receptor binds to two ligands, PD-L1 and PD-L2. Studies have shown that PD-1-PD-L interactions control the induction and maintenance of peripheral T cell tolerance and indicate a previously unknown function for PD-L1 on nonhematopoietic cells in protecting tissues from autoimmune attack. PD-1 and its ligands have also been exploited by a variety of microorganisms to attenuate antimicrobial immunity and facilitate chronic infection. Here we examine the functions of PD-1 and its ligands in regulating antimicrobial and self-reactive T cell responses and discuss the therapeutic potential of manipulating this pathway.
The quadrivalent (types 6, 11, 16, and 18) human papillomavirus (HPV) L1 virus-like-particle vaccine was 95%-100% effective in preventing cervical and genital disease related to HPV-6, -11, -16, and -18. Vaccine efficacy is thought to be mediated by humoral immunity. Here, we analyze the effect of the baseline characteristics of subjects on vaccine-induced immune responses.
Immunogenicity data from 12,343 subjects 9-26 years old randomized to quadrivalent HPV vaccine or placebo in phase 2/3 studies were analyzed. Covariates examined were day 1 HPV serostatus, age, race/ethnicity, region of residence, lactation status, hormonal contraceptive usage, smoking status, Pap test diagnosis, immunosuppressant or anti-inflammatory agent use, and number of sex partners. Anti-HPV responses were summarized as serum anti-HPV-6, -11, -16, or -18 geometric mean titers 1 month after dose 3.
Age at vaccination initiation was inversely proportional to the vaccine-induced anti-HPV response. Vaccination of subpopulations of subjects who were seropositive at day 1 to a vaccine HPV type resulted in more robust anti-HPV responses to that type, compared with those in subjects who were seronegative at baseline. Anti-HPV responses were comparable among the remaining demographic subgroups.
The immunogenicity of quadrivalent HPV vaccine was comparable among subjects with differing baseline characteristics. These data support vaccination with quadrivalent HPV vaccine across a broad range of baseline subject characteristics.
Conventional models suggest that long-term antibody responses are maintained by the continuous differentiation of memory B cells into antibody-secreting plasma cells. This is based on the notion that plasma cells are short-lived and need to be continually replenished by memory B cells. We examined the issue of plasma cell longevity by following the persistence of LCMV-specific antibody and plasma cell numbers after in vivo depletion of memory B cells and by adoptive transfer of virus-specific plasma cells into naive mice. The results show that a substantial fraction of plasma cells can survive and continue to secrete antibody for extended periods of time (>1 year) in the absence of any detectable memory B cells. This study documents the existence of long-lived plasma cells and demonstrates a new mechanism by which humoral immunity is maintained.
We have studied five cases suggesting a relation between Epstein-Barr virus infection and primary lymphoma of the central nervous system. A 48-year-old man had primary lymphoma of the central nervous system in the absence of systemic lymphoma or immunosuppression. Development of the tumor was associated with serologic evidence suggesting a recent primary infection with Epstein-Barr virus. DNA preparations from tumor tissue, but not from adjacent normal brain tissue, contained Epstein-Barr virus genomes when hybridized with a probe consisting of the BamHI K fragment of Epstein-Barr virus strain FF41. Evaluation of serum samples from four additional patients with central-nervous-system lymphoma revealed patterns of Epstein-Barr virus-specific antibody that were suggestive of an ongoing infection with EBV. Our results suggest induction of the lymphoma by Epstein-Barr virus.
In a study designed to determine whether cytotoxic T lymphocytes contribute to immunity against influenza virus infection, we inoculated 63 volunteers intranasally with live unattenuated influenza A/Munich/1/79 virus. Over the next seven days clinical observations were made, and the amount of virus shed was measured. The protective effects of preinfection serum antibody and of cytotoxic T-cell immunity against influenza A virus were assessed for each participant. All subjects with demonstrable T-cell responses cleared virus effectively. This response was observed in volunteers in all age groups, including those born after 1956, who did not have specific antibody and hence had probably not been exposed to this subtype of influenza A virus before. Cytotoxic T cells show cross-reactivity in their recognition of the different subtypes of influenza A virus, in contrast to the antibody response that is specific for each virus subtype. We conclude that cytotoxic T cells play a part in recovery from influenza virus infection.
Observations made on children with genetic deficiencies of their immune system reveal that those lacking the capacity to make antibodies nevertheless handle most viral infections as well as normal individuals do. Such a- or hypogammaglobulinemic children are often susceptible to bacterial infections. Conversely, children with genetic deficiencies in their ability to mount cell-mediated immune responses or those who acquire diseases of lymphoid tissues later in life are often susceptible to a range of viral infections (reviewed in Good 1991; Riches 1992).
Immune protection is based on long-lived memory cells and effector cells, which are either cytotoxic or secrete antibodies. The lifespan of these effector cells has not so far been determined. Here we show that antibody-secreting plasma cells from bone marrow are as long-lived as memory B cells.
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.
Production of antibodies can last for a lifetime, through mechanisms that remain poorly understood. Here, we show that human
memory B lymphocytes proliferate and differentiate into plasma cells in response to polyclonal stimuli, such as bystander
T cell help and CpG DNA. Furthermore, plasma cells secreting antibodies to recall antigens are produced in vivo at levels
proportional to the frequency of specific memory B cells, even several years after antigenic stimulation. Although antigen
boosting leads to a transient increase in specific antibody levels, ongoing polyclonal activation of memory B cells offers
a means to maintain serological memory for a human lifetime.
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.
Toll-like receptors (TLRs) are a family of pattern-recognition receptors that are an important link between innate and adaptive immunity. Many established, as well as experimental, vaccines incorporate ligands for TLRs, not only to protect against infectious diseases but also in therapeutic immunization against noninfectious diseases, such as cancer. We review the underlying mechanisms by which engagement of TLR signaling pathways might trigger an adaptive immune response after immunization. Although the engagement of TLR signaling pathways is a promising mechanism for boosting vaccine responses, questions of efficacy, feasibility and safety remain the subject of active investigation.
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Vaccination is the most effective means of preventing infectious diseases. Despite the success of many vaccines, there is presently little knowledge of the immunological mechanisms that mediate their efficacy. Such information will be critical in the design of future vaccines against old and new infectious diseases. Recent advances in immunology are beginning to provide an intellectual framework with which to address fundamental questions about how the innate immune system shapes adaptive immunity. In this review, we summarize current knowledge about how the innate immune system modulates the quantity and quality of long-term T and B cell memory and protective immune responses to pathogens. In addition, we point out unanswered questions and identify critical challenges, the solution of which, we believe, will greatly facilitate the rational design of novel vaccines against a multitude of emerging infections.
In the past few years progress has been made in understanding the molecular mechanisms that underlie the initial generation, and the ensuing differentiation and maintenance, of humoral and cellular immunity. Although B and T cell immunological memory contribute to protective immunity through fundamentally distinct effector functions, interesting analogies are becoming apparent between the two memory compartments. These include heterogeneity in function, anatomical location and phenotype, which probably relate to differential environmental cues during the early priming events as well as the later differentiation phases. Detailed definition of the molecular and cellular signals involved in the development of immunological memory, and the relative contributions of different memory subsets to protective immunity, remains an important goal.
The interface between an infectious agent and its host represents the ultimate battleground for survival: The microbe must
secure a niche for replication, whereas the host must limit the pathogen's advance. Among the host's arsenal of antimicrobial
factors, the type 1 interferons (IFNs) induce potent defense mechanisms against viruses and are key in the host-virus standoff.
Viruses have evolved multiple tricks to avoid the immediate antiviral effects of IFNs and, in turn, hosts have adapted use
of this innate cytokine system to galvanize multiple additional layers of immune defense. The plasticity that exists in these
interactions provides us with a lesson in détente.
The smallpox vaccine consists of live vaccinia virus and is generally considered the gold standard of vaccines, since it is the only one that has led to the complete eradication of an infectious disease from the human population. Renewed fears that smallpox might be deliberately released in an act of bioterrorism have led to resurgence in the study of immunity and immunological memory to vaccinia virus and other poxviruses. Here we review our current understanding of memory T-cell, memory B-cell, and antibody responses to vaccinia and related poxviruses, both in animal models and human subjects. Of particular interest are recent advances in understanding protective immunity to poxviruses, quantifying immunological memory to the smallpox vaccine in humans, and identifying major vaccinia-specific T-cell and B-cell epitopes. In addition, potential mechanisms for maintenance of immunological memory are discussed.
The idea of immunological memory originally arose from the observation that survivors of infections were subsequently resistant to disease caused by the same infection. While most immunologists accept a special 'remembering' memory quality, we have argued previously and document here that increased resistance against re-infection, i.e. immunity, reflects low-level antigen-driven T- and B-cell responses, resulting in elevated serum or mucosal titers of protective antibodies or of activated T cells, respectively. Periodic antigen re-exposure is from within, by persisting infection (long-term) or by immune complexes (short-term), or from without, by low-level re-infections. This simple concept is supported by clinical evidence and model experiments but is often ignored, although this concept, but not so-called 'immunological memory', as defined in textbooks (i.e. earlier and better responses of a primed host), is compatible with evolutionary maternal antibody transfer of protection as well as immunity against existing infections. The concept of 'immunity without immunological remembering memory' explains why it is easy to generate vaccines against acute cytopathic infections, particularly those of early childhood, where neutralizing antibodies are the key to protection, because it has been validated by adoptive transfer of maternal antibodies. It also explains why we have not succeeded (yet?) to generate truly protective vaccines against persisting infections, because we cannot imitate 'infection immunity' that is long-lasting, generating protective T- and B-cell stimulation against variable infections without causing disease by either immunopathology or tolerance.
We have outlined the carefully orchestrated process of CD4+ T-cell differentiation from naïve to effector and from effector to memory cells with a focus on how these processes can be studied in vivo in responses to pathogen infection. We emphasize that the regulatory factors that determine the quality and quantity of the effector and memory cells generated include (i) the antigen dose during the initial T-cell interaction with antigen-presenting cells; (ii) the dose and duration of repeated interactions; and (iii) the milieu of inflammatory and growth cytokines that responding CD4+ T cells encounter. We suggest that heterogeneity in these regulatory factors leads to the generation of a spectrum of effectors with different functional attributes. Furthermore, we suggest that it is the presence of effectors at different stages along a pathway of progressive linear differentiation that leads to a related spectrum of memory cells. Our studies particularly highlight the multifaceted roles of CD4+ effector and memory T cells in protective responses to influenza infection and support the concept that efficient priming of CD4+ T cells that react to shared influenza proteins could contribute greatly to vaccine strategies for influenza.
Natural FOXP3+CD25+CD4+ regulatory T cells (Tregs) actively suppress pathological and physiological immune responses, contributing to the maintenance of immunological self-tolerance and immune homeostasis. Various molecular and cellular events have been described to explain the mechanism(s) of Treg-mediated suppression. However, none of the proposed mechanisms can explain all aspects of suppression. It is probable that various combinations of several mechanisms are operating, depending on the milieu and the type of immune responses, although there might be a single key mechanism that has a predominant role. Further studies of suppression and search for Treg-specific cell surface molecules are required for potential clinical application to treat and prevent immunological diseases and to control immune responses for the benefit of the host.
The development and maintenance of regulatory T (T-reg) cells is crucial for determining the level of reactivity in the immune system. Until recently, however, surprisingly little was known about the factors involved in the development of these cells in the thymus or the mechanisms that maintain them in the periphery. Studies have now demonstrated that thymic development of T-reg cells is facilitated by TCRs with increased affinity for self-peptide-MHC complexes. Increased TCR affinity alone, however, is not sufficient to support the development of T-reg cells, and external factors such as CD80 and CD86, ligands for co-stimulatory receptor CD28, and interleukin 2 are required. These factors are also needed to maintain the T-reg cell subset in the periphery.
CD4(+) effector T cells have been categorized into two subsets: T helper type 1 (T(H)1) and T(H)2. Another subset of T cells that produce interleukin 17 (IL-17; 'T(H)-17 cells') has been identified that is highly proinflammatory and induces severe autoimmunity. Whereas IL-23 serves to expand previously differentiated T(H)-17 cell populations, IL-6 and transforming growth factor-beta (TGF-beta) induce the differentiation of T(H)-17 cells from naive precursors. These data suggest a dichotomy between CD4(+) regulatory T cells positive for the transcription factor Foxp3 and T(H)-17 cells: TGF-beta induces Foxp3 and generates induced regulatory T cells, whereas IL-6 inhibits TGF-beta-driven Foxp3 expression and together with TGF-beta induces T(H)-17 cells. Emerging data regarding T(H)-17 cells suggest a very important function for this T cell subset in immunity and disease.
Administration of a quadrivalent HPV-6/ 1/16/18 vaccine to 16- to 26-year-old women was highly effective in preventing HPV-6/ 1/16/18-related cervical/vulvar/vaginal precancerous lesions and genital warts. As the risk of acquiring HPV significantly rises after sexual debut, HPV vaccines should have the greatest benefit in sexually naive adolescents. We evaluated the tolerability and immunogenicity of quadrivalent vaccine in males and females 9 to 15 years of age through 18 months postenrollment.
In this randomized, double-blind trial, 1781 sexually naive children were assigned (2:1) to quadrivalent HPV-6/11/16/18 vaccine or saline placebo administered at day 1 and months 2 and 6. Serum neutralizing anti-HPV-6/11/16/18 responses were summarized as geometric mean titers (GMTs) and seroconversion rates. Primary analyses were done per-protocol (subjects received 3 doses, had no major protocol violations and were HPV type-specific seronegative at day 1). Adverse experiences were collected by diary card.
At month 7, seroconversion rates were > or =99.5% for the 4 vaccine-HPV-types. GMTs and seroconversion rates in boys were noninferior to those in girls (P < 0.001). At month 18, > or =91.5% of vaccine recipients were seropositive, regardless of gender. A higher proportion of vaccine recipients (75.3%) than placebo recipients (50.0%) reported one or more injection-site adverse experiences following any vaccination. Rates of fever were similar between vaccination groups. No serious vaccine-related adverse experiences were reported.
In 9- to 15-year-old adolescents, the quadrivalent vaccine was generally well tolerated and induced persistent anti-HPV serologic responses in the majority of subjects for at least 12 months following completion of a three-dose regimen. The vaccine durability supports universal HPV vaccination programs in adolescents to reduce the burden of clinical HPV disease, particularly cervical cancer and precancers.
Interleukin-10 determines viral clearance or persistence in vivo 36. Ejrnaes, M. et al. Resolution of a chronic viral infection after interleukin-10 receptor blockade
- D G Brooks
Brooks, D.G. et al. Interleukin-10 determines viral clearance or persistence in vivo. Nat. Med. 12, 1301–1309 (2006). 36. Ejrnaes, M. et al. Resolution of a chronic viral infection after interleukin-10 receptor blockade. J. Exp. Med. 203, 2461–2472 (2006).
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Linder, F.E. & Grove, R.D. Vital statistics rates in the United States: 1900–1940. (US Government Printing Office, Washington, D.C., 1947) < http://www.cdc.gov/nchs/data/ vsus/vsrates1900_40.pdf>. NATURE IMMUNOLOGY VOLUME 8 NUMBER 11 NOVEMBER 2007 1 1 9 3 R E V I E W © 2007 Nature Publishing Group http://www.nature.com/natureimmunology