Joanne White

Molecular and Epidemiological Review of Toxigenic Diphtheria Infections in England between 2007 and 2013

ABSTRACT Human infections caused by toxigenic corynebacteria occur sporadically across Europe. In this report, we undertook the epidemiological and molecular characterization of all toxigenic corynebacterium strains isolated in England between January 2007 and December 2013. Epidemiological aspects include case demographics, risk factors, clinical presentation, treatment, and outcome. Molecular characterization was performed using multilocus sequence typing (MLST) alongside traditional phenotypic methods. In total, there were 20 cases of toxigenic corynebacteria; 12 (60.0%) were caused by Corynebacterium ulcerans, where animal contact was the predominant risk factor. The remaining eight (40.0%) were caused by Corynebacterium diphtheriae strains; six were biovar mitis, which were associated with recent travel abroad. Adults 45 years and older were particularly affected (55.0%; 11/20), and typical symptoms included sore throat and fever. Respiratory diphtheria with the absence of a pharyngeal membrane was the most common presentation (50.0%; 10/20). None of the eight C. diphtheriae cases were fully immunized. Diphtheria antitoxin was issued in two (9.5%) cases; both survived. Two (9.5%) cases died, one due to a C. diphtheriae infection and one due to C. ulcerans. MLST demonstrated that the majority (87.5%; 7/8) of C. diphtheriae strains represented new sequence types (STs). By adapting several primer sequences, the MLST genes in C. ulcerans were also amplified, thereby providing the basis for extension of the MLST scheme, which is currently restricted to C. diphtheriae. Despite high population immunity, occasional toxigenic corynebacterium strains are identified in England and continued surveillance is required.

Coverage of the English National human papillomavirus (HPV) Immunisation Programme among 12 to 17 year-old females by area-level deprivation score, England, 2008 to 2011

The English national human papillomavirus (HPV) immunisation programme has offered vaccination to girls aged 12 years at the start of each school year since September 2008. A catch-up programme has offered vaccination to girls up to 18 years. Delivery is predominantly school-based, with some general practitioner (GP)-based immunisation. The relationship between HPV immunisation coverage and deprivation (index of multiple deprivation, IMD) was assessed by geographical area (N=151) for each school year offered the HPV vaccine between 2008 to 2011 using the Spearman’s rank correlation coefficient, and compared to that for adequate cervical screening of women aged 25 to 49 years. Coverage at age 12 showed no significant association with IMD at the area-level (p=0.12). Within the catch-up years, there was some suggestion of higher deprivation being associated with lower coverage. This was not significant for girls offered immunisation under 16 years (in compulsory education) (p=0.09), but was more marked and statistically significant for older girls (p<0.0001). The proportion of women aged 25 to 49 years with an adequate cervical screen was negatively associated with deprivation (p<0.0001). School-based HPV immunisation delivery appears to be successfully reducing inequalities in cervical cancer control at area-level. However, the catch-up cohorts above the age of compulsory education may face increased inequality. Further investigation is needed into individual-level factors associated with coverage.

Access to diphtheria antitoxin for therapy and diagnostics.

The most effective treatment for diphtheria is swift administration of diphtheria antitoxin (DAT) with conjunct antibiotic therapy. DAT is an equine immunoglobulin preparation and listed among the World Health Organization Essential Medicines. Essential Medicines should be available in functioning health systems at all times in adequate amounts, in appropriate dosage forms, with assured quality, and at prices individuals and the community can afford. However, DAT is in scarce supply and frequently unavailable to patients because of discontinued production in several countries, low economic viability, and high regulatory requirements for the safe manufacture of blood-derived products. DAT is also a cornerstone of diphtheria diagnostics but several diagnostic reference laboratories across the European Union (EU) and elsewhere routinely face problems in sourcing DAT for toxigenicity testing. Overall, global access to DAT for both therapeutic and diagnostic applications seems inadequate. Therefore--besides efforts to improve the current supply of DAT--accelerated research and development of alternatives including monoclonal antibodies for therapy and molecular-based methods for diagnostics are required. Given the rarity of the disease, it would be useful to organise a small stockpile centrally for all EU countries and to maintain an inventory of DAT availability within and between countries.

Childhood vaccination coverage by ethnicity within London between 2006/2007 and 2010/2011

Objectives To assess childhood vaccination coverage at first, second and fifth birthdays by ethnicity in London between 2006/2007 and 2010/2011 and identify factors relating to lower coverage. Design Data concerning receipt of diphtheria-containing vaccines were extracted from child health information systems (CHISs) and sent to the Health Protection Agency. Setting Nine London Primary Care Trusts (PCTs). Participants Records for 315 381 children born April 2001–March 2010. Main outcome measures Receipt of a full primary course of diphtheria-containing vaccines at first and second birthdays, and a primary course and preschool booster at fifth birthday. Results Consistently good vaccine coverage of the primary course (>88% at first birthday, >89% at second birthday) was achieved across the five largest ethnic groups. Coverage of the preschool booster at fifth birthday was >65% across the five largest ethnic groups. Lowest coverage was observed in smaller ethnic groups. Deprivation was not a strong indicator of coverage overall, and for most ethnic groups there was no relationship between deprivation and coverage. Coverage was significantly lower in children not assigned to a general practitioner practice in the CHIS. Conclusions Smaller, less well-established ethnic groups within a PCT may require specific targeting to ensure children are fully immunised and to improve record keeping. Unregistered children need particular attention and may be missed by current scheduling processes in London. In order to monitor the impact of the current National Health Service (NHS) reorganisation on inequalities in access to healthcare data on country of birth, in addition to ethnicity, should be available for analysis.

Phased introduction of a universal childhood influenza vaccination programme in England: population-level factors predicting variation in national uptake during the first year, 2013/14

INTRODUCTION Through a phased rollout, the UK is implementing annual influenza vaccination for all healthy children aged 2-16 years old. In the first year of the programme in England in 2013/14, all 2-3 year olds were offered influenza vaccine through primary care and a primary school age programme was piloted, mainly through schools, in geographically distinct areas. Equitable delivery is a key aim of the programme; it is unclear if concerns by some religious groups over influenza vaccine content have impacted on uptake. METHODS At the end of the 2013/14 season, variations in uptake for 2-3 year olds and 4-11 year olds were assessed and stratified by population-level predictors: deprivation, ethnicity, religious beliefs and rurality. GP practice or school level uptake was linearly regressed against these variables to determine potential predictors and changes in uptake, adjusting for significant factors. RESULTS Uptake varied considerably by geographic locality for both 2-3 year olds and 4-11 year olds. Lower uptake was seen in increasingly deprived areas, with an adjusted uptake in the most deprived quintile 12% and 8% lower than the least deprived areas by age-group respectively. By ethnicity, the highest non-white population quartile had an adjusted uptake 9% and 14% lower than the lowest non-white quartile by age-group respectively. Uptake also varied according to religious beliefs, with adjusted uptake in 4-11 year olds in the highest Muslim population tertile 8% lower than the lowest Muslim population tertile. CONCLUSION In the first season of the childhood influenza vaccination programme, uptake was not uniform across the country, with deprivation and ethnicity both predictors of low uptake in pre-school and primary school age children, and religious beliefs also an important factor, particularly the latter group. With the continued rollout of the programme, these population-level factors should be addressed to achieve sustained successful uptake, along with assessment of contribution of individual and household-level factors.

The importance of tetanus risk assessment during wound management

Public Health England undertakes surveillance of vaccine preventable diseases including enhanced surveillance of clinically suspected tetanus. In the United Kingdom, tetanus has become increasingly rare due to the success of the national routine immunization program. Consequently, few practitioners have experience of diagnosing and managing patients with clinical tetanus. We report two cases of tetanus where comparatively minor wounds proved fatal. These cases highlight the importance of the accurate identification and management of tetanus prone wounds and the fatal consequences from untreated injuries in susceptible individuals. We conclude that appropriate risk assessment for tetanus prophylaxis forms an essential part of wound management.

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.

HPV Serology Testing Confirms High HPV Immunisation Coverage in England

Background Reported human papillomavirus (HPV) vaccination coverage in England is high, particularly in girls offered routine immunisation at age 12 years. Serological surveillance can be used to validate reported coverage and explore variations within it and changes in serological markers over time. Methods Residual serum specimens collected from females aged 15–19 years in 2010–2011 were tested for anti-HPV16 and HPV18 IgG by ELISA. Based on these results, females were classified as follows: seronegative, probable natural infection, probable vaccine-induced seropositivity, or possible natural infection/possible vaccine-induced seropositivity. The proportion of females with vaccine-induced seropositivity was compared to the reported vaccination coverage. Results Of 2146 specimens tested, 1380 (64%) were seropositive for both types HPV16 and HPV18 and 159 (7.4%) positive for only one HPV type. The IgG concentrations were far higher for those positive for both HPV types than those positive for only one HPV type. 1320 (62%) females were considered to have probable vaccine-induced seropositivity. Among vaccine-induced seropositives, antibody concentrations declined with increasing age at vaccination and increasing time since vaccination. Conclusions The proportion of females with vaccine-induced seropositivity was closest to the reported 3-dose coverage in those offered the vaccination at younger ages, with a greater discrepancy in the older females. This suggests either some under-reporting of immunisations of older females and/or that partial vaccination (i.e. one- or two-doses) has provided high antibody responses in 13–17 year olds.

Current epidemiology of tetanus in England, 2001-2014.

Public Health England conducts enhanced national surveillance of tetanus, a potentially life-threatening vaccine-preventable disease. A standardized questionnaire was used to ascertain clinical and demographic details of individuals reported with clinically suspected tetanus. The 96 cases identified between 2001 and 2014 were analysed. The average annual incidence was 0·13/million (95% confidence interval 0·10-0·16) of which 50·0% were male. Where reported, 70·3% of injuries occurred in the home/garden (45/64). Overall, 40·3% (31/77) cases were in people who inject drugs (PWID), including a cluster of 22 cases during 2003-2004. Where known (n = 68), only 8·8% were age-appropriately immunized. The overall case-fatality rate was 11·0% (9/82). All tetanus-associated deaths occurred in adults aged >45 years, none of whom were fully immunized. Due to the success of the childhood immunization programme, tetanus remains a rare disease in England with the majority of cases occurring in older unimmunized or partially immunized adults. Minor injuries in the home/garden were the most commonly reported likely sources of infection, although cases in PWID increased during this period. It is essential that high routine vaccine coverage is maintained and that susceptible individuals, particularly older adults, are protected through vaccination and are offered timely post-exposure management following a tetanus-prone wound.

Extracting general practice data for timely vaccine coverage estimates: The England experience

In England, primary care providers use standardised coding systems to record health events such as vaccination as well as patient characteristics. This information can be automatically extracted to estimate coverage for vaccine programmes delivered through primary care, in the general population as well as in specific geographical, ethnic, age or clinical groups. This system provides timely vaccine coverage estimates as well as the flexibility to extract tailored data in order to directly inform a continuously evolving national vaccine programme. It is however limited by the quality and completeness of clinical coding in primary care. A centralised, individual-level register would however improve data quality, completeness and reliability and remains the gold standard.