Sonia Ribeiro

Effectiveness of maternal pertussis vaccination in England: an observational study

BACKGROUND In October, 2012, a pertussis vaccination programme for pregnant women was introduced in response to an outbreak across England. We aimed to assess the vaccine effectiveness and the overall effect of the vaccine programme in preventing pertussis in infants. METHODS We undertook an analysis of laboratory-confirmed cases and hospital admissions for pertussis in infants between Jan 1, 2008, and Sept 30, 2013, using data submitted to Public Health England as part of its enhanced surveillance of pertussis in England, to investigate the effect of the vaccination programme. We calculated vaccine effectiveness by comparing vaccination status for mothers in confirmed cases with estimates of vaccine coverage for the national population of pregnant women, based on data from the Clinical Practice Research Datalink. FINDINGS The monthly total of confirmed cases peaked in October, 2012 (1565 cases), and subsequently fell across all age groups. For the first 9 months of 2013 compared with the same period in 2012, the greatest proportionate fall in confirmed cases (328 cases in 2012 vs 72 cases in 2013, -78%, 95% CI -72 to -83) and in hospitalisation admissions (440 admissions in 2012 vs 140 admissions in 2013, -68%, -61 to -74) occurred in infants younger than 3 months, although the incidence remained highest in this age group. Infants younger than 3 months were also the only age group in which there were fewer cases in 2013 than in 2011 (118 cases in 2011 vs 72 cases in 2013), before the resurgence. 26?684 women included in the Clinical Practice Research Datalink had a livebirth between Oct 1, 2012 and Sept 3, 2013; the average vaccine coverage before delivery based on this cohort was 64%. Vaccine effectiveness based on 82 confirmed cases in infants born from Oct 1, 2012, and younger than 3 months at onset was 91% (95% CI 84 to 95). Vaccine effectiveness was 90% (95% CI 82 to 95) when the analysis was restricted to cases in children younger than 2 months. INTERPRETATION Our assessment of the programme of pertussis vaccination in pregnancy in England is consistent with high vaccine effectiveness. This effectiveness probably results from protection of infants by both passive antibodies and reduced maternal exposure, and will provide valuable information to international policy makers. FUNDING Public Health England.

A case-control study to estimate the effectiveness of maternal pertussis vaccination in protecting newborn infants in England and Wales, 2012-2013

BACKGROUND Infants with pertussis infection are at risk of severe clinical illness and death. Several countries, including the United Kingdom, have introduced maternal pertussis vaccination during pregnancy to protect infants from infection following national increases in pertussis notifications. The objective of this study was to estimate the effectiveness of maternal pertussis vaccination in protecting infants against laboratory-confirmed pertussis infection. METHODS A case-control study was undertaken in England and Wales between October 2012 and July 2013. Cases were infants aged <8 weeks at onset with pertussis infection tested by real-time polymerase chain reaction or culture. Family doctors of each case were asked to identify healthy infants born consecutively after the case in each practice, to act as controls. Fifty-eight cases and 55 controls were included in this study. Odds ratios (ORs) were calculated for the association between maternal vaccination and infant pertussis infection. The vaccine effectiveness (VE) was calculated as 1 - OR. This was adjusted for sex, geographical region, and birth period. RESULTS Mothers of 10 cases (17%) and 39 controls (71%) received pertussis vaccine in pregnancy. This gave an unadjusted VE of 91% (95% confidence interval [CI], 77%-97%). Adjusted VE was 93% (95% CI, 81%-97%). CONCLUSIONS Maternal pertussis vaccination is effective in preventing pertussis infection in infants aged <8 weeks and may be considered in other countries experiencing high levels of pertussis notifications.

Trends in bacterial, mycobacterial, and fungal meningitis in England and Wales 2004–11: an observational study

BACKGROUND Meningitis remains one of the most feared infectious diseases worldwide, yet there are few population-based studies on the epidemiology, causes, or trends over time in meningitis, especially in industrialised countries. Our aim was to do such a study using routinely reported data available in England and Wales. METHODS In England and Wales, UK National Health Service hospitals routinely report laboratory-confirmed pathogens electronically to Public Health England. Records of all positive bacterial, mycobacterial, and fungal results from cerebrospinal fluid or from blood cultures in patients with clinical meningitis were extracted for analysis. The percentage change in annual incidence was estimated using linear regression analysis of the log of the annual incidence. FINDINGS During 2004-11, 7061 cases of meningitis were reported (mean annual incidence 1·62 per 100,000 people, 95% CI 1·58-1·66), including 2594 cases in children (37%). The incidence of bacterial (1·44 per 100,000 people, 1·41-1·48), fungal (0·09, 0·08-0·10), and mycobacterial (0·09, 0·08-0·09) meningitis remained stable overall and across the age groups, apart from significant year-on-year increases in children younger than 3 months (978 cases; incidence 72·2 per 100,000 people; annual increase 7·4%, 5·1-9·8; p<0·0001) driven mainly by group B streptococci (GBS), and in adults aged 65 years or older (752 cases; incidence 1·2 per 100,000 people; annual increase 3·0%, 1·4-4·8; p<0·0001) primarily because of Escherichia coli. By contrast, meningococcal meningitis rates declined steadily, but remained the most common cause of meningitis in children. Overall, five groups of bacteria accounted for 60% (3790/6286) of bacterial meningitis cases: Neisseria meningitidis (1350 cases, 22%), Streptococcus pneumoniae (1143, 18%), Staphylococcus aureus (652, 10%), GBS (326, 5%), and E coli (319, 5%). INTERPRETATION In England and Wales, laboratory-based surveillance shows a remarkably stable incidence of bacterial, fungal, and mycobacterial meningitis in recent years, although there were differences in individual trends among the main pathogens causing meningitis in different age groups. FUNDING None.

Sustained Effectiveness of the Maternal Pertussis Immunization Program in England 3 Years Following Introduction

The effectiveness of maternal immunization in preventing infant pertussis was first demonstrated in England, 1 year after the program using diphtheria–tetanus–5-component acellular pertussis–inactivated polio vaccine (dT5aP-IPV) was introduced in 2012. Vaccine effectiveness against laboratory-confirmed pertussis has been sustained >90% in the 3 years following its introduction, despite changing to another acellular vaccine with different antigen composition. Consistent with this, disease incidence in infants <3 months of age has remained low despite high activity persisting in those aged 1 year and older. Vaccine effectiveness against infant deaths was estimated at 95% (95% confidence interval, 79%–100%). Additional protection from maternal immunization is retained in infants who received their first dose of the primary series. There is no longer evidence of additional protection from maternal vaccination after the third infant dose. Although numbers are small and ongoing assessment is required, there is no evidence of increased risk of disease after primary immunization in infants whose mothers received maternal vaccination.

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.

Survey of Household Contacts of Infants With Laboratory-confirmed Pertussis Infection During a National Pertussis Outbreak in England and Wales

Background: Highest rates of pertussis occur in infants <3 months of age, too young to be fully vaccinated. The 2012 national outbreak provided a valuable opportunity to study sources of infection for these infants at highest risk of severe complications and death. Methods: Households of infants <3 months of age with laboratory-confirmed pertussis between August 2012 and October 2013 were invited to complete a questionnaire with information on household members’ demographics, relationship with the infant, chronology of cough onset where relevant and vaccination history. Contacts were also invited to provide an oral fluid sample for antipertussis toxin IgG testing. Individuals with laboratory evidence of infection and cough onset up to 3 months before infant onset were considered probable sources of infection. Results: In total, 220 contacts from 63 families were included in the analysis. In 86% of households (54/63), at least one positive result was found with 44% (97/220) of all contacts testing positive. Around 29% (31/108) of noncoughers tested positive. A probable source of infection was found for 46% (29/63) of infant cases. Mothers were the probable source in 38% of cases, followed by siblings (31%) and fathers (10%). Conclusion: Household contacts play an important role in the transmission of pertussis to infants and when identified, mothers were the main sources of infection. Immunization during pregnancy has a key role in preventing infant disease through passive protection from birth and reduced maternal exposure.

Risk of invasive meningococcal disease in university students in England and optimal strategies for protection using MenACWY vaccine

PURPOSE In August 2015, in response to increasing group W invasive meningococcal disease (IMD) nationally, a MenACWY vaccine programme was introduced in the UK for 13-18year olds. We reviewed the epidemiology of IMD in young adults and university-associated cases in England during 2014-15 academic year and assessed the potential impact of different immunisation strategies. METHODS Public Health England national enhanced surveillance data were used to describe the epidemiology of IMD cases in 15-24year olds in England during 2014/15. Relative risks for IMD were calculated overall and by capsular group in students compared with non- student peers for 2014 and 2013 school leavers. Assuming stable future incidence and vaccine efficacy of 90% for five years, we estimated cases averted and numbers needed to vaccinate (NNV) for different MenACWY immunisation programmes: school-based adolescent, GP-based school leaver, and targeting freshers. RESULTS Between July 2014 and June 2015, 112 IMD cases were diagnosed in those born between 01/09/1991 and 31/08/2001 (∼15 to 24year-olds). During the 2014/15 academic year (September to June), 49 IMD cases were reported among students attending English universities, including 22 among 2014 school leavers. In this cohort, the relative risk of IMD was higher among students compared to non-students for all capsular groups (RR 11.6; 95% CI 4.7-28.7) and for groups A/C/W/Y (RR 14.8; 95% CI, 4.3-51.5). A school-based programme could potentially have averted 14 cases in 2014/15 and 24 cases over five years with a lower NNV (18,000) than other programmes. CONCLUSIONS University students, particularly first years entering direct from school, are at higher risk for IMD than non-students. With high vaccine coverage and timely completion, an adolescent school-based MenACWY programme has the greatest potential to prevent cases with the lowest NNV, but population impact through indirect (herd) protection could take longer.

Hospitalisation of preterm infants with pertussis in the context of a maternal vaccination programme in England

Aims To assess whether preterm infants are at increased risk of pertussis infection and whether this increased following introduction of a maternal pertussis vaccination in England, while examining characteristics of infants associated with more severe disease. Methods Infants aged <60 days admitted between 1 April 2009 and 31 March 2016 with a pertussis diagnosis code were extracted from Hospital Episode Statistics (HES) data. HES data were reconciled with existing surveillance systems to capture maternal vaccination status where available. Cases were compared preimplementation and postimplementation of the maternal programme with respect to demography, preterm or full-term birth and coinfection. Survival analysis was undertaken to assess the impact of variables on duration of hospital stay. Results The proportion of hospitalised preterm infants (138/1309, 10.6%) was higher than population estimates (7.4%), increasing from 9.8% (83/847) to 12.1% (56/462) following implementation of the maternal programme. Longer duration of hospital stay was associated with prematurity, younger age, additional respiratory illnesses and mothers unvaccinated in pregnancy. Of 13 deaths, 5 were preterm (38.5%) and 11 (84.6%) were female. A larger proportion of full-term infants’ (49/188, 26.1%) mothers had been vaccinated in pregnancy than preterm infants (7/49, 14.3%), with 14.3% of mothers of full-term cases vaccinated after 35 weeks. Conclusions Preterm infants are over-represented in hospitalised pertussis cases and have less benefit from the maternal pertussis vaccination programme in England due to reduced opportunity for maternal vaccination.

Short-term changes in the health state of children with group B meningococcal disease: a prospective, national cohort study

Objectives The short-term impact of childhood invasive meningococcal disease (IMD) on quality-of-life (QoL) remains largely unquantified. This study aimed to quantify QoL loss at the point when illness was at its worst, and assess health state recovery in the months following illness. Methods Parents of children aged <16 years with laboratory-confirmed meningococcal group B (MenB) disease in England, with onset dates from November 2012 to May 2013 were asked to complete a short questionnaire, which included EQ-5DY, a version of EQ-5D for 8–15 year-olds. The parents, or child if able, were asked to complete the questionnaires while considering the child’s health on the worst day of illness and on the date the questionnaires were completed. Results The overall response rate was 43% (109/254 children), with no significant differences between respondents and non-respondents. The median time from disease onset to questionnaire completion was 134 days (interquartile range (IQR), 92 to 156 days). After imputation, the median health index was -0.056 (IQR, -0.073 to 0.102) on the worst day of illness, and 1 (IQR 0.866 to 1.000) on the date of questionnaire completion. The respective Visual Analogue Scores (VAS) were 6.5/100.0 (IQR, 0.0 to 20.0) and 95.0/100.0 (IQR, 90.0 to 100.0). The health state of cases with long-term sequelae (n = 41) was significantly worse at follow-up than those who recovered uneventfully (n = 64; 90.0 vs. 98.0; p<0.001), although there was no significant difference on the worst day of illness (5.0 vs. 10.0; p = 0.671). Conclusions This work has provided, for the first time, a quantitative estimate of QoL loss at the peak of illness and in the months after MenB disease in children. The magnitude of QoL loss is staggering, with the reported health state being at, or close to, the worst possible outcome imaginable. This study highlights the difficulties in measuring the impact of illness in young children, who often have the highest burden of potentially preventable infectious diseases.

Meningococcal Group W Disease in Infants and Potential Prevention by Vaccination.

To the Editor: We recently reported that postvaccination serum samples from infants immunized with a novel, protein-based multicomponent meningococcal serogroup B (MenB) vaccine (Bexsero; GlaxoSmithKline Vaccines, Verona, Italy) have bactericidal activity against the hypervirulent meningococcal group W (MenW) strain belonging to the sequence type (ST) 11 clonal complex (1). Historically, MenW has been a rare cause of invasive meningococcal disease (IMD), accounting for <5% of confirmed cases in England and Wales (2). Since 2009, MenW cases caused by this hypervirulent strain have rapidly increased in England (2). During the 2014–15 epidemiologic year (July 1–June 30), this capsular group accounted for 176 (24%) of 724 IMD cases in England (3). In response to this outbreak, in August 2015, the United Kingdom introduced an emergency adolescent conjugate vaccination program against meningococcal capsular groups ACW and Y. Over 2 years, the program aims to provide vaccine to all youth 13–18 years of age and to new university entrants <25 years of age. This program is expected to protect adolescents (25 of 176 [14%] MenW cases during 2014–15 were in those 15–19 years of age), and, by targeting youth with the highest carriage rates, to protect others through indirect (herd) protection, which has been consistently observed in vaccine programs, including that for meningococcal group C (4,5). Indirect protection associated with the adolescent immunization program will likely take several years to manifest (6).