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1.  East London Experience with Enteric Fever 2007-2012 
PLoS ONE  2015;10(3):e0120926.
The clinical presentation and epidemiology for patients with enteric fever at two hospitals in East London during 2007–2012 is described with the aim to identify preventive opportunities and to reduce the cost of treatment.
A retrospective analysis of case notes from patients admitted with enteric fever during 2007 to 2012 with a microbiologically confirmed diagnosis was undertaken. Details on clinical presentation, travel history, demographic data, laboratory parameters, treatment, patient outcome and vaccination status were collected.
Clinical case notes were available for 98/129 (76%) patients including 69 Salmonella enterica serovar Typhi (S. Typhi) and 29 Salmonella enterica serovar Paratyphi (S. Paratyphi). Thirty-four patients (35%) were discharged from emergency medicine without a diagnosis of enteric fever and then readmitted after positive blood cultures. Seventy-one of the 98 patients (72%) were UK residents who had travelled abroad, 23 (23%) were foreign visitors/new entrants to the UK and four (4%) had not travelled abroad. Enteric fever was not considered in the initial differential diagnosis for 48/98 (49%) cases. The median length of hospital stay was 7 days (range 0–57 days). The total cost of bed days for managing enteric fever was £454,000 in the two hospitals (mean £75,666/year). Median time to clinical resolution was five days (range 1–20). Seven of 98 (7%) patients were readmitted with relapsed or continued infection. Six of the 71 (8%) patients had received typhoid vaccination, 34 (48%) patients had not received vaccination, and for 31 cases (44%) vaccination status was unknown.
Further interventions regarding education and vaccination of travellers and recognition of the condition by emergency medicine clinicians in travellers to South Asia is required.
PMCID: PMC4366366  PMID: 25790017
2.  The Application of a Novel Statistical Method for Syndromic Surveillance in England 
PMCID: PMC4512419
Syndromic surveillance; statistical methods; risk assessment; public health action
3.  The Burden of Disease and Health Care Use among Pertussis Cases in School Aged Children and Adults in England and Wales; A Patient Survey 
PLoS ONE  2014;9(11):e111807.
In 2011–2012 a large pertussis outbreak occurred in England. This provided an opportunity to estimate the disease burden in those aged 5 years and over. As pertussis is likely to be under reported both laboratory-confirmed and non-confirmed cases were included.
Laboratory-confirmed cases of pertussis, as well as their coughing but non-confirmed household members, were sent a questionnaire that collected information on clinical features and quality of life for the most severe day of disease and the day the patient filled in the questionnaire. The EuroQol-5 dimension questionnaire (EQ-5D) was used to evaluate quality of life. The duration of symptoms was obtained by contacting the patient every two weeks until symptoms stopped.
Data for 535 (out of 1262) laboratory confirmed pertussis patients and 44 (out of 140) coughing household contacts was available for analysis. On the most severe day, 56% of laboratory-confirmed cases reported they had 20+ more paroxysms, 58% reported they had a severe cough and 46% reported disruption of sleep for more than 4 hours. For non-confirmed coughing household contacts there were a similar number of coughing spells per day at the height, though the cough was reported to be less severe and to cause less sleep disruption. The main clinical symptoms on the worst day for both were shortness of breath, tiredness, sore ribs and vomiting. The duration of symptoms for both patient groups was around 160 days (162 and 168 days). Under base case assumptions the overall loss of quality of life was 0.097 QALY (0.089–0.106) for confirmed pertussis cases and 0.0365 QALY (0.023–0.054) for coughing household contacts.
Pertussis is a serious disease in those aged 5 years and over, causing disruption of sleep and daily activities over long period of time. The burden of illness due to undiagnosed pertussis is also considerable.
PMCID: PMC4244040  PMID: 25423321
4.  Validity of a reported history of chickenpox in targeting varicella vaccination at susceptible adolescents in England☆ 
Vaccine  2014;32(10):1213-1217.
•Chickenpox history may enable cost-effective vaccination of susceptible individuals.•We tested the validity of reported chickenpox history in adolescents.•Vaccine would be wasted in most adolescents with a negative or uncertain history.•6–9% of those with a positive chickenpox history would remain susceptible.•These data are needed to inform cost-effectiveness of proposed vaccine programmes.
In the UK, primary varicella is usually a mild infection in children, but can cause serious illness in susceptible pregnant women and adults. The UK Joint Committee on Vaccination and Immunisation is considering an adolescent varicella vaccination programme. Cost-effectiveness depends upon identifying susceptibles and minimising vaccine wastage, and chickenpox history is one method to screen for eligibility. To inform this approach, we estimated the proportion of adolescents with varicella antibodies by reported chickenpox history.
Recruitment occurred through secondary schools in England from February to September 2012. Parents were asked about their child's history of chickenpox, explicitly setting the context in terms of the implications for vaccination. 247 adolescents, whose parents reported positive (120), negative (77) or uncertain (50) chickenpox history provided oral fluid for varicella zoster virus-specific immunoglobulin-G (VZV-IgG) testing.
109 (90.8% [85.6–96.0%]) adolescents with a positive chickenpox history, 52 (67.5% [57.0–78.1%]) with a negative history and 42 (84.0% [73.7–94.3%]) with an uncertain history had VZV-IgG suggesting prior infection. Combining negative and uncertain histories, 74% had VZV-IgG (best-case). When discounting low total-IgG samples and counting equivocals as positive (worst-case), 84% had VZV-IgG. We also modelled outcomes by varying the negative predictive value (NPV) for the antibody assay, and found 74–87% under the best-case and 84–92% under the worst-case scenario would receive vaccine unnecessarily as NPV falls to 50%.
Reported chickenpox history discriminates between varicella immunity and susceptibility in adolescents, but significant vaccine wastage would occur if this approach alone were used to determine vaccine eligibility. A small but important proportion of those with positive chickenpox history would remain susceptible. These data are needed to determine whether reported history, with or without oral fluid testing in those with negative and uncertain history, is sufficiently discriminatory to underpin a cost-effective adolescent varicella vaccination programme.
PMCID: PMC3969712  PMID: 23871823
Varicella; Chickenpox; Reported history; Validity; Adolescent; Vaccination programme
5.  Guillain-Barré Syndrome and Adjuvanted Pandemic Influenza A (H1N1) 2009 Vaccines: A Multinational Self-Controlled Case Series in Europe 
PLoS ONE  2014;9(1):e82222.
The risk of Guillain-Barré syndrome (GBS) following the United States' 1976 swine flu vaccination campaign in the USA led to enhanced active surveillance during the pandemic influenza (A(H1N1)pdm09) immunization campaign. This study aimed to estimate the risk of GBS following influenza A(H1N1)pdm09 vaccination.
A self-controlled case series (SCCS) analysis was performed in Denmark, Finland, France, Netherlands, Norway, Sweden, and the United Kingdom. Information was collected according to a common protocol and standardised procedures. Cases classified at levels 1–4a of the Brighton Collaboration case definition were included. The risk window was 42 days starting the day after vaccination. Conditional Poisson regression and pooled random effects models estimated adjusted relative incidences (RI). Pseudo likelihood and vaccinated-only methods addressed the potential contraindication for vaccination following GBS.
Three hundred and three (303) GBS and Miller Fisher syndrome cases were included. Ninety-nine (99) were exposed to A(H1N1)pdm09 vaccination, which was most frequently adjuvanted (Pandemrix and Focetria). The unadjusted pooled RI for A(H1N1)pdm09 vaccination and GBS was 3.5 (95% Confidence Interval (CI): 2.2–5.5), based on all countries. This lowered to 2.0 (95% CI: 1.2–3.1) after adjustment for calendartime and to 1.9 (95% CI: 1.1–3.2) when we accounted for contra-indications. In a subset (Netherlands, Norway, and United Kingdom) we further adjusted for other confounders and there the RI decreased from 1.7 (adjusted for calendar month) to 1.4 (95% CI: 0.7–2.8), which is the main finding.
This study illustrates the potential of conducting European collaborative vaccine safety studies. The main, fully adjusted analysis, showed that the RI of GBS was not significantly elevated after influenza A(H1N1)pdm09 vaccination (RI = 1.4 (95% CI: 0.7–2.8). Based on the upper limits of the pooled estimate we can rule out with 95% certainty that the number of excess GBS cases after influenza A(H1N1)pdm09 vaccination would be more than 3 per million vaccinated.
PMCID: PMC3880265  PMID: 24404128
6.  Mortality Attributable to Influenza in England and Wales Prior to, during and after the 2009 Pandemic 
PLoS ONE  2013;8(12):e79360.
Very different influenza seasons have been observed from 2008/09–2011/12 in England and Wales, with the reported burden varying overall and by age group. The objective of this study was to estimate the impact of influenza on all-cause and cause-specific mortality during this period. Age-specific generalised linear regression models fitted with an identity link were developed, modelling weekly influenza activity through multiplying clinical influenza-like illness consultation rates with proportion of samples positive for influenza A or B. To adjust for confounding factors, a similar activity indicator was calculated for Respiratory Syncytial Virus. Extreme temperature and seasonal trend were controlled for. Following a severe influenza season in 2008/09 in 65+yr olds (estimated excess of 13,058 influenza A all-cause deaths), attributed all-cause mortality was not significant during the 2009 pandemic in this age group and comparatively low levels of influenza A mortality were seen in post-pandemic seasons. The age shift of the burden of seasonal influenza from the elderly to young adults during the pandemic continued into 2010/11; a comparatively larger impact was seen with the same circulating A(H1N1)pdm09 strain, with the burden of influenza A all-cause excess mortality in 15–64 yr olds the largest reported during 2008/09–2011/12 (436 deaths in 15–44 yr olds and 1,274 in 45–64 yr olds). On average, 76% of seasonal influenza A all-age attributable deaths had a cardiovascular or respiratory cause recorded (average of 5,849 influenza A deaths per season), with nearly a quarter reported for other causes (average of 1,770 influenza A deaths per season), highlighting the importance of all-cause as well as cause-specific estimates. No significant influenza B attributable mortality was detected by season, cause or age group. This analysis forms part of the preparatory work to establish a routine mortality monitoring system ahead of introduction of the UK universal childhood seasonal influenza vaccination programme in 2013/14.
PMCID: PMC3859479  PMID: 24348993
7.  Estimating the parasitaemia of Plasmodium falciparum: experience from a national EQA scheme 
Malaria Journal  2013;12:428.
To examine performance of the identification and estimation of percentage parasitaemia of Plasmodium falciparum in stained blood films distributed in the UK National External Quality Assessment Scheme (UKNEQAS) Blood Parasitology Scheme.
Analysis of performance for the diagnosis and estimation of the percentage parasitaemia of P. falciparum in Giemsa-stained thin blood films was made over a 15-year period to look for trends in performance.
An average of 25% of participants failed to estimate the percentage parasitaemia, 17% overestimated and 8% underestimated, whilst 5% misidentified the malaria species present.
Although the results achieved by participants for other blood parasites have shown an overall improvement, the level of performance for estimation of the parasitaemia of P. falciparum remains unchanged over 15 years. Possible reasons include incorrect calculation, not examining the correct part of the film and not examining an adequate number of microscope fields.
PMCID: PMC4222811  PMID: 24261625
8.  The Social Life of Infants in the Context of Infectious Disease Transmission; Social Contacts and Mixing Patterns of the Very Young 
PLoS ONE  2013;8(10):e76180.
Insight into how humans interact helps further understanding of the transmission of infectious diseases. For diseases such as pertussis, infants are at particular risk for severe outcomes. To understand the contact pattern of infants, especially those too young to be vaccinated, we sent contact diaries to a representative sample of 1000 mothers in the United Kingdom. We received 115 responses with a total of 758 recorded contacts. The average number of daily contacts for an infant was 6.68 overall and 5.7 for those aged ≤10 weeks. Of the latter, 2.1 (37%) contacts were with non-household members and were >15 minutes duration, suggesting that a cocooning programme may miss a substantial proportion of exposures leading to disease transmission. The least contact was between adolescents and infants. Thus the impact of adolescent (pertussis) vaccination on infants would likely be limited, unless it reduces transmission to other age groups whose contact with infants is greater.
PMCID: PMC3797797  PMID: 24146835
9.  Changes in Molecular Epidemiology of Streptococcus pneumoniae Causing Meningitis following Introduction of Pneumococcal Conjugate Vaccination in England and Wales 
Journal of Clinical Microbiology  2013;51(3):820-827.
The introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in September 2006 has markedly reduced the burden of invasive pneumococcal disease (IPD) including meningitis in England and Wales. This study examined changes in the molecular epidemiology of pneumococcal isolates causing meningitis from July 2004 to June 2009. The Health Protection Agency conducts enhanced pneumococcal surveillance in England and Wales. In addition to serotyping, pneumococcal isolates causing meningitis were genotyped by multilocus sequence typing (MLST). A total of 1,030 isolates were both serotyped and genotyped over the 5-year period. Fifty-two serotypes, 238 sequence types (STs), and 87 clonal complexes were identified, with no significant difference in the yearly Simpson's diversity index values (range, 0.974 to 0.984). STs commonly associated with PCV7 serotypes declined following PCV implementation, with a proportionally greater decline in ST124 (commonly associated with serotype 14). No other ST showed significant changes in distribution, even within individual serotypes. Replacement disease following PCV7 introduction was mainly due to serotypes 1, 3, 7F, 19A, 22F, and 33F through clonal expansion. A single instance of possible capsule switching was identified where one ST4327 clone expressed a serotype 14 capsule in 2005 and a serotype 28A capsule in 2009. In 2008 to 2009, ST191 (7F) became the most prevalent clone causing meningitis (10.3%). Case fatality (145 fatalities/1,030 cases; 14.1%) was high across all age groups and serotype groups. Thus, the introduction of PCV7 resulted in an increase in non-PCV7 serotypes, including some not covered by the 13-valent vaccine, such as serotypes 22F and 33F, emphasizing the importance of long-term epidemiological and molecular surveillance.
PMCID: PMC3592052  PMID: 23269742
10.  Statistical Models for Biosurveillance of Multiple Organisms 
To look at the diversity of the patterns displayed by a range of organisms, and to seek a simple family of models that adequately describes all organisms, rather than a well-fitting model for any particular organism.
There has been much research on statistical methods of prospective outbreak detection that are aimed at identifying unusual clusters of one syndrome or disease, and some work on multivariate surveillance methods (1). In England and Wales, automated laboratory surveillance of infectious diseases has been undertaken since the early 1990’s. The statistical methodology of this automated system is described in (2). However, there has been little research on outbreak detection methods that are suited to large, multiple surveillance systems involving thousands of different organisms.
We obtained twenty years’ data on weekly counts of all infectious disease organisms reported to the UK’s Health Protection Agency. We summarized the mean frequencies, trends and seasonality of each organism using log-linear models. To identify a simple family of models which adequately represents all organisms, the Poisson model, the quasi-Poisson model and the negative binomial model were investigated (3,4). Formal goodness-of-fit tests were not used as they can be unreliable with sparse data. Adequacy of the models was empirically studied using the relationships between the mean, variance and skewness. For this purpose, each data series was first subdivided into 41 half-years and de-seasonalized.
Trends and seasonality were summarized by plotting the distribution of estimated linear trend parameters for 2250 organisms, and modal seasonal period for 2254 organisms, including those organisms for which the seasonal effect is statistically significant.
Relationships between mean and variance were summarized as given in Figure 1.
Similar plots were used to summarize the relationships between mean and skewness.
Statistical outbreak detection models must be able to cope with seasonality and trends. The data analyses suggest that the great majority of organisms can adequately – though far from perfectly – be represented by a statistical model in which the variance is proportional to the mean, such as the quasi-Poisson or negative binomial models.
PMCID: PMC3692751
Biosurveillance; Public Health Surveillance; Data Analysis; Infectious Disease Outbreaks; Statistical Model
11.  An Improved Algorithm for Outbreak Detection in Multiple Surveillance Systems 
To improve the performance of the England and Wales large scale multiple statistical surveillance system for infectious disease outbreaks with a view to reducing the number of false reports, while retaining good power to detect genuine outbreaks.
There has been much interest in the use of statistical surveillance systems over the last decade, prompted by concerns over bioterrorism, the emergence of new pathogens such as SARS and swine flu, and the persistent public health problems of infectious disease outbreaks. In the United Kingdom (UK), statistical surveillance methods have been in routine use at the Health Protection Agency (HPA) since the early 1990s and at Health Protection Scotland (HPS) since the early 2000s (1,2). These are based on a simple yet robust quasi-Poisson regression method (1). We revisit the algorithm with a view to improving its performance.
We fit a quasi-Poisson regression model to baseline data.
One of the limitations of the current algorithm is the small number of baseline weeks used. We propose a simple seasonal adjustment using factors. We extend the model to include a 10-level factor.
We fit the trend component always irrespective of its statistical significance.
We are concerned that the existing weighting procedure is too drastic. The baseline at a certain week is down-weighted if the standardized Anscombe residual for that week is greater than 1. This condition was chosen empirically to avoid reducing the sensitivity of the system in the presence of large outbreaks in the baselines, but may be increasing the FPR unduly when there are no or only small outbreaks in the baselines. We investigate several other options, including reducing the down-weighting to cases where the Anscombe residuals are greater than 2 or 3.
We evaluate a new re-weighting scheme informed by past decisions. Using this adaptive scheme, baseline data where an alarm was flagged are down-weighted to reduce their effect on current predictions. The criterion we use for re-weighting, here, is the value of the exceedance score.
Finally, we investigate the validity of the upper threshold values based on the quasi-Poisson model when the data are generated using known negative binomial distributions.
Our evaluation of the existing algorithm showed that the false positive rate (FPR) is too high.
A novel feature of our new models is that they make use of much more baseline data. This resulted in a better estimation of the trend and variance and decreased the FPR. In addition, we found that the trend should always be fitted even when non-significant (or extreme). This decreases the discrepancies in the results when moving from one week to another.
The adaptive reweighting scheme was found to give broadly equivalent results to the reweighting method based on scaled Anscombe residuals. Using the latter as in the original HPA method, but with much higher threshold for reweighting decreased the FPR further.
Our investigations also suggest that the negative binomial model is a reasonable one, though not ideal in all circumstances. Thus, there is a good case for replacing the quasi-Poisson model with the negative binomial.
One of the unusual features of the HPA system is that it is run every week on a database of more than 3300 distinct organisms, which is likely to produce a large number of aberrances. We found that retaining the exceedance score approach based on the 0.995 quantile is perfectly reasonable. This involves ranking aberrant organisms in order of exceedance.
We have undertaken a thorough evaluation of the HPA’s outbreak detection system based on simulated and real data. The main conclusion from this evaluation is that the FPR is too high, owing to a combination of factors notably excessive down-weighting of high baselines and reliance on too few baseline weeks.
PMCID: PMC3692796
outbreak; negative binomial regression; quasi-Poisson
12.  Comparing the Immunogenicity of AS03-Adjuvanted 2009 Pandemic H1N1 Vaccine with Clinical Protection in Priority Risk Groups in England 
PLoS ONE  2013;8(2):e56844.
In England, during pandemic 2009 H1N1, vaccine efficacy and immunogenicity population studies in priority groups were rolled out in parallel to evaluate the pandemic vaccination programme. This provided a unique opportunity to compare immunogenicity and clinical protection in the same population and thus provide insights into the correlates of protection for the pandemic H1N1 2009 vaccine in risk groups. While clinical protection from AS03-adjuvanted pandemic 2009 H1N1 vaccine was high in those aged <25 years and pregnant women, effectiveness in older adults with chronic conditions has been found to be surprisingly poor. Here we present results from the immunogenicity study derived from the same population. Individuals from priority groups eligible for pandemic vaccination attending participating general practices were recruited. Pre and post-vaccination blood samples were collected and HI antibody testing to assess immune response to vaccination performed. The final cohort consisted of 610 individuals: 60 healthy children aged <5 years; 32 healthy pregnant women; 518 individuals from risk groups. Seroconversion rate in healthy children aged <5 years (87%, 95% CI: 75% to 94%) was higher than that of risk groups combined (65%, 95% CI: 61% to 69%) (p<0.001). Multivariable analysis of risk groups showed that the size of response in those who did seroconvert was lower in those who received the 2009/10 seasonal TIV (Fold effect: 0.52, 0.35 to 0.78). Predicted immunological boosting from higher pre-vaccine titres after 2009 pandemic H1N1 vaccination only occurred in children (seroconversion rate = 92%) and not in individuals aged 10 to 39 from risk groups (seroconversion rate = 74%). The lack of clinical protection identified in the same population in older adults from risk groups could be attributed to these lower seroresponses. Current immunogenicity licensing criteria for pandemic influenza vaccine may not correlate with clinical protection in individuals with chronic disease or immunocompromised.
PMCID: PMC3579930  PMID: 23451097
13.  Automated Biosurveillance Data from England and Wales, 1991–2011 
Emerging Infectious Diseases  2013;19(1):35-42.
Twenty years of data provide valuable insights for the design of large automated outbreak detection systems.
Outbreak detection systems for use with very large multiple surveillance databases must be suited both to the data available and to the requirements of full automation. To inform the development of more effective outbreak detection algorithms, we analyzed 20 years of data (1991–2011) from a large laboratory surveillance database used for outbreak detection in England and Wales. The data relate to 3,303 distinct types of infectious pathogens, with a frequency range spanning 6 orders of magnitude. Several hundred organism types were reported each week. We describe the diversity of seasonal patterns, trends, artifacts, and extra-Poisson variability to which an effective multiple laboratory-based outbreak detection system must adjust. We provide empirical information to guide the selection of simple statistical models for automated surveillance of multiple organisms, in the light of the key requirements of such outbreak detection systems, namely, robustness, flexibility, and sensitivity.
PMCID: PMC3557985  PMID: 23260848
algorithms; biosurveillance; data analysis; database; epidemiology; infectious disease outbreaks; public health surveillance; statistical model; England; Wales
14.  Invasive Pneumococcal Disease after Routine Pneumococcal Conjugate Vaccination in Children, England and Wales 
Emerging Infectious Diseases  2013;19(1):61-68.
Nonvaccine serotypes occur more often among children with comorbid conditions.
We assessed known risk factors, clinical presentation, and outcome of invasive pneumococcal disease (IPD) in children 3–59 months of age after introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in England and Wales. During September 2006–March 2010, a total of 1,342 IPD episodes occurred in 1,332 children; 14.9% (198/1,332) had comorbidities. Compared with IPD caused by PCV7 serotypes (44/248; 17.7%), comorbidities were less common for the extra 3 serotypes in the 10-valent vaccine (15/299; 5.0%) but similar to the 3 additional PCV13 serotypes (45/336; 13.4%) and increased for the 11 extra serotypes in 23-valent polysaccharide vaccine (PPV23) (39/186; 21.0%) and non-PPV23 serotypes (38/138; 27.5%). Fifty-two (3.9%) cases resulted from PCV7 failure; 9 (0.7%) case-patients had recurrent IPD. Case-fatality rate was 4.4% (58/1,332) but higher for meningitis (11.0%) and children with comorbidities (9.1%). Thus, comorbidities were more prevalent in children with IPD caused by non-PCV13 serotypes and were associated with increased case fatality.
PMCID: PMC3557991  PMID: 23259937
Invasive pneumococcal disease; risk factors; serotypes; meningitis; outcome; vaccination; bacteria; England; Wales; children
15.  Seroprevalence of Influenza A(H1N1)pdm09 Virus Antibody, England, 2010 and 2011 
Emerging Infectious Diseases  2012;18(11):1894-1897.
The intense influenza activity in England during the 2010–11 winter resulted from a combination of factors. Population-based seroepidemiology confirms that the third wave of influenza A(H1N1)pdm09 virus circulation was associated with a shift in age groups affected, with the highest rate of infection in young adults.
PMCID: PMC3559155  PMID: 23092684
influenza; influenza virus; influenza A(H1N1)pdm09 virus; serology; seroprevalence; antibody; pandemic; incidence; transmission; antigenic drift; vaccination; severity; surveillance; viruses; England
16.  Effect of Serotype on Focus and Mortality of Invasive Pneumococcal Disease: Coverage of Different Vaccines and Insight into Non-Vaccine Serotypes 
PLoS ONE  2012;7(7):e39150.
Differences in pathogenicity between pneumococcal serotypes are important when assessing the potential benefit of different valency vaccines. We investigated the effect of serotype on clinical presentation, outcome, and quality of life lost from invasive pneumococcal disease (IPD) in the context of the 7, 10, and 13 valent pneumococcal conjugate vaccines (PCV7, PCV10, PCV13).
Serotyped IPD cases in England were linked to the national dataset of hospital admissions for April 2002 to March 2011. Based on patients’ diagnostic codes and vital status at the end of the admission, disease focus (meningitis, empyema, sepsis, or respiratory disease) and case fatality rates by serotype and age group (5, 5–64, and 65 years and over) were obtained. Using these data the quality adjusted life years (QALY) lost from the IPD remaining when use of PCV7 stopped in 2010 was estimated for the serotypes covered by higher valency vaccines.
The linked dataset contained 23,688 cases with information on diagnosis, mortality, and serotype. There were significant differences between serotypes in the propensity to cause meningitis, death, and QALY loss in each of the investigated age groups. As a result, vaccines’ coverage of disease burden differed by endpoint. For example, in children under 5 years in 2009/10, PCV10 covered 39% of meningitis, 19% of deaths and 28% of the QALY loss of attributable to IPD, whereas the respective percentages for PCV13 were 65%, 67%, and 66%. The highest QALY loss per serotype in this age group was for 6A. Non-PCV serotypes causing the highest QALY loss were 22F and 33F in <5 year olds and 31 in older individuals.
Marked differences exist between serotypes in clinical presentation and outcome, and these should be considered when evaluating the potential impact of higher valency vaccines on overall disease burden and associated QALY loss.
PMCID: PMC3398022  PMID: 22815698
17.  Rapid estimation of excess mortality: nowcasting during the heatwave alert in England and Wales in June 2011 
A Heat-Health Watch system has been established in England and Wales since 2004 as part of the national heatwave plan following the 2003 European-wide heatwave. One important element of this plan has been the development of a timely mortality surveillance system. This article reports the findings and timeliness of a daily mortality model used to ‘nowcast’ excess mortality (utilising incomplete surveillance data to estimate the number of deaths in near-real time) during a heatwave alert issued by the Met Office for regions in South and East England on 24 June 2011.
Daily death registrations were corrected for reporting delays with historical data supplied by the General Registry Office. These corrected counts were compared with expected counts from an age-specific linear regression model to ascertain if any excess had occurred during the heatwave.
Excess mortality of 367 deaths was detected across England and Wales in ≥85-year-olds on 26 and 27 June 2011, coinciding with the period of elevated temperature. This excess was localised to the east of England and London. It was detected 3 days after the heatwave.
A daily mortality model was sensitive and timely enough to rapidly detect a small excess, both, at national and regional levels. This tool will be useful when future events of public health significance occur.
PMCID: PMC3433219  PMID: 22766783
Heatwave; excess mortality; nowcasting; influenza; mortality; epidemiology
18.  H1N1 Antibody Persistence 1 Year After Immunization With an Adjuvanted or Whole-Virion Pandemic Vaccine and Immunogenicity and Reactogenicity of Subsequent Seasonal Influenza Vaccine: A Multicenter Follow-on Study 
Two doses of AS03B-adjuvanted pandemic influenza vaccine may be sufficient to maintain seroprotection across 2 influenza seasons. Administration of trivalent influenza vaccine to children who previously received 2 doses of pandemic influenza vaccine is safe and is immunogenic for the H1N1 strain.
Background. We investigated antibody persistence in children 1 year after 2 doses of either an AS03B-adjuvanted split-virion or nonadjuvanted whole-virion monovalent pandemic influenza vaccine and assessed the immunogenicity and reactogenicity of a subsequent dose of trivalent influenza vaccine (TIV).
Methods. Children previously immunized at age 6 months to 12 years in the original study were invited to participate. After a blood sample was obtained to assess persistence of antibody against swine influenza A/H1N1(2009) pandemic influenza, children received 1 dose of 2010/2011 TIV, reactogenicity data were collected for 7 days, and another blood sample was obtained 21 days after vaccination.
Results. Of 323 children recruited, 302 received TIV. Antibody persistence (defined as microneutralization [MN] titer ≥1:40) 1 year after initial vaccination was significantly higher in the AS03B-adjuvanted compared with the whole-virion vaccine group, 100% (95% confidence interval [CI], 94.1%–100%) vs 32.4% (95% CI, 21.5%–44.8%) in children immunized <3 years old and 96.9% (95% CI, 91.3%–99.4%) vs 65.9% (95% CI, 55.3%–75.5%) in those 3–12 years old at immunization, respectively (P < .001 for both groups). All children receiving TIV had post-vaccination MN titers ≥1:40. Although TIV was well tolerated in all groups, reactogenicity in children <5 years old was slightly greater in those who originally received AS03B-adjuvanted vaccine.
Conclusions. This study provides serological evidence that 2 doses of AS03B-adjuvanted pandemic influenza vaccine may be sufficient to maintain protection across 2 influenza seasons. Administration of TIV to children who previously received 2 doses of either pandemic influenza vaccine is safe and is immunogenic for the H1N1 strain.
PMCID: PMC3275760  PMID: 22267719
19.  Accelerating Control of Pertussis in England and Wales 
Emerging Infectious Diseases  2012;18(1):38-47.
Pertussis incidence among infants can be reduced by early completion of the primary vaccination schedule.
PMCID: PMC3381681  PMID: 22260989
whooping cough; Bordetella pertussis; epidemiology; pertussis vaccine; program evaluation; bacteria; disease control; infants; England; Wales
20.  Using the Indirect Cohort Design to Estimate the Effectiveness of the Seven Valent Pneumococcal Conjugate Vaccine in England and Wales 
PLoS ONE  2011;6(12):e28435.
The 7-valent pneumococcal conjugate vaccine (PCV-7) was introduced in the United Kingdom in 2006 with a 2,3 and 13month schedule, and has led to large decreases in invasive pneumococcal disease (IPD) caused by the vaccine serotypes in both vaccinated and unvaccinated cohorts. We estimated the effectiveness of PCV-7 against IPD.
Methods and Findings
We used enhanced surveillance data, collated at the Health Protection Agency, on vaccine type (n = 153) and non vaccine type (n = 919) IPD cases eligible for PCV-7. The indirect cohort method, a case-control type design which uses non vaccine type cases as controls, was used to estimate effectiveness of various numbers of doses as well as for each vaccine serotype. Possible bias with this design, caused by differential serotype replacement in vaccinated and unvaccinated individuals, was estimated after deriving formulae to quantify the bias. The results showed good effectiveness, increasing from 56% (95% confidence interval (CI): -7-82) for a single dose given under one year of age to 93% (95% CI: 70-98) for two doses under one year of age plus a booster dose in the second year of life. Serotype specific estimates indicated higher effectiveness against serotypes 4, 14 and 18C and lower effectiveness against 6B. Under the assumption of complete serotype replacement by non vaccine serotypes in carriage, we estimated that effectiveness estimates may be overestimated by about 2 to 5%.
This study shows high effectiveness of PCV-7 under the reduced schedule used in the UK. This finding agrees with the large reductions seen in vaccine type IPD in recent years in England and Wales. The formulae derived to assess the bias of the indirect cohort method for PCV-7 can also be used when using the design for other vaccines that affect carriage such as the recently introduced 13 valent pneumococcal conjugate vaccine.
PMCID: PMC3229580  PMID: 22164292
21.  7-Valent Pneumococcal Conjugate Vaccination in England and Wales: Is It Still Beneficial Despite High Levels of Serotype Replacement? 
PLoS ONE  2011;6(10):e26190.
The UK introduced the 7-valent pneumococcal conjugate vaccine (PCV7) into the national vaccination program in September 2006. Previous modelling assumed that the likely impact of PCV7 on invasive pneumococcal disease (IPD) would be similar to the US experience with PCV7. However, recent surveillance data show a more rapid replacement of PCV7 IPD cases by non-PCV7 IPD cases than was seen in the US.
Methods and Findings
A previous model of pneumococcal vaccination was re-parameterised using data on vaccine coverage and IPD from England and Wales between 2006 and 2009. Disease incidence was adjusted for the increasing trend in reported IPD cases prior to vaccination. Using this data we estimated that individuals carrying PCV7 serotypes have much higher protection (96%;95% CI 72%-100%) against acquisition of NVT carriage than the 15% previously estimated from US data, which leads to greater replacement. However, even with this level of replacement, the annual number of IPD cases may be 560 (95% CI, -100 to 1230) lower ten years after vaccine introduction compared to what it may have been without vaccination. A particularly marked fall of 39% in children under 15 years by 2015/6 is predicted.
Our model suggests that PCV7 vaccination could result in a decrease in overall invasive pneumococcal disease, particularly in children, even in an environment of rapid replacement with non-PCV7 serotypes within 5 years of vaccine introduction at high coverage.
PMCID: PMC3193519  PMID: 22022559
22.  Safety and Immunogenicity of Coadministering a Combined Meningococcal Serogroup C and Haemophilus influenzae Type b Conjugate Vaccine with 7-Valent Pneumococcal Conjugate Vaccine and Measles, Mumps, and Rubella Vaccine at 12 Months of Age ▿  
The coadministration of the combined meningococcal serogroup C conjugate (MCC)/Haemophilus influenzae type b (Hib) vaccine with pneumococcal conjugate vaccine (PCV7) and measles, mumps, and rubella (MMR) vaccine at 12 months of age was investigated to assess the safety and immunogenicity of this regimen compared with separate administration of the conjugate vaccines. Children were randomized to receive MCC/Hib vaccine alone followed 1 month later by PCV7 with MMR vaccine or to receive all three vaccines concomitantly. Immunogenicity endpoints were MCC serum bactericidal antibody (SBA) titers of ≥8, Hib-polyribosylribitol phosphate (PRP) IgG antibody concentrations of ≥0.15 μg/ml, PCV serotype-specific IgG concentrations of ≥0.35 μg/ml, measles and mumps IgG concentrations of >120 arbitrary units (AU)/ml, and rubella IgG concentrations of ≥11 AU/ml. For safety assessment, the proportions of children with erythema, swelling, or tenderness at site of injection or fever or other systemic symptoms for 7 days after immunization were compared between regimens. No adverse consequences for either safety or immunogenicity were demonstrated when MCC/Hib vaccine was given concomitantly with PCV and MMR vaccine at 12 months of age or separately at 12 and 13 months of age. Any small differences in immunogenicity were largely in the direction of a higher response when all three vaccines were given concomitantly. For systemic symptoms, there was no evidence of an additive effect; rather, any differences between schedules showed benefit from the concomitant administration of all three vaccines, such as lower overall proportions with postvaccination fevers. The United Kingdom infant immunization schedule now recommends that these three vaccines may be offered at one visit at between 12 and 13 months of age.
PMCID: PMC3067384  PMID: 21191076
23.  A Controlled Trial of the Knowledge Impact of Tuberculosis Information Leaflets among Staff Supporting Substance Misusers: Pilot Study 
PLoS ONE  2011;6(6):e20875.
Information leaflets are widely used to increase awareness and knowledge of disease. Limited research has, to date, been undertaken to evaluate the efficacy of these information resources. This pilot study sought to determine whether information leaflets developed specifically for staff working with substance mis-users improved knowledge of tuberculosis (TB).
Staffs working with individuals affected by substance mis-use were recruited between January and May 2008. All participants were subjectively allocated by their line manager either to receive the TB-specific leaflet or a control leaflet providing information on mental health. Level of knowledge of TB was assessed using questionnaires before and after the intervention and data analysed using McNemar's exact test for matched pairs.
The control group showed no evidence of a change in knowledge of TB, whereas the TB questionnaire group demonstrated a significant increase in knowledge including TB being curable (81% correct before to 100% correct after), length of treatment required (42% before to 73% after), need to support direct observation (18% to 62%) and persistent fever being a symptom (56% to 87%). Among key workers, who have a central role in implementing a care plan, 88% reported never receiving any TB awareness-raising intervention prior to this study, despite 11% of all respondents having TB diagnosed among their clients.
Further randomized controlled trials are required to confirm the observed increase in short-term gain in knowledge and to investigate whether knowledge gain leads to change in health status.
PMCID: PMC3117836  PMID: 21698103
24.  Use of Antiviral Drugs to Reduce Household Transmission of Pandemic (H1N1) 2009, United Kingdom1 
Emerging Infectious Diseases  2011;17(6):990-999.
TOC Summary: Early treatment of primary case-patients and prophylaxis of household contacts provides effective protection.
The United Kingdom implemented a containment strategy for pandemic (H1N1) 2009 through administering antiviral agents (AVs) to patients and their close contacts. This observational household cohort study describes the effect of AVs on household transmission. We followed 285 confirmed primary cases in 259 households with 761 contacts. At 2 weeks, the confirmed secondary attack rate (SAR) was 8.1% (62/761) and significantly higher in persons <16 years of age than in those >50 years of age (18.9% vs. 1.2%, p<0.001). Early (<48 hours) treatment of primary case-patients reduced SAR (4.5% vs. 10.6%, p = 0.003). The SAR in child contacts was 33.3% (10/30) when the primary contact was a woman and 2.9% (1/34) when the primary contact was a man (p = 0.010). Of 53 confirmed secondary case-patients, 45 had not received AV prophylaxis. The effectiveness of AV prophylaxis in preventing infection was 92%.
PMCID: PMC3358196  PMID: 21749759
viruses; influenza; pandemic; prophylaxis; pandemic (H1N1) 2009; H1N1; household contacts; antimicrobial drugs; United Kingdom; research
25.  Effect of Pneumococcal Conjugate Vaccination on Serotype-Specific Carriage and Invasive Disease in England: A Cross-Sectional Study 
PLoS Medicine  2011;8(4):e1001017.
A cross sectional study by Stefan Flasche and coworkers document the serotype replacement of Streptococcus pneumoniae that has occurred in England since the introduction of PCV7 vaccination.
We investigated the effect of the 7-valent pneumococcal conjugate vaccine (PCV7) programme in England on serotype-specific carriage and invasive disease to help understand its role in serotype replacement and predict the impact of higher valency vaccines.
Methods and Findings
Nasopharyngeal swabs were taken from children <5 y old and family members (n = 400) 2 y after introduction of PCV7 into routine immunization programs. Proportions carrying Streptococcus pneumoniae and serotype distribution among carried isolates were compared with a similar population prior to PCV7 introduction. Serotype-specific case∶carrier ratios (CCRs) were estimated using national data on invasive disease. In vaccinated children and their contacts vaccine-type (VT) carriage decreased, but was offset by an increase in non-VT carriage, with no significant overall change in carriage prevalence, odds ratio 1.06 (95% confidence interval 0.76–1.49). The lower CCRs of the replacing serotypes resulted in a net reduction in invasive disease in children. The additional serotypes covered by higher valency vaccines had low carriage but high disease prevalence. Serotype 11C emerged as predominant in carriage but caused no invasive disease whereas 8, 12F, and 22F emerged in disease but had very low carriage prevalence.
Because the additional serotypes included in PCV10/13 have high CCRs but low carriage prevalence, vaccinating against them is likely to significantly reduce invasive disease with less risk of serotype replacement. However, a few serotypes with high CCRs could mitigate the benefits of higher valency vaccines. Assessment of the effect of PCV on carriage as well as invasive disease should be part of enhanced surveillance activities for PCVs.
Please see later in the article for the Editors' Summary
Editors' Summary
Pneumococcal diseases—major causes of illness and death in children and adults worldwide—are caused by Streptococcus pneumoniae, a bacterium that often colonizes the nasopharynx (the area of the throat behind the nose). Carriage of S. pneumoniae bacteria does not necessarily cause disease. However, these bacteria can cause local, noninvasive diseases such as ear infections and sinusitis and, more rarely, they can spread into the lungs, the bloodstream, or the covering of the brain, where they cause pneumonia, septicemia, and meningitis, respectively. Although these invasive pneumococcal diseases (IPDs) can be successfully treated if administered early, they can be fatal. Consequently, it is better to protect people against IPDs through vaccination than risk infection. Vaccination primes the immune system to recognize and attack disease-causing organisms (pathogens) rapidly and effectively by exposing it to weakened or dead pathogens or to pathogen molecules (antigens) that it recognizes as foreign.
Why Was This Study Done?
There are more than 90 S. pneumoniae variants or “serotypes” characterized by different polysaccharide (complex sugar) coats, which trigger the immune response against S. pneumoniae and determine each serotype's propensity to cause IPD. The pneumococcal conjugate vaccine PCV7 contains polysaccharides (linked to a protein carrier) from the seven serotypes mainly responsible for IPD in the US in 2000 when routine childhood PCV7 vaccination was introduced in that country. PCV7 prevents both IPD caused by the serotypes it contains and carriage of these serotypes, which means that, after vaccination, previously uncommon, nonvaccine serotypes can colonize the nasopharynx. If these serotypes have a high invasiveness potential, then “serotype replacement” could reduce the benefits of vaccination. In this cross-sectional study (a study that investigates the relationship between a disease and an intervention in a population at one time point), the researchers investigate the effect of the UK PCV7 vaccination program (which began in 2006) on serotype-specific carriage and IPD in England to understand the role of PCV7 in serotype replacement and to predict the likely impact of vaccines containing additional serotypes (higher valency vaccines).
What Did the Researchers Do and Find?
The researchers examined nasopharyngeal swabs taken from PCV7-vaccinated children and their families for S. pneumoniae, determined the serotype of any bacteria they found, and compared the proportion of people carrying S. pneumoniae (carrier prevalence) and the distribution of serotypes in this study population and in a similar population that was studied in 2000/2001, before the PCV vaccination program began. Overall, there was no statistically significant change in carrier prevalence, but carriage of vaccine serotypes decreased in vaccinated children and their contacts whereas carriage of nonvaccine serotypes increased. The serotype-specific case-to-carrier ratios (CCRs; a measure of serotype invasiveness that was estimated using national IPD data) of the replacing serotypes were generally lower than those of the original serotypes, which resulted in a net reduction in IPD in children. Moreover, before PCV7 vaccination began, PCV7-included serotypes were responsible for similar proportions of pneumococcal carriage and disease; afterwards, the additional serotypes present in the higher valency vaccines PVC10 and PVC13 were responsible for a higher proportion of disease than carriage. Finally, three serotypes not present in the higher valency vaccines with outstandingly high CCRs (high invasiveness potential) are identified.
What Do These Findings Mean?
These findings document the serotype replacement of S. pneumoniae that has occurred in England since the introduction of PCV7 vaccination and highlight the importance of assessing the effects of pneumococcal vaccines on carriage as well as on IPDs. Because the additional serotypes included in PCV10 and PCV13 have high CCRs but low carriage prevalence and because most of the potential replacement serotypes have low CCRs, these findings suggest that the introduction of higher valency vaccines should further reduce the occurrence of invasive disease with limited risk of additional serotype replacement. However, the emergence of a few serotypes that have high CCRs but are not included in PCV10 and PCV13 might mitigate the benefits of higher valency vaccines. In other words, although the recent introduction of PCV13 into UK vaccination schedules is likely to have an incremental benefit on the reduction of IPD compared to PCV7, this benefit might be offset by increases in the carriage of some high CCR serotypes. These serotypes should be considered for inclusion in future vaccines.
Additional Information
Please access these Web sites via the online version of this summary at
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of pneumococcal disease and pneumococcal vaccination
The US National Foundation for Infectious Diseases has a fact sheet on pneumococcal diseases
The UK Health Protection Agency provides information on pneumococcal disease and on pneumococcal vaccines
The World Health Organization also provides information on pneumococcal vaccines
MedlinePlus has links to further information about pneumococcal infections (in English and Spanish)
PMCID: PMC3071372  PMID: 21483718

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