Ifeanyichukwu O. Okike

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.

Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial

BACKGROUND Meningococcal conjugate vaccines protect individuals directly, but can also confer herd protection by interrupting carriage transmission. We assessed the effects of meningococcal quadrivalent glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in 18-24-year-olds. METHODS In this phase 3, observer-blind, randomised controlled trial, university students aged 18-24 years from ten sites in England were randomly assigned (1:1:1, block size of three) to receive two doses 1 month apart of Japanese Encephalitis vaccine (controls), 4CMenB, or one dose of MenACWY-CRM then placebo. Participants were randomised with a validated computer-generated random allocation list. Participants and outcome-assessors were masked to the treatment group. Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over 1 year. Primary outcomes were cross-sectional carriage 1 month after each vaccine course. Secondary outcomes included comparisons of carriage at any timepoint after primary analysis until study termination. Reactogenicity and adverse events were monitored throughout the study. Analysis was done on the modified intention-to-treat population, which included all enrolled participants who received a study vaccination and provided at least one assessable swab after baseline. This trial is registered with ClinicalTrials.gov, registration number NCT01214850. FINDINGS Between Sept 21 and Dec 21, 2010, 2954 participants were randomly assigned (987 assigned to control [984 analysed], 979 assigned to 4CMenB [974 analysed], 988 assigned to MenACWY-CRM [983 analysed]); 33% of the 4CMenB group, 34% of the MenACWY-CRM group, and 31% of the control group were positive for meningococcal carriage at study entry. By 1 month, there was no significant difference in carriage between controls and 4CMenB (odds ratio 1·2, 95% CI 0·8-1·7) or MenACWY-CRM (0·9, [0·6-1·3]) groups. From 3 months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (18·2% [95% CI 3·4-30·8] carriage reduction), capsular groups BCWY (26·6% [10·5-39·9] carriage reduction), capsular groups CWY (29·6% [8·1-46·0] carriage reduction), and serogroups CWY (28·5% [2·8-47·5] carriage reduction) compared with control vaccination. Significantly lower carriage rates were also noted in the MenACWY-CRM group compared with controls: 39·0% (95% CI 17·3-55·0) carriage reduction for serogroup Y and 36·2% (15·6-51·7) carriage reduction for serogroup CWY. Study vaccines were generally well tolerated, with increased rates of transient local injection pain and myalgia in the 4CMenB group. No safety concerns were identified. INTERPRETATION Although we detected no significant difference between groups at 1 month after vaccine course, MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates during 12 months after vaccination and therefore might affect transmission when widely implemented. FUNDING Novartis Vaccines.

Incidence, Etiology, and Outcome of Bacterial Meningitis in Infants Aged <90 Days in the United Kingdom and Republic of Ireland: Prospective, Enhanced, National Population-Based Surveillance

BACKGROUND Bacterial meningitis remains a major cause of morbidity and mortality in young infants. Understanding the epidemiology and burden of disease is important. METHODS Prospective, enhanced, national population-based active surveillance was undertaken to determine the incidence, etiology, and outcome of bacterial meningitis in infants aged <90 days in the United Kingdom and Ireland. RESULTS During July 2010-July 2011, 364 cases were identified (annual incidence, 0.38/1000 live births; 95% confidence interval [CI], .35-.42). In England and Wales, the incidence of confirmed neonatal bacterial meningitis was 0.21 (n = 167; 95% CI, .18-.25). A total of 302 bacteria were isolated in 298 (82%) of the cases. The pathogens responsible varied by route of admission, gestation at birth, and age at infection. Group B Streptococcus (GBS) (150/302 [50%]; incidence, 0.16/1000 live births; 95% CI, .13-.18) and Escherichia coli (41/302 [14%]; incidence, 0.04/1000; 95% CI, .03-.06) were responsible for approximately two-thirds of identified bacteria. Pneumococcal (28/302 [9%]) and meningococcal (23/302 [8%]) meningitis were rare in the first month, whereas Listeria meningitis was seen only in the first month of life (11/302 [4%]). In hospitalized preterm infants, the etiology of both early- and late-onset meningitis was more varied. Overall case fatality was 8% (25/329) and was higher for pneumococcal meningitis (5/26 [19%]) than GBS meningitis (7/135 [5%]; P = .04) and for preterm (15/90 [17%]) compared with term (10/235 [4%]; P = .0002) infants. CONCLUSIONS The incidence of bacterial meningitis in young infants remains unchanged since the 1980s and is associated with significant case fatality. Prevention strategies and guidelines to improve the early management of cases should be prioritized.

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.

Meningococcal carriage in adolescents in the United Kingdom to inform timing of an adolescent vaccination strategy.

OBJECTIVES Recent development of serogroup B meningococcal (MenB) vaccines highlights the importance of pharyngeal carriage data, particularly in adolescents and young adults, to inform implementation strategies. We describe current UK carriage prevalence in this high risk population and compare methods of carriage detection. METHODS In this multisite study, pharyngeal swabs were collected on 3-4 occasions over 6-12 months, from 1040 school and university students, aged 10-25 years. Meningococcal carriage was detected by standard culture combined with seroagglutination or PCR of cultured isolates, or by direct PCR from swab. The factor H binding protein (fHBP) variants present in meningococcal isolates were determined. RESULTS Meningococcal serogroups B and Y were most common, with carriage up to 6.5% and 5.5% respectively, increasing throughout adolescence. Identification by seroagglutination was often unreliable, and the sensitivity of direct PCR detection was 66% compared to culture combined with PCR. Of MenB isolates, 89.1% had subfamily A variants of fHBP. The acquisition rate of MenB carriage was estimated at 2.8 per 1000 person-months. CONCLUSIONS If vaccination is to precede the adolescent rise in MenB carriage, these data suggest it should take place in early adolescence. Studies assessing vaccine impact should use molecular methods to detect carriage.

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.

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.

Enterovirus infections in England and Wales, 2000–2011: the impact of increased molecular diagnostics

There have recently been significant changes in diagnostic practices for detecting enterovirus (EV) infections across England and Wales. Reports of laboratory-confirmed EV infections submitted by National Health Service (NHS) hospital laboratories to Public Health England (PHE) over a 12-year period (2000-2011) were analysed. Additionally, the PHE Virus Reference Department (VRD) electronic database containing molecular typing data from 2004 onwards was interrogated. Of the 13,901 reports, there was a decline from a peak of 2254 in 2001 to 589 in 2006, and then an increase year-on-year to 1634 in 2011. This increase coincided with increasing PCR-based laboratory diagnosis, which accounted for 36% of reported cases in 2000 and 92% in 2011. The estimated annual incidence in 2011 was 3.9/100,000 overall and 238/100,000 in those aged <3 months, who accounted for almost one-quarter of reported cases (n = 2993, 23%). During 2004-2011, 2770 strains were submitted for molecular typing to the VRD, who found no evidence for a predominance of any particular strain. Thus, the recent increase in reported cases closely reflects the increase in PCR testing by NHS hospitals, but is associated with a lower proportion of samples being submitted for molecular typing. The high EV rate in young infants merits further investigation to inform evidence-based management guidance.

Seven-fold increase in viral meningo-encephalitis reports in England and Wales during 2004–2013

OBJECTIVES In highly immunised populations viruses contribute to a substantially higher proportion of meningo-encephalitis cases. This national study aimed to describe population trends in laboratory-confirmed, viral meningo-encephalitis reports in England and Wales over a ten-year period. METHODS Laboratory-confirmed, viral meningo-encephalitis cases submitted by National Health Service hospitals in England and Wales during 2004-13 were analysed. RESULTS There were 9941 laboratory-confirmed reports of viral meningo-encephalitis in England and Wales over the 10-year period. Number of reports increased across all age-groups and for all viruses from 311 (incidence, 0.6/100,000) in 2004 to 2168 in 2013 (incidence, 3.9/100,000). Median age at diagnosis was 30.6 (IQR, 1.3-51.5) years, with a third of cases diagnosed in children. In 2013, infants aged <3 months accounted for 27% (588/2168) of cases, but had the highest incidence (329/100,000). Enteroviruses were responsible for 52% (5133/9941) of all cases and 92% (1952/2121) in <3 month-olds (incidence, 313/100,000 in 2013, equivalent to 77/100,000 live-births) followed by herpes simplex (2885/9941; 29%) and varicella zoster (1342/9941; 13%), mainly among ≥45 year-olds. CONCLUSION Increasing use of molecular testing has led to a 7-fold increase in laboratory-confirmed, viral meningo-encephalitis reports. Large clinical-observational studies are necessary to determine the burden of viral meningo-encephalitis, especially in infants.

Do we really need to worry about Listeria in newborn infants

L monocytogenes is a Gram-positive motile bacterium that causes infections mainly at the extreme ends of life (newborns and the elderly) in the immunocompromised and in pregnant women. Clinical presentation in pregnant mothers is often nonspecific, but disease may lead to stillbirths or early or late neonatal infections. Early presentation in neonates is most common (62%) and case fatality rates range from 14% to 56%. There are few studies that address long-term outcomes, but 1 study of 13 babies with L. monocytogenes meningitis in the 1980s revealed that 3 (23%) had moderate to severe disability at 10-year follow-up. Transmission to pregnant women is generally from contaminated foods, thus the best means of prevention is by through control of L. monocytogenes in the food processing environment by appropriate egulation as well as education of pregnant women. Appropriate antibiotic therapy for management of L. monocytogenes infections must include a penicillin and for this reason guidelines for empiric antibiotic therapy for babies with possible sepsis or meningitis generally include a penicillin or ampicillin. However, a recent audit of UK neonatal units revealed that 19% and 10%, respectively, failed to include adequate antibiotic cover for L. monocytogenes meningitis and sepsis in their empiric antibiotic policies. This is a concern if invasive neonatal listeriosis is to be treated optimally. Some clinicians argue that L. monocytogenes is not common or serious enough to warrant the widespread use of such empiric antibiotics. In order to address this we conducted a review of the published literature from the last 20 years, focusing on cases of listeria infection in neonates and in pregnancy.