Search

Rationale: A high proportion of influenza infections are asymptomatic. Animal and human challenge studies and observational studies suggest T cells protect against disease among those infected, but the impact of T-cell immunity at the population level is unknown.Objectives: To investigate whether naturally preexisting T-cell responses targeting highly conserved internal influenza proteins could provide cross-protective immunity against pandemic and seasonal influenza.Methods: We quantified influenza A(H3N2) virus-specific T cells in a population cohort during seasonal and pandemic periods between 2006 and 2010. Follow-up included paired serology, symptom reporting, and polymerase chain reaction (PCR) investigation of symptomatic cases.Measurements and Main Results: A total of 1,414 unvaccinated individuals had baseline T-cell measurements (1,703 participant observation sets). T-cell responses to A(H3N2) virus nucleoprotein (NP) dominated and strongly cross-reacted with A(H1N1)pdm09 NP (P < 0.001) in participants lacking antibody to A(H1N1)pdm09. Comparison of paired preseason and post-season sera (1,431 sets) showed 205 (14%) had evidence of infection based on fourfold influenza antibody titer rises. The presence of NP-specific T cells before exposure to virus correlated with less symptomatic, PCR-positive influenza A (overall adjusted odds ratio, 0.27; 95% confidence interval, 0.11-0.68; P = 0.005, during pandemic [P = 0.047] and seasonal [P = 0.049] periods). Protection was independent of baseline antibodies. Influenza-specific T-cell responses were detected in 43%, indicating a substantial population impact.Conclusions: Naturally occurring cross-protective T-cell immunity protects against symptomatic PCR-confirmed disease in those with evidence of infection and helps to explain why many infections do not cause symptoms. Vaccines stimulating T cells may provide important cross-protective immunity. [ABSTRACT FROM AUTHOR]

We conducted a longitudinal community cohort study of healthy adults in the UK. We found significantly higher incidence of influenza A(H1N1)pdm09 infection in 2010-11 than in 2009-10, a substantial proportion of subclinical infection, and higher risk for infection during 2010-11 among persons with lower preinfection antibody titers. [ABSTRACT FROM AUTHOR]

We conducted a longitudinal community cohort study of healthy adults in the UK. We found significantly higher incidence of influenza A(H1N1)pdm09 infection in 2010-11 than in 2009-10, a substantial proportion of subclinical infection, and higher risk for infection during 2010-11 among persons with lower preinfection antibody titers. [ABSTRACT FROM AUTHOR]

The role of T cells in mediating heterosubtypic protection against natural influenza illness in humans is uncertain. The 2009 H1N1 pandemic (pH1N1) provided a unique natural experiment to determine whether crossreactive cellular immunity limits symptomatic illness in antibody-naive individuals. We followed 342 healthy adults through the UK pandemic waves and correlated the responses of pre-existing T cells to the pH1N1 virus and conserved core protein epitopes with clinical outcomes after incident pH1N1 infection. Higher frequencies of pre-existing T cells to conserved CD8 epitopes were found in individuals who developed less severe illness, with total symptom score having the strongest inverse correlation with the frequency of interferon-γ (IFN-γ)+ interleukin-2 (IL-2)− CD8+ T cells (r = −0.6, P = 0.004). Within this functional CD8+IFN-γ+IL-2− population, cells with the CD45RA+ chemokine (C-C) receptor 7 (CCR7)− phenotype inversely correlated with symptom score and had lung-homing and cytotoxic potential. In the absence of crossreactive neutralizing antibodies, CD8+ T cells specific to conserved viral epitopes correlated with crossprotection against symptomatic influenza. This protective immune correlate could guide universal influenza vaccine development. [ABSTRACT FROM AUTHOR]

Objective To perform antiviral susceptibility monitoring of treated individuals in the community during the 2009 influenza A(H1N1) pandemic in England. Patients and methods Between 200 and 400 patients were enrolled daily through the National Pandemic Flu Service (NPFS) and issued with a self-sampling kit. Initially, only persons aged 16 and over were eligible, but from 12 November (week 45), self-sampling was extended to include school-age children (5 years and older). All samples received were screened for influenza A(H1N1)pdm09 as well as seasonal influenza [A(H1N1), A(H3N2) and influenza B] by a combination of RT–PCR and virus isolation methods. Influenza A(H1N1)pdm09 RT–PCR-positive samples were screened for the oseltamivir resistance-inducing H275Y substitution, and a subset of samples also underwent phenotypic antiviral susceptibility testing by enzyme inhibition assay. Results We were able to detect virus by RT–PCR in self-taken samples and recovered infectious virus enabling further virological characterization. The majority of influenza A(H1N1)pdm09 RT–PCR-positive NPFS samples (n = 1273) were taken after oseltamivir treatment had begun. No reduction in phenotypic susceptibility to neuraminidase inhibitors was detected, but five cases with minority quasi-species of oseltamivir-resistant virus (an H275Y amino acid substitution in neuraminidase) were detected. Conclusions Self-sampling is a useful tool for community surveillance, particularly for the follow-up of drug-treated patients. The virological study of self-taken samples from the NPFS provided a unique opportunity to evaluate the emergence of oseltamivir resistance in treated individuals with mild illness in the community, a target population that may not be captured by traditional sentinel surveillance schemes. [ABSTRACT FROM AUTHOR]

The 2009/10 pandemic (p H1 N1) highlighted the need for vaccines conferring heterosubtypic immunity against antigenically shifted influenza strains. Although cross-reactive T cells are strong candidates for mediating heterosubtypic immunity, little is known about the population-level prevalence, frequency, and cytokine-secretion profile of heterosubtypic T cells to p H1 N1. To assess this, p H1 N1 sero-negative adults were recruited. Single-cell IFN-γ and IL-2 cytokine-secretion profiles to internal proteins of p H1 N1 or live virus were enumerated and characterised. Heterosubtypic T cells recognising p H1 N1 core proteins were widely prevalent, being detected in 90% (30 of 33) of p H1 N1-naïve individuals. Although the last exposure to influenza was greater than 6 months ago, the frequency and proportion of the IFN-γ-only-secreting T-cell subset was significantly higher than the IL-2-only-secreting subset. CD8+ IFN-γ-only-secreting heterosubtypic T cells were predominantly CCR7− CD45 RA− effector-memory phenotype, expressing the tissue-homing receptor CXCR3 and degranulation marker CD107. Receipt of the 2008-09 influenza vaccine did not alter the frequency of these heterosubtypic T cells, highlighting the inability of current vaccines to maintain this heterosubtypic T-cell pool. The surprisingly high prevalence of pre-existing circulating p H1 N1-specific CD8+ IFN-γ-only-secreting effector memory T cells with cytotoxic and lung-homing potential in p H1 N1-seronegative adults may partly explain the low case fatality rate despite high rates of infection of the pandemic in young adults. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Evans et al. (2011) Has estimation of numbers of cases of pandemic influenza H1N1 in England in 2009 provided a useful measure of the occurrence of disease? Influenza and Other Respiratory Viruses 5(6), e504-e512. Background Surveillance indicators of influenza activity have generally provided robust comparative trend data for England. These indicators became less reliable, however, for monitoring trends in activity, or comparisons with previous years, during the influenza pandemic in 2009 because of changes in the perception of risk and changes in the systems of healthcare delivery. An approach was developed to estimate the number of cases of influenza-like illness (ILI) occurring because of infection with pandemic influenza virus. Methods and findings The number of cases was estimated each week in England on the basis of total number of patients consulting healthcare services with ILI; estimates of the proportion of individuals in the community experiencing an ILI-seeking health care; and the proportion of these positive on laboratory testing. Almost 800 000 cases (range 375 000-1·6 million) of symptomatic ILI cases were estimated to have occurred over the course of the two waves of pandemic activity in England. More cases were estimated to have occurred in the second wave than in the first. Conclusions These results underestimate the total number of infections as they do not include asymptomatic infections nor those with mild illness not meeting the definition of a case of ILI. Nevertheless, the case number estimates provide a useful indicator of the trend in influenza activity and weekly data were extensively used in media reports. Although surveillance methods differ between countries, the approach of synthesising available data sources to produce an overall estimate of case numbers could be applied more widely to provide comparative data. [ABSTRACT FROM AUTHOR]

We conducted a seroepidemiologic study during an outbreak of pandemic (H1N1) 2009 in a boarding school in England. Overall, 353 (17%) of students and staff completed a questionnaire and provided a serum sample. The attack rate was 40.5% and 34.1% for self-reported acute respiratory infection (ARI). Staff were less likely to be seropositive than students 13-15 years of age (staff 20-49 years, adjusted odds ratio [AOR] 0.30; ≥50 years AOR 0.20). Teachers were more likely to be seropositive than other staff (AOR 7.47, 95% confidence interval [CI] 2.31-24.2). Of seropositive persons, 44.6% (95% CI 36.2%-53.3%) did not report ARI. Conversely, of 141 with ARI and 63 with influenza-like illness, 45.8% (95% CI 37.0%-54.0%) and 30.2% (95% CI 19.2%-43.0%) had negative test results, respectively. A weak association was found between seropositivity and a prophylactic dose of antiviral agents (AOR 0.55, 95% CI 0.30-0.99); prophylactic antiviral agents lowered the odds of ARI by 50%. [ABSTRACT FROM AUTHOR]

Background: Oseltamivir, a specific influenza neuraminidase inhibitor, is an effective treatment for seasonal influenza. Emergence of drug-resistant influenza viruses after treatment has been reported, particularly in children in Japan, where the dosing schedule is different from that used throughout the rest of the world. We investigated the emergence of drug-resistant infection in children treated with a tiered weight-based dosing regimen. Methods: We analyzed sequential clinical nasopharyngeal samples, obtained before and after tiered weight-based oseltamivir therapy, from children with acute influenza during 2005-2007. We isolated viruses, tested for drug resistance with use of a fluorescence-based neuraminidase inhibition assay, performed neuraminidase gene sequencing, and determined quantitative viral loads. Results: Sixty-four children (34 with influenza A subtype H3N2, 11 with influenza A subtype H1N1, and 19 with influenza B virus) aged 1-12 years (median age, 3 years, 1 month) were enrolled. By days 4-7 after initiation of treatment, of 64 samples tested, 47 (73.4%) and 26 (40.6%) had virus detectable by reverse-transcriptase polymerase chain reaction and culture, respectively. By days 8-12 after initiation of treatment, of 53 samples tested, 18 (33.9%) and 1 (1.8%) had virus detectable by reverse-transcriptase polymerase chain reaction and culture, respectively. We found no statistically significant differences in the reduction of viral shedding or time to clearance of virus between viral subtypes. Antiviral-resistant viruses were recovered from 3 (27.3%) of 11 children with influenza A subtype H1N1, 1 (2.9%) of 34 children with influenza A subtype H3N2, and 0 (0%) of 19 children with influenza B virus, all of whom were treated with oseltamivir (P = .004 ) There was no evidence of prolonged illness in children infected with drug-resistant virus. Conclusions: Drug resistance emerges at a higher rate in influenza A subtype H1N1 virus than in influenza A subtype H3N2 or influenza B virus after tiered weight-based oseltamivir therapy. Virological surveillance for patterns of drug resistance is essential for determination of antiviral treatment strategies and for composition of pandemic preparedness stockpiles. [ABSTRACT FROM AUTHOR]

Presents information on a study which investigated recombinant respiratory syncytial virus (rRSV) in which M2 second translational reading frame (ORF2) was disrupted by a frame shift or by ablation of translational start sites and the introduction of stop codons. Mutagenesis of M2 ORF2; Effect of M2-2 mutations on minireplicon transcription and replications; Recovery and growth in vitro of rRSV containing the M2-2 mutations.

During the first year of enhanced MERS coronavirus surveillance in England, 77 persons traveling from the Middle East had acute respiratory illness and were tested for the virus. Infection was confirmed in 2 travelers with acute respiratory distress syndrome and 2 of their contacts. Patients with less severe manifestations tested negative. [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated the emergence of community transmission of influenza A/H1N1 in England based on results from self sampling of NHS Direct callers with influenza-like illness. People in six Strategic Health Authorities with cold of flu symptoms or both were involved in the study, who called the NHS Direct multi-channel health advice and information service. It was found that a reliable indication of local community transmission was provided by Testing in Health Protection Agency regional laboratories.