Hannah Christensen

Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review.

Objectives To evaluate the effects on non-specific and all cause mortality, in children under 5, of Bacillus Calmette-Guérin (BCG), diphtheria-tetanus-pertussis (DTP), and standard titre measles containing vaccines (MCV); to examine internal validity of the studies; and to examine any modifying effects of sex, age, vaccine sequence, and co-administration of vitamin A. Design Systematic review, including assessment of risk of bias, and meta-analyses of similar studies. Study eligibility criteria Clinical trials, cohort studies, and case-control studies of the effects on mortality of BCG, whole cell DTP, and standard titre MCV in children under 5. Data sources Searches of Medline, Embase, Global Index Medicus, and the WHO International Clinical Trials Registry Platform, supplemented by contact with experts in the field. To avoid overlap in children studied across the included articles, findings from non-overlapping birth cohorts were identified. Results Results from 34 birth cohorts were identified. Most evidence was from observational studies, with some from short term clinical trials. Most studies reported on all cause (rather than non-specific) mortality. Receipt of BCG vaccine was associated with a reduction in all cause mortality: the average relative risks were 0.70 (95% confidence interval 0.49 to 1.01) from five clinical trials and 0.47 (0.32 to 0.69) from nine observational studies at high risk of bias. Receipt of DTP (almost always with oral polio vaccine) was associated with a possible increase in all cause mortality on average (relative risk 1.38, 0.92 to 2.08) from 10 studies at high risk of bias; this effect seemed stronger in girls than in boys. Receipt of standard titre MCV was associated with a reduction in all cause mortality (relative risks 0.74 (0.51 to 1.07) from four clinical trials and 0.51 (0.42 to 0.63) from 18 observational studies at high risk of bias); this effect seemed stronger in girls than in boys. Seven observational studies, assessed as being at high risk of bias, have compared sequences of vaccines; results of a subset of these suggest that administering DTP with or after MCV may be associated with higher mortality than administering it before MCV. Conclusions Evidence suggests that receipt of BCG and MCV reduce overall mortality by more than would be expected through their effects on the diseases they prevent, and receipt of DTP may be associated with an increase in all cause mortality. Although efforts should be made to ensure that all children are immunised on schedule with BCG, DTP, and MCV, randomised trials are needed to compare the effects of different sequences.

The Global Meningococcal Initiative: global epidemiology, the impact of vaccines on meningococcal disease and the importance of herd protection

ABSTRACT Introduction: The 2015 Global Meningococcal Initiative (GMI) meeting discussed the global importance of meningococcal disease (MD) and its continually changing epidemiology. Areas covered: Although recent vaccination programs have been successful in reducing incidence in many countries (e.g. Neisseria meningitidis serogroup [Men]C in Brazil, MenA in the African meningitis belt), new clones have emerged, causing outbreaks (e.g. MenW in South America, MenC in Nigeria and Niger). The importance of herd protection was highlighted, emphasizing the need for high vaccination uptake among those with the highest carriage rates, as was the need for boosters to maintain individual and herd protection following decline of immune response after primary immunization. Expert commentary: The GMI Global Recommendations for Meningococcal Disease were updated to include a recommendation to enable access to whole-genome sequencing as for surveillance, guidance on strain typing to guide use of subcapsular vaccines, and recognition of the importance of advocacy and awareness campaigns.

Cost-effectiveness of vaccination against meningococcal B among Dutch infants: Crucial impact of changes in incidence.

Objective: Recently, a vaccine with the capacity to protect against serogroup B meningococcal (MenB) disease received a positive opinion of the European Medicines Agency. Previously, such a vaccine was estimated to be cost-effective. However, since then, the MenB disease incidence has declined drastically in the Netherlands. Therefore, we re-assessed the potential incremental cost-effectiveness ratio (ICER) of vaccinating infants in the Netherlands with a MenB vaccine. Methods: A cohort of 185,000 Dutch newborns was followed in a Markov model to compare routine vaccination against MenB disease with no vaccination. The ICER was estimated for different disease incidences. The study was performed from a societal perspective. Results: Routine infant vaccination (2, 3, 4+11 mo) could prevent 39 cases of MenB disease in a single birth cohort, corresponding to a total gain of 133 quality-adjusted life years (QALYs). However, this strategy is unlikely to be cost-effective if the vaccine costs €40 per dose (€243,778 per QALY). At a disease incidence of 5.7 per 100,000 person-years or a vaccine price of €10 per dose including administration costs, the ICER becomes more acceptable and remains below a threshold of €50,000 per QALY. Conclusions: At the current low level of disease incidence, introduction of routine infant vaccination, following a 2, 3, 4+11 mo schedule, against MenB disease is unlikely cost-effective in the Netherlands. If the MenB disease incidence increases or the vaccine price is substantially lower than €40, routine infant vaccination has the potential to be cost-effective.

Impact of Opioid Substitution Therapy on Antiretroviral Therapy Outcomes: a Systematic Review and Meta-Analysis

This meta-analysis provides strong evidence that opioid substitution therapy improves several key outcomes of the HIV care continuum among people who inject drugs, including recruitment onto antiretroviral therapy, retention in care, adherence, and viral suppression.

Outbreak of E. coli O157 infection in the south west of the UK: risks from streams crossing seaside beaches

In August 2004 seven cases of Escherichia coli O157 infection were identified in children on holiday in Cornwall, southwest England, all of whom had stayed at different sites in the area. Isolates from all seven cases were confirmed as E. coli serogroup O157 phage type 21/28. We carried out a case-control study among holidaymakers who visited the beach. A standardised questionnaire was administered by telephone to parents. They were asked where on the beach the children had played, whether they had had contact with the stream that flowed across the beach, and about their use of food outlets and sources of food eaten. Cases were more likely to have played in the stream than controls (OR [1.72- undefined]). The time spent in the stream by cases was twice spent there by controls. Cases and controls were equally exposed to other suspected risk factors. PFGE profiles for all the cases were indistinguishable. Increased numbers of coliforms were found in the stream prior to the outbreak. Cattle were found grazing upstream. We suggest that the vehicle of infection for an outbreak of acute gastrointestinal illness caused by E. coli O157 was a contaminated freshwater stream flowing across a seaside beach. The onset dates were consistent with a point source. Heavy rainfall in the days preceding the outbreak might have lead to faeces from the cattle potentially contaminated by E. coli O157 contaminating the stream, thereby leading to the outbreak. Control measures included fencing off the part of the stream in which children played, and putting up warning signs around the beach.

The TARGET cohort study protocol: a prospective primary care cohort study to derive and validate a clinical prediction rule to improve the targeting of antibiotics in children with respiratory tract illnesses

BackgroundChildren with respiratory tract infections are the single most frequent patient group to make use of primary care health care resources. The use of antibiotics remains highly prevalent in young children, but can lead to antimicrobial resistance as well as reinforcing the idea that parents should re-consult for similar symptoms. One of the main drivers of indiscriminate antimicrobial use is the lack of evidence for, and therefore uncertainty regarding, which children are at risk of poor outcome. This paper describes the protocol for the TARGET cohort study, which aims to derive and validate a clinical prediction rule to identify children presenting to primary care with respiratory tract infections who are at risk of hospitalisation.Methods/designThe TARGET cohort study is a large, multicentre prospective observational study aiming to recruit 8,300 children aged ≥3 months and <16 years presenting to primary care with a cough and respiratory tract infection symptoms from 4 study centres (Bristol, London, Oxford and Southampton). Following informed consent, symptoms, signs and demographics will be measured. In around a quarter of children from the Bristol centre, a single sweep, dual bacterial-viral throat swab will be taken and parents asked to complete a symptom diary until the child is completely well or for 28 days, whichever is sooner. A review of medical notes including clinical history, re-consultation and hospitalisations will be undertaken. Multivariable logistic regression will be used to identify the independent clinical predictors of hospitalisation as well as the prognostic significance of upper respiratory tract microbes. The clinical prediction rule will be internally validated using various methods including bootstrapping.DiscussionThe clinical prediction rule for hospitalisation has the potential to help identify a small group of children for hospitalisation and a much larger group where hospitalisation is very unlikely and antibiotic prescribing would be less warranted. This study will also be the largest natural history study to date of children presenting to primary care with acute cough and respiratory tract infections, and will provide important information on symptom duration, re-consultations and the microbiology of the upper respiratory tract.

Case-control study for risk factors for Q fever in southwest England and Northern Ireland.

Q fever (Coxiella burnetti) is thought to account for 1% (700 cases) of community acquired pneumonia in the United Kingdom each year, and can result in serious complications such as endocarditis. Although outbreaks have frequently been reported worldwide, the causes are often not clearly identified and there have been few studies of risk factors in sporadic cases. We conducted a matched case-control study. Cases of acute Q fever in people aged over 15 years in southwest England and Northern Ireland were identified from January 2002 to December 2004. Controls were matched for age, sex and the general practice at which they were registered. Questionnaires asking about contact with animals, and leisure and work activities, were posted to cases and controls. Questionnaires were completed by 39/50 (78%) of the cases and 90/180 (50%) of the controls. In the single variable analysis, occupational exposure to animals or animal products was the only risk factor associated with cases at the 5% level (P=0.05, odds ratio (OR) 3.4). Long term illness appeared to be significantly protective (P=0.03, OR 0.3). In multivariable analysis the strength of association between occupational exposure and illness remained high (OR 3.6, 95% confidence interval (CI) 0.9 to 14.8) and smoking emerged as a possible risk factor. This is the first case-control study to identify occupational exposure to animals or animal products as the most likely route of infection in sporadic cases as opposed to outbreaks.

Development and internal validation of a clinical rule to improve antibiotic use in children presenting to primary care with acute respiratory tract infection and cough: a prognostic cohort study

Summary Background Antimicrobial resistance is a serious threat to public health, with most antibiotics prescribed in primary care. General practitioners (GPs) report defensive antibiotic prescribing to mitigate perceived risk of future hospital admission in children with respiratory tract infections. We developed a clinical rule aimed to reduce clinical uncertainty by stratifying risk of future hospital admission. Methods 8394 children aged between 3 months and 16 years presenting with acute cough (for ≤28 days) and respiratory tract infection were recruited to a prognostic cohort study from 247 general practitioner practices in England. Exposure variables included demographic characteristics, parent-reported symptoms, and physical examination signs. The outcome was hospital admission for respiratory tract infection within 30 days, collected using a structured, blinded review of medical records. Findings 8394 (100%) children were included in the analysis, with 78 (0·9%, 95% CI 0·7%–1·2%) admitted to hospital: 15 (19%) were admitted on the day of recruitment (day 1), 33 (42%) on days 2–7; and 30 (39%) on days 8–30. Seven characteristics were independently associated (p<0·01) with hospital admission: age <2 years, current asthma, illness duration of 3 days or less, parent-reported moderate or severe vomiting in the previous 24 h, parent-reported severe fever in the previous 24 h or a body temperature of 37·8°C or more at presentation, clinician-reported intercostal or subcostal recession, and clinician-reported wheeze on auscultation. The area under the receiver operating characteristic (AUROC) curve for the coefficient-based clinical rule was 0·82 (95% CI 0·77–0·87, bootstrap validated 0·81). Assigning one point per characteristic, a points-based clinical rule consisting of short illness, temperature, age, recession, wheeze, asthma, and vomiting (mnemonic STARWAVe; AUROC 0·81, 0·76–0·85) distinguished three hospital admission risk strata: very low (0·3%, 0·2–0·4%) with 1 point or less, normal (1·5%, 1·0–1·9%) with 2 or 3 points, and high (11·8%, 7·3–16·2%) with 4 points or more. Interpretation Clinical characteristics can distinguish children at very low, normal, and high risk of future hospital admission for respiratory tract infection and could be used to reduce antibiotic prescriptions in primary care for children at very low risk. Funding National Institute for Health Research (NIHR).

Epidemiological impact and cost-effectiveness of universal vaccination with Bexsero® to reduce meningococcal group B disease in Germany

Bexsero, a new vaccine against serogroup B meningococcal disease (MenB), was licensed in Europe in January 2013. In Germany, Bexsero is recommended for persons at increased risk of invasive meningococcal disease, but not for universal childhood vaccination. To support decision making we adapted the independently developed model for England to the German setting to predict the potential health impact and cost-effectiveness of universal vaccination with Bexsero(®) against MenB disease. We used both cohort and transmission dynamic mathematical models, the latter allowing for herd effects, to consider the impact of vaccination on individuals aged 0-99 years. Vaccination strategies included infant and adolescent vaccination, alone or in combination, and with one-off catch-up programmes. German specific data were used where possible from routine surveillance data and the literature. We assessed the impact of vaccination through cases averted and quality adjusted life years (QALY) gained and calculated costs per QALY gained. Assuming 65% vaccine uptake and 82% strain coverage, infant vaccination was estimated to prevent 15% (34) of MenB cases over the lifetime of one birth cohort. Including herd effects from vaccination increased the cases averted by infant vaccination to 22%, with an estimated 8461 infants requiring vaccination to prevent one case. In the short term the greatest health benefit is achieved through routine infant vaccination with large-scale catch-up, which could reduce cases by 24.9% after 5 years and 27.9% after 10 years. In the long term (20+ years) policies including routine adolescent vaccination are most favourable if herd effects are assumed. Under base case assumptions with a vaccine list price of €96.96 the incremental cost-effectiveness ratio (ICER) was >€500,000 per QALY for all considered strategies. Given the current very low incidence of MenB disease in Germany, universal vaccination with Bexsero(®) would prevent only a small absolute number of cases, at a high overall cost.

Modelling the cost-effectiveness of catch-up 'MenB' (Bexsero) vaccination in England

Highlights • We modelled the cost-effectiveness catch-up ‘MenB’ vaccination in England.• Catch-up vaccination for 1 year old children could be cost-effective at ⩽£8 per dose.• Additionally vaccinating 2 year olds was less cost-effective.• With conservative vaccine assumptions vaccinating 2 year olds was not-cost-effective.• It was not cost-effective to extend vaccination further to 3–4 year olds.