Journal Pouch: Avian and Pandemic Influenza, 12 Nov 2012

Highlights

  • In The News
  • Featured: Pandemic Preparedness
  • Featured: Bat Influenza Virus
  • Influenza Research
  • Immunogenicity
  • Vaccines and Antivirals
  • Zoonoses & Animal Diseases
  • H1N1pdm09 Lessons Learned
  • Country Studies (Mexico, Spain, USA, Canada, et al.)

Recent Journal Articles

In The News
AUTISM AFTER INFECTION, FEBRILE EPISODES, AND ANTIBIOTIC USE DURING PREGNANCY: AN EXPLORATORY STUDY
Pediatrics (12 Nov 2012).
ABSTRACT: It has been suggested that maternal immune activation during pregnancy is associated with cardinal behaviors of autism in the offspring. Epidemiologic studies have yielded conflicting results concerning the association between any infection during pregnancy and the development of autism.This population-based cohort study investigated the association between specific common infectious diseases, febrile episodes, or use of antibiotics during pregnancy by using maternal population-based self-reported data.
SUSTAINED HIGH INFLUENZA VACCINATION RATES AND DECREASED SAFETY CONCERNS AMONG PREGNANT WOMEN DURING THE 2010–2011 INFLUENZA SEASON
Vaccine (11 Nov 2012). M. Drees et al.
ABSTRACT: Intense efforts to vaccinate pregnant women against 2009 H1N1 influenza resulted in much higher vaccine uptake than previously reported. We surveyed postpartum women to determine whether high vaccination rates were sustained during the 2010–11 influenza season. Methods We performed cross-sectional surveys of postpartum women delivering at our institution during February–April 2010 and February–March 2011. The surveys ascertained maternal characteristics, history of influenza vaccination, and reasons for lack of vaccination. Results During the 2010–11 season, 165 (55%) of 300 women surveyed reported receiving influenza vaccination, compared to 191 of 307 (62%) during 2009–10 (p =0.08). Vaccination by an obstetrical provider was common, but decreased compared to 2009–10 (60% vs. 71%, p =0.04). While most women (76%) in 2010–11 reported that their provider recommended influenza vaccination, significantly more reported lack of discussion about vaccination (24% vs. 11%, p <0.01) compared to 2009–10. Vaccine safety concerns were cited by most (66%) women declining vaccination during 2009–10 but only 27% of women in 2010–11. Conclusion Vaccination rates among pregnant women at our institution were relatively sustained, although fewer providers appear to be discussing influenza vaccination in pregnancy. Concern about vaccine safety, the primary barrier during 2009–10, was much less prominent. Highlights * Influenza vaccination rates in pregnancy were sustained in 2010–11 vs. 2009–10. * Fewer pregnant women were vaccinated by their obstetrical provider in 2010–11. * Twice as many women reported that their provider did not mention flu vaccination. * Vaccine safety concerns were much less prominent in 2010–11.
DYNAMIC MODELLING OF COSTS AND HEALTH CONSEQUENCES OF SCHOOL CLOSURE DURING AN INFLUENZA PANDEMIC
BMC Public Health (09 Nov 2012). Yiting Xue.
ABSTRACT: The purpose of this article is to evaluate the cost-effectiveness of school closure during a potential influenza pandemic and to examine the trade-off between costs and health benefits for school closure involving different target groups and different closure durations. Methods: We developed two models: a dynamic disease model capturing the spread of influenza and an economic model capturing the costs and benefits of school closure. Decisions were based on quality-adjusted life years gained using incremental cost-effectiveness ratios. The disease model is an age-structured SEIR compartmental model based on the population of Oslo. We studied the costs and benefits of school closure by varying the age targets (kindergarten, primary school, secondary school) and closure durations (1--10 weeks), given pandemics with basic reproductive number of 1.5, 2.0 or 2.5. Results: The cost-effectiveness of school closure varies depending on the target group, duration and whether indirect costs are considered. Using a case fatality rate (CFR) of 0.1-0.2% and with current cost-effectiveness threshold for Norway, closing secondary school is the only cost-effective strategy, when indirect costs are included. The most cost-effective strategies would be closing secondary schools for 8 weeks if R0=1.5, 6 weeks if R0=2.0, and 4 weeks if R0= 2.5. For severe pandemics with case fatality rates of 1-2%, similar to the Spanish flu, or when indirect costs are disregarded, the optimal strategy is closing kindergarten, primary and secondary school for extended periods of time. For a pandemic with 2009 H1N1 characteristics (mild severity and low transmissibility), closing schools would not be cost-effective, regardless of the age target of school children. Conclusions: School closure has moderate impact on the epidemic's scope, but the resulting disruption to society imposes a potentially great cost in terms of lost productivity from parents' work absenteeism.
Featured: Pandemic Preparedness
ARE WE PREPARED TO HELP LOW-RESOURCE COMMUNITIES COPE WITH A SEVERE INFLUENZA PANDEMIC?
Influenza and Other Respiratory Viruses (12 Nov 2012). Eric S. Starbuck et al.
ABSTRACT: Recent research involving lab-modified H5N1 influenza viruses with increased transmissibility and the ongoing evolution of the virus in nature should remind us of the continuing importance of preparedness for a severe influenza pandemic. Current vaccine technology and antiviral supply remain inadequate, and in a severe pandemic, most low-resource communities will fail to receive adequate medical supplies. However, with suitable guidance, these communities can take appropriate actions without substantial outside resources to reduce influenza transmission and care for the ill. Such guidance should be completed, and support provided to developing countries to adapt it for their settings and prepare for implementation.
Featured: Bat Influenza Virus
BAT INFLUENZA VIRUS N10 STRUCTURE AND FUNCTION [MICROBIOLOGY]
Proceedings of the National Academy of Sciences (13 Nov 2012). Li, Q. et al.
ABSTRACT: The recent discovery of the unique genome of influenza virus H17N10 in bats raises considerable doubt about the origin and evolution of influenza A viruses. It also identifies a neuraminidase (NA)-like protein, N10, that is highly divergent from the nine other well-established serotypes of influenza A NA (N1–N9).
STRUCTURES OF BAT FLU VIRUS N10 NA-LIKE PROTEINS [MICROBIOLOGY]
Proceedings of the National Academy of Sciences (13 Nov 2012). Zhu, X et al.
ABSTRACT: Recently, we reported a unique influenza A virus subtype H17N10 from little yellow-shouldered bats. Its neuraminidase (NA) gene encodes a protein that appears to be highly divergent from all known influenza NAs and was assigned as a new subtype N10.
THE NEURAMINIDASE OF BAT INFLUENZA VIRUSES [MICROBIOLOGY]
Proceedings of the National Academy of Sciences (13 Nov 2012). Garcia-Sastre, A.
ABSTRACT: Influenza A viruses are classified into subtypes according to their two viral glycoproteins, hemagglutinin (HA) and neuraminidase (NA). These viruses are known to infect multiple animal species, including humans, pigs, horses, dogs, sea mammals, chickens, ducks, and other birds.
Influenza Research
EVALUATION OF NANOPARTICLE TRACKING ANALYSIS FOR TOTAL VIRUS PARTICLE DETERMINATION
Virology Journal (12 Nov 2012). Petra Kramberger.
ABSTRACT: The NanoSight LM10 with Nanoparticle tracking analysis (NTA) software was evaluated for the quantification of latex particles, adenovirus 5, and influenza virus. The inter-day variability was determined by measuring the same sample over several consecutive days and the method's accuracy was demonstrated by using known concentrations of the subject particles. NTA analysis was also used to quantify chromatographic fractions of adenovirus and influenza virus after purification on a CIM monolithic column. NTA results were compared and evaluated against hemagglutination (HA) and end point dilution assay, determining total and infection virus particle number, respectively. The results demonstrated that nanoparticle tracking analysis is a method for fast estimation of virus concentration in different samples. In addition, it can provide a better insight into the sample status, regarding the level of virus aggregation.
EFFECTIVENESS OF INFLUENZA VACCINATION IN ELDERLY DIABETIC PATIENTS: A RETROSPECTIVE COHORT STUDY
Vaccine (13 Nov 2012). I.-Kuan Wang et al.
ABSTRACT: Studies regarding the clinical benefits of influenza vaccination in diabetic patients are limited. This study evaluated if the elderly diabetic patients who have had influenza vaccination would have benefits such as reduced medical care and mortality. Methods We used the universal insurance claims data from 2001 to 2009 in Taiwan to identify annual elderly patients with diabetes cohorts with (N =4454) and without (N =4571) influenza vaccination. The risk of developing pneumonia or influenza, respiratory failure, intensive care, hospitalization, and mortality were measured and compared between cohorts within one year of follow-up. Results The vaccine cohort had lower incidences of pneumonia or influenza and respiratory failure compared with the non-vaccine cohort. More importantly, the vaccine cohort had a hospitalization rate that was 11% less than the non-vaccine cohort (29.6 vs. 33.1 per 100 person-years) with an adjusted hazard ratio (HR) of 0.88 (95% CI 0.81–0.96). The vaccine cohort was also less likely to be admitted to the intensive care unit (ICU) [0.58 vs. 2.05 per 100 person-year; adjusted HR 0.30 (95% CI 0.19–0.47)] and less likely to expire [3.13 vs. 7.96 per 100 person-year; adjusted HR 0.44 (95% CI 0.36–0.54)]. Influenza vaccination reduced the hospitalization cost by 1282.6 USD, compared with patients without influenza vaccination (95% CI −2210.3, −354.8). Conclusion Influenza vaccination is associated with a reduced risk of morbidity, hospitalization, ICU admissions, and mortality. In addition, the hospitalization cost is reduced. Highlights * We used the universal insurance claims data from 2001 to 2009 in Taiwan. * The elderly diabetic patients with and without influenza vaccination were identified. * Influenza vaccination is associated with a reduced risk of morbidity, and mortality. * In addition, the hospitalization cost is less.
CD4 T-CELL EXPANSION PREDICTS NEUTRALIZING ANTIBODY RESPONSES TO MONOVALENT INACTIVATED PANDEMIC H1N1 INFLUENZA VACCINE
Journal of Infectious Diseases (12 Nov 2012). Nayak, J. L. et al.
ABSTRACT: The ability of influenza vaccines to elicit CD4 T cells and the relationship between induction of CD4 T cells and vaccine-induced neutralizing antibody responses has been controversial. The emergence of the swine-origin H1N1 influenza pandemic (pH1N1) in 2009 provided a unique opportunity to examine responses to an influenza vaccine composed of both novel and previously encountered antigens and to probe the relationship between B and T-cell responses to vaccination.Methods. We tracked CD4 T-cell and antibody responses of human subjects vaccinated with monovalent subunit pH1N1 vaccine. The specificity and magnitude of the CD4 T-cell response was evaluated using cytokine EliSpot assays in conjugation with peptide pools representing distinct influenza proteins.Results. Our studies revealed that vaccination induced readily detectable CD4 T cells specific for conserved portions of hemagglutinin (HA) and the internal viral proteins. Interestingly, expansion of HA-specific CD4 T cells was most tightly correlated with the antibody response.Conclusions. These results indicate that CD4 T-cell expansion may be a limiting factor in development of neutralizing antibody responses to pandemic influenza vaccines and suggest that approaches to facilitate CD4 T-cell recruitment may increase the neutralizing antibody produced in response to vaccines against novel influenza strains.
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS ASSOCIATED WITH INFLUENZA A (H1N1) INFECTION IN A PATIENT WITH CHRONIC LYMPHOCYTIC LEUKEMIA: AN AUTOPSY CASE REPORT AND REVIEW OF THE LITERATURE
Annals of Diagnostic Pathology (11 Nov 2012). Syeling Lai et al.
ABSTRACT: H1N1 influenza A virus can trigger fatal hemophagocytic lymphohistiocytosis in immunocompromised patients and in immunocompetent hosts, usually children. We present a case of a 50-year-old man with low-burden chronic lymphocytic leukemia who had sudden reactivation of his leukemia triggered by influenza A (H1N1) infection with hemophagocytic lymphohistiocytosis during the 2009 H1N1 pandemic. His rapid course was complicated by acute respiratory distress syndrome with diffuse alveolar damage, a 6-fold rise in lymphocyte count, disseminated intravascular coagulation, and, ultimately, cardiac arrest. Major findings at autopsy included: bilateral H1N1 pneumonitis with diffuse alveolar damage, intra-alveolar pulmonary hemorrhage, pulmonary microthromboemboli, pulmonary hemorrhagic infarction, hemophagocytic lymphohistiocytosis in multiple locations, and diffuse chronic lymphocytic leukemia. Hemophagocytic lymphohistiocytosis is a serious and often fatal condition, which may be primary or secondary. It may be associated with high-grade lymphoproliferative malignancies, especially in patients with therapy-related leukocytopenia, but only rarely is it seen in uncomplicated chronic lymphocytic leukemia. Hemophagocytic lymphohistiocytosis may be triggered by a variety of infections (viral, fungal, bacterial and parasitic), but H1N1 influenza A-associated hemophagocytic lymphohistiocytosis is often rapidly fatal, especially in children. This adult patient's clinical presentation with low tumor burden and leukocytosis is thus unique. We review the recently published autopsy findings in fatal influenza A (H1N1) infection and the association with resultant secondary hemophagocytic lymphohistiocytosis.
MAPPING THE PHOSPHOPROTEOME OF INFLUENZA A AND B VIRUSES BY MASS SPECTROMETRY
PLOS Pathogens (08 Nov 2012). Edward C. Hutchinson, et al.
ABSTRACT: Protein phosphorylation is a common post-translational modification in eukaryotic cells and has a wide range of functional effects. Here, we used mass spectrometry to search for phosphorylated residues in all the proteins of influenza A and B viruses – to the best of our knowledge, the first time such a comprehensive approach has been applied to a virus. We identified 36 novel phosphorylation sites, as well as confirming 3 previously-identified sites. N-terminal processing and ubiquitination of viral proteins was also detected. Phosphorylation was detected in the polymerase proteins (PB2, PB1 and PA), glycoproteins (HA and NA), nucleoprotein (NP), matrix protein (M1), ion channel (M2), non-structural protein (NS1) and nuclear export protein (NEP). Many of the phosphorylation sites detected were conserved between influenza virus genera, indicating the fundamental importance of phosphorylation for all influenza viruses. Their structural context indicates roles for phosphorylation in regulating viral entry and exit (HA and NA); nuclear localisation (PB2, M1, NP, NS1 and, through NP and NEP, of the viral RNA genome); and protein multimerisation (NS1 dimers, M2 tetramers and NP oligomers). Using reverse genetics we show that for NP of influenza A viruses phosphorylation sites in the N-terminal NLS are important for viral growth, whereas mutating sites in the C-terminus has little or no effect. Mutating phosphorylation sites in the oligomerisation domains of NP inhibits viral growth and in some cases transcription and replication of the viral RNA genome. However, constitutive phosphorylation of these sites is not optimal. Taken together, the conservation, structural context and functional significance of phosphorylation sites implies a key role for phosphorylation in influenza biology. By identifying phosphorylation sites throughout the proteomes of influenza A and B viruses we provide a framework for further study of phosphorylation events in the viral life cycle and suggest a range of potential antiviral targets. { by Edward C. Hutchinson et al. }
Immunogenicity
IMMUNE EVASION STRATEGIES OF FLAVIVIRUSES
Vaccine (13 Nov 2012). Jing Ye et al.
ABSTRACT: Flavivirus is a genus of the family Flaviviridae. It includes West Nile virus (WNV), dengue virus (DENV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), tick-borne encephalitis virus (TBEV), and several other viruses which lead to extensive morbidity and mortality in humans. To establish infection and replication in the hosts, flaviviruses have evolved a variety of strategies to modulate the host's immune responses. In this review, the strategies employed by flaviviruses to evade the innate and adaptive immunity of host are summarized based on current studies, with a major focus on the inhibition of interferon, complement, natural killer (NK) cell, B cell, and T cell responses. This review aims to provide an overview of the current understanding for the mechanisms used by flaviviruses to escape the host's immune response, which will facilitate the future studies on flavivirus pathogenesis and the development of anti-flavivirus therapeutics. Highlights * Flaviviruses have evolved a variety of strategies to modulate the immune responses of host. * Mechanisms by which flaviviruses evade the innate and adaptive immunity of the host are summarized based on current studies. * Flaviviruses limit type I IFN signaling by blocking the host gene expression, thus attenuating innate immunity. * Flaviviruses also inhibit the antiviral immune response of complement system and NK cells. * High genetic variability of viral antigens allows viral escape from both humoral and cellular immunity against flaviviruses.
IMMUNE RESPONSES AND PROTECTION IN CHILDREN IN DEVELOPING COUNTRIES INDUCED BY ORAL VACCINES
Vaccine (13 Nov 2012). Firdausi Qadri, et al.
ABSTRACT: Oral mucosal vaccines have great promise for generating protective immunity against intestinal infections for the benefit of large numbers of people especially young children. There however appears to be a caveat since these vaccines have to overcome the inbuilt resistance of mucosal surfaces and secretions to inhibit antigen stimulation and responses. Unfortunately, these vaccines are not equally immunogenic nor protective in different populations. When compared to industrialized countries, children living in developing countries appear to have lower responses, but the reasons for these lowered responses are not clearly defined. The most likely explanations relate to undernutrition, micronutrient deficiencies, microbial overload on mucosal surfaces, alteration of microbiome and microbolom and irreversible changes on the mucosa as well as maternal antibodies in serum or breast milk may alter the mucosal pathology and lower immune responses to interventions using oral vaccines. The detrimental effect of adverse environment and malnutrition may bring about irreversible changes in the mucosa of children especially in the first 1000 days of life from conception to after birth and up to two years of age. This review aims to summarize the information available on lowered immune responses to mucosal vaccines and on interventions that may help address the constraints of these vaccines when they are used for children living under the greatest stress and under harmful adverse circumstances. Highlights * Children in developing countries need different dosage/regimes of oral vaccines. * Ty21a vaccine induced serum and mucosal B and T-cell responses were observed. * Administration of rotavirus and OPV may lower the response to rotavirus vaccine. * Zinc has positive effect to immune response to Dukoral and pneumococcal vaccine.
DIFFERENTIAL LOCALIZATION AND FUNCTION OF ANTIBODY-FORMING CELLS RESPONSIVE TO INACTIVATED OR LIVE-ATTENUATED INFLUENZA VIRUS VACCINES
International Immunology (08 Nov 2012). Sealy, R. et al.
ABSTRACT: Currently, there are two different types of licensed influenza virus vaccines available in the USA, the live attenuated cold-adapted vaccine and the inactivated vaccine. Children greater than 2 years of age and adults younger than 50 years (apart from those suffering from immunodeficiencies or lung disease) may choose between the two vaccines. Previous studies have shown that both vaccines elicit significant serum antibody responses. However, comprehensive analyses of antibody-forming cells (AFCs) in the upper respiratory tract (URT), the critical site of pathogen entry, have been lacking. We therefore compared influenza virus-specific antibody and AFC activities in systemic and mucosal tissues following immunizations of cotton rats with inactivated or live-attenuated vaccines, including vaccines from the 2009-10 and 2010-11 seasons. Results demonstrated that inactivated and live-attenuated vaccines induced virus-specific AFCs, but patterns of residence and function were highly disparate. The inactivated vaccine elicited AFCs predominantly in the spleen and bone marrow; IgG was the main isotype. In contrast, the live attenuated vaccine elicited acute and long-sustained AFC responses in the diffuse nasal-associated lymphoid tissue (d-NALT) and lung, with IgA being the predominant isotype. The appearance of these d-NALT URT responses was confirmed by a similar study of the 2009-10 live attenuated vaccine in ferrets. Data emphasize that the inactivated and live-attenuated vaccines that are each capable of protecting humans from influenza virus disease do so by very different modes of immune surveillance.
IMMUNOGENICITY AND ACCEPTANCE OF INFLUENZA A (H1N1) VACCINE IN A COHORT OF CHRONIC HEPATITIS C PATIENTS RECEIVING PEGYLATED-INTERFERON TREATMENT
PLOS ONE (08 Nov 2012). Manuel Hernández-Guerra, et al.
ABSTRACT: Individuals at risk of (H1N1) influenza A infection are recommended to receive vaccination. Chronic hepatitis C (CHC) patients receiving treatment might be at a higher risk of respiratory bacterial infections after influenza infection. However, there are no observational studies evaluating the immunogenicity, tolerance and acceptance of 2009 influenza A vaccine in CHC patients. Methods We evaluated the immunogenicity of influenza A vaccine (Pandemrix®) by using the hemagglutination inhibition (HI) titers method in a well defined cohort of CHC patients receiving or not receiving pegylated-interferon and ribavirin, and compared it with healthy subjects (controls). A group of patients with inflammatory bowel disease (IBD) under immunosuppression, thought to have a lower immune response to seasonal influenza vaccine, were also included as a negative control group. In addition, tolerance to injection site reactions and acceptance was assessed by a validated questionnaire (Vaccinees' perception of injection-VAPI-questionnaire). Results Of 114 subjects invited to participate, 68% accepted and, after exclusions, 72 were included. Post-vaccination geometric mean titers and seroprotection/seroconversion rates were optimal in CHC patients with ongoing treatment (n?=?15; 232, CI95% 46–1166; 93%; 93%), without treatment (n?=?10; 226, CI95% 69–743: 100%; 100%) and controls (n?=?15;168, CI95% 42–680; 93%; 86%) with no differences between groups (P?=?0.8). In contrast, IBD patients had a significantly lower immunogenic response (n?=?27; 60, CI95% 42–680;66%;66%; P?=?0.006). All the groups showed a satisfactory tolerance although CHC patients with ongoing treatment showed more local discomfort after vaccine injection. Conclusion There appeared to be no differences between CHC patients and healthy controls in serological response and acceptance of (H1N1) influenza vaccination.
Vaccines and Antivirals
VACCINES: FROM EMPIRICAL DEVELOPMENT TO RATIONAL DESIGN
PLOS Pathogens (08 Nov 2012). Christine Rueckert, et al.
ABSTRACT: Infectious diseases are responsible for an overwhelming number of deaths worldwide and their clinical management is often hampered by the emergence of multi-drug-resistant strains. Therefore, prevention through vaccination currently represents the best course of action to combat them. However, immune escape and evasion by pathogens often render vaccine development difficult. Furthermore, most currently available vaccines were empirically designed. In this review, we discuss why rational design of vaccines is not only desirable but also necessary. We introduce recent developments towards specifically tailored antigens, adjuvants, and delivery systems, and discuss the methodological gaps and lack of knowledge still hampering true rational vaccine design. Finally, we address the potential and limitations of different strategies and technologies for advancing vaccine development. { by Christine Rueckert et al. }
ANTIVIRULENCE GENES: INSIGHTS INTO PATHOGEN EVOLUTION THROUGH GENE LOSS [MINIREVIEWS]
Infection and Immunity (12 Nov 2012). Bliven, K. A. et al.
ABSTRACT: The emergence of new pathogens and the exploitation of novel pathogenic niches by bacteria typically require the horizontal transfer of virulence factors and subsequent adaptation--a "fine-tuning" process--for the successful incorporation of these factors into the microbe's genome. The function of newly acquired virulence factors may be hindered by the expression of genes already present in the bacterium. Occasionally, certain genes must be inactivated or deleted for full expression of the pathogen phenotype to occur. These genes are known as antivirulence genes (AVGs). Originally identified in Shigella, AVGs have improved our understanding of pathogen evolution and provided a novel approach to drug and vaccine development. In this review, we revisit the AVG definition and update the list of known AVGs, which now includes genes from pathogens such as Salmonella, Yersinia pestis, and the virulent Francisella tularensis subspecies. AVGs encompass a wide variety of different roles within the microbe, including genes involved in metabolism, biofilm synthesis, lipopolysaccharide modification, and host vasoconstriction. More recently, the use of one of these AVGs (lpxL) as a potential vaccine candidate highlights the practical application of studying AVG inactivation in microbial pathogens.
MOLECULAR MECHANISMS UNDERLYING OSELTAMIVIR RESISTANCE MEDIATED BY AN I117V SUBSTITUTION IN THE NEURAMINIDASE OF SUBTYPE H5N1 AVIAN INFLUENZA A VIRUSES
Journal of Infectious Diseases (12 Nov 2012). Takano, R. et al.
ABSTRACT: The neuraminidase (NA) inhibitor oseltamivir is widely used to treat patients infected with influenza viruses. An Ile-to-Val change at position 117 in influenza A virus subtype H5N1 NA (NA-I117V) confers a reduction in susceptibility to oseltamivir carboxylate. However, the in vivo relevance and molecular basis of the decreased sensitivity mediated by this mutation are poorly understood.Methods. We created single-point-mutant viruses with 3 genetically different backgrounds (ie, 1 belonging to clade 1 and 2 belonging to clade 2.3.4) and evaluated the effects of the I117V mutation on oseltamivir susceptibility in vitro, in vivo, and in silico.Results. The NA-I117V mutation conferred a slight reduction in susceptibility to oseltamivir in vitro (1.3- to 6.3-fold changes), although it did not substantially compromise NA enzymatic activity. Mice infected with I117V virus exhibited reduced susceptibility to oseltamivir and decreased survival in 2 of 3 virus pairs tested. Molecular dynamics simulations revealed that I117V caused the loss of hydrogen bonds between an arginine at position 118 and the carboxyl group of oseltamivir, leading to a lower binding affinity for oseltamivir.Conclusions. Our findings provide new insight into the mechanism of NA-I117V-mediated oseltamivir resistance in highly pathogenic H5N1 avian influenza viruses.
EXACERBATION OF INFLUENZA VIRUS INFECTIONS IN MICE BY INTRANASAL TREATMENTS AND IMPLICATIONS FOR EVALUATION OF ANTIVIRAL DRUGS [ANTIVIRAL AGENTS]
Antimicrobial Agents and Chemotherapy (12 Nov 2012). Smee, D. F. et al.
ABSTRACT: Compounds lacking oral activity may be delivered intranasally to treat influenza virus infections in mice. However, intranasal treatments greatly enhance the virulence of such virus infections. This can be partially compensated for by giving reduced virus challenge doses. These can be 100- to 1,000-fold lower than infections without such treatment and still cause equivalent mortality. We found that intranasal liquid treatments facilitate virus production (probably through enhanced virus spread) and that lung pneumonia was delayed by only 2 days relative to a 1,000-fold higher virus challenge dose not accompanied by intranasal treatments. In one study, zanamivir was 90 to 100% effective at 10 mg/kg/day by oral, intraperitoneal, and intramuscular routes against influenza A/California/04/2009 (H1N1) virus in mice. However, the same compound administered intranasally at 20 mg/kg/day for 5 days gave no protection from death although the time to death was significantly delayed. A related compound, Neu5Ac2en (N-acetyl-2,3-dehydro-2-deoxyneuraminic acid), was ineffective at 100 mg/kg/day. Intranasal zanamivir and Neu5Ac2en were 70 to 100% protective against influenza A/NWS/33 (H1N1) virus infections at 0.1 to 10 and 30 to 100 mg/kg/day, respectively. Somewhat more difficult to treat was A/Victoria/3/75 virus that required 10 mg/kg/day of zanamivir to achieve full protection. These results illustrate that treatment of influenza virus infections by the intranasal route requires consideration of both virus challenge dose and virus strain in order to avoid compromising the effectiveness of a potentially useful antiviral agent. In addition, the intranasal treatments were shown to facilitate virus replication and promote lung pathology.
Zoonoses & Animal Diseases
POULTRY REARING AND SLAUGHTERING PRACTICES IN RURAL EGYPT: AN EXPLORATION OF RISK FACTORS FOR H5N1 VIRUS HUMAN TRANSMISSION
Influenza and Other Respiratory Viruses (12 Nov 2012). Anna-Leena Lohiniva et al.
ABSTRACT: Highly pathogenic avian influenza (H5N1) virus continues to cause infections in Egypt. This study describes the practices associated with raising and slaughtering household poultry to identify risk factors for H5N1 infection and reasons for non-compliance with preventive measures. Methods? An investigation was conducted of 56 households with household flocks (19 households with human H5N1 cases, 19 with poultry H5N1 cases, and 18 with no reported poultry or human H5N1 cases). Data were collected via structured observations and in-depth interviews. Results? Half of the households kept at least some free-range poultry and mixed at least some different species of poultry as it was considered beneficial for the poultry. Feeding and cleaning practices exposed children to contact with poultry; slaughtering contaminated homes; use of personal protective barriers was not a norm; waste management exposed the communities to slaughtering waste and dead chickens; and reporting of sick and dead poultry was not a practice. Only minor changes in poultry-handling took place following H5N1 virus outbreaks. Discussion? H5N1 virus prevention in Egypt represents both an epidemiological and socio-cultural challenge. Traditional poultry-rearing practices that likely increase exposures to H5N1-infected poultry are common throughout Egypt. Despite education campaigns following sporadic H5N1 outbreaks, no differences in these practices could be detected between households with previous H5N1 human or poultry cases and those households with any previous experience with H5N1. Development of H5N1 infection–related education campaign strategies should focus on perceptions underlying traditional practices in order to tailor public awareness messages that are meaningful for communities.
SEROLOGICAL AND MOLECULAR INVESTIGATION INTO THE ROLE OF WILD BIRDS IN THE EPIDEMIOLOGY OF WEST NILE VIRUS IN GREECE
Virology Journal (12 Nov 2012). George Valiakos.
ABSTRACT: A West Nile virus (WNV) disease outbreak occurred in 2010 in northern Greece with a total of 262 laboratory-confirmed human cases and 35 deaths. A serological and molecular surveillance was conducted on samples of wild birds hunter-harvested prior to and during the outbreak.FindingsSerum and tissue samples from 295 resident and migratory wild birds, hunter-harvested during the 2009--2010 and 2010--2011 hunting seasons at the epicenter of the outbreak in northern Greece, were tested for the presence of WNV-specific antibodies by immunofluorescence assay and virus neutralization test. WNV neutralizing antibodies were detected in 53 avian samples. Fourteen positive sera were obtained from birds hunter-harvested up to 8 months prior to the human outbreak. Specific genetic determinants of virulence (His249Pro NS3 mutation, E-glycosylation motif) were recognized in a WNV lineage 2 strain isolated from a hunter-harvested Eurasian magpie and a nucleotide mismatch was revealed between this strain and a mosquito WNV strain isolated one month earlier in the same area. Conclusions: This is the first report regarding exposure of wild birds to WNV prior to the 2010 outbreak, in Greece. Results provide evidence of the implication of wild birds in a local enzootic cycle that could allow WNV maintenance and amplification of the virus before and during the outbreak. Findings of past exposure of migratory birds to WNV upon their arrival in Greece during autumn migration, suggest avian species with similar migration traits as candidates for the introduction of WNV into Greece. The possibility that an endemic circulation of WNV could have caused the outbreak, after an amplification cycle due to favorable conditions cannot be excluded.
CELL-INTRINSIC INNATE IMMUNE CONTROL OF WEST NILE VIRUS INFECTION
Trends in Immunology (11 Nov 2012). Michael S. Diamond et al.
ABSTRACT: West Nile virus (WNV) is an enveloped positive-stranded RNA virus that has emerged over the past decade in North America to cause epidemics of meningitis, encephalitis, and acute flaccid paralysis in humans. WNV has broad species specificity, and replicates efficiently in many cell types, including those of the innate immune and central nervous systems. Recent studies have defined the pathogen recognition receptor (PRR) and signaling pathways by which WNV is detected, and several effector mechanisms that contribute to protective cell-intrinsic immunity. This review focuses on recent advances in identifying the host sensors that detect WNV, the adaptor molecules and signaling pathways that regulate the induction of interferon (IFN)-dependent defenses, and the proteins that limit WNV replication, spread, and disease pathogenesis.
WEST NILE VIRUS INFECTION AMONG HUMANS, TEXAS, USA, 2002–2011
Emerging Infectious Diseases (09 Nov 2012). M. S. Nolan et al.
H1N1pdm09 Lessons Learned
THE INFLUENCE OF CLIMATIC CONDITIONS ON THE TRANSMISSION DYNAMICS OF THE 2009 A/H1N1 INFLUENZA PANDEMIC IN CHILE
BMC Infectious Diseases (13 Nov 2012). Gerardo Chowell.
ABSTRACT: The role of demographic factors, climatic conditions, school cycles, and connectivity patternsin shaping the spatio-temporal dynamics of pandemic influenza is not clearly understood.Here we analyzed the spatial, age and temporal evolution of the 2009 A/H1N1 influenzapandemic in Chile, a southern hemisphere country covering a long and narrow stripcomprising latitudes 170S to 560S. Methods: We analyzed the dissemination patterns of the 2009 A/H1N1 pandemic across 15 regions ofChile based on daily hospitalizations for severe acute respiratory disease and laboratoryconfirmed A/H1N1 influenza infection from 01-May to 31-December, 2009. We explored theassociation between timing of pandemic onset and peak pandemic activity and everalgeographical and demographic indicators, school vacations, climatic factors, and internationalpassengers. We also estimated the reproduction number (R) based on the growth rate of theexponential pandemic phase by date of symptoms onset, estimated using maximumlikelihood methods. Results: While earlier pandemic onset was associated with larger population size, there was noassociation with connectivity, demographic, school or climatic factors. In contrast, there wasa latitudinal gradient in peak pandemic timing, representing a 16-39-day lag in diseaseactivity from the southern regions relative to the northernmost region (P
GLOBAL PRODUCTION CAPACITY OF SEASONAL INFLUENZA VACCINE IN 2011
Vaccine (11 Nov 2012). Jeffrey Partridge et al.
ABSTRACT: The effectiveness of vaccines to mitigate the impact of annual seasonal influenza epidemics and influenza pandemics has been well documented. However, the steady increase in global capacity to produce annual seasonal influenza vaccine has not been matched with increased demand, and thus actual vaccine production. Currently, without a significant increase in demand for seasonal influenza vaccine, global capacity will be far from able to meet even the essential needs for a monovalent vaccine in the event of a severe influenza pandemic. Global commitment to the development of influenza vaccine production capacity was renewed at a consultation leading to the Second Global Action Plan on Influenza Vaccines (GAP) in July 2011. To monitor progress on the GAP, the World Health Organization has carried out periodic surveys of influenza vaccine manufacturers. This latest survey compares current maximum global capacity and actual production of seasonal influenza vaccine in 2011 with data from surveys carried out in 2009 and 2010; analyses global influenza production capacity in the context of sustainability; and discusses options to increase demand, based on strong evidence of public health benefit. Highlights * Influenza vaccines effectively reduce the impact of seasonal epidemics and pandemics. * Higher demand for seasonal influenza vaccine is essential for pandemic preparedness. * We compared 2011 global capacity and actual production with 2009 data. * Global production capacity increased by 62% while actual production by only 8%. * Major geographic imbalances in production and access to vaccine remain.
RECONSTRUCTION OF THE EVOLUTIONARY DYNAMICS OF THE A(H1N1)PDM09 INFLUENZA VIRUS IN ITALY DURING THE PANDEMIC AND POST-PANDEMIC PHASES
PLOS ONE (09 Nov 2012). Gianguglielmo Zehender et al.
ABSTRACT: The aim of this study was to reconstruct the evolutionary dynamics of the A(H1N1)pdm09 influenza virus in Italy during two epidemic seasons (2009/2010 and 2010/2011) in the light of the forces driving the evolution of the virus. Nearly six thousands respiratory specimens were collected from patients with influenza-like illness within the framework of the Italian Influenza Surveillance Network, and the A(H1N1)pdm09 hemagglutinin (HA) gene was amplified and directly sequenced from 227 of these. Phylodynamic and phylogeographical analyses were made using a Bayesian Markov Chain Monte Carlo method, and codon-specific positive selection acting on the HA coding sequence was evaluated. The global and local phylogenetic analyses showed that all of the Italian sequences sampled in the post-pandemic (2010/2011) season grouped into at least four highly significant Italian clades, whereas those of the pandemic season (2009/2010) were interspersed with isolates from other countries at the tree root. The time of the most recent common ancestor of the strains circulating in the pandemic season in Italy was estimated to be between the spring and summer of 2009, whereas the Italian clades of the post-pandemic season originated in the spring of 2010 and showed radiation in the summer/autumn of the same year; this was confirmed by a Bayesian skyline plot showing the biphasic growth of the effective number of infections. The local phylogeography analysis showed that the first season of infection originated in Northern Italian localities with high density populations, whereas the second involved less densely populated localities, in line with a gravity-like model of geographical dispersion. Two HA sites, codons 97 and 222, were under positive selection. In conclusion, the A(H1N1)pdm09 virus was introduced into Italy in the spring of 2009 by means of multiple importations. This was followed by repeated founder effects in the post-pandemic period that originated specific Italian clades.
Country Studies
PANDEMIC INFLUENZA A/H1N1 VIRUS INFECTION AND TNF, LTA, IL1B, IL6, IL8, AND CCL POLYMORPHISMS IN MEXICAN POPULATION: A CASE-CONTROL STUDY
BMC Infectious Diseases (13 Nov 2012). Guadalupe Morales-García.
ABSTRACT: Some patients have a greater response to viral infection than do others having a similar levelof viral replication. Hypercytokinemia is the principal immunopathological mechanism thatcontributes to a severer clinical course in cases of influenza A/H1N1. The benefit produced,or damage caused, by these cytokines in severe disease is not known. The genes that code forthese molecules are polymorphic and certain alleles have been associated with susceptibilityto various diseases. The objective of the present study was to determine whether there was anassociation between polymorphisms of TNF, LTA, IL1B, IL6, IL8, and CCL1 and theinfection and severity of the illness caused by the pandemic A/H1N1 in Mexico in 2009. Methods: Case-control study. The cases were patients confirmed with real time PCR with infection bythe A/H1N1 pandemic virus. The controls were patients with infection like to influenza andnon-familial healthy contacts of the patients with influenza. Medical history and outcome ofthe disease was registered. The DNA samples were genotyped for polymorphisms TNFrs361525, rs1800629, and rs1800750; LTA rs909253; IL1B rs16944; IL6 rs1818879; IL8rs4073; and CCL1 rs2282691. Odds ratio (OR) and the 95% confidence interval (95% CI)were calculated. The logistic regression model was adjusted by age and severity of the illnessin cases. Results: Infection with the pandemic A/H1N1 virus was associated with the following genotypes:TNF rs361525 AA, OR = 27.00; 95% CI = 3.07-1248.77); LTA rs909253 AG (OR = 4.33,95% CI = 1.82-10.32); TNF rs1800750 AA (OR = 4.33, 95% CI = 1.48-12.64); additionally,LTA rs909253 AG showed a limited statistically significant association with mortality (p =0.06, OR = 3.13). Carriers of the TNF rs1800629 GA genotype were associated with highlevels of blood urea nitrogen (p = 0.05); those of the TNF rs1800750 AA genotype, with highlevels of creatine phosphokinase (p=0.05). The IL1B rs16944 AA genotype was associatedwith an elevated number of leukocytes (p
ECOLOGICAL FACTORS DRIVING AVIAN INFLUENZA VIRUS DYNAMICS IN SPANISH WETLAND ECOSYSTEMS
PLOS ONE (12 Nov 2012). Elisa Pérez-Ramírez et al.
ABSTRACT: Studies exploring the ecological interactions between avian influenza viruses (AIV), natural hosts and the environment are scarce. Most work has focused on viral survival and transmission under laboratory conditions and through mathematical modelling. However, more integrated studies performed under field conditions are required to validate these results. In this study, we combined information on bird community, environmental factors and viral epidemiology to assess the contribution of biotic and abiotic factors in the occurrence of low pathogenic AIV in Spanish wetlands. For that purpose, seven locations in five different wetlands were studied during two years (2007–2009), including seven sampling visits by location. In each survey, fresh faeces (n?=?4578) of wild birds and water samples were collected for viral detection. Also, the vegetation structure, water physical properties of wetlands, climatic conditions and wild bird community composition were determined. An overall AIV prevalence of 1.7%±0.4 was detected in faecal samples with important fluctuations among seasons and locations. Twenty-six AIV were isolated from the 78 RRT-PCR positive samples and eight different haemagglutinines and five neuraminidases were identified, being the combination H3N8 the most frequent. Variation partitioning procedures identified the combination of space and time variables as the most important pure factor – independently to other factors – explaining the variation in AIV prevalence (36.8%), followed by meteorological factor (21.5%) and wild bird community composition/vegetation structure (21.1%). These results contribute to the understanding of AIV ecological drivers in Spanish ecosystems and provide useful guidelines for AIV risk assessment identifying potential hotspots of AIV activity. { by Elisa Pérez-Ramírez et al. }
DISTRIBUTION OF INFLUENZA-LIKE ILLNESS (ILI) BY OCCUPATION IN WASHINGTON STATE, SEPTEMBER 2009–AUGUST 2010
PLOS ONE (12 Nov 2012). Naomi J. Anderson et al.
ABSTRACT: We aim to estimate the prevalence of influenza-like illness (ILI) by occupation and to identify occupations associated with increased ILI prevalence. Methods Between September 2009 and August 2010, the Centers for Disease Control (CDC) included questions on ILI symptoms on the Behavioral Risk Factor Surveillance System (BRFSS). Washington State collects the occupation of all employed BRFSS respondents. ILI prevalence and prevalence ratios (PR) were calculated by occupational group. Results There were 8,758 adult, currently employed, non-military respondents to the Washington BRFSS during the study period. The ILI prevalence for all employed respondents was 6.8% (95% Confidence Interval (95% CI)?=?6.1, 7.6). PRs indicated a lower prevalence of ILI in Technicians (PR?=?0.4, 95% CI?=?0.2, 0.9) and Truck Drivers (PR?=?0.2, 95% CI?=?0.1, 0.7) and higher prevalence in Janitors and Cleaners (PR?=?2.5, 95% CI?=?1.3, 4.7) and Secretaries (PR?=?2.4, 95% CI?=?1.1, 5.4). Conclusions Some occupations appear to have higher prevalence of ILI than others. These occupational differences may be explained, in part, by differing levels of social contact with the public or contact with contaminated surfaces at work, or by other occupational factors such as stress or access to health care resources.
OUTBREAKS OF INFLUENZA-LIKE ILLNESS IN LONG-TERM CARE FACILITIES IN WINNIPEG, CANADA
Influenza and Other Respiratory Viruses (12 Nov 2012). Salaheddin M. Mahmud et al.
ABSTRACT: Outbreaks of influenza-like illness (ILI) are common in long-term care facilities (LTCFs) and result in significant morbidity and mortality among residents. Objectives? We describe patterns of reported ILI outbreaks in LTCFs in Winnipeg, Canada, and examine LTCF and outbreak characteristics that influence the clinical outcomes of these outbreaks. Methods? We analyzed the electronic records of all ILI outbreaks reported by LTCFs in Winnipeg from 2003 to 2011. Outbreak duration, ILI attack rates among staff and residents, and residents’ death rates were calculated by presumed viral etiology, staff vaccination rates, type of influenza chemoprophylaxis used, and time to notification to public health. Results? Of a total of 154 reported outbreaks, most (N = 80) were attributed to influenza, and these outbreaks tended to have higher attack and death rates among LTCF residents compared with outbreaks caused by other respiratory viruses (12) or those of unknown etiology (62). About 92% of residents and 38% of staff of the average LTCFs were vaccinated. Chemoprophylaxis was used in 57·5% of influenza outbreaks. Regardless of presumed viral etiology, outbreaks reported within 3 days of onset ended sooner and had lower attack and mortality rates among residents. Conclusions? Influenza-like illness outbreaks still occur among highly immunized LTCF residents, so in addition to vaccination of staff and residents, it is important to maintain competent infection control practices. Early identification and notification to public health authorities and possibly early initiation of control measures could improve clinical outcomes of ILI outbreaks.
BURDEN OF PAEDIATRIC INFLUENZA IN WESTERN EUROPE: A SYSTEMATIC REVIEW
BMC Public Health (12 Nov 2012). Evgeniya Antonova.
ABSTRACT: Influenza illness in children causes significant clinical and economic burden. Although some European countries have adopted influenza immunisation policies for healthy children, the debate about paediatric influenza vaccination in most countries of the European Union is ongoing. Our aim was to summarise influenza burden (in terms of health outcomes and economic burden) in children in Western Europe via a systematic literature review. Methods: We conducted a systematic literature search of PubMed, EMBASE, and the Cochrane Library (1970-April 2011) and extracted data on influenza burden in children (defined as aged
CORRELATES OF SEASONAL FLU VACCINATION AMONG U.S. HOME HEALTH AIDES
Vaccine (11 Nov 2012). Alberto J. Caban-Martinez et al.
ABSTRACT: Home health aides (HAs) receive limited training and reach many older patient populations highly susceptible to influenza virus. We sought to examine socio-demographic correlates of seasonal flu vaccination receipt among HAs. Methods We analyzed data from the 2007 U.S. National Home Health Aide Survey, a nationally representative sample of HAs reporting on occupational status, job and demographic characteristics and receipt of seasonal flu vaccine (n =3377). Results Seasonal flu vaccine receipt was low among all types of HAs (43.9%). After adjustment for socio-demographic indicators (i.e. age, gender, race and health insurance), home health, home care, hospice and personal care attendants were significantly less likely to report receiving seasonal flu vaccine as compared to licensed nursing assistants (adjusted odds ratio, AOR=0.42, 95% CI [0.20–0.85]; 0.41, [0.17–0.99]; 0.50, [0.26–0.97], and 0.53, [0.26–0.99], respectively). Conclusion Targeted effective vaccination campaigns are needed to improve vaccination rates among home health aides.

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