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Network authors: Portugal - Raquel Guiomar, Pedro Pechirra, National Influenza Reference Laboratory, Infectious Diseases Department, National Institute of Health Dr. Ricardo Jorge, Lisbon, Portugal Background: The 2018/2019 influenza season in the WHO European Region was dominated by influenza A (H1N1)pdm09 and (H3N2) viruses, with very few influenza B viruses detected. Methods: Countries in the European Region reported virus characterization data to The European Surveillance System for weeks 40/2018 to 20/2019. These virus antigenic and genetic characterization and haemagglutinin (HA) sequence data were analysed to describe and assess circulating viruses relative to the 2018/2019 vaccine virus components for the northern hemisphere. Results: Thirty countries reported 4776 viruses characterized genetically and 3311 viruses antigenically. All genetically characterized A(H1N1)pdm09 viruses fell in subclade 6B.1A, of which 90% carried the amino acid substitution S183P in the HA gene. Antigenic data indicated that circulating A(H1N1)pdm09 viruses were similar to the 2018/2019 vaccine virus. Genetic data showed that A(H3N2) viruses mostly fell in clade 3C.2a (75%) and 90% of which were subclade 3C.2a1b. A lower proportion fell in clade 3C.3a (23%) and were antigenically distinct from the vaccine virus. All B/Victoria viruses belonged to clade 1A; 30% carried a double amino acid deletion in HA and were genetically and antigenically similar to the vaccine virus component, while 55% carried a triple amino acid deletion or no deletion in HA; these were antigenically distinct from each other and from the vaccine component. All B/Yamagata viruses belonged to clade 3 and were antigenically similar to the virus component in the quadrivalent vaccine for 2018/2019. Conclusions: A simultaneous circulation of genetically and antigenically diverse A(H3N2) and B/Victoria viruses was observed and represented a challenge to vaccine strain selection. Highlights: Co-circulation of different clades/subclades of influenza A viruses in 2018/2019 in the Region; Most circulating A(H1N1)pdm09 viruses (6B.1A) carried S183P in hemagglutinin; Genetically heterogeneous A(H3N2) viruses, with co-circulation of clades 3C.2a and 3C.3a; Antigenically distinct A(H3N2) clade 3C.3a viruses were increasingly detected until 02/2019 and then decreased; Co-circulation of genetically and antigenically diverse A(H3N2) strains challenges vaccine strain selection. info:eu-repo/semantics/publishedVersion

Influenza season started in Italy during the month of October 2018, approaching the epidemic peak in January 2019. This report aim to explore the mid-term virologic surveillance data of the 2018–2019 influenza season in Sicily and to estimate the effectiveness of seasonal influenza vaccine (VE) against A(H1N1)pdm09 and A(H3N2) influenza viruses. A test-negative design was used to evaluate influenza VE. In Sicily, almost all influenza infections were sustained by influenza type A viruses, of which 62.3% were A(H3N2) and 36.3% A(H1N1)pdm09. A reduction of laboratory confirmed influenza cases in Sicilian population immunized against influenza were observed. In particular, an overall significant protective values were observed for any influenza A viruses (Adj-VE = 44.0%; 95%CI: 11.2–64.7%), especially among 15–64 years old age group (Adj-VE = 59.5%; 95%CI: 0.03–83.1) and among the elderly (Adj-VE = 73.6%; 95% CI: 29.4–90.2).

We report the virological monitoring and the antiviral therapy adopted for the treatment of a patient affected by chronic B lymphocytic leukemia, who experienced a severe pneumonia with long-term shedding of influenza virus A(H1N1)pdm09, characterized by an early development of oseltamivir resistance.

Assessment of influenza vaccine effectiveness (VE) and identification of relevant influencing factors are the current priorities for optimizing vaccines to reduce the impacts of influenza. To date, how the difference between epidemic strains and vaccine strains at genetic scale affects age-specific vaccine performance remains ambiguous. This study investigated the association between genetic mismatch on hemagglutinin and neuraminidase genes and A(H1N1)pdm09 VE in different age groups with a novel computational approach. We found significant linear relationships between VE and genetic mismatch in children, young adults, and middle-aged adults. In the children’s group, each 3-key amino acid mutation was associated with an average of 10% decrease in vaccine effectiveness in a given epidemic season, and genetic mismatch exerted no influence on VE for the elderly group. We demonstrated that present vaccines were most effective for children, while protection for the elderly was reduced and indifferent to vaccine component updates. Modeling such relationships is practical to inform timely evaluation of VE in different groups of populations during mass vaccination and may inform age-specific vaccination regimens.

Resumen Introduccion Las infecciones respiratorias agudas de causa viral son unas entidades muy frecuentes. La dificultad para valorar la deteccion de un determinado virus en estas entidades podria solucionarse con la determinacion de la carga viral. Metodos Se ha realizado un estudio prospectivo sobre el valor medio de los Ct (cycle threshold value) detectados frente al VRS-A, VRS-B y los virus gripales A (H1N1)pdm09, A(H3N2) y B en pacientes de diferente procedencia y edad. La deteccion se ha realizado mediante una tecnica de amplificacion molecular (RT-PCR) comercial. Resultados Se han detectado valores medios de Ct distintos para cada virus. En las infecciones por VRS, no se han observado diferencias entre las causadas por el VRS-A o VRS-B en pediatria. De acuerdo con la edad de los pacientes solo se ha observado significacion estadistica en los incluidos en los grupos de 0-4 meses para el VRS-A y este grupo y el de 5-12 meses para el VRS-B (valores mas elevados). En los pacientes adultos se ha detectado una carga viral menor que en los pediatricos. En las infecciones gripales no se ha observado significacion estadistica en los valores medios detectados en los pacientes procedentes de la Red Centinela, en los diagnosticados en las urgencias de adultos ni en los ingresados hospitalarios. En los pacientes adultos ingresados en la UCI solo se ha observado un valor medio algo mas bajo en los infectados por el virus gripal A (H1N1)pdm09 pero sin significacion estadistica. No hubo ningun paciente ingresado en la UCI con infeccion por gripe B. Conclusion La deteccion de la carga viral podria ser una buena herramienta para la evaluacion, seguimiento y pronostico de las infecciones respiratorias agudas viricas. A excepcion de las causadas por el VRS, no se han observado diferencias significativas en las infecciones gripales, salvo en los pacientes pediatricos de menor edad.

Every season, circulating influenza viruses change, therefore, vaccines must be reformulated each year. We aimed to estimate vaccine effectiveness (VE) against severe influenza infection for the 2018/19 season in Italy. We conducted a test-negative design case-control study at five Italian hospitals. We estimated influenza VE against severe acute respiratory infection (SARI) requiring hospitalisation overall, and by virus subtype, vaccine brand, and age. The 2018/19 season was characterised by A(H1N1)pmd09 and A(H3N2) influenza viruses. Vaccine coverage among &lt, 18 years recruited SARI cases was very low (3.2%). Seasonal vaccines were moderately effective against type A influenza overall (adjusted VE = 40.5%, 95% confidence interval (CI) = 18.7&ndash, 56.4%) and subtype A(H1N1)pmd09 viruses (adjusted VE = 55%, 95% CI = 34.5&ndash, 69.1%), but ineffective against subtype A(H3N2) viruses (adjusted VE = 2.5%, 95% CI = &minus, 50.0&ndash, 36.7%). Both Fluad and Fluarix Tetra vaccines were effective against type A influenza overall and subtype A(H1N1)pdm09 viruses. VE appeared to be similar across age groups (0&ndash, 64 years, &ge, 65 years). Seasonal influenza vaccines in the 2018/19 season were moderately effective in preventing SARI caused by A(H1N1)pdm09 influenza but ineffective against A(H3N2).

Highlights • Influenza A(H3N2) circulated in Europe in 2016–17 and 2017–18 and A(H1N1)pdm09 in 2017–18. • Changed A(H1N1)pdm09 vaccine component VE was 58% against A(H1N1)pdm09 in 2017–18. • A(H3N2) VE was 13% and 28% among all ages in 2016–17 and 2017–18, respectively., Introduction Influenza A(H3N2) viruses predominated in Europe in 2016–17. In 2017–18 A(H3N2) and A(H1N1)pdm09 viruses co-circulated. The A(H3N2) vaccine component was the same in both seasons; while the A(H1N1)pdm09 component changed in 2017–18. In both seasons, vaccine seed A(H3N2) viruses developed adaptations/alterations during propagation in eggs, impacting antigenicity. Methods We used the test-negative design in a multicentre primary care case-control study in 12 European countries to measure 2016–17 and 2017–18 influenza vaccine effectiveness (VE) against laboratory-confirmed influenza A(H1N1)pdm09 and A(H3N2) overall and by age group. Results During the 2017–18 season, the overall VE against influenza A(H1N1)pdm09 was 59% (95% CI: 47–69). Among those aged 0–14, 15–64 and ≥65 years, VE against A(H1N1)pdm09 was 64% (95% CI: 37–79), 50% (95% CI: 28–66) and 66% (95% CI: 42–80), respectively. Overall VE against influenza A(H3N2) was 28% (95% CI: 17–38) in 2016–17 and 13% (95% CI: −15 to 34) in 2017–18. Among 0–14-year-olds VE against A(H3N2) was 28% (95%CI: −10 to 53) and 29% (95% CI: −87 to 73), among 15–64-year-olds 34% (95% CI: 18–46) and 33% (95% CI: −3 to 56) and among those aged ≥65 years 15% (95% CI: −10 to 34) and −9% (95% CI: −74 to 32) in 2016–17 and 2017–18, respectively. Conclusions Our study suggests the new A(H1N1)pdm09 vaccine component conferred good protection against circulating strains, while VE against A(H3N2) was

Understanding the genetic evolution of A(H1N1)pdm09 and H3N2 viruses can help better select strains to be included in the annual influenza vaccine. There is little information on their evolution in Jordan so this study investigated the genetic and antigenic variability of A(H1N1)pdm09 and H3N2 viruses in Jordan by performing phylogenetic and genetic analyses of the HA and NA genes of A(H1N1)pdm09 and H3N2 viruses between 2011 and 2013. The full HA and NA genes of 16 H1N1-positive samples obtained in our study and 21 published HA sequences and 20 published NA sequences from Jordanian viruses that were available on online gene databases were analysed. For H3N2, we generated 20 HA and 19 NA sequences and included 19 published HA and NA sequences each in the analysis. Jordanian H1N1 viruses had mutations that are characteristic of antigenic group 6 while H3N2 virus mutations belonged to group 3. No markers of resistance to oseltamivir were detected. The individual mutations are described in detail.

The aim of this study was to assess 5-years catamnesis of children from mothers who had A(H1N1)pdm09 influenza during pregnancy. The design of the research: cohort cross-sectional retrospective �case � control� study. The study group included 227 children of mothers who had A(H1N1)pdm09 influenza during pregnancy, and the control group was consisted of 227 children whose mothers didn�t have A(H1N1)pdm09 influenza in epidemic period during pregnancy. It was shown that 11,9 % of children born to mothers with influenza infection during pregnancy vs 1,8 % of children of the control group to 5-year age formed a cohort of patients with recurrent respiratory tract infections (p < 0,001). Acute respiratory infections were complicated by pneumonia in 15,4 % of study group children vs 8,8 % of children in the comparison group (p = 0,044). We founded a significant association between maternity A(H1N1)pdm09 influenza during 1st and 2nd trimesters of gestation and increased frequency of asthma in their children.

Background: Evidence on influenza vaccine effectiveness (VE) in preventing mortality and morbidity in the elderly is weak. Our aim was to measure the VE against severe outcomes in the elderly.Metho...

Background: During the influenza pandemic 2009-2010, an AS03-adjuvanted A(H1N1) pdm09 vaccine was used extensively in children 6 months of age and older, and during the 2010-2011 influenza season, the A(H1N1) pdm09 strain was included in the seasonal trivalent inactivated influenza vaccine (TIV) without adjuvant. We evaluated the immunogenicity and safety of TIV in children previously vaccinated with the AS03-adjuvanted A(H1N1) pdm09 vaccine. Methods: Healthy children were randomized (1:1) to receive TIV or a control vaccine. Children were aged 6 months to 9 years (n = 154) and adolescents 10-17 years (n = 77) when they received AS03-adjuvanted A(H1N1) pdm09 vaccine at least 6 months before study enrolment. Hemagglutination inhibition (HI) and neutralizing antibody responses against the A(H1N1) pdm09 strain were evaluated before (day 0) and at day 28 and month 6 after study vaccination. Reactogenicity was assessed during the 7 day postvaccination period, and safety was assessed for 6 months. Results: At day 0, >93.9% of all children had HI titers >= 1:40 for the A(H1N1) pdm09 strain, which increased to 100% at both day 28 and month 6 in the TIV group. Between days 0 and 28, HI antibody geometric mean titers against A(H1N1) pdm09 increased by 9-fold and 4-fold in children 6 months to 9 years of age and 10-17 years of age, respectively. Conclusion: AS03-adjuvanted A(H1N1) pdm09 vaccine-induced robust immune responses in children that persisted into the next season, yet were still boosted by TIV containing A(H1N1) pdm09. The reactogenicity and safety profile of TIV did not appear compromised by prior receipt of AS03adjuvanted A(H1N1) pdm09 vaccine.

In 2012-2013, we examined 1729 laboratory-confirmed A(H1N1)pdm09 influenza cases matched 1:1 with healthy controls and estimated influenza vaccine effectiveness (VE) for trivalent inactivated influenza vaccine (IIV3) to be 67% (95% confidence interval=58-74%) for ages 8 months to 6 years old. Among children aged 8-35 months old, VE for fully vaccinated children (73%, 60-81%) was significantly higher than VE for partially vaccinated children (55%, 33-70%). Significant cross-season protection from prior IIV3 was noted, including VE of 31% (8-48%) from IIV3 received in 2010-2011 against influenza illness in 2012--2013 without subsequent boosting doses.

To determine the differences in the clinical features of hospitalized elderly patients with influenza between the A (H1N1) pdm09 and the A (H3N2)-dominant seasons, 12 adult patients (mean age, 76.5 years) with influenza who were hospitalized during the 2015-2016 A (H1N1) pdm09-dominant season were compared with 26 adult patients (mean age, 82.5 years) with influenza who were hospitalized during the 2016-2017 A (H3N2)-dominant season. Compared with the A (H3N2)-dominant 2016-2017 season, the A (H1N1) pdm09-dominant 2015-2016 season had fewer non-survivors, but had significantly fewer patients who required oxygenation/respirator support and intravenous anti-influenza agents, such as peramivir. Among the severe patients who received oxygenation/respirator support, the outcomes were better in the A (H3N2)-dominant 2016-2017 season than in the A (H1N1) pdm09-dominant 2015-2016 season. The pneumonia types and detected bacteria did not differ between the two seasons, but the use of sulbactam/ampicillin was more frequent in the A (H1N1) pdm09-dominant 2015-2016 season than in the A (H3N2)-dominant 2016-2017 season. These data suggest that peramivir treatment and oxygenation/respirator support, but not sulbactam/ampicillin administration, may improve the outcome of severe elderly patients hospitalized for influenza, especially the A (H3N2) type.

Singapore is a tropical country with influenza seasons occurring bi-annually. We compared the profile of severely ill patients with laboratory confirmed influenza A(H1N1)pdm09 infection in Singapore during the pandemic and post-pandemic periods, and studied their risk factors associated with mortality.Three periods were defined for this study; pandemic period from 18 June to 29 August 2009, early post-pandemic period from 30 August 2009 to 12 February 2010, and late post-pandemic period from 13 February to 10 August 2010.A total of 172 severely ill patients were admitted to hospitals from 18 June 2009 to 10 August 2010, of whom 23.8% died. The median age in the late post-pandemic period was significantly older than that in the early post-pandemic period (52 years versus 35 years, P=0.02). The median age of patients who died was significantly older than those who survived (52 years versus 44 years, P0.01). The median length of stay under intensive care in the late post-pandemic period was twice that in the early post-pandemic (6 days versus 3 days, P=0.045). The proportion who died in the late post-pandemic period was more than 2.5 times that in the early post-pandemic period (29.8% versus 11.1%, P=0.043).Severely ill patients were of older age in the late post-pandemic period. Older age was also significantly associated with mortality. It is important to maintain heightened vigilance and continue the surveillance of severely ill patients with influenza post-pandemic, so that patients with suspected infections could be promptly identified for early diagnosis and treatment.

The A(H1N1)pdm09 virus emerged in 2009 and continues to circulate in human populations. Recent A(H1N1)pdm09 viruses, that is, A(H1N1)pdm09 viruses circulating in the post-pandemic era, can cause more or less severe infections than those caused by the initial pandemic viruses. To evaluate the changes in pathogenicity of the A(H1N1)pdm09 viruses during their continued circulation in humans, we compared the nucleotide and amino acid sequences of ten A(H1N1)pdm09 viruses isolated in Japan between 2009 and 2015, and experimentally infected mice with each virus. The severity of infection caused by these Japanese isolates ranged from milder to more severe than that caused by the prototypic pandemic strain A/California/04/2009 (CA04/09), however, specific mutations responsible for their pathogenicity have not yet been identified.

To identify factors associated with vaccine receipt among correctional facilities during the A(H1N1)pdm09 influenza pandemic, this study surveyed one third of U.S. correctional facilities. Analysis of the association of average daily population (ADP) on A(H1N1)pdm09 influenza vaccine receipt found that an ADP increase of 100 inmates resulted in a 32% increased likelihood of receiving influenza vaccine among smaller jails. Zero percent of large jails, 14% of federal prisons, 11% of nonfederal prisons, and 57% of small jails reported never receiving pandemic influenza vaccine. A qualitative assessment identified barriers to vaccine delivery, lessons learned from pandemic response, and recommendations for public health partners. Building stronger relationships between public health entities and correctional facilities to collaborate in influenza pandemic preparedness efforts may help protect correctional and community populations.

Parental attitudes towards vaccination significantly influence vaccine uptake. The A(H1N1)pdm09 influenza pandemic was followed in 2010 by an unprecedented increase in febrile reactions in children receiving trivalent inactivated influenza vaccine manufactured by bioCSL. Uptake of TIV in children5 years in Western Australia (WA) decreased in 2010 and has remained low. The impact of pandemic A(H1N1)pdm09 and adverse-events on parental attitudes towards vaccination is uncertain.A parental attitudes survey towards influenza illness and vaccination was conducted as part of the West Australian Influenza Vaccine Effectiveness study. Vaccination status was assessed by parental interview and confirmed by the national register and/or vaccine providers. Parental attitudes from vaccinated and unvaccinated children and attitudes in 2008-2009 and 2010-2012 were compared. Principal Component Analysis was conducted to determine core attitudes that influenced vaccine uptake.Vaccination history and parental attitude surveys were available from 2576 children. Parents of fully vaccinated children less frequently stated that influenza was a mild disease, more frequently stated that influenza vaccine was safe and were less frequently worried about vaccine side effects. Uptake of influenza vaccine decreased significantly from 2010 onwards. From 2010, parents were less concerned about severe influenza, but more concerned about vaccine side effects and safety. Despite this significant shift in attitudes towards influenza vaccine, parental acceptance of vaccines on the national immunisation program did not change. Principal Component Analysis revealed that attitudes around vaccine safety and efficacy were the most important attitudes impacting on vaccine uptake.Parental attitudes to influenza vaccine changed from 2010. Confidence in the WA preschool influenza vaccination program remains low yet appeared unchanged for other vaccines. Restoring public confidence in childhood influenza vaccination is needed before uptake can be improved.

To understand the epidemic resurgence of influenza due to the 2009 pandemic influenza A(H1N1) strain (A[H1N1]pdm09) during the 2013-2014 influenza season, we compared age-related cross-sectional estimates of seroprotection before the pandemic (during 2009) and after the pandemic (during 2010 and 2013) to subsequent surveillance-based, laboratory-confirmed incidence of influenza due to A(H1N1)pdm09 in British Columbia, Canada. Prepandemic seroprotection was negligible except for very old adults (defined as adults aged ≥ 80 years), among whom 80% had seroprotection. Conversely, postpandemic seroprotection followed a U-shaped distribution, with detection in approximately 35%-45% of working-aged adults but in ≥ 70% of very old adults and young children, excluding children aged

Background Healthy volunteer challenge studies provide an opportunity to better understand influenza pathogenesis and correlates of protection. The development of vaccines and therapeutics has relied on these studies as will future universal vaccine candidates. The first fully validated wild-type human infection model with A(H1N1)pdm09 was developed at the NIH Clinical Center (CC) in 2012 and this study represents the first validation of a wild-type seasonal H3N2 human infection model. The objective of this study was to characterize a wild-type Influenza A/Texas-like H3N2 challenge virus in healthy volunteers. Methods Healthy volunteers were isolated at the NIH CC for a minimum of 9 days. Subjects received a single dose of a reverse genetics, cell-based, GMP, wild-type A H3N2 virus intranasally. Dose escalation was performed from 104 to 107 TCID50. Viral shedding and clinical disease were evaluated daily, including clinician assessments and a validated patient-reported outcome tool, FLU-PRO©. Results A total of 37 subjects were challenged. Sixteen (43%) subjects had viral shedding and 27 (73%) developed influenza symptoms, with 12 subjects (32%) experiencing mild-to-moderate influenza disease (MMID) defined as symptoms and shedding. Only subjects receiving the 106 and 107 TCID50 doses experienced MMID at 44% and 40%, respectively. Nose and throat symptoms were most common and peaked by Days 2–3 post-challenge. Although serum antibody responses were observed, many of these responses were limited in a significant number of subjects. Conclusion The A/Texas-like H3N2 Influenza challenge virus safely induced MMID in healthy volunteers, but was less effective than the A(H1N1)pdm09 challenge virus. This lower MMID rate of 40% was observed at the 107 TCID50 dose and was driven by less detection of shedding as the incidence of symptoms was similar to A(H1N1)pdm09. The limited serum antibody responses observed demonstrate that preexisting immunity in healthy volunteers against the seasonal H3N2 lineage may limit shedding compared with the more recently emerged seasonal A(H1N1)pdm09 lineage. The successful characterization of this H3N2 model makes future studies using this model to explore viral pathogenesis or evaluate vaccines possible. This research was supported by the Intramural Research Program of the NIH, NIAID. Disclosures All authors: No reported disclosures.

Background Influenza infection is known to be an exacerbating factor in the control of asthma, therfore its prevention is critical in managing asthma. The aim of this study was to investigate the influenza A H1N1 2009 pandemic virus (H1N1 pdm09) infection in adult asthmatic patients. Methods Data were obtained from a questionnaire-based survey of asthmatic patients conducted from September to October 2010 in Niigata Prefecture. Patient background, H1N1 pdm09 infection, vaccination status, and asthma exacerbation due to influenza infection were analyzed. Results In total, 2,555 cases were analyzed. The incidence of the infection was 6.7% (95% confidence interval [CI]: 5.7-7.6), and the rate of vaccination was 63.9% (95% CI: 62.1-65.8). The odds ratio (OR) for vaccination against the infection among adult patients and younger patients (≤ the median age) were 0.61 (95% CI: 0.45-0.84) and 0.62 (95% CI: 0.42-0.90), respectively. However, OR among the older patient (> median age) were 1.38 (95%CI: 0.66-2.89). The rate of infection-induced asthma exacerbation was 23.2% (95% CI: 18.6-29.6), and the OR for vaccination against the infection-induced asthma exacerbation was 1.42 (95% CI: 0.69-2.92). Conclusions The effectiveness of the vaccination against the H1N1 pdm09 virus was confirmed during the first pandemic season, but it was limited. Further investigation on H1N1 pdm09 virus infection in asthmatics will be required.

We examined the incidence of oseltamivir-resistant seasonal A(H1N1) and A(H1N1)pdm09 influenza viruses from the 2007/2008 to 2012/2013 season in Nara Prefecture, Japan. To detect the oseltamivir resistance marker in neuraminidase (NA), 365 influenza viruses (60 seasonal A(H1N1) and 305 A(H1N1)pdm09) were sequenced. The H275Y mutation in the NA gene, which confers resistance to oseltamivir, was identified in 93.8% (30/32) of seasonal A(H1N1) viruses that were circulating during the 2008/2009 season. Moreover, the detection rate of oseltamivir-resistant A(H1N1)pdm09 viruses was 4.1% (3/74) and 2.8% (5/180) in the 2009/2010 and 2010/2011 season, respectively. Four cases of oseltamivir-resistant A(H1N1)pdm09 virus infection occurred in the same hematology ward during the 2010/2011 season. Our data show a low frequency of oseltamivir-resistant A(H1N1)pdm09 virus in Nara Prefecture but suggested the possibility of human-to-human transmission of this virus.

BACKGROUND: We report on a follow-up clinical and serological investigation of 274 children who received seasonal influenza vaccine (trivalent inactivated vaccine [TIV]) 1 year after receipt of either AS03(B)-adjuvanted subunit or whole virus monovalent A(H1N1)pdm09 vaccine and describe the antibody responses to the H3N2 A/Perth/16/2009 and B/Brisbane/60/2008 components of TIV. METHODS: Vaccine responses were analyzed using hemagglutination inhibition (HAI) assays. In children aged 3 years, responses to the H3 and B components of TIV were similar between vaccine groups. Sera taken before and after the pandemic vaccine were also analyzed by HAI using A/Perth/16/2009 virus. This analysis showed that 11.1% of children receiving the AS03(B)-adjuvanted vaccine but only 1.4% in the nonadjuvanted group had a 4-fold rise to A/Perth/16/2009. CONCLUSION: AS03B-adjuvanted A(H1N1)pdm09 influenza vaccine generates a cross-reactive antibody response to H3N2 in children and enhances responses to heterologous subtypes in children aged

SUMMARYIn Finland, the pandemic influenza virus A(H1N1)pdm09 was the dominant influenza strain during the pandemic season in 2009/2010 and presented alongside other influenza types during the 2010/2011 season. The true number of infected individuals is unknown, as surveillance missed a large portion of mild infections. We applied Bayesian evidence synthesis, combining available data from the national infectious disease registry with an ascertainment model and prior information on A(H1N1)pdm09 influenza and the surveillance system, to estimate the total incidence and hospitalization rate of A(H1N1)pdm09 infection. The estimated numbers of A(H1N1)pdm09 infections in Finland were 211 000 (4% of the population) in the 2009/2010 pandemic season and 53 000 (1% of the population) during the 2010/2011 season. Altogether, 1·1% of infected individuals were hospitalized. Only 1 infection per 25 was ascertained.

To study influenza viruses in pigs in Sri Lanka, we examined samples from pigs at slaughterhouses. Influenza (H3N2) and A(H1N1)pdm09 viruses were prevalent during 2004-2005 and 2009-2012, respectively. Genetic and epidemiologic analyses of human and swine influenza viruses indicated 2 events of A(H1N1)pdm09 virus spillover from humans to pigs.

OBJECTIVE To analyze relationships between occupational exposure and influenza infection and hospitalization during the 2009-2010 pandemic wave and the 2010-2011 influenza seasonal epidemic in Spain. METHODS Occupations were classified as high, medium, or low risk of influenza exposure. To assess the risk of infection, 588 outpatient cases of influenza confirmed by reverse-transcription polymerase-chain-reaction (RT-PCR) were compared with 588 outpatients without influenza symptoms. To assess the risk of hospitalization, 337 outpatient influenza cases were compared with 337 inpatient influenza cases. RESULTS The high risk of occupational exposure group was composed only of health care workers. After adjustment for age, sex, vaccination status, and predictive variables of influenza infection, patients with a high risk of occupational exposure had an aOR of 2.14 (95%CI: 1.25-3.66) of being an outpatient influenza case and an aOR of 0.43 (95%CI: 0.20-0.95) of being an inpatient influenza case, compared with those with a low risk. CONCLUSIONS A high risk of occupational exposure is a risk factor for influenza infection but not for hospitalization.

were collected and tested by RT-PCR of which 22.7% (487) were confirmed A(H1N1)pdm09; H3N2, H1N1, and B were positive in 2.2%, 1.1%, and 7.2%, respectively. The highest rate of A(H1N1)pdm09 cases (57.4%) was detected in the 6-20 year-old age group. Importantly, Bhutan increased from 3 sentinel sites in April 2009 to 11 a year later, and in April 2010 established PCR capability for influenza. Conclusions Despite relative isolation, the A(H1N1)pdm09 reached Bhutan within 3 months of identification in Mexico. The H1N1 pandemic has made Bhutan more prepared for epidemics in the future.

Objectives To investigate disease history before A(H1N1)pdm09 vaccination as a risk factor for narcolepsy. Methods Case-control study in Sweden. Cases included persons referred for a Multiple Sleep Latency Test between 2009 and 2010, identified through diagnostic sleep centres and confirmed through independent review of medical charts. Controls, selected from the total population register, were matched to cases on age, gender, MSLT-referral date and county of residence. Disease history (prescriptions and diagnoses) and vaccination history was collected through telephone interviews and population-based healthcare registers. Conditional logistic regression was used to investigate disease history before A(H1N1)pdm09 vaccination as a risk-factor for narcolepsy. Results In total, 72 narcolepsy cases and 251 controls were included (range 3–69 years mean19-years). Risk of narcolepsy was increased in individuals with a disease history of nervous system disorders (OR range = 3.6–8.8) and mental and behavioural disorders (OR = 3.8, 95% CI 1.6–8.8) before referral. In a second analysis of vaccinated individuals only, nearly all initial associations were no longer statistically significant and effect sizes were smaller (OR range = 1.3–2.6). A significant effect for antibiotics (OR = 0.4, 95% CI 0.2–0.8) and a marginally significant effect for nervous system disorders was observed. In a third case-only analysis, comparing cases referred before vaccination to those referred after; prescriptions for nervous system disorders (OR = 26.0 95% CI 4.0–170.2) and ADHD (OR = 35.3 95% CI 3.4–369.9) were statistically significant during the vaccination period, suggesting initial associations were due to confounding by indication. Conclusion The findings of this study do not support disease history before A(H1N1)pdm09 vaccination as a risk factor for narcolepsy.

(臨床神経 2015;55:270-271) 拝啓 本誌第 54 巻第 2 号に掲載された「脳梁離断症候群を示した インフルエンザワクチン接種後急性散在性脳脊髄炎の 1 例」 (臨床神経 2014;54:135-139)についてご意見をいただきあり がとうございました.私の論文は急性散在性脳脊髄炎(acute disseminated encephalomyelitis; ADEM)ではまれな脳梁の単 一病変による左手一側性の観念性失行と,漢字よりも仮名の 障害が高度な一側性失書についての報告なので,ADEM に関 する情報は一部割愛しました.使用されたワクチンの製造株は A/California/7/2009 (H1N1) pdm09,A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 です. インフルエンザワクチン接種後ADEMの発生頻度は,私が 引用したNakayamaらの論文 に記載された 1994年から 2004 年の間と比較して「A/H1N1 がワクチンに加えられてから ADEM 出現頻度はいちじるしく増加している可能性が考慮 されます」というご指摘です.私が確認できた範囲では 1991 年度から 2009 年度まで日本で製造されたワクチンはすべて A (H1N1),A (H3N2) と B 型をふくむ 3 価ワクチンなので, 2010 年度以降に製造された A (H1N1) pdm09 をふくむワクチ ンによって ADEM の発生頻度がいちじるしく増加している可 能性がある,というご指摘であると理解して回答いたします. 第 1 に,論文発表された症例数から ADEM の発生頻度を推 測することは困難と思われます.A (H1N1) pdm09パンデミッ クという未経験の事象に関連した神経系合併症に対する高い 関心のため,より多くの論文が採用された可能性が否定でき ません.引用された第 1 回新型インフルエンザ予防接種後副 反応検討会の資料 は全国調査による多数例の集計結果で す.資料 1-1の脚注には「製造販売業者からの報告には,医 療機関から報告された症例と重複している症例がふくまれて いる可能性がある」と書かれています.重篤な副反応である ADEM ではその可能性が高く,資料 1-5 に記載された患者 数を数えてもそれが正確な症例数であるという保証はありま せん. 第 2 に,予防接種を受けた人数を考慮しないと発生頻度を 議論できません.資料 1-5によると A (H1N1) pdm09 をふく まない 2009 年度のワクチンの推定接種可能人数(回分)は 20,754,363 ですが,A (H1N1) pdm09 をふくむ 2010 年度のワ クチンの推定接種可能人数(回分)は 49,460,846 と前年度の 約 2.4 倍となり,少なくともこれを上回る ADEM 症例数の増 加がないと発生頻度が増えたとはいえません.ワクチン接種 後 ADEM 症例の報告は 2009 年度に医療機関から 7 例,そし て 2010 年度には医療機関から 7 例,製造販売業者から 8 例で した.この医療機関からの 7 例すべてが製造販売業者からの 報告例にふくまれているばあいとまったく重複がないばあい を想定して計算しても,二つの年度の ADEM 発生頻度に有意 差はみとめられませんでした(Fisherの正確検定,P = 1.0000). 以上の観点から,A (H1N1) pdm09をふくむワクチンを使用 するようになって ADEM の発生頻度が「いちじるしく増加し た」との結論を導きだすことはできないと判断しました.今 後,ADEM の発生頻度に変化がみられるかどうか検討を要す るものと思われます. 敬具 ※本論文に関連し,開示すべき COI 状態にある企業,組織,団体 はいずれも有りません. Reply from the Author

The aim of this paper was to analyze the spatiotemporal variations of cases of influenza A(H1N1)pdm09 in Argentina. A space-time permutation scan statistic was performed to test the non-randomness in the interaction between space and time in reported influenza A(H1N1)pdm09 cases. In 2009, two clusters were recorded in the east of Buenos Aires Province (May and June) and in the central and northern part of Argentina (July and August). Between 2011 and 2012, clusters near areas bordering other countries were registered. Within the clusters, in 2009, the high notification rates were first observed in the school-age population and then extended to the older population (15-59 years). From 2011 onwards, higher rates of reported cases of influenza A(H1N1)pdm09 occurred in children under five years in center of the country. Two stages of transmission of influenza A(H1N1)pdm09 can be characterized. The first stage had high rates of notification and a possible interaction with individuals from other countries in the major cities of Argentina (pattern of hierarchy), and the second stage had an increased interaction in some border areas without a clear pattern of hierarchy. These results suggest the need for greater coordination in the Southern Cone countries, in order to implement joint prevention and vaccination policies. El objetivo de este trabajo es analizar las variaciones espaciotemporales de los casos de gripe A(H1N1)pdm09 en Argentina. Se realizó un escaneo estadístico espacio-temporal por permutaciones para poner a prueba la no aleatoriedad en la interacción entre espacio y tiempo de los casos registrados de gripe A(H1N1)pdm09. Durante 2009 se identificaron dos conglomerados espacio-temporales, en el este de la provincia de Buenos Aires (mayo y junio) y en la mayor parte del centro-norte de la Argentina (julio y agosto). Durante 2011 y 2012 se registraron conglomerados próximos a zonas limítrofes con otros países. Al interior de los conglomerados, primero se observaron mayores tasas de notificación en población de edad escolar para luego extenderse a población mayor (15-59 años). A partir de 2011, las mayores tasas se observaron en menores de 5 años residentes en el centro del país. Se pudieron caracterizar dos etapas de transmisión espacio-temporal de la gripe A(H1N1)pdm09. La primera etapa se caracterizó por altas tasas de notificación y una posible interacción con individuos provenientes de otros países llegados a las grandes ciudades de la Argentina (patrón de jerarquía). La segunda etapa mostró una mayor interacción en algunas zonas fronterizas y sin un patrón claro de jerarquía. Estos resultados plantean la necesidad de generar una mayor coordinación en países del Cono Sur, con el objetivo de implementar políticas más efectivas de prevención y vacunación.

To the Editor: Central nervous system (CNS) manifestations of influenza are uncommon, especially in adults (1,2), and influenza-associated cerebellitis is exceedingly rare: 8 cases have been reported (3–7; Technical Appendix). We describe a case of cerebellitis caused by influenza A(H1N1)pdm09 in an adult woman.

We isolated a novel influenza virus A(H1N2) strain from a pig on January 13, 2012, in Gunma Prefecture, Japan. Phylogenetic analysis showed that the strain was a novel type of double-reassortant virus derived from the swine influenza virus strains H1N1pdm09 and H1N2, which were prevalent in Gunma at that time.

To determine the number of emergency department visits attributable to influenza A(H1N1)pdm09 in Davidson County, Tennessee, USA, we used active, population-based surveillance and laboratory-confirmed influenza data. We estimated ≈10 visits per 1,000 residents during the pandemic period. This estimate should help emergency departments prepare for future pandemics.

Background: Prediction of timing for the onset and peak of an influenza pandemic is of vital importance for preventive measures. In order to identify common spatiotemporal patterns and climate influences for pandemics in Sweden we have studied the propagation in space and time of A(H1N1)pdm09 (10,000 laboratory verified cases), the Asian Influenza 1957-1958 (275,000 cases of influenza-like illness (ILI), reported by local physicians) and the Russian Influenza 1889-1890 (32,600 ILI cases reported by physicians shortly after the end of the outbreak). Methods: All cases were geocoded and analysed in space and time. Animated video sequences, showing weekly incidence per municipality and its geographically weighted mean (GWM), were created to depict and compare the spread of the pandemics. Daily data from 1957-1958 on temperature and precipitation from 39 weather stations were collected and analysed with the case data to examine possible climatological effects on the influenza dissemination. Results: The epidemic period lasted 11 weeks for the Russian Influenza, 10 weeks for the Asian Influenza and 9 weeks for the A(H1N1)pdm09. The Russian Influenza arrived in Sweden during the winter and was immediately disseminated, while both the Asian Influenza and the A(H1N1)pdm09 arrived during the spring. They were seeded over the country during the summer, but did not peak until October-November. The weekly GWM of the incidence moved along a line from southwest to northeast for the Russian and Asian Influenza but northeast to southwest for the A(H1N1)pdm09. The local epidemic periods of the Asian Influenza were preceded by falling temperature in all but one of the locations analysed. Conclusions: The power of spatiotemporal analysis and modeling for pandemic spread was clearly demonstrated. The epidemic period lasted approximately 10 weeks for all pandemics. None of the pandemics had its epidemic period before late autumn. The epidemic period of the Asian Influenza was preceded by falling temperatures. Climate influences on pandemic spread seem important and should be further investigated.

The role of influenza virus as a cause of child mortality in South Asia is under-recognized. We aimed to determine the incidence and case fatality rate of influenza A(H1N1)pdm09 infections in hospitalized children in Karachi, Pakistan. Children less than 5 y old admitted with respiratory illnesses to the Aga Khan University Hospital, Karachi, from 17 August 2009 to 16 September 2011, were tested for influenza A(H1N1)pdm09 using a real-time reverse transcriptase polymerase chain reaction. Out of 2650 children less than 5 y old admitted with a respiratory illness during the study period, 812 (31%) were enrolled. Influenza A(H1N1)pdm09 virus was detected in 27 (3.3%) children. There were 4 deaths in children who tested positive for influenza A(H1N1)pdm09 (case fatality rate of 15%). Children with influenza A(H1N1)pdm09 were 5 times more likely to be admitted or transferred to the intensive care unit, 5.5 times more likely to be intubated, and 12.9 times more likely to die as compared to children testing negative for influenza A(H1N1)pdm09.

Item does not contain fulltext BACKGROUND: In 2009 the pandemic influenza virus A(H1N1)pdm09 emerged with guidance that people at risk should be vaccinated. It is unclear how this event affected the underlying seasonal vaccination rate in subsequent years. PURPOSE: To investigate the association of pandemic influenza A(H1N1)pdm09 and seasonal flu vaccination status in 2009 with vaccination rates in 2010 and 2011. METHODS: Data were collected in 40 Dutch family practices on patients at risk for influenza during 2009-2011; data analysis was conducted in 2012. RESULTS: A multilevel logistic regression model (n=41,843 patients) adjusted for practice and patient characteristics (age and gender, as well as those patient groups at risk), showed that people who were vaccinated against A(H1N1)pdm09 in 2009 were more likely to have been vaccinated in 2010 (OR 6.02; 95%CI 5.62-6.45, p

We looked for cross-reactive antibodies in 122 persons with paired serum samples collected during the 2009 pandemic of influenza virus A(H1N1)pdm09. Eight (12%) of 67 persons with A(H1N1)pdm09 infection confirmed by reverse transcription PCR and/or serology also seroconverted to the seasonal A/Brisbane/59/2007 (H1N1) virus, compared with 1 (2%) of 55 A(H1N1)pdm09-negative persons (p

Countries across Europe developed a range of database systems to register pandemic influenza A(H1N1)pdm09 cases. Anecdotal reports indicate that some systems were not as useful as expected. This was a cross-sectional, semi-structured survey of health professionals who collected and reported pandemic influenza A(H1N1)pdm09 cases in 23 countries within the 27 European Union (EU) Member States plus Norway. We describe here the experiences of using pandemic case register systems developed before and during the pandemic, whether the systems were used as intended and, what problems, if any, were encountered. We conducted the survey to identify improvements that could be made to future pandemic case registers at national and EU level. Despite many inter-country differences, 17 respondents felt that a standardised case register template incorporating a limited number of simple standard variables specified in advance and agreed between the World Health Organization and the European Centre for Disease Prevention and Control could be useful. Intra- and inter-country working groups could facilitate information exchange, clearer system objectives and improved interoperability between systems.

Influenza surveillance was carried out in a subset of patients with influenza-like illness (ILI) presenting at an Employee Health Clinic (EHS) at All India Institute of Medical Sciences (AIIMS), New Delhi (urban) and pediatric out patients department of civil hospital at Ballabhgarh (peri-urban), under the Comprehensive Rural Health Services Project (CRHSP) of AIIMS, in Delhi region from January 2007 to December 2010. Of the 3264 samples tested, 541 (17%) were positive for influenza viruses, of which 221 (41%) were pandemic Influenza A(H1N1)pdm09, 168 (31%) were seasonal influenza A, and 152 (28%) were influenza B. While the Influenza viruses were detected year-round, their types/subtypes varied remarkably. While there was an equal distribution of seasonal A(H1N1) and influenza B in 2007, predominance of influenza B was observed in 2008. At the beginning of 2009, circulation of influenza A(H3N2) viruses was observed, followed later by emergence of Influenza A(H1N1)pdm09 with co-circulation of influenza B viruses. Influenza B was dominant subtype in early 2010, with second wave of Influenza A(H1N1)pdm09 in August-September, 2010. With the exception of pandemic H1N1 emergence in 2009, the peaks of influenza activity coincided primarily with monsoon season, followed by minor peak in winter at both urban and rural sites. Age group analysis of influenza positivity revealed that the percent positivity of Influenza A(H1N1)pdm09 influenza virus was highest in >5–18 years age groups (OR 2.5; CI = 1.2–5.0; p = 0.009) when compared to seasonal influenza. Phylogenetic analysis of Influenza A(H1N1)pdm09 from urban and rural sites did not reveal any major divergence from other Indian strains or viruses circulating worldwide. Continued surveillance globally will help define regional differences in influenza seasonality, as well as, to determine optimal periods to implement influenza vaccination programs among priority populations.

Cross-protection by seasonal trivalent influenza vaccines (TIVs) against pandemic influenza A H1N1 2009 (now known as A[H1N1]pdm09) infection is controversial; and the vaccine effectiveness (VE) of A(H1N1)pdm09 vaccines has important health-policy implications. Systematic reviews and meta-analyses are needed to assess the impacts of both seasonal TIVs and A(H1N1)pdm09 vaccines against A(H1N1)pdm09.We did a systematic literature search to identify observational and/or interventional studies reporting cross-protection of TIV and A(H1N1)pdm09 VE from when the pandemic started (2009) until July 2011. The studies fulfilling inclusion criteria were meta-analysed. For cross-protection and VE, respectively, we stratified by vaccine type, study design and endpoint. Seventeen studies (104,781 subjects) and 10 studies (2,906,860 subjects), respectively, reported cross-protection of seasonal TIV and VE of A(H1N1)pdm09 vaccines; six studies (17,229 subjects) reported on both. Thirteen studies (95,903 subjects) of cross-protection, eight studies (859,461 subjects) of VE, and five studies (9,643 subjects) of both were meta-analysed and revealed: (1) cross-protection for confirmed illness was 19% (95% confident interval=13-42%) based on 13 case-control studies with notable heterogeneity. A higher cross-protection of 34% (9-52%) was found in sensitivity analysis (excluding five studies with moderate/high risk of bias). Further exclusion of studies that recruited early in the pandemic (when non-recipients of TIV were more likely to have had non-pandemic influenza infection that may have been cross-protective) dramatically reduced heterogeneity. One RCT reported cross-protection of 38% (19-53%) for confirmed illness. One case-control study reported cross-protection of 50% (40-59%) against hospitalisation. (2) VE of A(H1N1)pdm09 for confirmed illness was 86% (73-93%) based on 11 case-control studies and 79% (22-94%) based on two cohort studies; VE against medically-attended ILI was 32% (8-50%) in one cohort study. TIVs provided moderate cross-protection against both laboratory-confirmed A(H1N1)pdm09 illness (based on eight case-control studies with low risk of bias and one RCT) and also hospitalisation. A finding of increased risk from seasonal vaccine was limited to cases recruited early in the pandemic. A(H1N1)pdm09 vaccines were highly effective against confirmed A(H1N1)pdm09 illness. Although cross-protection was less than the direct effect of strain-specific vaccination against A(H1N1)pdm09, TIV was generally beneficial before A(H1N1)pdm09 vaccine was available.