Andrew Collinson

Neonatal infections in England: the NeonIN surveillance network.

Introduction Neonatal infection is an important cause of morbidity and mortality. Neonatal infection surveillance networks are necessary for defining the epidemiology of infections and monitoring changes over time. Design Prospective multicentre surveillance using a web-based database. Setting 12 English neonatal units. Participants Newborns admitted in 2006–2008, with positive blood, cerebrospinal fluid or urine culture and treated with antibiotics for at least 5 days. Outcome measure Incidence, age at infection, pathogens and antibiotic resistance profiles. Results With the inclusion of coagulase negative Staphylococci (CoNS), the incidence of all neonatal infection was 8/1000 live births and 71/1000 neonatal admissions (2007–2008). The majority of infections occurred in premature (<37 weeks) and low birthweight (<2500 g) infants (82% and 81%, respectively). The incidence of early onset sepsis (EOS; ≤48 h of age) was 0.9/1000 live births and 9/1000 neonatal admissions, and group B Streptococcus (58%) and Escherichia coli (18%) were the most common organisms. The incidence of late onset sepsis (LOS; >48 h of age) was 3/1000 live births and 29/1000 neonatal admissions (7/1000 live births and 61/1000 admissions including CoNS) and the most common organisms were CoNS (54%), Enterobacteriaceae (21%) and Staphylococcus aureus (18%, 11% of which were methicillin resistant S aureus). Fungi accounted for 9% of LOS (72% Candida albicans). The majority of pathogens causing EOS (95%) and LOS (84%) were susceptible to commonly used empiric first line antibiotic combinations of penicillin/gentamicin and flucloxacillin/gentamicin, respectively (excluding CoNS). Conclusions The authors have established NeonIN in England and defined the current epidemiology of neonatal infections. These data can be used for benchmarking among units, international comparisons and as a platform for interventional studies.

Safety and immunogenicity of AS03B adjuvanted split virion versus non-adjuvanted whole virion H1N1 influenza vaccine in UK children aged 6 months-12 years: open label, randomised, parallel group, multicentre study.

Objectives To compare the safety, reactogenicity, and immunogenicity of an adjuvanted split virion H1N1 vaccine and a non-adjuvanted whole virion vaccine used in the pandemic immunisation programme in the United Kingdom. Design Open label, randomised, parallel group, phase II study. Setting Five UK centres (Oxford, Southampton, Bristol, Exeter, and London). Participants Children aged 6 months to less than 13 years for whom a parent or guardian had provided written informed consent and who were able to comply with study procedures were eligible. Those with laboratory confirmed pandemic H1N1 influenza or clinically diagnosed disease meriting antiviral treatment, allergy to egg or any other vaccine components, or coagulation defects, or who were severely immunocompromised or had recently received blood products were excluded. Children were grouped by age: 6 months-<3 years (younger group) and 3-<13 years (older group). Recruitment was by media advertising and direct mailing. Recruitment visits were attended by 949 participants, of whom 943 were enrolled and 937 included in the per protocol analysis. Interventions Participants were randomised 1:1 to receive AS03B (tocopherol based oil in water emulsion) adjuvanted split virion vaccine derived from egg culture or non-adjuvanted whole virion vaccine derived from cell culture. Both were given as two doses 21 days apart. Reactogenicity data were collected for one week after immunisation by diary card. Serum samples were collected at baseline and after the second dose. Main outcome measures Primary reactogenicity end points were frequency and severity of fever, tenderness, swelling, and erythema after vaccination. Immunogenicity was measured by microneutralisation and haemagglutination inhibition assays. The primary immunogenicity objective was a comparison between vaccines of the percentage of participants showing seroconversion by the microneutralisation assay (fourfold rise to a titre of ≥1:40 from before vaccination to three weeks after the second dose). Results Seroconversion rates were higher after the adjuvanted split virion vaccine than after the whole virion vaccine, most notably in the youngest children (163 of 166 participants with paired serum samples (98.2%, 95% confidence interval 94.8% to 99.6%) v 157 of 196 (80.1%, 73.8% to 85.5%), P<0.001) in children under 3 years and 226 of 228 (99.1%, 96.9% to 99.9%) v 95.9%, 92.4% to 98.1%, P=0.03) in those over 3 years). The adjuvanted split virion vaccine was more reactogenic than the whole virion vaccine, with more frequent systemic reactions and severe local reactions in children aged over 5 years after dose one (13 (7.2%, 3.9% to 12%) v 2 (1.1%, 0.1% to 3.9%), P<0.001) and dose two (15 (8.5%, 4.8% to 13.7%) v 2 (1.1%, 0.1% to 4.1%), P<0.002) and after dose two in those under 5 years (15 (5.9%, 3.3% to 9.6%) v 0 (0.0%, 0% to 1.4%), P<0.001). Dose two of the adjuvanted split virion vaccine was more reactogenic than dose one, especially for fever ≥38ºC in those aged under 5 (24 (8.9%, 5.8% to 12.9%) v 57 (22.4%, 17.5% to 28.1%), P<0.001). Conclusions In this first direct comparison of an AS03B adjuvanted split virion versus whole virion non-adjuvanted H1N1 vaccine, the adjuvanted vaccine, while more reactogenic, was more immunogenic and, importantly, achieved high seroconversion rates in children aged less than 3 years. This indicates the potential for improved immunogenicity of influenza vaccines in this age group. Trial registration Clinical trials.gov NCT00980850; ISRCTN89141709.

Observational study of vaccine efficacy 14 years after trial of hepatitis B vaccination in Gambian children

Abstract Objective: To determine the duration of protection from hepatitis B vaccine given in infancy and early childhood. Design: Cross sectional serological study of hepatitis B virus infection in children of various ages 14 years after the start of a trial of vaccination regimens. Setting: Two villages in the Gambia. Participants: Children and adolescents given hepatitis B vaccine in infancy or early childhood: 232 were aged 1-5 years, 225 aged 5-9 years, 220 aged 10-14 years, and 175 aged 15-19 years. Main outcome measures: Vaccine efficacy against infection and against chronic infection in the different age groups. Results: Vaccine efficacy against chronic carriage of hepatitis B virus was 94% (95% confidence interval 89% to 97%), which did not vary significantly between the age groups. Efficacy against infection was 80% (76% to 84%). This was significantly lower in the oldest age group (65%, 56 to 73). Of the uninfected participants in this age group, 36% had no detectable hepatitis B virus surface antibody. Time since vaccination and a low peak antibody response were the most powerful risk factors for breakthrough infection (P<0.001 in each case). Low peak antibody response was also a risk factor for chronic carriage (odds ratio 95, 19 to 466). Conclusions: Children vaccinated in infancy are at increased risk of hepatitis B virus infection in the late teens. The risk of chronic carriage after sexual exposure needs further assessment to determine if booster vaccines are necessary.

Open-label, randomised, parallel-group, multicentre study to evaluate the safety, tolerability and immunogenicity of an AS03(B)/oil-in-water emulsion-adjuvanted (AS03(B)) split-virion versus non-adjuvanted whole-virion H1N1 influenza vaccine in UK children 6 months to 12 years of age.

OBJECTIVE To evaluate the safety, tolerability and immunogenicity of an AS03(B)/oil-in-water emulsion-adjuvanted (AS03(B)) split-virion versus non-adjuvanted whole-virion H1N1 influenza vaccine in UK children aged 6 months to 12 years. DESIGN Multicentre, randomised, head-to-head, open-label trial. SETTING Five UK sites (Oxford, Bristol, Southampton, Exeter and London). PARTICIPANTS Children aged 6 months to < 13 years, for whom a parent or guardian had provided written informed consent and who were able to comply with study procedures, were eligible for inclusion. INTERVENTIONS A tocopherol/oil-in-water emulsion-adjuvanted (AS03(B)) egg culture-derived split-virion H1N1 vaccine and a non-adjuvanted cell culture-derived whole-virion vaccine, given as a two-dose schedule, 21 days apart, were compared. Participants were grouped into those aged 6 months to < 3 years (younger group) and 3 years to < 13 years of age (older group) and were randomised by study investigators (1 : 1 ratio) to receive one of the two vaccines. Vaccines were administered by intramuscular injection (deltoid or anterior-lateral thigh, depending on age and muscle bulk). Local reactions and systemic symptoms were collected for 1 week post immunisation, and serum was collected at baseline and after the second dose. To assess safety and tolerability, parents or guardians recorded the following information in diary cards from days 0-7 post vaccination: axillary temperature, injection site reactions, solicited and unsolicited systemic symptoms, and medications. MAIN OUTCOME MEASURE Comparison between vaccines of the percentage of participants demonstrating seroconversion by microneutralisation assay. RESULTS Among 937 children receiving vaccine, per-protocol seroconversion rates were higher after the AS03(B)-adjuvanted vaccine than after the whole-virion vaccine (98.2% vs 80.1% in children < 3 years, 99.1% vs 95.9% among those aged 3-12 years), as were severe local reactions (3.6% vs 0.0% in those under 5 years, 7.8% vs 1.1% in those aged 5-12 years), irritability in children < 5 years (46.7% vs 32.0%), and muscle pain in older children (28.9% vs 13.2%). The second dose of the adjuvanted vaccine was more reactogenic than the first, especially for fever > 38.0°C in those under 5 years of age (8.9% vs 22.4%). CONCLUSION The adjuvanted vaccine, although reactogenic, was more immunogenic, especially in younger children, indicating the potential for improved immunogenicity of influenza vaccines in this age group. TRIAL REGISTRATION NUMBER ISRCTN89141709.

Missed opportunities for preventing group B streptococcus infection

Background: Group B streptococcus (GBS) is the most common cause of early onset (EO) neonatal infection in the UK. National guidelines for its prevention were introduced in 2003. We assessed the opportunities for prevention amongst cases of EO GBS using the electronic Neonatal Infection Surveillance Network (NeonIN). Methods: Culture proven EO GBS cases occurring between 2004 and 2007 were identified prospectively in eight neonatal units participating in NeonIN. Data concerning risk factors, intrapartum antibiotic (IAP) use and infant outcome were collected retrospectively. Results: There were 48 cases of GBS over the 4 years (0.52/1000 live-births); 22 male, median gestation 38 weeks. The most common clinical presentation was sepsis and the GBS-attributable mortality was 6%. Risk factors were present in 67% (32) and adequate IAP was given to six of these mothers (19%). If all women with risk factors received prophylaxis, 23 cases (48%) may have been prevented. Conclusions: Better GBS prevention strategies are required in the UK.

Leptin, malnutrition, and immune response in rural Gambian children

Background: The adipocyte derived hormone, leptin, has cytokine like function and may mediate the effects of starvation on immunity. Mice with congenital leptin deficiency (ob/ob) have small hypocellular thymuses and impaired cellular immunity. In humans leptin influences the differentiation of naïve and memory cells in vitro, and genetic leptin deficiency has been associated with an ill defined susceptibility to infection. Aims: To describe the in vivo relation of leptin and immune function in children. Methods: Fasting plasma leptin concentrations, immune function (T and B cell mediated vaccine responses and delayed type hypersensitivity), and mucosal function (dual sugar permeability test and salivary sIgA concentrations) were measured in a cohort of 472 moderately undernourished rural Gambian children. Results: Leptin concentrations correlated with body fat assessed by mid upper arm circumference or BMI for age Z scores, and were very low compared to well nourished European norms (males 1.8 v 11.1 ng/ml; females 2.4 v 13.8 ng/ml). No detectable relations were found between leptin concentrations and any of the measures of immune or mucosal function. Conclusions: The data confirm that leptin acts as a peripheral signal of energy restriction, but do not support an association between fasting plasma leptin levels and immune function in children of this age.

Predictors of immune response and reactogenicity to AS03B-adjuvanted split virion and non-adjuvanted whole virion H1N1 (2009) pandemic influenza vaccines

In 2009, 943 children aged 6 months to 10 years were randomised to receive two doses of an oil-in water AS03B-adjuvanted split virion or a non-adjuvanted whole virion H1N1 (2009) vaccine. The large numbers allowed investigation of possible predictors of immune response and reactogenicity. We used regression analysis to examine the effect of variables including past receipt of seasonal vaccine, antipyretics post-vaccination, interval between doses and pre-existing antibodies to H1N1 (2009) on immunogenicity. We also examined the relationship between immunogenicity and reactogenicity and whether prior infection or underlying conditions affected reactogenicity. For both vaccines, haemagglutination-inhibition titres were 60% higher in children with fever ≥38 °C after vaccination and 29% lower in those previously given seasonal vaccine. Early use of antipyretics did not affect immunogenicity. Post-vaccination titres were higher with longer intervals between doses and in those with evidence of prior infection, but reactogenicity in the latter was unaffected. In the adjuvanted vaccine group, reactions were more common in children with atopy. Both vaccines were safe and immunogenic in those with prior infection. Reduction in the interval between doses for earlier protection would be at the cost of reduced immunogenicity. The effect of seasonal vaccine on immunogenicity merits further investigation.

Interventions to reduce acute paediatric hospital admissions: a systematic review

Objective To compare the effectiveness of interventions aimed at reducing the rate of acute paediatric hospital admissions. Design Systematic review. Data sources Medline, Embase, PsychINFO, The Cochrane Library, Science Citation Index Expanded from inception to September 2010; hand searches of the reference lists of included papers and other review papers identified in the search. Review methods Controlled trials were included. Articles were screened for inclusion independently by two reviewers. Data extraction and quality appraisal were performed by one reviewer and checked by a second with discrepancies resolved by discussion with a third if necessary. Results Seven papers were included. There is some evidence to suggest that short stay units may reduce admission rates. However, there is a general lack of detail in the reporting of interventions and the methods used in their evaluation which precludes detailed interpretation and extrapolation of the results. The authors found no evidence that the use of algorithms and guidelines to manage the admission decision was effective in reducing acute admission rates. Furthermore, the authors were unable to locate any eligible papers reporting the effects on admission rates of admission decision by paediatric consultant, telephone triage by paediatric consultant or the establishment of next day emergency paediatric clinics. Conclusion There is little published evidence upon which to base an optimal strategy for reducing paediatric admission rates. The evidence that does exist is subject to substantial bias. There is a pressing need for high quality, well conducted research to enable informed service change.

Maternal malnutrition and the risk of infection in later life.

Considerable evidence now exists to suggest that events during early life can influence future susceptibility to certain non-communicable diseases (NCDs). The fetal origins hypothesis states that cardiovascular disease and non-insulin-dependent diabetes originate through adaptations that the fetus makes when it is undernourished. These adaptations, which include slowing of growth, permanently change the structure and function of the body [1]. We have now added to the NCD observation with evidence from rural Gambia that we have found that an individual’s susceptibility to infectious diseases may also be programmed by events early in life, particularly maternal undernutrition. In this review, we describe the existing evidence to support the hypothesis that immune function may be permanently programmed by nutritional status early in life, and describe the findings from our ongoing program of work in this area.

Expediting clinical trials in a Pandemic

In response to the urgent need for paediatric data comparing the two new variant A/H1N1 vaccines in the UK before the onset of a second wave of flu,1 and a call for proposals related to new variant A/H1N1 by the National Institute for Health Research (NIHR),2 we designed a clinical trial of immunogenicity and tolerability in children aged 6 months-12 years. We submitted a collaborative funding application to NIHR on 24 July 2009, receiving an award letter …