Differences in nasal immunoglobulin A responses to influenza vaccine strains after live attenuated influenza vaccine (LAIV) immunization in children.

Different vaccine strains included in the live attenuated influenza vaccine (LAIV) have variable efficacy. The reasons for this are not clear and may include differences in immunogenicity. We report a Phase IV open-label study on the immunogenicity of a single dose of quadrivalent LAIV (Fluenz™ Tetra) in children during the 2015/16 season, to investigate the antibody responses to different strains. Eligible children were enrolled to receive LAIV; nasal samples were collected before and approximately 4 weeks after immunization. There was a significant increase in nasal immunoglobulin (Ig)A to the H3N2, B/Victoria lineage (B/Brisbane) and B/Yamagata lineage (B/Phuket) components, but not to the H1N1 component. The fold change in nasal IgA response was inversely proportional to the baseline nasal IgA titre for H1N1, H3N2 and B/Brisbane. We investigated possible associations that may explain baseline nasal IgA, including age and prior vaccination status, but found different patterns for different antigens, suggesting that the response is multi-factorial. Overall, we observed differences in immune responses to different viral strains included in the vaccine; the reasons for this require further investigation.

Retrospective assessment of rapid outbreak investigation for gastrointestinal diseases using only cases and background exposure data.

For outbreaks of gastrointestinal disease, rapid identification of the source is crucial to enable public health intervention and prevent further cases. Outbreak investigation comprises analyses of exposure information from cases and, if required, undertaking analytical epidemiological studies. Hypothesis generation has been reliant on empirical knowledge of exposures historically associated with a given pathogen. Epidemiology studies are resource-intensive and prone to bias, one of the reasons being the difficulties in recruiting appropriate controls. For this paper, the information from cases was compared against pre-defined background exposure information. As exemplars, three past outbreaks were used, one of common and two of rare exposures. Information from historical case trawling questionnaires was used to define background exposure having removed any exposures implicated with the outbreak. The case-background approach showed good sensitivity and specificity, identifying correctly all outbreak-related exposures. One additional exposure related to a retailer was identified and four food items where all cases had been exposed. In conclusion, the case-background method, a development of the case-case design, can be used to assist with hypothesis generation or when a case-control study may not be possible to carry out.

Trends in the burden of varicella in UK general practice.

Childhood varicella vaccination has not yet been introduced in the UK. To inform decision-making about future vaccine programmes, data on the burden of varicella in general practice over a 10-year period (01/01/2005-31/12/2014) was calculated by age and ethnicity, using anonymised data from >8 million individuals in the Clinical Practice Research Datalink. Varicella consultations peaked at 20 603 in 2007, then decreased annually in all age groups to 11 243 in 2014. Each year, consultation rates were common among infants, were highest among 1-3 year olds (61·2 consultations/1000 person-years in 2007, 39·7/1000 person-years in 2014) and then fell with increasing age to <1·0/1000 person-years at ages ⩾20 years. Varicella acquisition appeared to be delayed in some ethnic groups, with lower consultation rates for children aged <3 years but increased rates for older children and adults aged ⩽40 years among those of black African, Afro-Caribbean, South Asian or other Asian ethnicity. Decreasing general practice consultation rates over time could reflect changes in healthcare utilisation, with patients seeking care in alternative settings such as Accident and Emergency Departments, although current data prevent full assessment of this. Availability of data on varicella diagnoses across all health settings would enable estimation of the total healthcare burden due to varicella and the cost-effectiveness of introducing varicella vaccination.

Is it appropriate to use fixed assay cut-offs for estimating seroprevalence?

Population seroprevalence can be estimated from serosurveys by classifying quantitative measurements into positives (past infection/vaccinated) or negatives (susceptible) according to a fixed assay cut-off. The choice of assay cut-offs has a direct impact on seroprevalence estimates. A time-resolved fluorescence immunoassay (TRFIA) was used to test exposure to human parvovirus 4 (HP4). Seroprevalence estimates were obtained after applying the diagnostic assay cut-off under different scenarios using simulations. Alternative methods for estimating assay cut-offs were proposed based on mixture modelling with component distributions for the past infection/vaccinated and susceptible populations. Seroprevalence estimates were compared to those obtained directly from the data using mixture models. Simulation results showed that when there was good distinction between the underlying populations all methods gave seroprevalence estimates close to the true one. For high overlap between the underlying components, the diagnostic assay cut-off generally gave the most biased estimates. However, the mixture model methods also gave biased estimates which were a result of poor model fit. In conclusion, fixed cut-offs often produce biased estimates but they also have advantages compared to other methods such as mixture models. The bias can be reduced by using assay cut-offs estimated specifically for seroprevalence studies.

A simulation study to compare three self-controlled case series approaches: correction for violation of assumption and evaluation of bias.

PURPOSE: The assumption that the occurrence of outcome event must not alter subsequent exposure probability is critical for preserving the validity of the self-controlled case series (SCCS) method. This assumption is violated in scenarios in which the event constitutes a contraindication for exposure. In this simulation study, we compared the performance of the standard SCCS approach and two alternative approaches when the event-independent exposure assumption was violated. METHODS: Using the 2009 H1N1 and seasonal influenza vaccines and Guillain-Barré syndrome as a model, we simulated a scenario in which an individual may encounter multiple unordered exposures and each exposure may be contraindicated by the occurrence of outcome event. The degree of contraindication was varied at 0%, 50%, and 100%. The first alternative approach used only cases occurring after exposure with follow-up time starting from exposure. The second used a pseudo-likelihood method. RESULTS: When the event-independent exposure assumption was satisfied, the standard SCCS approach produced nearly unbiased relative incidence estimates. When this assumption was partially or completely violated, two alternative SCCS approaches could be used. While the post-exposure cases only approach could handle only one exposure, the pseudo-likelihood approach was able to correct bias for both exposures. CONCLUSIONS: Violation of the event-independent exposure assumption leads to an overestimation of relative incidence which could be corrected by alternative SCCS approaches. In multiple exposure situations, the pseudo-likelihood approach is optimal; the post-exposure cases only approach is limited in handling a second exposure and may introduce additional bias, thus should be used with caution.

Impact analysis of rotavirus vaccination in various geographic regions in Western Europe.

BACKGROUND: Universal mass vaccination (UMV) against rotavirus has been implemented in many but not all European countries. This study investigated the impact of UMV on rotavirus incidence trends by comparing European countries with UMV: Belgium, England/Wales and Germany versus countries without UMV: Denmark and the Netherlands. METHODS: For this observational retrospective cohort study, time series data (2001-2016) on rotavirus detections, meteorological factors and population demographics were collected. For each country, several meteorological and population factors were investigated as possible predictors of rotavirus incidence. The final set of predictors were incorporated in negative binomial models accounting for seasonality and serial autocorrelation, and time-varying incidence rate ratios (IRR) were calculated for each age group and country separately. The overall vaccination impact two years after vaccine implementation was estimated by pooling the results using a random effects meta-analyses. Independent t-tests were used to compare annual epidemics in the pre-vaccination and post-vaccination era to explore any changes in the timing of rotavirus epidemics. RESULTS: The population size and several meteorological factors were predictors for the rotavirus epidemiology. Overall, we estimated a 42% (95%-CI 23;56%) reduction in rotavirus incidence attributable to UMV. Strongest reductions were observed for age-groups 0-, 1- and 2-years (IRR 0.47, 0.48 and 0.63, respectively). No herd effect induced by UMV in neighbouring countries was observed. In all UMV countries, the start and/or stop and corresponding peak of the rotavirus season was delayed by 4-7 weeks. CONCLUSIONS: The introduction of rotavirus UMV resulted in an overall reduction of 42% in rotavirus incidence in Western European countries two years after vaccine introduction and caused a change in seasonal pattern. No herd effect induced by UMV neighbouring countries was observed for Denmark and the Netherlands.

Risk factors for recurrent tuberculosis in England and Wales, 1998-2005.

BACKGROUND: Information on recurrent tuberculosis can provide an indication of the effectiveness of tuberculosis services and identify patients who are most vulnerable. The objective of this study was to estimate the incidence of, and investigate risk factors for, recurrent episodes of tuberculosis in England and Wales. METHODS: Episodes of recurrent tuberculosis were identified among prospectively collected records of tuberculosis cases reported to the Health Protection Agency between 1998 and 2005. An episode of recurrent tuberculosis was defined as a re-notified case in the same patient after at least 12 months from the date of the initial notification. To estimate incidence, follow-up time was calculated for all cases until re-notification or censure. Multivariable Cox proportionate hazard models were used to determine hazard ratios (HR) for recurrence of tuberculosis and investigate the risk associated with clinical, demographic and microbiological factors. RESULTS: Five hundred and eighty-eight recurrent tuberculosis events were identified among 53 214 cases reported between 1998 and 2005, a rate of 4.1 (95% CI 3.8 to 4.5) episodes per 1000 person years of follow-up. Factors independently associated with a greater risk of recurrent tuberculosis were HIV co-infection (HR 1.64, 95% CI 1.13 to 2.38) and belonging to a South Asian ethnic group (HR 1.54, 95% CI 1.23 to 1.93). CONCLUSION: Tuberculosis recurrence is uncommon in England and Wales despite the absence of a universal directly observed treatment policy. The identification of HIV co-infection as a risk factor for recurrent tuberculosis is consistent with findings elsewhere. The higher risk among South Asians, however, requires further investigation.

The risk of Kawasaki disease after pneumococcal conjugate & meningococcal B vaccine in England: A self-controlled case-series analysis.

Kawasaki disease (KD) is an uncommon condition occasionally reported after childhood vaccination. Admissions with a KD-compatible diagnosis identified from a national database in England were linked to immunisation records to investigate the risk after pneumococcal conjugate (PCV) or meningococcal B (MenB) vaccines. Both are given at 2/4/12 months of age but were introduced sequentially, allowing their effects to be separately assessed. A total of 553 linked admissions in 512 individuals were validated as KD. The relative incidence (RI) within 28 days of PCV doses 1 or 2 measured by the self-controlled case-series method was 0.62 (95% confidence interval (CI) 0.38-1.00) with a significantly decreased risk after dose 3 (RI 0.30 (95% CI 0.11-0.77)). For MenB vaccine, the RI after doses 1 or 2 was 1.03 (95% CI 0.51-2.05) and 0.64 (95% CI 0.08-5.26) after dose 3. This study shows no evidence of an increased risk of KD after either vaccine.

Time resolved fluorometric immunoassay, using europium labelled antihuman IgG, for the detection of human tetanus antitoxin in serum.

A time resolved fluorometric immunoassay (TRFIA) has been developed and compared with an in house enzyme linked immunosorbent assay (ELISA) and commercial ELISA (Bindazyme) for the detection of tetanus antitoxin in human sera. A panel of 132 sera submitted for routine testing was used. Scatterplots showed a high degree of correlation between all three assays, although some divergence of results was apparent for low titre sera when comparing in house ELISA results with Bindazyme ELISA and TRFIA results. The TRFIA appeared to be more sensitive than the in house ELISA, and the Bindazyme assay compared well with the TRFIA. The intra-assay precision of all three assays, in terms of percentage coefficient of variation (%CV), was between 2.0% and 4.0%. The interassay precision ranged from 5% to 8% for the in house ELISA, 13% to 19% for the Bindazyme assay, and 11% to 13% for TRFIA. Both Bindazyme and TRFIA assays were simple to perform, accurate, reproducible, and amenable to automation. A particular benefit of the TRFIA was its large dynamic range, enabling tetanus antitoxin values of 0.01 IU/ml to 50 IU/ml to be measured with just one dilution of serum. TRFIA appears to be a useful serological technique worthy of further development.

Routine antenatal screening for hepatitis B using pooled sera: validation and review of 10 years experience.

AIMS: To validate the sensitivity of universal antenatal screening for hepatitis B surface antigen (HBsAg) by testing pools of 10 sera, and to review 10 years' experience using this method. METHODS: 66,945 antenatal patients were tested between 1986 and 1996 using the pooled method. All sera from 1996 (n = 6050) were retrieved and retrospectively tested individually. An in vitro determination of the effect of pooling on sensitivity was performed by checkerboard neutralisation assay. RESULTS: 26 HBsAg positive women were detected by universal screening over 10 years; 12 had non-European surnames and five had known risk factors for hepatitis B infection. High titre anti-HBs sera in the pool reduced the sensitivity of the HBsAg assay, though the effect was only significant at low levels of HBsAg carriage. CONCLUSIONS: The prevalence of hepatitis B is extremely low in the antenatal population served by Plymouth PHL. Pooling is unlikely to reduce sensitivity enough to lead to significant preventable vertical transmission, and is a cost-effective and valid strategy in areas of low seroprevalence.

Measurement of IgG antibodies to Chlamydia trachomatis by commercial enzyme immunoassays and immunofluorescence in sera from pregnant women and patients with infertility, pelvic inflammatory disease, ectopic pregnancy, and laboratory diagnosed Chlamydia psittaci/Chlamydia pneumoniae infection.

BACKGROUND: Screening for Chlamydia trachomatis specific antibodies is valuable in diagnosing asymptomatic pelvic inflammatory disease (PID) and tubal damage following repeated episodes of PID. The assays in current use are unsuitable for screening large numbers of samples so there is a need to develop more suitable assays. AIMS: To compare the performance of several commercial C trachomatis enzyme immunoassays (EIAs) (SeroCT, C tracho(pep), Medac p-EIA, Vircell and Labsystems C trachomatis IgG EIAs) using major outer membrane protein (MOMP), an inactivated organism EIA (Genzyme Virotech EIA), and a genus specific EIA (Platelia Chlamydia IgG) with the whole cell inclusion immunofluorescence (WIF) assay. In addition, to adapt, using time resolved fluorescence technology, the assay showing the highest correlation with WIF. METHODS: Ninety sera from patients presenting with ectopic pregnancies, 187 sera from those with a variety of types of infertility, 33 sera from cases of PID where a fourfold rise in WIF titre occurred, and 90 sera from antenatal clinic attenders were tested. A panel of 36 sera from laboratory diagnosed cases of Chlamydia psittaci/Chlamydia pneumoniae infection was also tested. RESULTS: The Genzyme Virotech EIA showed the highest rank correlation coefficient (0.82) with WIF, particularly at high WIF titres. The MOMP specific assays varied in their correlation with WIF, with rank correlation coefficients ranging from 0.70 (Medac p-EIA) to 0.80 (Vircell EIA). The Genzyme Virotech assay showed poor specificity (5.6%; 95% confidence interval (CI), 0.68% to 18.7%)--it was reactive with 34 of the panel of 36 C psittaci/C pneumoniae positive sera. The MOMP based EIAs showed high specificity, particularly the Medac p-ELISA (97.2%; 95% CI, 85.5% to 99.9%)--only one serum was reactive. In view of the good correlation between WIF and the Genzyme Virotech EIA, a time resolved fluorescence immunoassay (TRFIA) was developed using the Genzyme Virotech antigen. Using an appropriate cut off the TRFIA assay showed excellent correlation with WIF. CONCLUSIONS: The TRFIA assay may be useful as a screening assay, possibly in conjunction with one of the highly specific EIAs studied (for example, Medac p-EIA) to confirm the antibody specificity of sera selected by the screening assay.

Factors affecting results obtained with European Community tests for pasteurized milk sampled at the heat treatment establishment.

A total of 3000 samples of pasteurized milk taken at the heat treatment establishment over a 1-year period were examined for the presence of phosphatase and by a plate count at 30 degrees C, a coliform count at 30 degrees C, and a plate count at 21 degrees C after pre-incubation of the sample for 5 days at 6 degrees C, performed as prescribed in EC Directive 85/397/EEC. Samples were also examined for presence of Listeria species. Of 2690 samples (1713 from small dairies and 977 from large commercial premises) received at 4 degrees C or less, 96 (3.6%) has a plate count at 30 degrees C exceeding 30,000 organisms per ml, 608 (22.6%) contained 1 or more coliforms per ml, and in 1327 (49.3%) the pre-incubated count exceeded 100,000 organisms per ml. Thirty two samples from 23 dairies contained phosphatase. Listeria species were detected in 25 samples; only three of these strains were identified as Listeria monocytogenes. Results were analysed to determine relationships between factors which might affect test results. Samples from small dairies showed significantly higher coliform counts and pre-incubated plate counts than did those from large commercial premises. They were also more likely to contain phosphatase or Listeria species. Samples were significantly more likely to contain coliforms when taken in the July-September quarter or if received in glass containers.

Assessment of baseline age-specific antibody prevalence and incidence of infection to novel influenza A/H1N1 2009.

OBJECTIVES: The objectives of the H1N1 2009 serological surveillance project were twofold: to document (1) the prevalence of cross-reactive antibodies to H1N1 2009 by age group in the population of England prior to arrival of the pandemic strain virus in the UK and (2) the age-specific incidence of infection by month as the pandemic progressed by measuring increases in the proportion of individuals with antibodies to H1N1 2009 by age. METHODS: Residual aliquots of samples submitted to 16 microbiology laboratories in eight regions in England in defined age groups in 2008 and stored by the Health Protection Agency serological surveillance programme were used to document age-stratified prevalence of antibodies to H1N1 2009 prior to the arrival of the pandemic in the UK. Functional antibodies to the H1N1 2009 virus were measured by haemagglutination inhibition (HI) and microneutralisation (MN) assays. For timely measurement of monthly incidence of infection with H1N1 2009 between August 2009 and April 2010, the microbiology serum collections were supplemented by collection of residual sera from chemical pathology laboratories in England. Monthly seroincidence samples were tested by HI only, apart from the final sera collected post pandemic in 2010, which were also tested by MN. Incidence during the pandemic was estimated from changes in prevalence between time points and also by a likelihood-based method. SETTING: Eight regions of England. PARTICIPANTS: Serum samples from patients accessing health care in England from whom blood samples were taken for unrelated microbiological or chemical pathology testing. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Baseline age-specific prevalence of functional antibodies to the H1NI 2009 virus prior to the arrival of the pandemic; changes in antibody prevalence during the period August 2009 to April 2010. RESULTS: Pre-existing cross-reactive antibodies to H1N1 2009 were detected in the baseline sera and increased with age, particularly in those born before 1950. The prediction of immunological protection derived from the baseline serological analysis was consistent with the lower clinical attack rates in older age groups. The high levels of susceptibility in children < 15 years, together with their mixing within school, resulted in the highest attack rates in this age group. Serological analysis by region confirms that there were geographical differences in timing of major pandemic waves. London had a big first wave among the 5- to 14-year age group, with the rest of the country reducing the gap after the second wave. Cumulative incidence in London remained higher throughout the pandemic in each age group. By the end of the second wave it is estimated that as many as 70% of school-aged children in London had been infected. Taken together, these observations are consistent with observations from previous pandemics in 1918, 1957 and 1968 - that the major impact of influenza pandemics is on younger age groups, with a pattern of morbidity and mortality distinct from seasonal influenza epidemics. CONCLUSIONS: Serological analysis of appropriately structured, age-stratified and geographically representative samples can provide an immense amount of information to set in context other measures of pandemic impact in a population, and provide the most accurate measures of population exposure. National scale seroepidemiology studies require cross-agency coordination, multidisciplinary working, and considerable scientific resource. FUNDING: The National Institute for Health Research Health Technology Assessment programme and the Health Protection Agency.

Estimating influenza vaccine effectiveness using routinely collected laboratory data.

BACKGROUND: Estimation of influenza vaccine effectiveness (V/E) is needed early during influenza outbreaks in order to optimise management of influenza--a need which will be even greater in a pandemic situation. OBJECTIVE: Examine the potential of routinely collected virological surveillance data to generate estimates of V/E in real-time during winter seasons. METHODS: Integrated clinical and virological community influenza surveillance data collected over three winters 2004/5-2006/7 were used. We calculated the odds of vaccination in persons that were influenza-virus-positive and the odds in those that were negative and provided a crude estimate of V/E. Logistic regression was used to obtain V/E estimates adjusted for confounding variables such as age. RESULTS: Multivariable analysis suggested that adjustments to the crude V/E estimate were necessary for patient age and month of sampling. The annual adjusted V/E was 2005/6, 67% (95% CI 41% to 82%); 2006/7 55% (26% to 73%) and 2007/8 67% (41% to 82%). The adjusted V/E in persons <65 years was 70% (57% to 78%) and 65 years and over 46% (-17% to 75%). Estimates differed by small insignificant amounts when calculated separately for influenza A and B; by interval between illness onset and swab sample; by analysis for the period November to January in each year compared with February to April and according to viral load. CONCLUSION: We have demonstrated the potential of using routine virological and clinical surveillance data to provide estimates of V/E early in season and conclude that it is feasible to introduce this approach to V/E measurement into evaluation of national influenza vaccination programs.

Prevalence and incidence of hepatitis C in injecting drug users attending genitourinary medicine clinics.

Surveillance reports and prevalence studies have indicated that injecting drug users (IDUs) contribute more to the hepatitis C epidemic in the United Kingdom than any other risk group. Information on both the prevalence and incidence of hepatitis C in IDUs is therefore essential to understanding the epidemiology of this infection. The prevalence of hepatitis C in specimens from the Unlinked Anonymous Prevalence Monitoring Programme collected in 1995, 1996, 1998, 1999, 2000, and 2001 was determined using residual syphilis serology specimens from IDUs attending 15 genitourinary medicine (GUM) clinics in and outside London. These specimens were tested for antibodies to hepatitis C virus (anti-HCV). Using this cross-sectional design, anti-HCV-negative specimens were tested for HCV RNA to identify incident infections during the 'window' period of infection, and thus to estimate HCV incidence. Results of the multivariable analysis showed that there was marked variation in prevalence by clinic (P<0.0001) and age (P<0.0001). Overall the majority of infections were in males and the overall prevalence in injectors declined over the study period from 36.9% to 28.7%. The annual incidence in these injectors was estimated as being 3.01% (95% CI 1.25-6.73). Over the study period HCV incidence decreased by 1.2% per year. Genotyping of the incident infections identified the most common genotype as type 1 with type 3 being more frequently seen after 1998. Of the prevalent infections, genotype 1 was the most common. The study has confirmed a higher prevalence of anti-HCV in IDUs in the London area compared to those outside London. How representative of the current injecting drug user population are IDUs attending GUM clinics is unclear. Even so, such studies allow prevalence and incidence to be estimated in individuals who have ever injected drugs and inform ongoing public health surveillance.

The burden of parvovirus B19 infection in women of childbearing age in England and Wales.

A serological survey has been used to investigate the epidemiology of parvovirus B19 infection in England and Wales. A total of 2835 sera representing the complete age range were selected from a convenience collection obtained in 1996 that reflects the general population and screened for parvovirus B19-specific IgG. Antibody prevalence rose nonlinearly with age from 21% in those aged 1-4 years to >75% in adults aged > or = 45 years. Force-of-infection estimates were similar to those previously made in 1991, being highest in those aged <15 years. There was no association between evidence of previous infection and sex or region. Quantitatively strongest antibody responses were found in those aged 15-34 years and IgG levels in females were 28.5% higher than those found in males (P=0.004, 95% CI 8.2-52.6). Applying the upper 95% confidence interval for the force of infection to maternity estimates for England and Wales in 1996, parvovirus infection in pregnancy was estimated to occur on average in up to 1 in every 512 pregnancies each year. This represents 1257 maternal infections, causing up to an estimated 59 fetal deaths and 11 cases of hydrops fetalis annually. An analysis of all available laboratory-confirmed parvovirus infections found a mean of 944 infections per year in women aged 15-44 years highlighting a need for enhanced surveillance of maternal parvovirus B19 infection in England and Wales, including information on both pregnancy and outcome of pregnancy.

Survival of a national cohort of hepatitis C virus infected patients, 16 years after exposure.

The aim of this study was to describe the natural history of HCV after 16 years of infection, in a cohort of individuals who acquired their infections on a known date in the United Kingdom. A total of 924 HCV-infected transfusion recipients (cases) and 475 anti-HCV negative transfusion recipients (controls) were eligible for inclusion in the study. Survival was compared between cases and controls to see if there was any excess mortality attributable to HCV. The results show that all-cause mortality was not significantly different between cases and controls (hazard ratio 1.17, 95% CI 0.92-1.49, P=0.21). However, the risk of death directly from liver disease was higher in cases than controls (hazard ratio 2.71, 95% CI 1.09-6.75, P=0.03). Nearly 30% of those HCV-infected cases who died directly from liver disease were known to have consumed excess alcohol.