Search

Reported mpox cases in England continued at a low but steady frequency during 2023. Of 137 cases reported in 2023, approximately half were acquired overseas and half were in vaccinated persons. Estimated effectiveness of 2-dose vaccine was 80%, and no vaccinated mpox patient was hospitalized.

Objective To assess the feasibility of identifying markers of health-seeking behaviour and healthcare access in UK electronic health records (EHR), for identifying populations at risk of poor health outcomes and adjusting for confounding in epidemiological studies.Design Cross-sectional observational study using the Clinical Practice Research Datalink Aurum prelinked to Hospital Episode Statistics.Setting Individual-level routine clinical data from 13 million patients across general practices (GPs) and secondary data in England.Participants Individuals aged ≥66 years on 1 September 2019.Main outcome measures We used the Theory of Planned Behaviour (TPB) model and the literature to iteratively develop criteria for markers selection. Based on this we selected 15 markers: those that represented uptake of public health interventions, markers of active healthcare access/use and markers of lack of access/underuse. We calculated the prevalence of each marker using relevant lookback periods prior to the index date (1 September 2019) and compared with national estimates. We assessed the correlation coefficients (phi) between markers with inferred hierarchical clustering.Results We included 1 991 284 individuals (mean age: 75.9 and 54.0% women). The prevalence of markers ranged from

ABSTRACTMeasurement of IgG antibodies against group B streptococcus (GBS) capsular polysaccharide (CPS) by use of a standardized and internationally accepted multiplex immunoassay is important for the evaluation of candidate maternal GBS vaccines in order to compare results across studies. A standardized assay is also required if serocorrelates of protection against invasive GBS disease are to be established in infant sera for the six predominant GBS serotypes since it would permit the comparison of results across the six serotypes. We undertook an interlaboratory study across five laboratories that used standardized assay reagents and protocols with a panel of 44 human sera to measure IgG antibodies against GBS CPS serotypes Ia, Ib, II, III, IV, and V. The within-laboratory intermediate precision, which included factors like the lot of coated beads, laboratory analyst, and day, was generally below 20% relative standard deviation (RSD) for all six serotypes, across all five laboratories. The cross-laboratory reproducibility was

ABSTRACTAcute disseminated encephalomyelitis (ADEM) has been identified as an Adverse Event of Special Interest in the COVID-19 vaccine programme due to its long-standing temporal association with a wide range of other vaccines. Case reports of ADEM shortly following COVID−19 vaccination have now been documented. There were 217 ADEM admissions in 215 individuals in the period 8th December 2020 to 31st March 2023. An increased risk of ADEM following the first dose of ChAdOx1 vaccine was observed (relative incidence (RI) = 3.13, 95% Confidence Interval (CI) [1.56–6.25]) with a vaccine attributable risk of 0.39 per million doses. When doses 1 and 2 were combined this increased risk remained just significant (1.96 [95%CI 1.01–3.82]). No significant increased risk was observed with any other vaccine or dose. This small, elevated risk after the first dose of ChAdOx1-S vaccine demonstrates how large national electronic datasets can be used to identify very rare risks and provides reassurance that any risk of ADEM following the ChAdOx1-S COVID-19 vaccination is extremely small. Given the rarity of this risk, further studies in settings with access to data on large populations should be carried out to verify these findings.

Background Group B streptococcus (GBS) remains a leading cause of infant sepsis, meningitis and death despite intrapartum antibiotic prophylaxis. A vaccine is urgently required, and two candidates are in advanced clinical trials. For successful GBS vaccine implementation, especially if a vaccine is licensed based on an immunological threshold, there must be cross-sector engagement, effective advocacy, robust plans for phase IV studies and equitable access. Meeting A round-table discussion, held at St George’s University of London, reviewed the current position of GBS vaccines in the UK context, focusing on phase IV plans, convening a diverse group of stakeholders from across the UK, with a role in GBS vaccine licensure, advocacy, implementation or effectiveness evaluation. Presentations outlined the latest UK epidemiology, noting the rising infant invasive GBS (iGBS) infection rates from 1996 to 2021 for both early and late onset disease, with the highest disease rates in Black infants (1.1/1000 livebirths vs white infants (0.81/1000 livebirths). Potential coverage of the candidate vaccines was high (>95%). Regulatory input suggested that EU regulators would consider waiving the need for a pre-licensure efficacy study if a putative correlate of protection could be adequately justified. Phase IV study methodologies for a GBS vaccine were considered, largely based on previous UK maternal vaccine assessments, such as a nationwide cohort study design using a vaccine register and a maternal services dataset. Other strategies were also discussed such as a cluster or stepped-wedge randomised trial to evaluate implementation outcomes. Opportunities for advocacy, education and engagement with additional key partners were discussed and identified. Conclusions With an approved GBS vaccine a near possibility, planning of phase IV studies and identification of critical barriers to implementation are urgently needed. Cross-sector engagement is essential and will facilitate a successful pathway.

Summary: Background: The Sanofi/GSK AS03-adjuvanted (VidPrevtyn Beta) vaccine and the Pfizer-BioNTech mRNA (Comirnaty Original/Omicron BA.4-5) bivalent vaccine were offered to adults aged 75 years and over in England from 3rd April 2023. This is the first time an adjuvanted COVID-19 vaccine has been administered as part of a UK COVID-19 vaccination programme. In clinical trials, antibody levels generated were comparable with mRNA vaccines but there are no real-world data on the effectiveness or duration of protection. Methods: We used a test-negative case–control study design to estimate the incremental vaccine effectiveness of the Sanofi/GSK and Pfizer bivalent BA.4-5 boosters against hospitalisation amongst those aged 75 years and older in England. Cases (those testing positive) and controls (those testing negative) were identified from the national COVID-19 PCR testing data undertaken in hospital settings. The study period included tests from 3rd April 2023 to 27th August 2023. Tests were linked to the COVID-19 vaccination register and to the national hospital admission database, restricting to those with an acute respiratory infection coded in the primary diagnosis field. Vaccine effectiveness was estimated using multivariable logistic regression amongst those who had last received an autumn 2022 booster given at least 3 months prior. The test result was the outcome and vaccination status the exposure. Analyses were adjusted for week of test, gender, age, clinical risk group status, care home resident status, region, index of multiple deprivation, ethnicity, influenza vaccination status and recent COVID-19 positivity. Findings: There were 14,169 eligible tests from hospitalised individuals aged 75 years and older; 3005 cases (positive tests) and 11,164 controls (negative tests). Effectiveness was highest in the period 9–13 days post vaccination for both manufacturers at about 50%; 43.7% (95% CI, 20.1–60.3%) and 56.1% (95% CI, 25.2–74.2%) for Sanofi/GSK and Pfizer BA.4-5, respectively. There was evidence of waning with a reduction to about 30% for both manufacturers after 5–9 weeks. The longest time interval post vaccination for which we were able to estimate effectiveness was 10+ weeks post vaccination, at which point vaccine effectiveness was 17.6% (95% CI, −3.6 to 34.5%) and 37.9% (95% CI, 13.2–55.5%) for the Sanofi/GSK and Pfizer BA.4-5 boosters, respectively. Interpretation: Both boosters provided good protection against hospitalisation amongst older adults. The finding that the adjuvanted vaccine targeting the distant Beta strain had similar effectiveness to the bivalent mRNA vaccine targeting more closely matched Omicron sub-lineages is notable and highlights the need for further real-world studies into the effectiveness of vaccines from different vaccine platforms and formulations in the presence of matched and unmatched strains. Funding: No external funding.

BackgroundPrepandemic sentinel surveillance focused on improved management of winter pressures, with influenza-like illness (ILI) being the key clinical indicator. The World Health Organization (WHO) global standards for influenza surveillance include monitoring acute respiratory infection (ARI) and ILI. The WHO’s mosaic framework recommends that the surveillance strategies of countries include the virological monitoring of respiratory viruses with pandemic potential such as influenza. The Oxford-Royal College of General Practitioner Research and Surveillance Centre (RSC) in collaboration with the UK Health Security Agency (UKHSA) has provided sentinel surveillance since 1967, including virology since 1993. ObjectiveWe aim to describe the RSC’s plans for sentinel surveillance in the 2023-2024 season and evaluate these plans against the WHO mosaic framework. MethodsOur approach, which includes patient and public involvement, contributes to surveillance objectives across all 3 domains of the mosaic framework. We will generate an ARI phenotype to enable reporting of this indicator in addition to ILI. These data will support UKHSA’s sentinel surveillance, including vaccine effectiveness and burden of disease studies. The panel of virology tests analyzed in UKHSA’s reference laboratory will remain unchanged, with additional plans for point-of-care testing, pneumococcus testing, and asymptomatic screening. Our sampling framework for serological surveillance will provide greater representativeness and more samples from younger people. We will create a biomedical resource that enables linkage between clinical data held in the RSC and virology data, including sequencing data, held by the UKHSA. We describe the governance framework for the RSC. ResultsWe are co-designing our communication about data sharing and sampling, contextualized by the mosaic framework, with national and general practice patient and public involvement groups. We present our ARI digital phenotype and the key data RSC network members are requested to include in computerized medical records. We will share data with the UKHSA to report vaccine effectiveness for COVID-19 and influenza, assess the disease burden of respiratory syncytial virus, and perform syndromic surveillance. Virological surveillance will include COVID-19, influenza, respiratory syncytial virus, and other common respiratory viruses. We plan to pilot point-of-care testing for group A streptococcus, urine tests for pneumococcus, and asymptomatic testing. We will integrate test requests and results with the laboratory-computerized medical record system. A biomedical resource will enable research linking clinical data to virology data. The legal basis for the RSC’s pseudonymized data extract is The Health Service (Control of Patient Information) Regulations 2002, and all nonsurveillance uses require research ethics approval. ConclusionsThe RSC extended its surveillance activities to meet more but not all of the mosaic framework’s objectives. We have introduced an ARI indicator. We seek to expand our surveillance scope and could do more around transmissibility and the benefits and risks of nonvaccine therapies.

Abstract National test-negative-case-control (TNCC) studies are used to monitor COVID-19 vaccine effectiveness in the UK. A questionnaire was sent to participants from the first published TNCC COVID-19 vaccine effectiveness study conducted by the UK Health Security Agency, to assess for potential biases and changes in behaviour related to vaccination. The original study included symptomatic adults aged ≥70 years testing for COVID-19 between 08/12/2020 and 21/02/2021. A questionnaire was sent to cases and controls tested from 1–21 February 2021. In this study, 8648 individuals responded to the questionnaire (36.5% response). Using information from the questionnaire to produce a combined estimate that accounted for all potential biases decreased the original vaccine effectiveness estimate after two doses of BNT162b2 from 88% (95% CI: 79–94%) to 85% (95% CI: 68–94%). Self-reported behaviour demonstrated minimal evidence of riskier behaviour after vaccination. These findings offer reassurance to policy makers and clinicians making decisions based on COVID-19 vaccine effectiveness TNCC studies.

Summary: Background: The protection of fourth dose mRNA vaccination against SARS-CoV-2 is relevant to current global policy decisions regarding ongoing booster roll-out. We aimed to estimate the effect of fourth dose vaccination, prior infection, and duration of PCR positivity in a highly-vaccinated and largely prior-COVID-19 infected cohort of UK healthcare workers. Methods: Participants underwent fortnightly PCR and regular antibody testing for SARS-CoV-2 and completed symptoms questionnaires. A multi-state model was used to estimate vaccine effectiveness (VE) against infection from a fourth dose compared to a waned third dose, with protection from prior infection and duration of PCR positivity jointly estimated. Findings: 1298 infections were detected among 9560 individuals under active follow-up between September 2022 and March 2023. Compared to a waned third dose, fourth dose VE was 13.1% (95% CI 0.9 to 23.8) overall; 24.0% (95% CI 8.5 to 36.8) in the first 2 months post-vaccination, reducing to 10.3% (95% CI −11.4 to 27.8) and 1.7% (95% CI −17.0 to 17.4) at 2–4 and 4–6 months, respectively. Relative to an infection >2 years ago and controlling for vaccination, 63.6% (95% CI 46.9 to 75.0) and 29.1% (95% CI 3.8 to 43.1) greater protection against infection was estimated for an infection within the past 0–6, and 6–12 months, respectively. A fourth dose was associated with greater protection against asymptomatic infection than symptomatic infection, whilst prior infection independently provided more protection against symptomatic infection, particularly if the infection had occurred within the previous 6 months. Duration of PCR positivity was significantly lower for asymptomatic compared to symptomatic infection. Interpretation: Despite rapid waning of protection, vaccine boosters remain an important tool in responding to the dynamic COVID-19 landscape; boosting population immunity in advance of periods of anticipated pressure, such as surging infection rates or emerging variants of concern. Funding: UK Health Security Agency, Medical Research Council, NIHR HPRU Oxford, Bristol, and others.

Background The ability of SARS-CoV-2 vaccines to protect against infection and onward transmission determines whether immunisation can control global circulation. We estimated the effectiveness of Pfizer-BioNTech mRNA vaccine (BNT162b2) and Oxford AstraZeneca adenovirus vector vaccine (ChAdOx1) vaccines against acquisition and transmission of the Alpha and Delta variants in a prospective household study in England. Methods Households were recruited based on adult purported index cases testing positive after reverse transcription-quantitative (RT-q)PCR testing of oral-nasal swabs. Purported index cases and their household contacts took oral-nasal swabs on days 1, 3 and 7 after enrolment and a subset of the PCR-positive swabs underwent genomic sequencing conducted on a subset. We used Bayesian logistic regression to infer vaccine effectiveness against acquisition and transmission, adjusted for age, vaccination history and variant. Results Between 2 February 2021 and 10 September 2021, 213 index cases and 312 contacts were followed up. After excluding households lacking genomic proximity (N=2) or with unlikely serial intervals (N=16), 195 households with 278 contacts remained, of whom 113 (41%) became PCR positive. Delta lineages had 1.53 times the risk (95% Credible Interval: 1.04 – 2.20) of transmission than Alpha; contacts older than 18 years old were 1.48 (1.20 – 1.91) and 1.02 (0.93 – 1.16) times more likely to acquire an Alpha or Delta infection than children. Effectiveness of two doses of BNT162b2 against transmission of Delta was 36% (-1%, 66%) and 49% (18%, 73%) for ChAdOx1, similar to their effectiveness for Alpha. Protection against infection with Alpha was higher than for Delta, 69% (9%, 95%) vs. 18% (-11%, 59%), respectively, for BNT162b2 and 24% (-41%, 72%) vs. 9% (-15%, 42%), respectively, for ChAdOx1. Conclusions BNT162b2 and ChAdOx1 reduce transmission of the Delta variant from breakthrough infections in the household setting, although their protection against infection within this setting is low.

Vaccination against invasive pneumococcal disease is recommended for older adults but the optimal age group to target has not been determined and may vary by epidemiological setting. Here, the authors use statistical modelling to estimate the optimal ages for vaccination in Brazil, England, Malawi, and South Africa.

A single SARS-CoV-2 vaccine dose reduces onward transmission from case-patients. We assessed the potential effects of receiving 2 doses on household transmission for case-patients in England and their household contacts. We used stratified Cox regression models to calculate hazard ratios (HRs) for contacts becoming secondary case-patients, comparing contacts of 2-dose vaccinated and unvaccinated index case-patients. We controlled for age, sex, and vaccination status of case-patients and contacts, as well as region, household composition, and relative socioeconomic condition based on household location. During the Alpha-dominant period, HRs were 0.19 (0.13–0.28) for contacts of 2-dose BNT162b2-vaccinated case-patients and 0.54 (0.41–0.69) for contacts of 2-dose Ch4dOx1-vaccinated case-patients; during the Delta-dominant period, HRs were higher, 0.74 (0.72–0.76) for BNT162b2 and 1.06 (1.04–1.08) for Ch4dOx1. Reduction of onward transmission was lower for index case-patients who tested positive ≥2 months after the second dose of either vaccine.

Vaccine effectiveness of a ChAdOx1-S booster was estimated in a test-negative case-control study in England. Protection was found to be moderate against mild disease but remained high and comparable to that of an mRNA booster against hospitalisation with Omicron.

SARS-CoV-2 variants of concern have been associated with reduced vaccine effectiveness, even after a booster dose. In this study, authors aim to estimate vaccine effectiveness against hospitalisation with the Omicron and Delta variants, using different definitions of hospitalisation in secondary care data.

BackgroundAn increased risk of myocarditis or pericarditis after priming with mRNA Coronavirus Disease 2019 (COVID-19) vaccines has been shown but information on the risk post-booster is limited. With the now high prevalence of prior Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, we assessed the effect of prior infection on the vaccine risk and the risk from COVID-19 reinfection.Methods and findingsWe conducted a self-controlled case series analysis of hospital admissions for myocarditis or pericarditis in England between 22 February 2021 and 6 February 2022 in the 50 million individuals eligible to receive the adenovirus-vectored vaccine (ChAdOx1-S) for priming or an mRNA vaccine (BNT162b2 or mRNA-1273) for priming or boosting. Myocarditis and pericarditis admissions were extracted from the Secondary Uses Service (SUS) database in England and vaccination histories from the National Immunisation Management System (NIMS); prior infections were obtained from the UK Health Security Agency's Second-Generation Surveillance Systems. The relative incidence (RI) of admission within 0 to 6 and 7 to 14 days of vaccination compared with periods outside these risk windows stratified by age, dose, and prior SARS-CoV-2 infection for individuals aged 12 to 101 years was estimated. The RI within 27 days of an infection was assessed in the same model. There were 2,284 admissions for myocarditis and 1,651 for pericarditis in the study period. Elevated RIs were only observed in 16- to 39-year-olds 0 to 6 days postvaccination, mainly in males for myocarditis. Both mRNA vaccines showed elevated RIs after first, second, and third doses with the highest RIs after a second dose 5.34 (95% confidence interval (CI) [3.81, 7.48]; p < 0.001) for BNT162b2 and 56.48 (95% CI [33.95, 93.97]; p < 0.001) for mRNA-1273 compared with 4.38 (95% CI [2.59, 7.38]; p < 0.001) and 7.88 (95% CI [4.02, 15.44]; p < 0.001), respectively, after a third dose. For ChAdOx1-S, an elevated RI was only observed after a first dose, RI 5.23 (95% CI [2.48, 11.01]; p < 0.001). An elevated risk of admission for pericarditis was only observed 0 to 6 days after a second dose of mRNA-1273 vaccine in 16 to 39 year olds, RI 4.84 (95% CI [1.62, 14.01]; p = 0.004). RIs were lower in those with a prior SARS-CoV-2 infection than in those without, 2.47 (95% CI [1.32,4.63]; p = 0.005) versus 4.45 (95% [3.12, 6.34]; p = 0.001) after a second BNT162b2 dose, and 19.07 (95% CI [8.62, 42.19]; p < 0.001) versus 37.2 (95% CI [22.18, 62.38]; p < 0.001) for mRNA-1273 (myocarditis and pericarditis outcomes combined). RIs 1 to 27 days postinfection were elevated in all ages and were marginally lower for breakthrough infections, 2.33 (95% CI [1.96, 2.76]; p < 0.001) compared with 3.32 (95% CI [2.54, 4.33]; p < 0.001) in vaccine-naïve individuals respectively.ConclusionsWe observed an increased risk of myocarditis within the first week after priming and booster doses of mRNA vaccines, predominantly in males under 40 years with the highest risks after a second dose. The risk difference between the second and the third doses was particularly marked for the mRNA-1273 vaccine that contains half the amount of mRNA when used for boosting than priming. The lower risk in those with prior SARS-CoV-2 infection, and lack of an enhanced effect post-booster, does not suggest a spike-directed immune mechanism. Research to understand the mechanism of vaccine-associated myocarditis and to document the risk with bivalent mRNA vaccines is warranted.

Background: We investigated whether COVID-19 vaccination reduced SARS-CoV-2 infection risk among adult household contacts of COVID-19 index cases during the Alpha, Delta, and Omicron waves in England. Methods: Between February 2021 and February 2022, SARS-CoV-2 RT-PCR nasal swabs were collected from COVID-19-confirmed index cases aged ≥20 years and their household contacts at enrolment and three and seven days thereafter. Generalized Estimating Equations models were fitted with SARS-CoV-2 positivity as the outcome and household contacts’ vaccination status as the main exposure while adjusting for confounders. Results: SARS-CoV-2 infection was confirmed in 238/472 household contacts (50.4%) aged ≥20 years. The adjusted relative risk (95% confidence interval) of infection in vaccinated versus unvaccinated household contacts was 0.50 (0.35–0.72) and 0.69 (0.53–0.90) for receipt of two doses 8–90 and >90 days ago, respectively, and 0.34 (0.23–0.50) for vaccination with three doses 8–151 days ago. Primary vaccination protected household contacts against infection during the Alpha and Delta waves, but only three doses protected during the Omicron wave. Vaccination with three doses in the index case independently reduced contacts’ infection risk: 0.45 (0.23–0.89). Conclusions: Vaccination of household contacts reduces their risk of infection under conditions of household exposure though, for Omicron, only after a booster dose.

Abstract Background Pertussis vaccines containing three or five pertussis antigens are recommended in pregnancy in many countries, but no studies have compared the effect on infants’ antigen-specific immunoglobulin G (IgG) concentrations. The aim of this study was to compare anti-pertussis IgG responses following primary immunization in infants of mothers vaccinated with TdaP5-IPV (low dose diphtheria toxoid, tetanus toxoid, acellular pertussis [five antigens] and inactivated polio) or TdaP3-IPV in pregnancy (three pertussis antigens). Methods This multi-centre phase IV randomized clinical trial was conducted in a tertiary referral centre and primary care sites in England. Women were randomized to receive TdaP5-IPV (n = 77) or TdaP3-IPV (n = 77) at 28–32 gestational weeks. A non-randomized control group of 44 women who had not received a pertussis-containing vaccine in pregnancy and their 47 infants were enrolled post-partum. Results Following infant primary immunization, there was no difference in the geometric mean concentrations (GMCs) of anti-pertussis toxin, filamentous haemagglutinin or pertactin IgG between infants born to women vaccinated with TdaP5-IPV (n = 67) or TdaP3-IPV (n = 63). However, the GMC of anti-pertussis toxin IgG was lower in infants born to TdaP5-IPV- and TdaP3-IPV-vaccinated mothers compared to infants born to unvaccinated mothers (n = 45) (geometric mean ratio 0.71 [0.56–0.90] and 0.78 [0.61–0.98], respectively); by 13 months of age, this difference was no longer observed. Conclusion Blunting of anti-pertussis toxin IgG response following primary immunization occurs in infants born to women vaccinated with TdaP5-IPV and TdaP3-IPV, with no difference between maternal vaccines. The blunting effect had resolved by 13 months of age. These results may be helpful for countries considering which pertussis-containing vaccine to recommend for use in pregnancy. Trial registration ClinicalTrials.gov , NCT02145624 , registered 23 May 2014

Abstract Background Characterising the size and distribution of the population at risk of severe COVID-19 is vital for effective policy and planning. Older age, and underlying health conditions, are associated with higher risk of death from COVID-19. This study aimed to describe the population at risk of severe COVID-19 due to underlying health conditions across the United Kingdom. Methods We used anonymised electronic health records from the Clinical Practice Research Datalink GOLD to estimate the point prevalence on 5 March 2019 of the at-risk population following national guidance. Prevalence for any risk condition and for each individual condition is given overall and stratified by age and region with binomial exact confidence intervals. We repeated the analysis on 5 March 2014 for full regional representation and to describe prevalence of underlying health conditions in pregnancy. We additionally described the population of cancer survivors, and assessed the value of linked secondary care records for ascertaining COVID-19 at-risk status. Results On 5 March 2019, 24.4% of the UK population were at risk due to a record of at least one underlying health condition, including 8.3% of school-aged children, 19.6% of working-aged adults, and 66.2% of individuals aged 70 years or more. 7.1% of the population had multimorbidity. The size of the at-risk population was stable over time comparing 2014 to 2019, despite increases in chronic liver disease and diabetes and decreases in chronic kidney disease and current asthma. Separately, 1.6% of the population had a new diagnosis of cancer in the past 5 y. Conclusions The population at risk of severe COVID-19 (defined as either aged ≥70 years, or younger with an underlying health condition) comprises 18.5 million individuals in the UK, including a considerable proportion of school-aged and working-aged individuals. Our national estimates broadly support the use of Global Burden of Disease modelled estimates in other countries. We provide age- and region- stratified prevalence for each condition to support effective modelling of public health interventions and planning of vaccine resource allocation. The high prevalence of health conditions among older age groups suggests that age-targeted vaccination strategies may efficiently target individuals at higher risk of severe COVID-19.

Vaccination during pregnancy could protect women and their infants from invasive Group B Streptococcus (GBS) disease. To understand if neonatal dried blood spots (DBS) can be used to determine the amount of maternally derived antibody that protects infants against invasive GBS disease, a retrospective case-control study was conducted in England between 1 April 2014 and 30 April 2015. The DBS of cases with invasive GBS disease (n = 61) were matched with healthy controls (n = 125). The haematocrit, DBS storage temperature, freeze-thaw cycle, and paired serum/DBS studies were set up to optimise the antibody assessment. The samples were analysed using a multiplex immunoassay, and the results were assessed using parametric and nonparametric tests. Antibody concentrations were stable at haematocrits of up to 50% but declined at 75%. DBS storage at room temperature was stable for three months compared with storage from collection at −20 °C and rapidly degraded thereafter. Total IgG levels measured in DBS and paired serum showed a good correlation (r2 = 0.99). However, due to suboptimal storage conditions, no difference was found in the GBS IgG levels between DBS samples from cases and controls. We have demonstrated a proof of concept that assays utilising DBS for assessing GBS serotype-specific antibodies in infants is viable. This method could be used to facilitate future large sero-correlate studies, but DBS samples must be stored at −20 °C for long term preservation of antibody.

Objective To determine characteristics associated with COVID-19 vaccine coverage among individuals aged 50 years and above in England since the beginning of the programme.Design Observational cross-sectional study assessed by logistic regression and mean prevalence margins.Setting COVID-19 vaccinations delivered in England from 8 December 2020 to 17 May 2021.Participants 30 624 257/61 967 781 (49.4%) and 17 360 045/61 967 781 (28.1%) individuals in England were recorded as vaccinated in the National Immunisation Management System with a first dose and a second dose of a COVID-19 vaccine, respectively.Interventions Vaccination status with COVID-19 vaccinations.Main outcome measures Proportion, adjusted ORs and mean prevalence margins for individuals not vaccinated with dose 1 among those aged 50–69 years and dose 1 and 2 among those aged 70 years and above.Results Of individuals aged 50 years and above, black/African/Caribbean ethnic group was the least likely of all ethnic groups to be vaccinated with dose 1 of the COVID-19 vaccine. However, of those aged 70 years and above, the odds of not having dose 2 was 5.53 (95% CI 5.42 to 5.63) and 5.36 (95% CI 5.29 to 5.43) greater among Pakistani and black/African/Caribbean compared with white British ethnicity, respectively. The odds of not receiving dose 2 was 1.18 (95% CI 1.16 to 1.20) higher among individuals who lived in a care home compared with those who did not. This was the opposite to that observed for dose 1, where the odds of being unvaccinated was significantly higher among those not living in a care home (0.89 (95% CI 0.87 to 0.91)).Conclusions We found that there are characteristics associated with low COVID-19 vaccine coverage. Inequalities, such as ethnicity are a major contributor to suboptimal coverage and tailored interventions are required to improve coverage and protect the population from SARS-CoV-2.

Abstract Background Several studies have found increased risks of thrombosis with thrombocytopenia syndrome (TTS) following the ChAdOx1 vaccination. However, case ascertainment is often incomplete in large electronic health record (EHR)‐based studies. Objectives To assess for an association between clinically validated TTS and COVID‐19 vaccination. Methods We used the self‐controlled case series method to assess the risks of clinically validated acute TTS after a first COVID‐19 vaccine dose (BNT162b2 or ChAdOx1) or severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. Case ascertainment was performed uninformed of vaccination status via a retrospective clinical review of hospital EHR systems, including active ascertainment of thrombocytopenia. Results One hundred seventy individuals were admitted to the hospital for a TTS event at the study sites between January 1 and March 31, 2021. A significant increased risk (relative incidence [RI], 5.67; 95% confidence interval [CI], 1.02‐31.38) of TTS 4 to 27 days after ChAdOx1 was observed in the youngest age group (18‐ to 39‐year‐olds). No other period had a significant increase, although for ChAdOx1 for all ages combined the RI was >1 in the 4‐ to 27‐ and 28‐ to 41‐day periods (RI, 1.52; 95% CI, 0.88‐2.63; and (RI, 1.70; 95% CI, 0.73‐3.8, respectively). There was no significant increased risk of TTS after BNT162b2 in any period. Increased risks of TTS following a positive SARS‐CoV‐2 test occurred across all age groups and exposure periods. Conclusions We demonstrate an increased risk of TTS in the 4 to 27 days following COVID‐19 vaccination, particularly for ChAdOx1. These risks were lower than following SARS‐CoV‐2 infection. An alternative vaccine may be preferable in younger age groups in whom the risk of postvaccine TTS is greatest.

ABSTRACT Seroepidemiological studies to monitor antibody kinetics are important for assessing the extent and spread of SARS-CoV-2 in a population. Noninvasive sampling methods are advantageous for reducing the need for venipuncture, which may be a barrier to investigations, particularly in pediatric populations. Oral fluids are obtained by gingiva-crevicular sampling from children and adults and are very well accepted. Enzyme immunoassays (EIAs) based on these samples have acceptable sensitivity and specificity compared to conventional serum-based antibody EIAs and are suitable for population-based surveillance. We describe the development and evaluation of SARS-CoV-2 IgG EIAs using SARS-CoV-2 viral nucleoprotein (NP) and spike (S) proteins in IgG isotype capture format and an indirect receptor-binding-domain (RBD) IgG EIA, intended for use in children as a primary endpoint. All three assays were assessed using a panel of 1,999 paired serum and oral fluids from children and adults participating in school SARS-CoV-2 surveillance studies during and after the first and second pandemic wave in the United Kingdom. The anti-NP IgG capture assay was the best candidate, with an overall sensitivity of 75% (95% confidence interval [CI]: 71 to 79%) and specificity of 99% (95% CI: 78 to 99%) compared with paired serum antibodies. Sensitivity observed in children (80%, 95% CI: 71 to 88%) was higher than that in adults (67%, CI: 60% to 74%). Oral fluid assays (OF) using spike protein and RBD antigens were also 99% specific and achieved reasonable but lower sensitivity in the target population (78%, 95% CI [68% to 86%] and 53%, 95% CI [43% to 64%], respectively). IMPORTANCE We report on the first large-scale assessment of the suitability of oral fluids for detection of SARS-CoV-2 antibody obtained from healthy children attending school. The sample type (gingiva-crevicular fluid, which is a transudate of blood but is not saliva) can be self collected. Although detection of antibodies in oral fluids is less sensitive than that in blood, our study suggests an optimal format for operational use. The laboratory methods we have developed can reliably measure antibodies in children, who are able to take their own samples. Our findings are of immediate practical relevance for use in large-scale seroprevalence studies designed to measure exposure to infection, as they typically require venipuncture. Overall, our data indicate that OF assays based on the detection of SARS-CoV-2 antibodies are a tool suitable for population-based seroepidemiology studies in children and highly acceptable in children and adults, as venipuncture is no longer necessary.

ABSTRACT In March 2020, the Rare and Imported Pathogens Laboratory at the UK Health Security Agency (UKHSA) (formerly Public Health England [PHE]) Porton Down, was tasked by the Department of Health and Social Care with setting up a national surveillance laboratory facility to study SARS-CoV-2 antibody responses and population-level sero-surveillance in response to the growing SARS-CoV-2 outbreak. In the following 12 months, the laboratory tested more than 160,000 samples, facilitating a wide range of research and informing UKHSA, DHSC, and UK government policy. Here we describe the implementation and use of the Euroimmun anti-SARS-CoV-2 IgG assay and provide an extended evaluation of its performance. We present a markedly improved overall sensitivity of 91.39% (≥14 days 92.74%, ≥21 days 93.59%) compared to our small-scale early study, and a specificity of 98.56%. In addition, we detail extended characteristics of the Euroimmun assay: intra- and interassay precision, correlation to neutralization, and assay linearity. IMPORTANCE Serology assays have been useful in determining those with previous SARS-CoV-2 infection in a wide range of research and serosurveillance projects. However, assays vary in their sensitivity at detecting SARS-CoV-2 antibodies. Here, we detail an extended evaluation and characterization of the Euroimmun anti-SARS-CoV-2 IgG assay, one that has been widely used within the United Kingdom on over 160,000 samples to date.

The distribution of the generation time (the interval between individuals becoming infected and transmitting the virus) characterises changes in the transmission risk during SARS-CoV-2 infections. Inferring the generation time distribution is essential to plan and assess public health measures. We previously developed a mechanistic approach for estimating the generation time, which provided an improved fit to data from the early months of the COVID-19 pandemic (December 2019-March 2020) compared to existing models (Hart et al., 2021). However, few estimates of the generation time exist based on data from later in the pandemic. Here, using data from a household study conducted from March to November 2020 in the UK, we provide updated estimates of the generation time. We considered both a commonly used approach in which the transmission risk is assumed to be independent of when symptoms develop, and our mechanistic model in which transmission and symptoms are linked explicitly. Assuming independent transmission and symptoms, we estimated a mean generation time (4.2 days, 95% credible interval 3.3–5.3 days) similar to previous estimates from other countries, but with a higher standard deviation (4.9 days, 3.0–8.3 days). Using our mechanistic approach, we estimated a longer mean generation time (5.9 days, 5.2–7.0 days) and a similar standard deviation (4.8 days, 4.0–6.3 days). As well as estimating the generation time using data from the entire study period, we also considered whether the generation time varied temporally. Both models suggest a shorter mean generation time in September-November 2020 compared to earlier months. Since the SARS-CoV-2 generation time appears to be changing, further data collection and analysis is necessary to continue to monitor ongoing transmission and inform future public health policy decisions.

A variety of in vitro techniques are available to estimate the level of antibodies present in human serum samples. Such tests are highly specific and are used to determine prior exposure to a pathogen or to estimate the magnitude, breadth and durability of individual and population level vaccine immunity. Multiplex (or multi-analyte) platforms are increasingly being used to evaluate immune responses against multiple antigens at the same time, usually at reduced per sample cost and a more efficient use of available samples. Consequently, multiplex serology is an essential component of a wide range of public health programmes. Human papillomavirus (HPV) serology is limited to a small number of academic, public health and vaccine manufacturer laboratories globally. Such platforms include indirect binding to the major (L1) capsid protein virus-like particles (VLP), monoclonal antibody competition against L1 VLP and indirect binding to L1 and L2 (minor capsid protein) VLP on multiplex (Luminex®, Meso Scale Discovery®) and standard (ELISA) platforms. The methodology described here utilizes a common multi-analyte platform and L1L2-based VLP expressed in house, which allows the simultaneous detection and quantification of antibody responses against nine vaccine-relevant HPV genotypes.

Background: Military personnel in enclosed societies are at increased risk of respiratory infections. We investigated an outbreak of Coronavirus Disease 2019 in a London Army barracks early in the pandemic. Methods: Army personnel, their families and civilians had nasal and throat swabs for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by reverse transcriptase -polymerase chain reaction (RT-PCR), virus isolation and whole genome sequencing, along with blood samples for SARS-CoV-2 antibodies. All tests were repeated 36 days later. Findings: During the first visit, 304 (254 Army personnel, 10 family members, 36 civilians, 4 not stated) participated and 24/304 (8%) were SARS-CoV-2 RT-PCR positive. Infectious virus was isolated from 7/24 (29%). Of the 285 who provided a blood sample, 7% (19/285) were antibody positive and 63% (12/19) had neutralising antibodies. Twenty-two (22/34, 64%) individuals with laboratory-confirmed infection were asymptomatic. Nine SARS-CoV-2 RT-PCR positive participants were also antibody positive but those who had neutralising antibodies did not have infectious virus. At the second visit, no new infections were detected, and 13% (25/193) were seropositive, including 52% (13/25) with neutralising antibodies. Risk factors for SARS-CoV-2 antibody positivity included contact with a confirmed case (RR 25.2; 95% CI 14–45), being female (RR 2.5; 95% CI 1.0–6.0) and two-person shared bathroom (RR 2.6; 95% CI 1.1–6.4). Interpretation: We identified high rates of asymptomatic SARS-CoV-2 infection. Public Health control measures can mitigate spread but virus re-introduction from asymptomatic individuals remains a risk. Most seropositive individuals had neutralising antibodies and infectious virus was not recovered from anyone with neutralising antibodies. Funding: PHE

BackgroundEarly studies of narcolepsy after AS03-adjuvanted pandemic A/H1N12009 vaccine (Pandemrix) could not define the duration of elevated risk post-vaccination nor the risk in children aged under 5 years who may not present until much older.Methods/findingsClinical information and sleep test results, extracted from hospital notes at 3 large pediatric sleep centers in England between September 2017 and June 2018 for narcolepsy cases aged 4-19 years with symptom onset since January 2009, were reviewed by an expert panel to confirm the diagnosis. Vaccination histories were independently obtained from general practitioners (GPs). The odds of vaccination in narcolepsy cases compared with the age-matched English population was calculated after adjustment for clinical conditions that were indications for vaccination. GP questionnaires were returned for 242 of the 244 children with confirmed narcolepsy. Of these 5 were under 5 years, 118 were 5-11 years, and 119 were 12-19 years old at diagnosis; 39 were vaccinated with Pandemrix before onset. The odds ratio (OR) for onset at any time after vaccination was 1.94 (95% confidence interval [CI] 1.30-2.89), The elevated risk period was restricted to onsets within 12 months of vaccination (OR 6.65 [3.44-12.85]) and was highest within the first 6 months. After one year, ORs were not significantly different from 1 up to 8 years after vaccination. The ORs were similar in under five-year-olds and older ages. The estimated attributable risk was 1 in 34,500 doses. Our study is limited by including cases from only 3 sleep centers, who may differ from cases diagnosed in nonparticipating centers, and by imprecision in defining the centers' catchment population. The potential for biased recall of onset shortly after vaccination in cases aware of the association cannot be excluded.ConclusionsIn this study, we found that vaccine-attributable cases have onset of narcolepsy within 12 months of Pandemrix vaccination. The attributable risk is higher than previously estimated in England because of identification of vaccine-attributable cases with late diagnoses. Absence of a compensatory drop in risk 1-8 years after vaccination suggests that Pandemrix does not trigger onsets in those in whom narcolepsy would have occurred later.

Objectives To assess the impact of herpes zoster vaccination in the 5 years after introduction for 70- to 79-year-olds in England in September 2013.Design Population based ecological impact assessment.Setting Hospitals covering the whole English population for the period 2008 to 2018 and 293 general practices (GP) for the period 2005 to 2018, in England.Participants Over the period the population contributed 117·5 million person-years for hospitalisation events and 6.96 million person-years for GP events in individuals aged 60 to 89.Interventions Live attenuated herpes zoster vaccination (Zostavax), first used on 1st September 2013, in 70- and 79-year-olds with continued use in new 70 year-olds and with a staged catch-up of those aged 71 to 78 years in 2013.Outcome measures Herpes zoster and postherpetic neuralgia (PHN) consultation and hospitalisation rates in age-cohorts according to vaccine eligibility. Incidence rate ratios in age-cohorts eligible for vaccination compared with those non-eligible were calculated by Poisson regression. This was used to estimate prevented cases and, along with vaccine coverage, to estimate vaccine effectiveness.Results Large and prolonged reductions in herpes zoster and PHN consultations and hospitalisations were observed in the 5 years post-implementation. For example, in 79 year-olds first eligible in 2013, the incidence rate ratio for consultations 5 years later was 0·65 (95% CI: 0·52 to 0·81). Over the whole period an estimated 40 500 fewer zoster consultations and 1840 fewer zoster hospitalisations occurred because of the vaccination programme. These reductions were consistent with effectiveness in the routine cohorts (vaccinated aged 70) of between 37% (for hospitalised zoster) and 75% (for PHN consultations) and, in catch up cohorts (vaccinated aged 78 to 79) of between 49% (for hospitalised PHN) and 66% (for PHN consultations).Conclusion Given the clear and sustained impact of herpes zoster vaccination over the 5-year period since introduction, optimising vaccination coverage is important to attain maximum benefit.

There is a strong and continuously growing interest in using large electronic healthcare databases to study health outcomes and the effects of pharmaceutical products. However, concerns regarding disease misclassification (i.e. classification errors of the disease status) and its impact on the study results are legitimate. Validation is therefore increasingly recognized as an essential component of database research. In this work, we elucidate the interrelations between the true prevalence of a disease in a database population (i.e. prevalence assuming no disease misclassification), the observed prevalence subject to disease misclassification, and the most common validity indices: sensitivity, specificity, positive and negative predictive value. Based on this, we obtained analytical expressions to derive all the validity indices and true prevalence from the observed prevalence and any combination of two other parameters. The analytical expressions can be used for various purposes. Most notably, they can be used to obtain an estimate of the observed prevalence adjusted for outcome misclassification from any combination of two validity indices and to derive validity indices from each other which would otherwise be difficult to obtain. To allow researchers to easily use the analytical expressions, we additionally developed a user-friendly and freely available web-application.

Background: Group B streptococcus is the leading cause of infection in infants. Currently, intrapartum antibiotic prophylaxis is the major strategy to prevent invasive group B streptococcus disease. However, intrapartum antibiotic prophylaxis does not prevent maternal sepsis, premature births, stillbirths or late-onset disease. Maternal vaccination may offer an alternative strategy. Multivalent polysaccharide protein conjugate vaccine development is under way and a serocorrelate of protection is needed to expedite vaccine licensure. Objectives: The ultimate aim of this work is to determine the correlate of protection against the major group B streptococcus disease-causing serotypes in infants in the UK. The aim of this feasibility study is to test key operational aspects of the study design. Design: Prospective cohort study of pregnant women and their infants in a 6-month period (1 July to 31 December 2018). Setting: Five secondary and tertiary hospitals from London and South England. National iGBS disease surveillance was conducted in all trusts in England and Wales. Participants: Pregnant women aged ≥ 18 years who were delivering at one of the selected hospitals and who provided consent during the study period. There were no exclusion criteria. Interventions: No interventions were performed. Main outcome measures: (1) To test the feasibility of collecting serum at delivery from a large cohort of pregnant women. (2) To test the key operational aspects for a proposed large serocorrelates study. (3) To test the feasibility of collecting samples from those with invasive group B streptococcus. Results: A total of 1823 women were recruited during the study period. Overall, 85% of serum samples were collected at three sites collecting only cord blood. At the two sites collecting maternal, cord and infant blood samples, the collection rate was 60%. A total of 614 women were screened for group B streptococcus with a colonisation rate of 22% (serotype distribution: 30% III, 25% Ia, 16% II, 14% Ib, 14% V and 1% IV). A blood sample was collected from 34 infants who were born to colonised women. Maternal and infant blood and the bacterial isolates for 15 newborns who developed invasive group B streptococcal disease during the study period were collected (serotype distribution: 29% III, 29% II, 21% Ia, 7% Ib, 7% IV and 7% V). Limitations: Recruitment and sample collection were dependent on the presence of research midwives rather than the whole clinical team. In addition, individualised consent limited the number of women who could be approached each day, and site set-up for the national surveillance study and the limited time period of this feasibility study limited recruitment of all eligible participants. Conclusions: We have verified the feasibility of collecting and processing rectovaginal swabs and blood samples in pregnant women, as well as samples from those with invasive group B streptococcal disease. We have made recommendations for the recruitment of cases within the proposed GBS3 study and for controls both within GBS3 and as an extension of this feasibility study. Future work: A large case–control study comparing specific immunoglobulin G levels in mothers whose infants develop invasive group B streptococcal disease with those in colonised mothers whose infants do not develop invasive group B streptococcal disease is recommended. Trial registration: Current Controlled Trials ISRCTN49326091; IRAS project identification number 246149/REC reference number 18/WM/0147. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 67. See the NIHR Journals Library website for further project information.

Abstract Background The seven-valent pneumococcal conjugate vaccine (PCV) was introduced in England in September 2006, changing to the 13-valent vaccine in April 2010. PCV impact on invasive pneumococcal disease (IPD) has been extensively reported, but less described is its impact on the burden of pneumonia, sepsis and otitis media in the hospital. Methods Using details on all admissions to hospitals in England, we compared the incidence of pneumococcal-specific and syndromic disease endpoints in a 24-month pre-PCV period beginning April 2004 to the 24-month period ending March 2015 to derive incidence rate ratios (IRRs). To adjust for possible secular trends in admission practice, IRRs were compared to the IRRs for five control conditions over the same period and the relative change assessed using the geometric mean of the five control IRRs as a composite, and individually for each control condition to give the min-max range. Relative changes were also compared with IRRs for IPD from the national laboratory database. The effect of stratifying cases into those with and without clinical risk factors for pneumococcal infection was explored. Results Relative reductions in pneumococcal pneumonia were seen in all age groups and in those with and without risk factors; in children under 15 years old reductions were similar in magnitude to reductions in IPD. For pneumonia of unspecified cause, relative reductions were seen in those under 15 years old (maximum reduction in children under 2 years of 34%, min-max: 11–49%) with a relative increase in 65+ year olds most marked in those with underlying risk conditions (41%, min-max: 0–82%). Reductions in pneumococcal sepsis were seen in all age groups, with the largest reduction in children younger than 2 years (67%, min-max 56–75%). Reductions in empyema and lung abscess were also seen in under 15 year olds. Results for other disease endpoints were varied. For disease endpoints showing an increase in raw IRR, the increase was generally reduced when expressed as a relative change. Conclusions Use of a composite control and stratification by risk group status can help elucidate the impact of PCV on non-IPD disease endpoints and in vulnerable population groups. We estimate a substantial reduction in the hospitalised burden of pneumococcal pneumonia in all age groups and pneumonia of unspecified cause, empyema and lung abscess in children under 15 years of age since PCV introduction. The increase in unspecified pneumonia in high-risk 65+ year olds may in part reflect their greater susceptibility to develop pneumonia from less pathogenic serotypes that are replacing vaccine types in the nasopharynx.

During the first 12 months of an emergency meningococcal ACWY vaccination program for teenagers in England, coverage among persons who left school in 2015, the first cohort to be vaccinated, was 36.6%. There were 69% fewer group W meningococcal cases than predicted by trend analysis and no cases in vaccinated teenagers.

One hundred and ninety eight females aged 12–15 y were enrolled in an observer-blinded randomized trial to assess the immunogenicity and reactogenicity of the tetravalent HPV vaccine Gardasil® (group 2), in comparison to the bivalent HPV vaccine, Cervarix® (group 1), which was routinely offered in the national vaccination schedule at the time. Participants were blinded to treatment group until all 3 vaccinations had been given, while laboratory staff were masked during testing. For the majority of local and general reactions, recipients of both vaccines reported comparable frequencies. Local and systemic events were rarely of high severity, except for tenderness at the injection site which reached a severe level after at least one of the doses in 24% of the Cervarix® group and 7% of the Gardasil® group (p = 0.001 comparing groups). For most reactions, no dose response was recorded, except for swelling with higher reporting at dose 3 (17.7%) than dose 1 (3.1%) for Cervarix®. SAE reporting was low (n = 3) and considered unrelated to either vaccine. This paper supports the body of evidence that Gardasil® has an acceptable safety profile when compared with Cervarix® and other vaccines given in the national program.

BACKGROUND:In October 2017, the United Kingdom Joint Committee on Vaccination and Immunisation (JCVI) recommended removal of one primary dose of the 13-valent pneumococcal conjugate vaccine (PCV13) from the existing 2+1 schedule (2, 4, 12 months). We conducted a mathematical modelling study to investigate the potential impact of a 1+1 (3, 12 month) schedule on invasive pneumococcal disease (IPD) and pneumococcal community-acquired pneumonia (CAP). Our results and those from a 1+1 immunogenicity study formed the key evidence reviewed by JCVI. METHODS AND FINDINGS:We developed age-structured, dynamic, deterministic models of pneumococcal transmission in England and Wales to describe the impact on IPD of 7-valent PCV (PCV7; introduced in 2006) and PCV13 (introduced in 2010). Key transmission and vaccine parameters were estimated by fitting to carriage data from 2001/2002 and post-PCV IPD data to 2015, using vaccine coverage, mixing patterns between ages, and population data. We considered various models to investigate potential reasons for the rapid increase in non-PCV13 (non-vaccine serotype [NVT]) IPD cases since 2014. After searching a large parameter space, 500 parameter sets were identified with a likelihood statistically close to the maximum and these used to predict future cases (median, prediction range from 500 parameter sets). Our findings indicated that the emergence of individual NVTs with higher virulence resulting from ongoing replacement was likely responsible; the NVT increase was predicted to plateau from 2020. Long-term simulation results suggest that changing to a 1+1 schedule would have little overall impact, as the small increase in vaccine-type IPD would be offset by a reduction in NVT IPD. Our results were robust to changes in vaccine assumptions in a sensitivity analysis. Under the base case scenario, a change to a 1+1 schedule in 2018 was predicted to produce 31 (6, 76) additional IPD cases over five years and 83 (-10, 242) additional pneumococcal-CAP cases, with together 8 (-2, 24) additional deaths, none in children under 15 years. Long-term continuation with the 2+1 schedule, or changing to a 1+1, was predicted to sustain current reductions in IPD cases in under-64-year-olds, but cases in 65+-year-olds would continue to increase because of the effects of an aging population. Limitations of our model include difficulty in fitting to past trends in NVT IPD in some age groups and inherent uncertainty about future NVT behaviour, sparse data for defining the mixing matrix in 65+-year-olds, and the methodological challenge of defining uncertainty on predictions. CONCLUSIONS:Our findings suggest that, with the current mature status of the PCV programme in England and Wales, removing one primary dose in the first year of life would have little impact on IPD or pneumococcal CAP cases or associated deaths at any age. A reduction in the number of priming doses would improve programmatic efficiency and facilitate the introduction of new vaccines by reducing the number of coadministered vaccines given at 2 and 4 months of age in the current UK schedule. Our findings should not be applied to other settings with different pneumococcal epidemiology or with immature programmes and poor herd immunity.

Most pathological pain conditions in patients and rodent pain models result in marked alterations in mechanosensation and the gold standard way to measure this is by use of von Frey fibers. These graded monofilaments are used to gauge the level of stimulus-evoked sensitivity present in the affected dermal region. One of the most popular methods used to determine von Frey thresholds is the up–down testing paradigm introduced by Dixon for patients in 1980 and by Chapman and colleagues for rodents in 1994. Although the up–down method is very accurate, leading to its widespread use, defining the 50% threshold from primary data is complex and requires a relatively time-consuming analysis step. We developed a computer program, the Up–Down Reader (UDReader), that can locate and recognize handwritten von Frey assessments from a scanned PDF document and translate these measurements into 50% pain thresholds. Automating the process of obtaining the 50% threshold values negates the need for reference tables or Microsoft Excel formulae and eliminates the chance of a manual calculation error. Our simple and straightforward method is designed to save research time while improving data collection accuracy and is freely available at https://sourceforge.net/projects/updownreader/ or in supplementary files attached to this manuscript.

Background: In 2013, a herpes zoster vaccination programme was introduced in England for adults aged 70 years with a phased catch-up programme for those aged 71–79 years. We aimed to evaluate the effect of the first 3 years of the vaccination programme on incidence of herpes zoster and postherpetic neuralgia in this population. Methods: In this population-based study, we extracted data from the Royal College of General Practitioners sentinel primary care network on consultations with patients aged 60–89 years for herpes zoster and postherpetic neuralgia occurring between Oct 1, 2005, and Sept 30, 2016, obtaining data from 164 practices. We identified individual data on herpes zoster vaccinations administered and consultations for herpes zoster and postherpetic neuralgia, and aggregated these data to estimate vaccine coverage and incidence of herpes zoster and postherpetic neuralgia consultations. We defined age cohorts to identify participants targeted in each year of the programme, and as part of the routine or catch-up programme. We modelled incidence according to age, region, gender, time period, and vaccine eligibility using multivariable Poisson regression with an offset for person-years. Findings: Our analysis included 3·36 million person-years of data, corresponding to an average of 310 001 patients aged 60–89 years who were registered at an RCGP practice each year. By Aug 31, 2016, uptake of the vaccine varied between 58% for the recently targeted cohorts and 72% for the first routine cohort. Across the first 3 years of vaccination for the three routine cohorts, incidence of herpes zoster fell by 35% (incidence rate ratio 0·65 [95% 0·60–0·72]) and of postherpetic neuralgia fell by 50% (0·50 [0·38–0·67]). The equivalent reduction for the four catch-up cohorts was 33% for herpes zoster (incidence rate ratio 0·67 [0·61–0·74]) and 38% for postherpetic neuralgia (0·62 [0·50–0·79]). These reductions are consistent with a vaccine effectiveness of about 62% against herpes zoster and 70–88% against postherpetic neuralgia. Interpretation: The herpes zoster vaccination programme in England has had a population impact equivalent to about 17 000 fewer episodes of herpes zoster and 3300 fewer episodes of postherpetic neuralgia among 5·5 million eligible individuals in the first 3 years of the programme. Communication of the public health impact of this programme will be important to reverse the recent trend of declining vaccine coverage. Funding: Public Health England.

BACKGROUND:Studies of vaccine effectiveness (VE) rely on accurate identification of vaccination and cases of vaccine-preventable disease. In practice, diagnostic tests, clinical case definitions and vaccination records often present inaccuracies, leading to biased VE estimates. Previous studies investigated the impact of non-differential disease misclassification on VE estimation. METHODS:We explored, through simulation, the impact of non-differential and differential disease- and exposure misclassification when estimating VE using cohort, case-control, test-negative case-control and case-cohort designs. The impact of misclassification on the estimated VE is demonstrated for VE studies on childhood seasonal influenza and pertussis vaccination. We additionally developed a web-application graphically presenting bias for user-selected parameters. RESULTS:Depending on the scenario, the misclassification parameters had differing impacts. Decreased exposure specificity had greatest impact for influenza VE estimation when vaccination coverage was low. Decreased exposure sensitivity had greatest impact for pertussis VE estimation for which high vaccination coverage is typically achieved. The impact of the exposure misclassification parameters was found to be more noticeable than that of the disease misclassification parameters. When misclassification is limited, all study designs perform equally. In case of substantial (differential) disease misclassification, the test-negative design performs worse. CONCLUSIONS:Misclassification can lead to significant bias in VE estimates and its impact strongly depends on the scenario. We developed a web-application for assessing the potential (joint) impact of possibly differential disease- and exposure misclassification that can be modified by users to their own study scenario. Our results and the simulation tool may be used to guide better design, conduct and interpretation of future VE studies.

In April 2010, 13-valent pneumococcal conjugate vaccine (PCV13) replaced PCV7 in the infant immunisation schedule in England and Wales. Despite limited serotype replacement in invasive pneumococcal disease (IPD) during the first four post-PCV13 years, non-vaccine type (NVT) IPD increased substantially in 2014/15. We undertook a carriage study in 2015/16 to help understand the reasons for this increase.Families with a child aged twenty years) were cultured and serotyped for Streptococcus pneumoniae. Results were compared with those from three previous household studies conducted in the same populations between 2001 to 2013, and with the serotypes causing IPD to estimate case-carrier ratios (CCRs). Overall carriage prevalence did not differ between the four carriage studies with reductions in vaccine-type carriage offset by increases in NVT carriage. While no individual NVT serotype showed an increase in CCR from 2012/13, the composition of the serotypes comprising the NVT group differed such that the overall CCR of the NVT group had significantly increased since 2012/13. Carriage of two PCV13 serotypes, 3 and 19A, was found in 2015/16 (3/650 = 0.5% and 2/650 = 0.3% respectively) with no overall reduction in carriage prevalence of PCV13-7 serotypes since 2012/13, though 6C prevalence, a vaccine-related serotype, had reduced from 1.8% in 2012/13 to 2/648 (0.3%) in 2015/16, p = 0.013.There was continuing evolution in carried NVTs six years after PCV13 introduction which, in addition to being vaccine-driven, could also reflect natural secular changes in certain NVTs. This poses challenges in predicting future trends in IPD. Elimination of carriage and disease due to serotypes 3 and 19A may not be achieved by PCV13.

This study aimed at establishing baseline key epidemiological parameters for varicella zoster virus (VZV) infection in Vojvodina, Serbia, with the ultimate goal to quantify the VZV transmission potential in the population. Seroprevalence data generated during the first large cross-sectional VZV serosurvey were modelled, using a two-tiered modelling approach to calculate age-specific forces of infection (FOI), the basic reproduction number (R0) and herd immunity threshold (H). Seroprevalence and modelling data were compared with corresponding pre-vaccination epidemiological parameters from 11 countries participating in the European Sero-Epidemiology Network 2 (ESEN2) project. Serbia fits into the general dynamic VZV transmission patterns in Europe in the pre-vaccine era, with estimated R0 = 4.12, (95% CI: 2.69-7.07) and H = 0.76 (95% CI: 0.63-0.86). The highest VZV transmission occurs among preschool children, as evidenced by the estimation of the highest FOI (0.22, 95% CI: 0.11-0.34) in the 0.5-4 age group, with a peak FOI of 0.25 at 2.23 years. Seroprevalence was consistently lower in 5-14 year-olds, resulting in considerable shares of VZV-susceptible adolescents (7.3%), and young adults (6%), resembling the situation in a minority of European countries. The obtained key epidemiological parameters showed most intense VZV transmission in preschool children aged

Prevalence of depression is higher in patients with cancer than in the general population. Sustained systemic inflammation has been associated with depressive behavior and it has been reported that depressed patients commonly display alterations in their immune system. We previously showed that cancer in mice induces a systemic environment that promotes neutrophil activation and leukocytosis. We thus hypothesized that the peripheral systemic response to a solid tumor leads to endothelial activation, which may promote inflammatory changes in the brain with behavioral consequences. Using the Lewis lung carcinoma (LLC) model, we show that tumor growth induces a progressive increase in peripheral inflammation as observed by elevated interleukin-6 (IL-6). In behavioral studies, tumor-bearing mice showed no sign of motor, coordination or short term working memory deficits as assessed by rotarod, balance-beam, and novel object recognition tests. However, there was an impairment in the grip strength test and interestingly, an anxious and despair-like phenotype in the elevated plus-maze, and tail suspension tests, respectively. Immunostaining of perfused brains revealed fibrin accumulation in the vasculature with some leakage into the parenchyma, a process known to activate endothelial cells. Taken together, our results suggest that the inflamed and prothrombotic systemic environment created by the growth of a peripherally-located solid tumor induces endothelial activation, accumulation of fibrin in the brain and astrocyte activation, perhaps leading to depressive-like behavior.

ABSTRACT Objective Near real-time vaccine safety surveillance (NRTVSS) using electronic health records (EHR) is an option for post-licensure vaccine safety assessment. NRTVSS requires timely recording of outcomes in the database used. Our study aimed to examine recording delays in the Clinical Practice Research Datalink (CPRD) to inform the feasibility of implementing NRTVSS in England using these data. Approach To examine delays we selected 4 outcomes of interest for NRTVSS: Guillain-Barre syndrome (GBS), Bell’s palsy (BP), optic neuritis (ON), and seizures for the period January 2005 to July 2015. Timeliness of CPRD records was assessed in two ways: 1) Using linked CPRD-hospital episode (HES) data to compare the hospital diagnosis date with the date the record was entered in CPRD (system date), 2) Looking at delays in recording (e.g. due to feedback from specialist referral) in stand-alone CPRD. For the latter the event date was compared with the system date. However, system dates can be changed when practice software is updated or there is mass transfer of a patient’s records. After investigation, we excluded these uninformative system dates by excluding records from patients who had more than 100 records with the system date on the same day. Results 67813 patients were identified in CPRD (GBS:n=1081, BP:n=15835, ON:n=2236, seizures:n=48866), 64527 in HES (GBS:n=1680, BP:n=8468, ON:n=1746, seizures:n=53080) and 14104 in both databases (GBS:n=356, BP:n=1511, ON:n=226, seizures:n=12036). For the CPRD-HES comparison, 11843 patients with a diagnosis of interest both in CPRD and HES were included (GBS:n=321, BP:n=1374, ON:n=190, seizures:n=9976). Of these, the majority had a record in CPRD before or within 1 month of the HES record (GBS:49.5%, BP:83.8%, ON:66.8%, seizures:69.8%). For 6 months the corresponding percentage was more than 85% for all conditions examined (GBS:85.4%, BP:92.9%, ON:90.0%, seizures:86.6%). For stand-alone CPRD 57317 patients were included (GBS:n=972, BP:n=14275, ON:n=1958, seizures:n=40327). The majority had a record within one month of the event date (GBS:67.9%, BP:89.3%, ON:71.8%, seizures:83%). More than 87% of records occurred within 6 months of the event date (GBS:87.9%, BP:94.4%, ON:91.6%, seizures:94.9%). Conclusion This work shows that most diagnoses examined were recorded with a delay of ≤30 days, making NRTVSS possible. The distribution of the delays was condition-specific and the weekly delay distribution could be used to adjust for delays in the NRTVSS analysis. CPRD can be a viable data source to use in this kind of analysis; next steps will include trial implementation of the system using these data.

The intense influenza activity in England during the 2010–11 winter resulted from a combination of factors. Population-based seroepidemiology confirms that the third wave of influenza A(H1N1)pdm09 virus circulation was associated with a shift in age groups affected, with the highest rate of infection in young adults.

Results of an accelerated pertussis vaccination schedule for infants introduced in 1990 in England and Wales were examined. Earlier scheduling and sustained high vaccine coverage resulted in fewer reported cases of pertussis among infants, reinforcing the World Health Organization drive for on-time completion of the infant vaccination schedule. As determined by using the screening method, the first dose of vaccine was 61.7% effective in infants

The United Kingdom implemented a containment strategy for pandemic (H1N1) 2009 through administering antiviral agents (AVs) to patients and their close contacts. This observational household cohort study describes the effect of AVs on household transmission. We followed 285 confirmed primary cases in 259 households with 761 contacts. At 2 weeks, the confirmed secondary attack rate (SAR) was 8.1% (62/761) and significantly higher in persons 50 years of age (18.9% vs. 1.2%, p

We analyzed data from hospital admissions and enhanced mumps surveillance to assess mumps complications during the largest mumps outbreak in England and Wales, 2004–2005, and their association with mumps vaccination. When compared with nonoutbreak periods, the outbreak was associated with a clear increase in hospitalized patients with orchitis, meningitis, and pancreatitis. Routine mumps surveillance and hospital data showed that 6.1% of estimated mumps patients were hospitalized, 4.4% had orchitis, 0.35% meningitis, and 0.33% pancreatitis. Enhanced surveillance data showed 2.9% of mumps patients were hospitalized, 6.1% had orchitis, 0.3% had meningitis, and 0.25% had pancreatitis. Risk was reduced for hospitalization (odds ratio [OR] 0.54, 95% confidence interval [CI] 0.43–0.68), mumps orchitis (OR 0.72, 95% CI 0.56–0.93) and mumps meningitis (OR 0.28, 95% CI 0.14–0.56) when patient had received 1 dose of measles, mumps, and rubella vaccine. The protective effect of vaccination on disease severity is critical in assessing the total effects of current and future mumps control strategies.