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The meningococcal group B vaccine, 4CMenB, is a broad-spectrum, recombinant protein vaccine that is licensed for protection against meningococcal group B disease in children and adults. Over the past decade, several observational studies supported by laboratory studies have reported protection by 4CMenB against gonorrhoea, a sexually transmitted infection caused by Neisseria gonorrhoeae. Gonorrhoea is a major global public health problem, with rising numbers of diagnoses and increasing resistance to multiple antibiotics. In England, more than 82 000 cases of gonorrhoea were diagnosed in 2022, with nearly half of the cases diagnosed among gay, bisexual, and other men who have sex with men. There are currently no licensed vaccines against gonorrhoea but 4CMenB is estimated to provide 33-47% protection against gonorrhoea. On Nov 10, 2023, the UK Joint Scientific Committee on Vaccination and Immunisation agreed that a targeted programme should be initiated using 4CMenB to prevent gonorrhoea among individuals at higher risk of infection attending sexual health services in the UK. This decision was made after reviewing evidence from retrospective and prospective observational studies, laboratory and clinical data, national surveillance reports, and health economic analyses. In this Review, we summarise the epidemiology of invasive meningococcal disease and gonorrhoea in England, the evidence supporting the use of 4CMenB for protection against gonorrhoea, and the data needed to inform long-term programme planning and extension to the wider population., Competing Interests: Declaration of interests PJW has received payment from Pfizer for teaching of mathematical modelling of infectious disease transmission and vaccination. RB performs contract serology on behalf of UKHSA for GlaxoSmithKline, Pfizer, and Sanofi but receives no personal remuneration. SNL performs contract research for St George's University of London for vaccine manufacturers but receives no personal remuneration. All other authors declare no competing interests., (Crown Copyright © 2024 Published by Elsevier Ltd. All rights reserved.)

Background: The UK transition from a 2 + 1 to a 1 + 1 infant immunisation schedule with the 13-valent pneumococcal conjugate vaccine (PCV13) on Jan 1, 2020, coincided with the start of the COVID-19 pandemic. We describe the epidemiology of invasive pneumococcal disease (IPD) in England over 6 financial years (April 1 to March 31) between 2017-18 and 2022-23., Methods: We used prospective national surveillance data, including serotyping and whole-genome sequencing of invasive isolates, to analyse IPD trends in England by age and financial year. We compared breakthrough infections and vaccine failure rates in 2022-23 among children eligible for the 1 + 1 schedule with rates in cohorts of children eligible for the 2 + 1 schedule between 2017-18 and 2019-20. We assessed genomic changes over time by comparing Global Pneumococcal Sequencing Clusters and multilocus sequence types among PCV13 serotypes causing IPD., Findings: There were 4598 laboratory-confirmed IPD cases in 2022-23, 3025 in 2021-22, 1240 in 2020-21, and 5316 in 2019-20. IPD incidence in 2022-23 was 14% lower than in 2019-20 (incidence rate ratio [IRR] 0·86, 95% CI 0·81-0·91; p<0·001). IPD incidence in 2022-23 compared with 2019-20 was 34% higher in children (aged <15 years) (378 cases vs 292 cases; IRR 1·34, 95% CI 1·08-1·68; p=0·009) and 17% lower in adults (aged 15 years and older; 4220 vs 5024; 0·83, 0·78-0·88; p<0·001). The proportion of PCV13-type IPD increased from 19·4% (95% CI 18·2-20·4; 957 of 4947) in 2019-20 to 29·7% (28·3-31·0; 1283 of 4326) in 2022-23, mainly due to serotype 3, but also serotypes 19F, 19A, and 4, alongside a decrease in non-PCV13 serotypes 8, 12F, and 9N. The increase in IPD incidence due to serotypes 3, 19A, and 19F was driven by clonal expansion of previously circulating strains, whereas serotype 4 expansion was driven by newer strains (ie, sequence types 801 and 15603). Breakthrough infections and vaccine failure rates were similar in children eligible for the 1 + 1 (1·08 per 100 000 person-years) and 2 + 1 (0·76 per 100 000 person-years; IRR 1·42, 95% CI 0·78-2·49; p=0·20) PCV13 schedules., Interpretation: Overall, IPD incidence in England was lower in 2022-23, 2 years after removal of pandemic restrictions, than in 2019-20. Breakthrough and vaccine failure rates were not significantly different between children who received the 1 + 1 compared with the 2 + 1 PCV13 immunisation schedule. The post-pandemic increase in childhood IPD incidence and especially PCV13-type IPD will require close monitoring., Funding: None., Competing Interests: Declaration of interests The Immunisation and Vaccine Preventable Diseases Division (UKHSA) provides vaccine manufacturers with post-marketing surveillance reports on pneumococcal and meningococcal infections, which the companies are required to submit to the Medicines and Healthcare products Regulatory Agency in compliance with the companies' Risk Management Strategy. A cost recovery charge is made for these reports. SNL performs contract research on behalf of St George's University of London and the UKHSA for pharmaceutical companies but receives no personal remuneration. The Respiratory and Vaccine Preventable Bacteria Reference Unit (UKHSA) has received grant funding from vaccine manufacturers for investigator-led research projects on pneumococcal surveillance. All other authors declare no competing interests., (Crown Copyright © 2024 Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

Background: Invasive Haemophilus influenzae serotype a (Hia) disease is rare, with most cases reported among Indigenous populations in North America. In England, national surveillance was enhanced following an increase in laboratory-confirmed invasive Hia disease since the 2016-17 epidemiological year. This study aimed to describe the epidemiological trends, clinical characteristics of cases, and assess potential genomic drivers., Methods: Hospital laboratories in England routinely submit invasive H influenzae isolates to the UK Health Security Agency for confirmation and serotyping. In this prospective national surveillance study we contacted the general practitioners and clinicians of all patients with laboratory-confirmed invasive Hia from the 2008-09 to the 2021-22 epidemiological year to complete a clinical questionnaire on demographics, underlying conditions, clinical presentation, complications, outcomes, and travel history of the patient. All Hia invasive isolates from residents in England were included in the study; non-invasive isolates were excluded. Multilocus sequence typing (MLST), whole genome single-nucleotide polymorphism, and k-mer-based analysis of bacterial isolates were performed following Illumina whole-genome sequencing (WGS). Outcomes included epidemiological trends, clinical characteristics of confirmed Hia cases, and genomic analyses., Findings: From the 2008-09 to the 2021-22 epidemiological years, there were 52 cases of invasive infection with H influenzae serotype a in England (25 [48%] in female patients and 27 [52%] in male patients). There were zero to two annual Hia cases (accounting for <0·5% of serotyped H influenzae isolates) until 2015-16, after which cases increased across England to 19 cases in 2021-22 (incidence 0·03 cases per 100 000), when Hia accounted for 19 (4%) of 484 serotyped H influenzae isolates, 19 (19%) of 100 capsulated cases, and 37% (19 of 52) of all H influenzae cases between 2008-09 and 2021-22. Most of the recent increase in cases occurred among individuals aged 65 years and older (17 [33%] of 52), who typically presented with bacteraemic pneumonia (13 [76%] of 17), and infants younger than 1 year, who had the highest incidence and were more likely to present with meningitis (five [50%] of ten). Overall case fatality rate was 7·7% (95% CI 2·1-19·7; four of 52 patients). WGS found that closely related MLST sequence types ST1511 (20 [39%] of 51), ST23 (13 [25%] of 51), and ST56 (seven [14%] of 51) accounted for most cases, with no evidence of serotype b strains switching capsule to Hia. Duplication of the capsule operon, associated with more severe disease, was present in 32 (80%) of 40 of these sequence types. Analysis of the core and accessory genome content grouped most isolates into a single strain., Interpretation: The persistent increase in invasive Hia cases across England and across all age groups suggests widespread transmission, consistent with reports from other European countries, and will require close monitoring., Funding: UK Health Security Agency., Competing Interests: Declaration of interests SNL conducts contract research on behalf of St George's University of London and the UKHSA for pharmaceutical companies, including vaccine manufacturers, but receives no personal remuneration. All other authors declare no competing interests., (Crown Copyright © 2023 Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

Background: In response to a national mpox (formerly known as monkeypox) outbreak in England, children exposed to a confirmed mpox case were offered modified vaccinia Ankara-Bavaria Nordic (MVA-BN), a third-generation smallpox vaccine, for post-exposure prophylaxis. We aimed to assess the safety and reactogenicity and humoral and cellular immune response, following the first reported use of MVA-BN in children., Methods: This is an assessment of children receiving MVA-BN for post-exposure prophylaxis in response to a national mpox outbreak in England. All children receiving MVA-BN were asked to complete a post-vaccination questionnaire online and provide a blood sample 1 month and 3 months after vaccination. Outcome measures for the questionnaire included reactogenicity and adverse events after vaccination. Blood samples were tested for humoural, cellular, and cytokine responses and compared with unvaccinated paediatric controls who had never been exposed to mpox., Findings: Between June 1 and Nov 30, 2022, 87 children had one MVA-BN dose and none developed any serious adverse events or developed mpox disease after vaccination. Post-vaccination reactogenicity questionnaires were completed by 45 (52%) of 87 children. Their median age was 5 years (IQR 5-9), 25 (56%) of 45 were male, and 22 (49%) of 45 were White. 16 (36%) reported no symptoms, 18 (40%) reported local reaction only, and 11 (24%) reported systemic symptoms with or without local reactions. Seven (8%) of 87 children provided a first blood sample a median of 6 weeks (IQR 6·0-6·5) after vaccination and five (6%) provided a second blood sample at a median of 15 weeks (14-15). All children had poxvirus IgG antibodies with titres well above the assay cutoff of OD 450nm 0·1926 with mean absorbances of 1·380 at six weeks and 0·9826 at 15 weeks post-vaccination. Assessment of reactivity to 27 recombinant vaccina virus and monkeypox virus proteins showed humoral antigen recognition, primarily to monkeypox virus antigens B6, B2, and vaccina virus antigen B5, with waning of humoral responses observed between the two timepoints. All children had a robust T-cell response to whole modified vaccinia Ankara virus and a select pool of conserved pan-Poxviridae peptides. A balanced CD4 + and CD8 + T-cell response was evident at 6 weeks, which was retained at 15 weeks after vaccination., Interpretation: A single dose of MVA-BN for post-exposure prophylaxis was well-tolerated in children and induced robust antibody and cellular immune responses up to 15 weeks after vaccination. Larger studies are needed to fully assess the safety, immunogenicity, and effectiveness of MVA-BN in children. Our findings, however, support its on-going use to prevent mpox in children as part of an emergency public health response., Funding: UK Health Security Agency., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The UK experienced a national outbreak of mpox (formerly known as monkeypox) disease that started in May, 2022, as did many other countries worldwide, with case numbers rising rapidly, mainly among gay, bisexual, and other men who have sex with men (GBMSM). To control the outbreak, Modified Vaccinia Ankara-Bavaria Nordic (MVA-BN), an attenuated smallpox vaccine, was offered to at-risk GBMSM. We aimed to assess the effectiveness of a single MVA-BN dose against symptomatic mpox disease in at-risk GBMSM., Methods: In this case-coverage study, mpox cases in England were sent questionnaires collecting information on demographics, vaccination history, symptoms, and sexual orientation. Returned questionnaires were linked to laboratory data and a public health case management system (HP Zone) to obtain additional information on symptom onset and specimen date. Cases with a rash onset date (or alternative proxy) between July 4 and Oct 9, 2022, were included. Females, heterosexual men, and those with missing vaccination information were excluded. Vaccine effectiveness was calculated using the case-coverage method in which vaccine coverage among cases is compared with coverage in the eligible population, estimated from doses given to GBMSM and the estimated size of at-risk GBMSM. Sensitivity analyses included an increase and decrease of 20% differences in the estimated high-risk GBMSM population size., Findings: By Nov 3, 2022, 1102 people had responded to questionnaires, of which 739 were excluded (52 females or self-declared male heterosexuals, 590 with an index date outside of the study period, and 97 missing a vaccination date). 363 cases were included in the analyses. Vaccine uptake among eligible GBMSM increased steadily from July, 2022, reaching 47% by Oct 9, 2022. Of the 363 confirmed cases, eight cases either did occur or were likely to have occurred at least 14 days after vaccination, 32 within 0-13 days after vaccination, and the rest were unvaccinated. The estimated vaccine effectiveness against symptomatic mpox at least 14 days after a single dose was 78% (95% CI 54 to 89) ranging from 71 to 85 in sensitivity analyses. Vaccine effectiveness within 0-13 days after vaccination was -4% (95% CI -50 to 29)., Interpretation: A single MVA-BN dose was highly protective against symptomatic mpox disease among at-risk GBMSM, making it a useful tool for mpox outbreak control when rapid protection is needed. For cases in which numbers at highest risk of infection exceed vaccine supply, there might be benefit in prioritising delivery of first doses., Funding: UK Health Security Agency., Competing Interests: Declaration of interests We declare no competing interests., (Crown Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

Competing Interests: We declare no competing interests.

Background: Little is known about protection against SARS-CoV-2 infection following previous infection with specific individual SARS-CoV-2 variants, COVID-19 vaccination, and a combination of previous infection and vaccination (hybrid immunity) in adolescents. We aimed to estimate protection against symptomatic PCR-confirmed infection with the delta (B.1.617.2) and omicron (B.1.1.529) variants in adolescents with previous infection, mRNA vaccination, and hybrid immunity., Methods: We conducted an observational, test-negative, case-control study using national SARS-CoV-2 testing and COVID-19 mRNA vaccination data in England. Symptomatic adolescents aged 12-17 years who were unvaccinated or had received primary BNT162b2 immunisation at symptom onset and had a community SARS-CoV-2 PCR test were included. Vaccination and previous SARS-CoV-2 infection status in adolescents with PCR-confirmed COVID-19 (cases) were compared with vaccination and previous infection status in adolescents who had a negative SARS-CoV-2 PCR test (controls). Vaccination data were collected from the National Immunisation Management System, and were linked to PCR testing data. The primary outcome was protection against SARS-CoV-2 delta and omicron infection (defined as 1 - odds of vaccination or previous infection in cases divided by odds of vaccination or previous infection in controls)., Findings: Between Aug 9, 2021, and March 31, 2022, 1 161 704 SARS-CoV-2 PCR tests were linked to COVID-19 vaccination status, including 390 467 positive tests with the delta variant and 212 433 positive tests with the omicron variants BA.1 and BA.2. In unvaccinated adolescents, previous SARS-CoV-2 infection with wildtype, alpha (B.1.1.7), or delta strains provided greater protection against subsequent delta infection (>86·1%) than against subsequent omicron infection (<52·4%); previous delta or omicron infection provided similar protection against omicron reinfection (52·4% [95% CI 50·9-53·8] vs 59·3% [46·7-69·0]). In adolescents with no previous infection, vaccination provided lower protection against omicron infection than against delta infection, with omicron protection peaking at 64·5% (95% CI 63·6-65·4) at 2-14 weeks after dose two and 62·9% (60·5-65·1) at 2-14 weeks after dose three, with waning protection after each dose. Adolescents with hybrid immunity from previous infection and vaccination had the highest protection, irrespective of the SARS-CoV-2 strain in the primary infection. The highest protection against omicron infection was observed in adolescents with vaccination and previous omicron infection, reaching 96·4% (95% CI 84·4-99·1) at 15-24 weeks after vaccine dose two., Interpretation: Previous infection with any SARS-CoV-2 variant provided some protection against symptomatic reinfection, and vaccination added to this protection. Vaccination provides low-to-moderate protection against symptomatic omicron infection, with waning protection after each dose, while hybrid immunity provided the most robust protection. Although more data are needed to investigate longer-term protection and protection against infection with new variants, these data question the need for additional booster vaccine doses for adolescents in populations with already high protection against SARS-CoV-2 infection., Funding: None., Competing Interests: Declaration of interests We declare no competing interests., (Crown Copyright © 2023 Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

Competing Interests: We declare no competing interests. NA and SNL contributed equally. UKHSA has legal permission, provided by Regulation 3 of The Health Service (Control of Patient Information) Regulations 2002, to process patient confidential information for national surveillance of communicable diseases and as such, individual patient consent is not required to access records.

Background: Timely vaccination is critical for providing early protection against meningococcal B (MenB) disease because of the high incidence in early childhood. We assessed the timeliness of vaccination in children with confirmed MenB disease after 4CMenB (a recombinant protein-based vaccine) implementation into the national infant immunisation programme in England., Methods: Public Health England (PHE) conducts surveillance of invasive meningococcal disease (IMD) in England. Children born since 01 July 2015 who developed MenB disease between 01 September 2015 and 31 August 2019 (four surveillance years) were included in the analysis., Results: There were 276 children with laboratory-confirmed MenB disease, including 36 infants who were too young for vaccination, 59 who were eligible for one 4CMenB dose, 104 for two doses and 77 for 3 doses before they developed MenB disease. Prior to developing MenB disease, there were 59 opportunities for vaccination with two 4CMenB doses in 48/104 (46.5%) eligible infants and 41 opportunities in 28/77 (36.6%) children aged ≥ 1 year who were under-immunised. A schedule with a shorter interval at 8 and 12 weeks of age, compared to the current schedule at 8 and 16 weeks, had the potential to offer an additional 4CMenB dose to 35/58 infants (58.6%) who developed MenB disease between 10 and 18 weeks of age., Conclusions: A high proportion of infants and toddlers with laboratory-confirmed MenB disease had not received their scheduled 4CMenB vaccine prior to developing MenB disease. An infant priming schedule with a shorter interval of 4 weeks has the potential to provide earlier protection against MenB disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

Background: The incidence of invasive meningococcal disease in the UK decreased by approximately four times from 1999 to 2014, with reductions in serogroup C and serogroup B disease. Lower serogroup C invasive meningococcal disease incidence was attributable to implementation of the meningococcal serogroup C conjugate vaccine in 1999, through direct and indirect protection, but no vaccine was implemented against serogroup B disease. UK Meningococcal Carriage surveys 1-3 (UKMenCar1-3), conducted in 1999, 2000, and 2001, were essential for understanding the impact of vaccination. To investigate the decline in invasive meningococcal disease incidence, we did a large oropharyngeal carriage survey in 2014-15, immediately before the changes to meningococcal vaccines in the UK national immunisation schedule., Methods: UKMenCar4 was a cross-sectional survey in adolescents aged 15-19 years who were enrolled from schools and colleges geographically local to one of 11 UK sampling centres between Sept 1, 2014, and March 30, 2015. Participants provided an oropharyngeal swab sample and completed a questionnaire on risk factors for carriage, including social behaviours. Samples were cultured for putative Neisseria spp, which were characterised with serogrouping and whole-genome sequencing. Data from this study were compared with the results from the UKMenCar1-3 surveys (1999-2001)., Findings: From the 19 641 participants (11 332 female, 8242 male, 67 not stated) in UKMenCar4 with culturable swabs and completed risk-factor questionnaires, 1420 meningococci were isolated, with a carriage prevalence of 7·23% (95% CI 6·88-7·60). Carriage prevalence was substantially lower in UKMenCar4 than in the previous surveys: carriage prevalence was 16·6% (95% CI 15·89-17·22; 2306/13 901) in UKMenCar1 (1999), 17·6% (17·05-18·22; 2873/16 295) in UKMenCar2 (2000), and 18·7% (18·12-19·27; 3283/17 569) in UKMenCar3 (2001). Carriage prevalence was lower for all serogroups in UKMenCar4 than in UKMenCar1-3, except for serogroup Y, which was unchanged. The prevalence of carriage-promoting social behaviours decreased from 1999 to 2014-15, with individuals reporting regular cigarette smoking decreasing from 2932 (21·5%) of 13 650 to 2202 (11·2%) of 19 641, kissing in the past week from 6127 (44·8%) of 13 679 to 7320 (37·3%) of 19 641, and attendance at pubs and nightclubs in the past week from 8436 (62·1%) of 13 594 to 7662 (39·0%) of 19 641 (all p<0·0001)., Interpretation: We show that meningococcal carriage prevalence in adolescents sampled nationally during a low incidence period (2014-15) was less than half of that in an equivalent population during a high incidence period (1999-2001). Disease and carriage caused by serogroup C was well controlled by ongoing vaccination. The prevalence of behaviours associated with carriage declined, suggesting that public health policies aimed at influencing behaviour might have further reduced disease., Funding: Wellcome Trust, UK Department of Health, and National Institute for Health Research., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: A 15-valent pneumococcal conjugate vaccine (PCV15) aims to protect against serotype 22F and 33F in addition to the serotypes within the 13-valent PCV (PCV13) which was introduced to the UK childhood immunisation programme in April 2010. Little is known about the specific epidemiology, clinical features or outcomes of invasive pneumococcal disease (IPD) due to these two serotypes., Methods: Public Health England (PHE) conducts enhanced IPD surveillance in England. Hospital laboratories routinely submit invasive pneumococcal isolates to PHE for serotyping and enhanced clinical information is collected through questionnaires sent to general practitioners. IPD due to serotypes 22F and 33F diagnosed during 2014/15-2018/19 were compared with IPD due to PCV13 serotypes and remaining serotypes., Results: In total, 25,415 isolates (93.4%) were serotyped and questionnaires were completed for 22,097 (86.9%) cases. Serotype 22F was responsible for 1,788 (7.0%) and serotype 33F for 893 (3.5%) cases compared to 19.9% (n = 5,047) for PCV13 and 69.6% (n = 17,687) for the remaining serotypes. IPD incidence increased for both serotypes since 2005/06, especially in older adults, but plateaued after PCV13 introduction. Comorbidity prevalence was 68.7% (n = 1,037) for serotype 22F and 67.2% (n = 505) for serotype 33F, with invasive pneumonia being the most common clinical presentation 1,067/1,482; 72.0%, and 514/755; 68.1%, respectively. There were 3,617 deaths within 30 days of disease onset, including 236 (CFR, 15.4%) among 22F, 128 (CFR, 16.5%) among 33F and 21.3% (925/4,350) among PCV13-type IPD cases. When compared with PCV13-type IPD, serotype 22F (aOR 0.58, 95%CI 0.49-0.68, p < 0.001) and 33F (aOR 0.73, 95%CI 0.59-0.91, p = 0.004) were independently associated with lower odds of death. The major circulating sequence types (STs) in 22F (ST 433, ST698) and 33F (ST717, ST100, ST673) were not associated with an increased risk of death compared to the other STs., Conclusions: Serotype 22F and 33F-type IPD are associated with a lower risk of death compared to PCV13-type, with those presenting with septicaemia more likely to have a fatal outcome compared to pneumonia. PCV15 has the potential to prevent up to an additional 10% of IPD cases in England., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The Immunisation and Countermeasures Division has provided vaccine manufacturers with post-marketing surveillance reports on pneumococcal and meningococcal infection which the companies are required to submit to the UK Licensing authority in compliance with their Risk Management Strategy. A cost recovery charge is made for these reports. SNL performs contract research on behalf of St. George’s University of London (SGUL) and Public Health England (PHE) for pharmaceutical companies but receives no personal remuneration., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Pneumococcal conjugate vaccines (PCVs) are highly effective in preventing invasive and non-invasive pneumococcal infections in all age groups through a combination of direct and indirect protection. In many industrialised countries with established PCV programmes, the maximum benefit of the PCV programme has already been achieved, with most cases now due to non-PCV serotypes. On Jan 1, 2020, the UK changed its childhood pneumococcal immunisation programme from a two-dose infant priming schedule with the 13-valent PCV at 8 and 16 weeks after birth, to a single priming dose at 12 weeks after birth, while retaining the 12-month booster. This decision was made after reviewing the evidence from surveillance data, clinical trials, epidemiological analyses, vaccine effectiveness estimates, and modelling studies to support the reduced schedule. In this Review, we summarise the epidemiology of pneumococcal disease in the UK, the evidence supporting the decision to implement a reduced schedule, and the national and global implications of the proposed schedule., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

High incidence of childhood invasive pneumococcal disease (IPD) in the US declined steeply after 7-valent pneumococcal conjugate vaccine (PCV7) introduction, outweighing reductions observed elsewhere. We re-analysed aggregate published data and compared pre- and post-PCV IPD-incidence in different countries to explore PCV impact on hospitalised and outpatient IPD separately. The proportion of hospitalised IPD cases was consistently high (>80%) in England&Wales, Finland, the Netherlands, and Quebec/Canada, but only 32% in the US before PCV introduction, increasing to 69% during the PCV era. In the US, a higher reduction in outpatient IPD incidence (94% in 2015 versus 1998-99) was observed compared to hospitalised IPD (79%); a 51% reduction in the non-PCV13-type IPD incidence among outpatient cases was estimated compared to a >2-fold increase for hospitalised cases. After stratification by hospitalization status, PCV programmes resulted in similar impact and serotype replacement in hospitalised IPD in US when compared to other countries., Competing Interests: Declaration of Competing Interest AAP and MT report grants from GlaxoSmithKline, Pfizer, and Sanofi to the Finnish Institute for Health and Welfare for research projects in which they are investigators. PDW received research grants from GSK, Pfizer and Sanofi. SNL performs contract work on behalf of St. George’s University of London for pharmaceutical companies, including vaccine manufacturers but does not receive any personal remuneration. EAMS reports grant from GlaxoSmithKline and Pfizer to the University Medical Center Utrecht for research projects in which she was an investigator. All other authors declare no competing interests., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

Background: Understanding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and transmission in educational settings is crucial for ensuring the safety of staff and children during the COVID-19 pandemic. We estimated the rate of SARS-CoV-2 infection and outbreaks among staff and students in educational settings during the summer half-term (June-July, 2020) in England., Methods: In this prospective, cross-sectional analysis, Public Health England initiated enhanced national surveillance in educational settings in England that had reopened after the first national lockdown, from June 1 to July 17, 2020. Educational settings were categorised as early years settings (<5-year-olds), primary schools (5-11-year-olds; only years 1 and 6 allowed to return), secondary schools (11-18-year-olds; only years 10 and 12), or mixed-age settings (spanning a combination of the above). Further education colleges were excluded. Data were recorded in HPZone, an online national database for events that require public health management. RT-PCR-confirmed SARS-CoV-2 event rates and case rates were calculated for staff and students, and direction of transmission was inferred on the basis of symptom onset and testing dates. Events were classified as single cases, coprimary cases (at least two confirmed cases within 48 h, typically within the same household), and outbreaks (at least two epidemiologically linked cases, with sequential cases diagnosed within 14 days in the same educational setting). All events were followed up for 28 days after educational settings closed for the summer holidays. Negative binomial regression was used to correlate educational setting events with regional population, population density, and community incidence., Findings: A median of 38 000 early years settings (IQR 35 500-41 500), 15 600 primary schools (13 450-17 300), and 4000 secondary schools (3700-4200) were open each day, with a median daily attendance of 928 000 students (630 000-1 230 000) overall. There were 113 single cases of SARS-CoV-2 infection, nine coprimary cases, and 55 outbreaks. The risk of an outbreak increased by 72% (95% CI 28-130) for every five cases per 100 000 population increase in community incidence (p<0·0001). Staff had higher incidence than students (27 cases [95% CI 23-32] per 100 000 per day among staff compared with 18 cases [14-24] in early years students, 6·0 cases [4·3-8·2] in primary schools students, and 6·8 cases [2·7-14] in secondary school students]), and most cases linked to outbreaks were in staff members (154 [73%] staff vs 56 [27%] children of 210 total cases). Probable direction of transmission was staff to staff in 26 outbreaks, staff to student in eight outbreaks, student to staff in 16 outbreaks, and student to student in five outbreaks. The median number of secondary cases in outbreaks was one (IQR 1-2) for student index cases and one (1-5) for staff index cases., Interpretation: SARS-CoV-2 infections and outbreaks were uncommon in educational settings during the summer half-term in England. The strong association with regional COVID-19 incidence emphasises the importance of controlling community transmission to protect educational settings. Interventions should focus on reducing transmission in and among staff., Funding: Public Health England., (Crown Copyright © 2021 Published by Elsevier Ltd. All rights reserved.)

Background: The 7-valent pneumococcal conjugate vaccine (PCV7) was introduced into the UK childhood immunisation programme in 2006 and replaced with a 13-valent vaccine (PCV13) in 2010. Both vaccines led to rapid declines in vaccine-serotype invasive pneumococcal disease (IPD). Here, we assessed the long-term vaccine-effectiveness (VE) of both vaccines in England., Methods: Public Health England conducts enhanced national surveillance of IPD in England. VE against IPD was estimated using vaccine-serotype IPD cases and non-vaccine serotype IPD controls among vaccine-eligible children from September 2006 to June 2018 (the Broome method)., Results: Vaccine history was available for 3421 IPD cases, including 1299 due to the additional PCV13 serotypes and the PCV13-related serotype 6C, 274 PCV7 serotypes and 1848 non-PCV13 serotypes. For the complete 2 + 1 schedule, both PCV7 and PCV13 showed high effectiveness against PCV7 serotypes with a combined VE of 92.0% (95%CI, 81.7-96.7). For the 2 + 1 schedule, PCV13 VE against the additional PCV13 serotypes plus 6C was 73.7% (31.1-89.9) compared to 90.0% (75.3 - 96.0) for PCV7 against PCV7 serotypes, although PCV13 VE increased to 84.8% (58.7-94.4) if serotype 3 was excluded; all 36 eligible serotype 3 IPD cases were fully-vaccinated with PCV13. Case numbers were low in older ages but there was evidence of waning, which was significant for serotype 19A for which there were sufficient numbers of cases for analysis., Conclusions: PCVs are highly effective in preventing vaccine-serotype IPD except for serotype 3 which has been increasing in incidence. Serotype 19A IPD has also persisted, likely due to a slightly lower VE and/or more rapid waning of protection., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The epidemiology of invasive meningococcal disease (IMD) is constantly changing as new strains are introduced into a population and older strains are removed through vaccination, population immunity or natural trends. Consequently, the clinical disease associated with circulating strains may also change over time. In England, IMD incidence has declined from 1.8/100,000 in 2010/2011 to 1.1/100,000 in 2013/2014, with a small increase in 2014/2015 to 1.3/100,000. Between 01 January 2011 and 30 June 2015, MenB was responsible for 73.0% (n = 2489) of 3411 laboratory-confirmed IMD cases, followed by MenW (n = 371, 10.9%), MenY (n = 373, 10.9%) and MenC (n = 129, 3.8%); other capsular groups were rare (n = 49, 1.4%). Detailed questionnaires were completed for all 3411 laboratory-confirmed cases. Clinical presentation varied by capsular group and age. Atypical presentations were uncommon (244/3411; 7.2%), increasing from 1.2% (41/3411) in children to 3.5% (120/3411) in older adults. Known IMD risk factors were rare (18/3411; 0.5%) and included complement deficiency (n = 11), asplenia (n = 6) or both (n = 1). Nearly a third of cases required intensive care (1069/3411; 31.3%), with rates highest in adults. The 28-day CFR was 6.9% (n = 237), with the lowest rates in 0-14 year-olds (85/1885, 4.5%) and highest among 85+ year-olds (30/94, 31.9%). These observations provide a useful baseline for the current burden of IMD in a European country with enhanced national surveillance., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Pneumococcal conjugate vaccines (PCVs) have substantially reduced the incidence of invasive pneumococcal disease caused by vaccine serotypes; however, replacement disease with non-PCV serotypes remains a concern. We describe the population effect of the seven-valent and 13-valent PCVs (PCV7 and PCV13) on invasive pneumococcal disease in England and Wales., Methods: Using national invasive pneumococcal disease surveillance data for 2016/17, we compared incidence rate ratios (IRRs) against pre-PCV13 (2008/09-2009/10) and pre-PCV7 (2000/01-2005/06) baselines. We also estimated the number of invasive pneumococcal disease cases prevented since the introduction of PCVs., Findings: In 2016/17, overall invasive pneumococcal disease incidence (9·87 cases per 100 000; 5450 cases) across all age groups was 37% lower (IRR 0·63, 95% CI 0·60-0·65) than pre-PCV7 incidence (14·79 per 100 000; 8167 cases) and 7% lower (0·93; 0·89-0·97) than pre-PCV13 incidence (10·13 per 100 000; 5595 cases). By 2016/17, PCV7-type invasive pneumococcal disease incidence across all age groups had decreased by 97% (0·24 per 100 000; 0·03, 0·02-0·04) compared with the pre-PCV7 period, whereas additional PCV13-type invasive pneumococcal disease decreased by 64% (1·66 per 100 000; 0·36, 0·32-0·40) since the introduction of PCV13. Invasive pneumococcal disease incidence due to non-PCV13 serotypes doubled (7·97 per 100 000; 1·97, 1·86-2·09) since the introduction of PCV7, and accelerated since 2013/14-especially serotypes 8, 12F, and 9N, which were responsible for more than 40% of invasive pneumococcal disease cases by 2016/17. Invasive pneumococcal disease incidence in children younger than 5 years remained stable since 2013/14, with nearly all replacement disease occurring in adults. We estimated 38 366 invasive pneumococcal disease cases were prevented in the 11 years since the introduction of PCV7., Interpretation: Both PCV7 and PCV13 have had a major effect in reducing the burden of invasive pneumococcal disease in England and Wales; however, rapid increases in some non-PCV13 serotypes are compromising the benefits of the programme., Funding: Public Health England., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: In September 2015, the United Kingdom became the first country to introduce the multicomponent group B meningococcal vaccine (4CMenB) into a national infant immunisation programme. In early clinical trials 51-61% of infants developed a fever when 4CMenB was administered with other routine vaccines. Whilst administration of prophylactic paracetamol is advised, up to 3% of parents may seek medical advice for fever following vaccination. We used research-level general practitioner consultations to identify any increase in attendances for all-cause fever in vaccine-eligible infants following 4CMenB introduction in England., Methods: Consultations for infant all-cause fever in the year following the vaccine introduction were identified from The Phoenix Partnership (TPP) ResearchOne general practice database using Read (CTV3) codes. Average daily consultation rates and incidence rate ratios (IRRs) were calculated for vaccine-eligible age groups and compared to the two years preceding vaccine introduction. The difference between pre- and post-vaccine all-cause fever consultations was estimated., Results: All-cause fever consultations in vaccine-eligible 7-10 week olds were 1.6-fold higher (IRR, 1.58; 95% CI, 1.22-2.05) compared to the two previous years and 1.5-fold higher (IRR 1.47; 95% CI, 1.17-1.86) in 15-18 week-olds. There were no significant differences in 0-6 or 11-14 week-olds. Applying the difference between pre- and post-vaccine consultation rates to the 4CMenB vaccine-eligible age groups across England estimated 1825 additional fever consultations in the year following 4CMenB introduction., Conclusions: We found a small but significant difference in all-cause fever consultation rates in vaccine-eligible infants who would have received 4CMenB with other vaccines., (Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.)

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., (Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.)

Background: The UK introduced 4CMenB-a multicomponent vaccine against serogroup B meningococcal disease-into the national infant immunisation programme in September, 2015. The Meningococcal Antigen Typing System (MATS) was used to estimate coverage by 4CMenB of invasive meningococcal group B isolates obtained during 2007-08 in England and Wales (MATS coverage). We aimed to repeat the MATS survey for invasive meningococcal group B isolates obtained during 2014-15, before 4CMenB introduction; compare strain coverage between 2007-08 and 2014-15; and investigate associations between MATS coverage, age, region, and disease outcomes., Methods: Invasive serogroup B meningococcal isolates from cases in England, Wales, and Northern Ireland during 2014-15 were assayed using MATS and compared with 2007-08 data. MATS coverage was assessed by geographical region and age group. Clinical characteristics, risk factors, and outcomes were assessed according to MATS coverage for 2014-15 English cases., Findings: In 2014-15, 165 of 251 (66%; 95% CI 52-80) meningococcal group B isolates were estimated by MATS to be covered by 4CMenB, compared with 391 of 535 (73%; 95% CI 57-87) in 2007-08. The proportion of MATS-positive isolates with one vaccine antigen increased from 23% (122 of 535) in 2007-08 to 31% (78 of 251) in 2014-15, whereas the proportion with more than one antigen fell from 50% (269 of 535) to 35% (87 of 251). This effect reflected changes in circulating strains, particularly ST-269 clonal complex strains. MATS coverage increased with age, varied by geographical region, and was associated with more severe disease., Interpretation: In 2014-15, two-thirds of meningococcal group B isolates were predicted to be covered by 4CMenB. Temporal changes in MATS coverage underscore the need for continued monitoring of antigen expression and diversity, particularly in countries with 4CMenB programmes., Funding: Public Health England, GlaxoSmithKline., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Children who develop invasive Haemophilus influenzae serotype b (Hib) disease after immunisation with a highly-effective conjugate vaccine are more likely to have been infected with Hib strains possessing multiple copies of the capsulation locus. Using a recently-validated serum bactericidal antibody (SBA) assay, we tested convalescent sera from 127 Hib vaccine failure cases against clinical Hib strains expressing 1-5 copies of the capsulation locus. SBA titres correlated weakly with anti-capsular IgG antibody concentrations and there was no association between SBA geometric mean titres and number of capsulation locus copies. After infection, children with Hib vaccine failure were equally protected against Hib strains with 1-5 copies of the capsulation locus., (Copyright © 2016. Published by Elsevier Ltd.)

Background: A recently-licensed 10-valent pneumococcal conjugate vaccine (PHiD-CV; Synflorix, GSK) uses Protein D from Haemophilus influenzae as a carrier protein. PHiD-CV therefore has the potential to provide additional protection against nontypeable H. influenzae (NTHi). NTHi frequently causes respiratory tract infections and is associated with significant morbidity and mortality worldwide and there is currently no vaccine., Methods: We developed mouse models of NTHi infection and influenza/NTHi superinfection. Mice were immunized with PHiD-CV, heat-killed NTHi, or a 13-valent pneumococcal conjugate vaccine that did not contain Protein D (PCV13; Prevenar, Pfizer) and then infected intranasally with NTHi., Results: Infection with NTHi resulted in weight loss, inflammation and airway neutrophilia. In a superinfection model, prior infection with pandemic H1N1 influenza virus (strain A/England/195/2009) augmented NTHi infection severity, even with a lower bacterial challenge dose. Immunization with PHiD-CV produced high levels of antibodies that were specific against Protein D, but not heat-killed NTHi. Immunization with PHiD-CV led to a slight reduction in bacterial load, but no change in disease outcome., Conclusions: PHiD-CV induced high levels of Protein D-specific antibodies, but did not augment pulmonary clearance of NTHi. We found no evidence to suggest that PHiD-CV will offer added benefit by preventing NTHi lung infection., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The 13-valent pneumococcal conjugate vaccine (PCV13) protects against key serotypes that increased after routine immunisation with the seven-valent vaccine (PCV7), but its potential for herd protection and serotype replacement is uncertain. The aim of this study was to analyse the effect of the 13-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in England and Wales 4 years after its introduction., Methods: We used a national dataset of electronically reported and serotyped invasive pneumococcal disease cases in England and Wales to estimate incidence rate ratios (IRRs) for vaccine and non-vaccine type invasive pneumococcal disease between July, 2013, and June, 2014, versus the pre-PCV13 and pre-PCV7 baseline. Incidence rates were corrected for missing serotype data and changes in surveillance sensitivity over time. An over-dispersed Poisson model was used to estimate IRRs and confidence intervals., Findings: Incidence of invasive pneumococcal disease in the epidemiological year 2013/14 decreased by 32% compared with the pre-PCV13 baseline (incidence 10·14 per 100,000 in 2008-10 vs 6·85 per 100,000 in 2013/14; IRR 0·68, 95% CI 0·64-0·72). This was due to an 86% reduction of the serotypes covered by PCV7 (1·46 vs 0·20 per 100,000; IRR 0·14, 0·10-0·18) and a 69% reduction of the additional six serotypes covered by PCV13 (4·48 vs 1·40 per 100,000; IRR 0·31, 0·28-0·35). When compared with the pre-PCV7 baseline, there was a 56% overall reduction in invasive pneumococcal disease (15·63 vs 6·85 per 100,000; IRR 0·44, 95% CI 0·43-0·47). Compared with the pre-PCV13 baseline, the incidence of non-PCV13 serotypes increased (incidence all ages 4·19 vs 5·25 per 100,000; IRR 1·25, 95% CI 1·17-1·35) due to increases across a broad range of serotypes in children younger than 5 years and in people aged 45 years or more. In children younger than 5 years, incidence of non-PCV13 serotypes in 2013/14 was higher than in 2012/13 (age <2 years: 12·03 vs 10·83 per 100,000; age 2-4 years: 4·08 vs 3·63 per 100,000)., Interpretation: 8 years of PCV use in England and Wales has reduced the overall incidence of invasive pneumococcal disease by more than 50%. The herd protection induced by PCV7 is continuing, and similar indirect protection is occurring from the additional serotypes covered by PCV13. There is, however, evidence of increasing invasive pneumococcal disease due to non-PCV13 serotypes, particularly in children younger than 5 years in 2014. If this increase continues, the maximum benefit of the PCV13 programme in children might already have been achieved., Funding: Public Health England funds national surveillance of invasive pneumococcal disease., (Copyright © 2015 Waight et al. Open Access article distributed under the terms of CC BY-NC-ND. Published by Elsevier Ltd.. All rights reserved.)

An open, non-randomised study was undertaken in England during 2011-12 to evaluate vaccine antibody responses in infants after completion of the routine primary infant immunisation schedule, which included two doses of meningococcal group C (MenC) conjugate (MCC) vaccine at 3 and 4 months. Any of the three licensed MCC vaccines could be used for either dose, depending on local availability. Healthy term infants registered at participating general practices (GPs) in Hertfordshire and Gloucestershire, UK, were recruited prospectively to provide a single blood sample four weeks after primary immunisation, which was administered by the GP surgery. Vaccination history was obtained at blood sampling. MenC serum bactericidal antibody (SBA) and IgG antibodies against Haemophilus influenzae b (Hib), pertussis toxin (PT), diphtheria toxoid (DT), tetanus toxoid (TT) and thirteen pneumococcal serotypes were analysed according to MCC vaccines received. MenC SBA responses differed significantly (P<0.001) according to MCC vaccine schedule as follows: MenC SBA geometric mean titres (GMTs) were significantly lower in infants receiving a diphtheria cross-reacting material-conjugated MCC (MCC-CRM) vaccine followed by TT-conjugated MCC (MCC-TT) vaccine (82.0; 95% CI, 39-173; n=14) compared to those receiving two MCC-CRM (418; 95% CI, 325-537; n=82), two MCC-TT (277; 95% CI, 223-344; n=79) or MCC-TT followed by MCC-CRM (553; 95% CI, 322-949; n=18). The same group also had the lowest Hib geometric mean concentrations (0.60 μg/mL, 0.27-1.34) compared to 1.85 μg/mL (1.23-2.78), 2.86 μg/mL (2.02-4.05) and 4.26 μg/mL (1.94-9.36), respectively. Our results indicate that MCC vaccines with different carrier proteins are not interchangeable. When several MCC vaccines are available, children requiring more than one dose should receive MCC vaccines with the same carrier protein or, alternatively, receive MCC-TT first wherever possible., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Prior to routine immunisation, Haemophilus influenzae serotype b (Hib) was a major cause of serious bacterial infections, particularly in young children. In the United Kingdom, introduction of the Hib conjugate vaccine into the national childhood immunisation schedule has led to a sustained decline in invasive Hib disease across all age-groups. Evaluation of the immune response to Hib conjugate vaccines involves measurement of serum IgG antibodies against the capsular polyribosyl-ribitol-phosphate (PRP) polysaccharide by enzyme-linked immunosorbent assay (ELISA), with accepted short-term and long-term protective thresholds of ≥0.15μg/mL and ≥1.0μg/mL, respectively. These levels were derived by passive immunisation or immunisation with pure polysaccharide, and their relevance for protection following immunisation with conjugate vaccines remains unclear. This study aimed to modify and optimise a serum bactericidal antibody (SBA) assay to evaluate the functional activity of Hib antibodies generated following Hib conjugate vaccination. Validation of the Hib SBA assay was deemed acceptable for all assay parameters tested. A strong correlation between anti-PRP IgG concentrations and SBA titres was observed in vaccinated adults (r=0.81), as well as infants after primary immunisation at 2, 3, and 4 months (r=0.635) and after the 12-month booster (r=0.746). The assay identified some children with high anti-PRP IgG but low SBA activity and vice versa. The predictive protective SBA titre corresponding to a post-booster anti-PRP IgG of 1.0μg/mL was 8. Thus, the optimised Hib SBA assay was specific and reproducible and correlated with anti-PRP IgG. Such assays may have a role in evaluating immune responses to conjugate vaccines in addition to measuring capsular antibodies., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Efficacy of the 13-valent pneumococcal conjugate vaccine (PCV13) was inferred before licensure from an aggregate correlate of protection established for the seven-valent vaccine (PCV7). We did a postlicensure assessment of serotype-specific vaccine effectiveness and immunogenicity in England, Wales, and Northern Ireland to derive the correlates of protection for individual serotypes., Methods: We assessed vaccine effectiveness against invasive pneumococcal disease using the indirect cohort method. We measured serotype-specific IgG concentration in infants after they were given two priming doses of PCV7 (n=126) or PCV13 (n=237) and opsonophagocytic antibody titre from a subset of these infants (n=100). We derived correlates of protection by relating percentage protection to a threshold antibody concentration achieved by an equivalent percentage of infants. We used multivariable logistic regression to estimate vaccine effectiveness and reverse cumulative distribution curves to estimate correlates of protection., Findings: For the 706 cases of invasive pneumococcal disease included in the study, PCV13 vaccine effectiveness after two doses before age 12 months or one dose from 12 months was 75% (95% CI 58-84). Vaccine effectiveness was 90% (34-98) for the PCV7 serotypes and 73% (55-84) for the six additional serotypes included in PCV13. Protection was shown for four of the six additional PCV13 serotypes (vaccine effectiveness for serotype 3 was not significant and no cases of serotype 5 infection occurred during the observation period). The vaccine effectiveness for PCV13 and PCV7 was lower than predicted by the aggregate correlate of protection of 0·35 μg/mL used during licensing. Calculated serotype-specific correlates of protection were higher than 0·35 μg/mL for serotypes 1, 3, 7F, 19A, 19F, and lower than 0·35 μg/mL for serotypes 6A, 6B, 18C, and 23F. Opsonophagocytic antibody titres of 1 in 8 or higher did not predict protection., Interpretation: PCV13 provides significant protection for most of the vaccine serotypes. Although use of the aggregate correlate of protection of 0·35 μg/mL has enabled the licensing of effective new PCVs, serotype-specific correlates of protection vary widely. The relation between IgG concentration after priming and long-term protection needs to be better understood., Funding: Public Health England and UK Department of Health Research and Development Directorate., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background/aims: In April 2010 the 7-valent pneumococcal conjugate vaccine (PCV7) was replaced by the 13-valent PCV. We investigated pneumococcal carriage in children eligible for PCV7 or PCV13 and their household contacts., Methods: Eligible families in Hertfordshire and Gloucester were identified and a nasopharyngeal swab obtained from consenting household members between July 2012 and March 2013. Samples were cultured for Streptococcus pneumoniae and serotyped by standard methods. For each serotype the ratio of its prevalence in invasive pneumococcal disease (IPD) to its carriage prevalence (case:carrier ratio, CCR) was calculated. Results were compared with previous carriage studies in 2001/2002 and 2008/2009, before and after PCV7 introduction., Results: 217 households were included. Among <5-year olds 47.7% (95% confidence interval 41.8-53.5) were carrying a pneumococcus compared with 51.0% (95% CI: 44.0-58.0) in 2008/2009 and 48.4% (95% CI: 44.1-52.7) in 2001/2002. The odds of carrying a PCV7 serotype was significantly reduced in 2008/2009 (0.07, 95% CI: 0.03-0.16) and 2012/2013 (0.01 95% CI: 0.00-0.07) relative to 2001/2002, while the odds of carrying any of the extra six PCV13 serotypes increased after PCV7 introduction (1.38, 95%CI: 0.73-2.59) but declined significantly after PCV13 introduction (0.05, 95%CI: 0.01-0.37). The CCRs for the frequently carried serotypes were relatively low, with the highest CCR observed for serotypes 7F, 19A, 3, 8, and 33F. Across the three carriage studies, CCR estimates were stable for nearly all serotypes., Conclusion: Carriage of additional PCV13 serotypes has rapidly reduced post-PCV13 introduction in both vaccinated and unvaccinated individuals with a continued decline in transmission of PCV7 serotypes. Carriage rates in children remain unchanged, but the low CCRs of replacing serotypes would be expected to further reduce overall IPD across all age groups., (Copyright © 2014. Published by Elsevier Ltd.)

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., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Introduction: In the UK, primary varicella is usually a mild infection in children, but can cause serious illness in susceptible pregnant women and adults. The UK Joint Committee on Vaccination and Immunisation is considering an adolescent varicella vaccination programme. Cost-effectiveness depends upon identifying susceptibles and minimising vaccine wastage, and chickenpox history is one method to screen for eligibility. To inform this approach, we estimated the proportion of adolescents with varicella antibodies by reported chickenpox history., Methods: Recruitment occurred through secondary schools in England from February to September 2012. Parents were asked about their child's history of chickenpox, explicitly setting the context in terms of the implications for vaccination. 247 adolescents, whose parents reported positive (120), negative (77) or uncertain (50) chickenpox history provided oral fluid for varicella zoster virus-specific immunoglobulin-G (VZV-IgG) testing., Results: 109 (90.8% [85.6-96.0%]) adolescents with a positive chickenpox history, 52 (67.5% [57.0-78.1%]) with a negative history and 42 (84.0% [73.7-94.3%]) with an uncertain history had VZV-IgG suggesting prior infection. Combining negative and uncertain histories, 74% had VZV-IgG (best-case). When discounting low total-IgG samples and counting equivocals as positive (worst-case), 84% had VZV-IgG. We also modelled outcomes by varying the negative predictive value (NPV) for the antibody assay, and found 74-87% under the best-case and 84-92% under the worst-case scenario would receive vaccine unnecessarily as NPV falls to 50%., Conclusion: Reported chickenpox history discriminates between varicella immunity and susceptibility in adolescents, but significant vaccine wastage would occur if this approach alone were used to determine vaccine eligibility. A small but important proportion of those with positive chickenpox history would remain susceptible. These data are needed to determine whether reported history, with or without oral fluid testing in those with negative and uncertain history, is sufficiently discriminatory to underpin a cost-effective adolescent varicella vaccination programme., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The epidemiology of invasive meningococcal disease continues to change rapidly, even in the three years since the first Meningococcal Exchange Meeting in 2008. Control of disease caused by serogroup C has been achieved in countries that have implemented meningococcal C or quadrivalent meningococcal ACWY conjugate vaccines. Initiation of mass immunization programs with meningococcal A conjugate vaccines across the meningitis belt of Africa may lead to the interruption of cyclical meningococcal epidemics. A meningococcal B vaccination program in New Zealand has led to a decreased incidence of high rates of endemic serogroup B disease. Increases in serogroup Y disease have been observed in certain Nordic countries which, if they persist, may require consideration of use of a multiple serogroup vaccine. The imminent availability of recombinant broadly protective serogroup B vaccines may provide the tools for further control of invasive meningococcal disease in areas where serogroup B disease predominates. Continued surveillance of meningococcal disease is essential; ongoing global efforts to improve the completeness of reporting are required., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

A number of meningococcal vaccines have either been recently licensed or are in late-phase clinical trials. To inform national vaccination policy, it is important to define the burden of disease and the potential impact of any new vaccine. This study describes the epidemiology of invasive meningococcal disease across all age groups in England and Wales for recent epidemiological years between 2006 and 2010. The Health Protection Agency (HPA) conducts enhanced national meningococcal surveillance through a combination of clinical and laboratory reporting. Between 2006/07 and 2010/11, the average annual incidence of invasive meningococcal disease across all age groups was 2.0/100,000. Capsular group B (MenB) accounted for 87% (4777/5471) cases, with an overall incidence of 1.8/100,000. The highest MenB incidence observed among infants (36.2/100,000) where cases increased from birth to 5 months of age then gradually declined. An annual average of 245 MenB cases occurred in infants (135 in those aged ≤ 6 months) representing 26% (and 14%) of all MenB cases, respectively. After infancy, MenB rates declined until the age of 12 years, rising to a second smaller peak at 18 years. MenB case fatality ratio (CFR) was 5.2% (247/4777 cases) overall and was highest among ≥ 65 year-olds (28/161; 17.4%). The largest number of deaths (n=125), however, occurred among <5 year-olds. Clonal complexes cc269 and cc41/44 each accounted for around a third of cases across the age groups. Other capsular groups rarely caused invasive disease, although capsular group Y (MenY) cases more than doubled from 35 in 2006/07 to 86 in 2010/11. Thus, universal meningococcal vaccination with an effective broad-spectrum formulation has potential to prevent most disease, particularly if the vaccine is immunogenic early in infancy, but, there is currently little justification for routine quadrivalent ACWY conjugate vaccination in the UK, although the increase in MenY disease warrants continued surveillance., (Copyright © 2012 Elsevier Ltd. All rights reserved.)