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Highlights • Potential detrimental non-specific effects of DTwP are controversial. • Diverse relative risks (RRs) of mortality after DTwP in low-income settings. • Meta-regression to explore impact of risk of bias and confounding on RRs. • Increased RR might be confined to West-African countries. • Bias and confounding cannot be ruled out as explanation of the increased RRs. Abstract Introduction It has been suggested that some vaccines have effects beyond protection against the diseases they target, called non-specific effects (NSEs). In 2016, a systematic review by Higgins et al., commissioned by the WHO Strategic Advisory Group of Experts (SAGE) on immunization, estimated the relative risk (RR) of all-cause mortality after whole-cell Diphtheria-Tetanus-Pertussis (DTwP) vaccination to be 1.38 (95% CI: 0.92–2.08), and described these potential NSEs as inconsistent. However, the selection of studies for meta-analysis, based on their proneness to bias and confounding, was debated. Objective To identify study characteristics and postulated risks of bias and confounding that might have impacted the RR of all-cause mortality after DTwP vaccination in observational studies conducted in low-income countries. Methods Based on methodological considerations on study design and analysis, we systematically assessed all 17 DTwP studies from the Higgins et al. review for risk of selection bias, exposure and outcome misclassification, confounding and differential co-interventions. We used meta-regression to assess the impact of study characteristics and the postulated risks of bias and confounding on the RR estimates, and looked for outlying and influential risk estimates. Permutation tests were performed to control for false-positive findings. Results The overall RR of all-cause mortality after DTwP vaccination including all but one outlying and influential study was 1.32 (95% CI: 0.83–2.08). Based on uni-variable meta-regression, we found that study location (p = 0.01), studies using the landmark approach (p = 0.015) and studies at high risk of exposure misclassification (p = 0.036) were significantly associated with increased RR estimates whereas studies at high risk of selection bias (p = 0.059) showed borderline significance. The results further suggest these effect modifiers are clustered in studies conducted in West-Africa. Conclusion The increased RR of all-cause mortality after DTwP might be confined to West-African countries and/or certain postulated risks of bias might have inflated these RRs. [ABSTRACT FROM AUTHOR]

Purpose To assess the effect of an intravitreal ocriplasmin injection on visual function, measured using visual acuity ( VA) and vision-related quality of life. Methods Post hoc analysis of prespecified secondary end-points in two multicentre, randomized, double-masked, phase 3 clinical trials. A total of 652 participants with symptomatic vitreomacular adhesion were enrolled, of whom 464 received a single intravitreal injection of 125 μg ocriplasmin and 188 received a single intravitreal placebo injection. Based on principal components analysis results, visual function response ( VFR) was defined as either a VA improvement of ≥2 lines; or an improvement in the composite score of the National Eye Institute Visual Function Questionnaire ( VFQ-25) exceeding the minimal clinically important difference ( MCID), estimated using the standard error of measurement approach; or an improvement in the VFQ-25 driving subscale score exceeding the MCID. The main outcome measure was VFR at 6 months. Results A VFR occurred in 55.1% of the ocriplasmin group versus 34.2% of the placebo injection group (p < 0.0001). This comprised 23.7% versus 11.2% (p = 0.0003) with a ≥ 2-line VA improvement, 35.9% versus 22.7% (p = 0.0016) for the VFQ-25 composite score, and 10.2% versus 6.2% (p = 0.1697) for the driving subscale. Conclusion Ocriplasmin produces a clinically meaningful visual function benefit. [ABSTRACT FROM AUTHOR]

Background: Norovirus is the leading cause of community-acquired and nosocomial acute gastroenteritis. Routine testing for norovirus is seldom undertaken, and diagnosis is mainly based on presenting symptoms. This makes understanding the burden of medically attended norovirus-attributable gastroenteritis (MA-NGE) and targeting care and prevention strategies challenging.Methods: We used linked population-based healthcare datasets (Clinical Practice Research Datalink General Practice OnLine Database linked with Hospital Episode Statistics Admitted Patient Care) to model the incidence of MA-NGE associated with primary care consultations or hospitalizations according to age groups in England in the period July 2007-June 2013.Results: Mean annual incidence rates of MA-NGE were 4.9/1000 person-years and 0.7/1000 person-years for episodes involving primary care or hospitalizations, respectively. Incidence rates were highest in children aged <5 years: 34.0 consultations/1000 person-years and 3.3 hospitalizations/1000 person-years. Medically attended norovirus-attributable gastroenteritis hospitalization rates were second highest in adults aged >65 years (1.7/1000 person-years).Conclusions: In this particular study, the burden of MA-NGE estimated from healthcare datasets was higher than previously estimated in small cohort studies in England. Routinely collected primary care and hospitalization datasets are useful resources to estimate and monitor the burden of MA-NGE in a population over time. [ABSTRACT FROM AUTHOR]

Background: The burden of disease due to norovirus infection has been well described in the general United States population, but studies of norovirus occurrence among persons with chronic medical conditions have been limited mostly to the immunocompromised. We assessed the impact of norovirus gastroenteritis on health care utilization in US subjects with a range of chronic medical conditions. Methods: We performed a retrospective cohort study using MarketScan data from July 2002 to December 2013, comparing the rates of emergency department visits, outpatient visits and hospitalizations among patients with chronic conditions (renal, cardiovascular, respiratory, immunocompromising, gastrointestinal, hepatic/pancreatic and neurological conditions and diabetes) with those in a healthy population. We estimated the rates of these outcomes due to norovirus gastroenteritis using an indirect modelling approach whereby cases of gastroenteritis of unknown cause and not attributed to a range of other causes were assumed to be due to norovirus. Results: Hospitalization rates for norovirus gastroenteritis were higher in all of the risk groups analyzed compared with data in otherwise healthy subjects, ranging from 3.2 per 10,000 person-years in persons with chronic respiratory conditions, to 23.1 per 10,000 person-years in persons with chronic renal conditions, compared to 2.1 per 10,000 among persons without chronic conditions. Over 51% of all norovirus hospitalizations occurred in the 37% of the population with some form of chronic medical condition. Outpatient visits for norovirus gastroenteritis were also increased in persons with chronic gastrointestinal or immunocompromising conditions. Conclusion: Norovirus gastroenteritis leads to significantly higher rates of healthcare utilization in patients with a chronic medical condition compared to patients without any such condition. [ABSTRACT FROM AUTHOR]

Abstract: Newly licensed vaccines against human papillomavirus (HPV) and hepatitis B (HBV), and several vaccines in development, including a vaccine against genital herpes simplex virus (HSV), contain a novel Adjuvant System, AS04, composed of 3-O-desacyl-4′ monophosphoryl lipid A and aluminium salts. Given the background incidence of autoimmune disorders in some of the groups targeted for immunisation with these vaccines, it is likely that autoimmune events will be reported in temporal association with vaccination, even in the absence of a causal relationship. The objective of this integrated analysis was to assess safety of AS04 adjuvanted vaccines with regard to adverse events (AEs) of potential autoimmune aetiology, particularly in adolescents and young adults. All randomised, controlled trials of HPV-16/18, HSV and HBV vaccines were analysed in an integrated analysis of individual data (N =68,512). A separate analysis of the HPV-16/18 vaccine trials alone was also undertaken (N =39,160). All data were collected prospectively during the vaccine development programmes (mean follow-up of 21.4 months), and included in the analysis up to a pre-defined data lock point. Reporting rates of overall autoimmune events were around 0.5% and did not differ between the AS04 and control groups. The relative risk (AS04/control) of experiencing any autoimmune event was 0.98 (95% confidence intervals 0.80, 1.21) in the integrated analysis and 0.92 (0.70, 1.22) in the HPV-16/18 vaccine analysis. Relative risks calculated overall, for disease category or for individual events were close to 1, and all confidence intervals around the relative risk included 1, indicating no statistically significant difference in event rates between the AS04 and control groups. This integrated analysis of over 68,000 participants who received AS04 adjuvanted vaccines or controls demonstrated a low rate of autoimmune disorders, without evidence of an increase in relative risk associated with AS04 adjuvanted vaccines. [Copyright &y& Elsevier]

Objective. To assess the possible toxicity of thimerosal-containing vaccines (TCVs) among infants. Methods. A 2-phased retrospective cohort study was conducted using computerized health maintenance organization (HMO) databases. Phase I screened for associations between neurodevelopmental disorders and thimerosal exposure among 124 170 infants who were born during 1992 to 1999 at 2 HMOs (A and B). In phase II, the most common disorders associated with exposure in phase I were reevaluated among 16 717 children who were born during 1991 to 1997 in another HMO (C). Relative risks for neurodevelopmental disorders were calculated per increase of 12.5 µg of estimated cumulative mercury exposure from TCVs in the first, third, and seventh months of life. Results. In phase I at HMO A, cumulative exposure at 3 months resulted in a significant positive association with tics (relative risk [RR]: 1.89; 95% confidence interval [CI]: 1.05-3.38). At HMO B, increased risks of language delay were found for cumulative exposure at 3 months (RR: 1.13; 95% CI: 1.01-1.27) and 7 months (RR: 1.07; 95% CI: 1.01-1.13). In phase II at HMO C, no significant associations were found. In no analyses were significant increased risks found for autism or attention-deficit disorder. Conclusions. No consistent significant associations were found between TCVs and neurodevelopmental outcomes. Conflicting results were found at different HMOs for certain outcomes. For resolving the conflicting findings, studies with uniform neurodevelopmental assessments of children with a range of cumulative thimerosal exposures are needed. Pediatrics 2003;112:1039-1048; cohort study, computerized medical... [ABSTRACT FROM AUTHOR]

Objective. Varicella breakthrough, the occurrence of varicella disease >42 days after vaccination, is indicative of vaccination failure. A sevenfold increased risk of breakthrough among vaccinated children with asthma was observed in a 1996 varicella outbreak in a child care center. More recent outbreak investigations have also identified age at vaccination as a potential risk factor for breakthrough. We assessed the association of varicella breakthrough with asthma, steroids, age at varicella vaccination, and timing of measles-mumps-rubella (MMR) vaccination. Methods. We performed a retrospective cohort study among children born after 1993 and followed up through 1999 at 2 health maintenance organizations ([HMOs] A and B) in the United States. Information was obtained from automated vaccination, clinic, hospital discharge, and pharmacy records. Results. We identified 268 and 97 breakthrough cases among 80 584 and 8181 children vaccinated against varicella at HMOs A and B, respectively. Varicella breakthrough was not associated with asthma, inhaled steroids prescribed at any time, and oral steroids prescribed before vaccination. An increased risk of varicella breakthrough was found in the 3 months immediately after prescription for oral steroids at HMO A (adjusted relative risk [aRR]: 2.4; 95% confidence interval [CI]: 1.3-4.4) and HMO B (aRR: 2.8; 95% CI: 1.0-7.8), when varicella vaccine was given before 15 months of age at HMO A (aRR: 1.4; 95% CI: 1.1-1.9), and when varicella vaccination followed MMR vaccine within 28 days at HMO A (aRR: 3.1; 95% CI: 1.5-6.4). Conclusions. Varicella vaccine failure in children... [ABSTRACT FROM AUTHOR]

The association between rotavirus serotypes and severity is not well established. Analysis of a clinical trial conducted in Latin America points at more-severe disease associated with serotype G9. Thus, demonstration of efficacy against G9 will be an important asset of any rotavirus vaccine to be introduced into a Latin American country or any country where G9 has been shown to be prevalent. [ABSTRACT FROM AUTHOR]

Background: Norovirus is an important cause of acute gastroenteritis globally. However, norovirus is rarely laboratory confirmed or recorded explicitly as a cause of hospitalization. In recent years, there has been an interest in using medical databases and indirect modelling methods to estimate the incidence of norovirus gastroenteritis. The objective of this study was to estimate the incidence of hospitalizations for norovirus gastroenteritis in Europe (2004-2015) using nationwide in-patient discharge records from different European countries.Methods: National hospital discharge registers in all 28 European Union countries (at that time) and all 4 European Free Trade Association countries were contacted and invited to participate in the study. Discharges with ICD9/ICD10 codes for acute gastroenteritis (AGE) as first-listed (principal) diagnosis were extracted to assess hospitalization rates for AGE and norovirus gastroenteritis (NGE), overall, by age group, country, month, and seasonal year. The number of cause-unspecified episodes was regressed against pathogen-specific AGE episodes: Rotavirus, Clostridium difficile, Other Bacterial, Other Viral and Parasitic separately. NGE hospital discharges were estimated for each month by calculating the difference between observed cause-unspecified and model-predicted counts, assuming that any remaining seasonality not otherwise captured in the model was due to norovirus, and adding those to the coded NGE episodes to get the total number of norovirus-associated episodes.Results: Data were available from 15 countries, representing 68% of the total population in Europe. Only 24.4% of all AGE discharges were coded as cause-specified. We estimated that between 2004 and 2015, the overall rate of NGE hospital discharges in Europe was 3.9 per 10,000 person-years, ranging from 1.2 (Portugal) to 10.7 (Lithuania). Norovirus was predicted to be responsible for 17% of all AGE hospital discharges in Europe in this period. Norovirus affects individuals of all ages, but NGE discharge rates were highest in children < 5 years (24.8 per 10,000 person-years), and adults aged ≥80 years (10.7 per 10,000 person-years).Conclusion: We estimated that 1 in 400 hospitalizations in Europe can be attributed to Norovirus. In the absence of routine norovirus testing and recording in hospital settings, modelling methods are useful resources to estimate the incidence of norovirus gastroenteritis. [ABSTRACT FROM AUTHOR]

Background: Acute gastroenteritis (AGE) is the leading cause of illness among returning travelers seeking medical care. Multiple types of enteric pathogens can cause travel-acquired AGE and, while bacterial pathogens have a predominant role, the importance of viruses, such as norovirus, is increasingly recognized. There is a lack of information on travel-acquired norovirus incidence among symptomatic and asymptomatic individuals irrespective of healthcare-seeking behavior. Our aim is to estimate the incidence of travel-acquired AGE due to norovirus and to characterize the burden of disease among international travelers from the United States and Europe.Methods: We describe a prospective cohort study implemented in five US and European sites to estimate the role of AGE due to norovirus among adult international travelers. We enrolled individuals aged 18 years and older who are traveling to regions of moderate-high risk of AGE, or via cruise ship with an international port stop, with a trip duration of 3-15 days. The study will generate a wide range of health and travel-related data for pre-, during, and up to 6-months post-travel. We will identify laboratory-confirmed travel-acquired norovirus infections among both symptomatic and asymptomatic individuals from self-collected whole stool samples tested via quantitative RT-PCR. Coinfections will be identified in a subset of travelers with AGE using a multiplex molecular-based assay.Discussion: This study is unique in design and breadth of data collected. The prospective collection of health and behavioral data, as well as biologic samples from travelers irrespective of symptoms, will provide useful data to better understand the importance of norovirus AGE among international travelers. This study will provide data to estimate the incidence of norovirus infections and AGE and the risk of post-infectious sequelae in the 6-month post-travel period serving as a baseline for future norovirus AGE vaccination studies. This study will contribute valuable information to better understand the role of norovirus in travel-acquired AGE risk and the impact of these infections on a broad set of outcomes. [ABSTRACT FROM AUTHOR]

We assessed the seroepidemiology of SARS-CoV-2 infection and the incidence of coronavirus disease 2019 (COVID-19) before and during the rollout of COVID-19 vaccines, in a prospective observational cohort study on healthcare workers (HCWs) in a large tertiary hospital in Mainz, Germany. Antibody status was assessed during six visits between September 2020 and February 2022. Self-reported symptoms were collected using a smartphone application; symptomatic HCWs were tested using real-time polymerase chain reaction (RT-PCR) assays for SARS-CoV-2. Rates of virologically confirmed and severe COVID-19 were estimated using the U.S. Food and Drug Administration (FDA) and Coalition for Epidemic Preparedness Innovations (CEPI) case definitions, respectively, and were contrasted to background community transmission and circulating SARS-CoV-2 variants. A total of 3665 HCWs were enrolled (mean follow-up time: 18 months); 97 met the FDA definition of virologically confirmed COVID-19 (incidence rate (IR) 2.3/1000 person-months (PMs), one severe case). Most cases reported ≥2 symptoms, commonly, cough and anosmia or ageusia. Overall, 263 individuals seroconverted (IR 6.6/1000 PMs—2.9 times the estimated IR of COVID-19), indicating many cases were missed, either due to asymptomatic infections or to an atypical presentation of symptoms. A triphasic trend in anti-SARS-CoV-2 seroprevalence and seroconversion was observed, with an initial increase following the rollout of COVID-19 vaccines, a two-fold decline six months later, and finally a six-fold increase by the end of the study when Omicron was the dominant circulating variant. Despite the increase in infection rates at the end of the study due to the circulation of the Omicron variant, the infection and disease rates observed were lower than the published estimates in HCWs and rates in the general local population. Preferential vaccination of HCWs and the strict monitoring program for SARS-CoV-2 infection are the most likely reasons for the successful control of COVID-19 in this high-risk population. [ABSTRACT FROM AUTHOR]

Introduction New adjuvants have been developed to improve the efficacy of vaccines and for dose-sparing capacity and may overcome immuno senescence in the elderly. We reviewed the safety of newly-adjuvanted vaccines in older adults. Methods We searched Medline for clinical trials (CTs) including new adjuvant systems (AS01, AS02, AS03, or MF59), used in older adults, published between 01/1995 and 09/2017. Safety outcomes were: serious adverse events (SAEs); solicited local and general AEs (reactogenicity); unsolicited AEs; and potentially immune-mediated diseases (pIMDs). Standard random effects meta-analyses were conducted by type of safety event and adjuvant type, reporting Relative Risks (RR) with 95% confidence intervals (95% CI). Results We identified 1040 publications, from which we selected 7, 7, and 12 CTs on AS01/AS02, AS03 and MF59, respectively. 47,602 study participants received newly-adjuvanted vaccine and 44,521 control vaccine, or placebo. Rates of SAEs (RR = 0.99, 95% CI = 0.96–1.02), deaths (RR = 0.99, 95% CI = 0.92–1.06) and pIMDs (RR = 0.94, 95% CI = 0.79–1.1) were comparable in newly-adjuvanted and control groups. Vaccine-related SAEs occurred in <1% of the subjects in both groups. The reactogenicity of AS01/AS02 and AS03 adjuvanted vaccines was higher compared to control vaccines, whereas MF59-adjuvanted vaccines resulted only in more pain. Grade 3 reactogenicity was reported infrequently, with fatigue (RR = 2.48, 95% CI = 1.69–3.64), headache (RR = 2.94, 95% CI = 1.24–6.95), and myalgia (RR = 2.68, 95% CI = 1.86–3.80) occurring more frequently in newly-adjuvanted groups. Unsolicited AEs occurred slightly more frequently in newly-adjuvanted groups (RR = 1.04, 95% CI = 1.00–1.08). Conclusions Our review suggests that, within the clinical trial setting, the use of new adjuvants in older adults has not led to any safety concerns, with no increase in SAEs or fatalities. Higher rates for solicited AEs were observed, especially for AS01/AS02 and AS03 adjuvanted vaccines, but AEs were mostly mild and transient. Further evidence will need to come from the use of new adjuvants in the real-world setting, where larger numbers can be studied to potentially detect rare reactions. [ABSTRACT FROM AUTHOR]

Background Safety signal detection in spontaneous reporting system databases and electronic healthcare records is key to detection of previously unknown adverse events following immunization. Various statistical methods for signal detection in these different datasources have been developed, however none are geared to the pediatric population and none specifically to vaccines. A reference set comprising pediatric vaccine-adverse event pairs is required for reliable performance testing of statistical methods within and across data sources. Methods The study was conducted within the context of the Global Research in Paediatrics (GRiP) project, as part of the seventh framework programme (FP7) of the European Commission. Criteria for the selection of vaccines considered in the reference set were routine and global use in the pediatric population. Adverse events were primarily selected based on importance. Outcome based systematic literature searches were performed for all identified vaccine-adverse event pairs and complemented by expert committee reports, evidence based decision support systems (e.g. Micromedex), and summaries of product characteristics. Classification into positive (PC) and negative control (NC) pairs was performed by two independent reviewers according to a pre-defined algorithm and discussed for consensus in case of disagreement. Results We selected 13 vaccines and 14 adverse events to be included in the reference set. From a total of 182 vaccine-adverse event pairs, we classified 18 as PC, 113 as NC and 51 as unclassifiable. Most classifications (91) were based on literature review, 45 were based on expert committee reports, and for 46 vaccine-adverse event pairs, an underlying pathomechanism was not plausible classifying the association as NC. Conclusion A reference set of vaccine-adverse event pairs was developed. We propose its use for comparing signal detection methods and systems in the pediatric population. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor in response to commentaries on an article about the link between thimerosal-containing vaccines and neurodevelopmental delays.

A letter to the editor is presented in response to an article by John H. Noseworthy and Gregory A. Poland about multiple sclerosis which appeared in the September 18, 2000 issue.

• Norovirus (NoV) was frequent among 1294 children with acute gastroenteritis (AGE). • 24% of AGE outpatient episodes and 18% of AGE hospitalizations were NoV-positive. • The predominant NoV genotype was GII.4, present in 58% of NoV infections. • Brazil, with rotavirus vaccination, had the highest prevalence of NoV infection. Noroviruses (NoVs) cause acute gastroenteritis (AGE) worldwide, affecting children in particular. We aimed to estimate the burden of disease due to NoV among children aged <6 years in Brazil, Chile, Philippines and Thailand. This was a prospective, hospital-based, observational study. Children were recruited over one year between 2014 and 2017. Four cohorts were analysed: community-acquired AGE outpatients and inpatients, nosocomial AGE inpatients, and asymptomatic outpatients. We collected demographic and clinical data, and a stool sample that was tested for NoV. Positive samples were tested for Rotavirus (RV) and NoV-genotyped. Disease severity was assessed by the Vesikari and modified Vesikari scores. Prevalence and incidence of NoV-AGE were estimated by cohort and country. 1637 participants yielded valid laboratory results. The proportion of NoV-positive cases was 23.8% (95% CI 20.8-27.2) in the outpatient cohort, 17.9% (15.0-21.3) in the hospital cohort, 21.4% (12.7-33.8) in the nosocomial cohort and 9.6% (6.9-13.2) in the asymptomatic cohort. Genotype GII.4 was predominant (58%). Less than 4% samples had RV coinfection. In general, NoV-positive subjects had more severe presentations than NoV-negative subjects. NoV caused AGE with substantial burden throughout the studied settings, with higher relative frequency in Brazil where RV vaccination coverage is high. [ABSTRACT FROM AUTHOR]

Background Escherichia coli is the most common cause of bacteremia in high-income countries. To enable the development and implementation of effective prevention strategies, a better understanding of the current epidemiology of invasive E. coli infections is needed. Methods A systematic review of literature published between 1 January 2007 and 31 March 2018 on the burden and epidemiology of E. coli bacteremia in populations that include adults in high-income countries was conducted. Meta-analysis was performed for descriptive purposes. Results During the studied time interval, the estimated incidence rate of E. coli bacteremia was 48 per 100 000 person-years, but this increased considerably with age: rates per 100 000 person-years were >100 in 55-to-75-year-olds and >300 in 75-to-85-year-olds. Overall, E. coli accounted for 27% of documented bacteremia episodes: 18% if hospital acquired, 32% if community-onset healthcare associated, and 33% if community acquired. The estimated case fatality rate was 12%. Approximately 44% of episodes were community acquired, 27% community-onset healthcare associated, and 27% hospital acquired. Urinary tract infection (UTI) was the primary source for 53% of episodes. Conclusions This systematic review confirms the substantial burden of E. coli bacteremia in older adults and justifies the implementation of community-level programs to prevent E. coli bacteremia and ideally UTI in this age group. [ABSTRACT FROM AUTHOR]

We estimated numbers of hospitalizations for norovirus gastroenteritis (NGE) and associated medical costs in Germany, where norovirus testing is high because reimbursement is affected. We extracted aggregate data for patients hospitalized with a primary or secondary code from the International Classification of Diseases, 10th Revision (ICD-10), NGE diagnosis during 2007-2012 from the German Federal Statistics Office. We assessed reliability of the coding system in patient records from a large academic hospital. Approximately 53,000-90,000 NGE hospitalizations occurred annually in Germany (21,000-33,000 with primary and 32,000-57,000 with secondary ICD-10-coded NGE diagnoses). Rates of hospitalization with NGE as primary diagnosis were highest in children <2 years of age; rates of hospitalization with NGE as secondary diagnosis were highest in adults >85 years of age. The average annual reimbursed direct medical cost of NGE hospitalizations was €31-43 million. Among patients with a NGE ICD-10 code, 87.6% had positive norovirus laboratory results. [ABSTRACT FROM AUTHOR]

Abstract Background Global efforts to adequately monitor safety of new vaccines for pregnant women in low and middle-income countries (LMICs) are needed. The Global Alignment of Immunization Safety Assessment in pregnancy (GAIA) project recently published case definitions based on levels of diagnostic certainty for pregnancy- and neonatal outcomes and maternal vaccination. As a preliminary step to assessing the applicability of these definitions in LMICs, WHO selected sites and conducted a feasibility assessment to evaluate their ability to identify and classify selected outcomes (preterm birth, neonatal death, neonatal invasive bloodstream infection (NI-BSI), stillbirth) and maternal vaccination. Methods Candidate sites were initially screened using a questionnaire. For each outcome, eligible sites were asked to retrospectively identify and collect information for three individuals born in 2016. Subsequently, outcomes were classified by level of diagnostic certainty. Results Fifty-one sites (15 countries) were screened; 32 of them (9 countries) participated in the assessment and identified 315 subjects with the outcomes of interest. Twenty-four sites (8 countries) identified at least one subject per outcome and agreed to continue participating. The majority (80%) of preterm births, neonatal deaths, and NI-BSI subjects, but only 50% of stillbirths, could be assessed for diagnostic certainty. The main reasons for not classifying stillbirths were insufficient information to distinguish between antepartum and intrapartum stillbirth (29%); or that not all data for one subject fit into a single level of diagnostic certainty (35%). Forty-nine percent of mothers were considered vaccinated, 6% not-vaccinated, and vaccination status could not be assessed in 44% of them. Discussion GAIA case definitions for four neonatal outcomes and maternal vaccination were successfully piloted in 24 sentinel sites across four WHO regions. Our assessment found that modification of the stillbirth definition could help avoid potential misclassification. Vaccine safety monitoring in LMICs will benefit from systematic recording of all vaccinations during pregnancy. [ABSTRACT FROM AUTHOR]

Background: The burden of medically-attended acute gastro-enteritis (MA-AGE) that can be attributed to norovirus is not well established in Japan. Using a nationwide database of medical care insurance claims, we estimated the incidence of medically-attended norovirus-attributable gastroenteritis (MA-NGE) in Japan. Methods: The incidences of MA-NGE outpatient consultations or hospitalization in Japan were modelled on seasonal patterns of MA-AGE for unspecified causes derived from the Japan Medical Data Center (JMDC) database for the period July 2007 to June 2015. Results: Mean age-adjusted annual incidence rates (per 10,000 person-years) of MA-NGE associated with outpatient care or hospitalization were 389 (95% CI 269–558) and 13 (95% CI 9–20), respectively. Highest rates were in children under 5 years of age: 1,569 (95% CI 1,325–1,792) for outpatient consultations and 48 (95% CI 39–56) for hospitalizations. Of all gastroenteritis episodes associated with outpatient care or hospitalization, 29% and 31% were attributed to norovirus, respectively. Norovirus was estimated to be responsible for 4,964,000 outpatient visits (95% CI 3,435,000–7,123,000) and 171,000 hospitalizations (95% CI 110,000–251,000) per year across Japan. Conclusions: Incidence rates of MA-AGE are high in Japan, and norovirus-attributable disease is at least as high as in some other developed countries. [ABSTRACT FROM AUTHOR]

Background: Varicella is generally considered a mild disease. Disease burden is not well known and country-level estimation is challenging. As varicella disease is not notifiable, notification criteria and rates vary between countries. In general, existing surveillance systems do not capture cases that do not seek medical care, and most are affected by underreporting and underascertainment. We aimed to estimate the overall varicella disease burden in Europe to provide critical information to support decision-making regarding varicella vaccination.Methods: We conducted a systematic literature review to identify all available epidemiological data on varicella IgG antibody seroprevalence, primary care and hospitalisation incidence, and mortality. We then developed methods to estimate age-specific varicella incidence and annual number of cases by different levels of severity (cases in the community, health care seekers in primary care and hospitals, and deaths) for all countries belonging to the European Medicines Agency (EMA) region and Switzerland.Results: In the absence of universal varicella immunization, the burden of varicella would be substantial with a total of 5.5 million (95% CI: 4.7-6.4) varicella cases occurring annually across Europe. Variation exists between countries but overall the majority of cases (3 million; 95% CI: 2.7-3.3) would occur in children <5 years. Annually, 3-3.9 million patients would consult a primary care physician, 18,200-23,500 patients would be hospitalised, and 80 varicella-related deaths would occur (95% CI: 19-822).Conclusions: Varicella disease burden is substantial. Most cases occur in children <5 years old but adults require hospitalisation more often and are at higher risk of death. This information should be considered when planning and evaluating varicella control strategies. A better understanding of the driving factors of country-specific differences in varicella transmission and health care utilization is needed. Improving and standardizing varicella surveillance in Europe, as initiated by the European Centre for Disease Prevention and Control (ECDC), is important to improve data quality to facilitate inter-country comparison. [ABSTRACT FROM AUTHOR]

Background: An increase in narcolepsy cases was observed in Finland and Sweden towards the end of the 2009 H1N1 influenza pandemic. Preliminary observational studies suggested a temporal link with the pandemic influenza vaccine Pandemrix™, leading to a number of additional studies across Europe. Given the public health urgency, these studies used readily available retrospective data from various sources. The potential for bias in such settings was generally acknowledged. Although generally advocated by key opinion leaders and international health authorities, no systematic quantitative assessment of the potential joint impact of biases was undertaken in any of these studies. Methods: We applied bias-level multiple-bias analyses to two of the published narcolepsy studies: a pediatric cohort study from Finland and a case-control study from France. In particular, we developed Monte Carlo simulation models to evaluate a potential cascade of biases, including confounding by age, by indication and by natural H1N1 infection, selection bias, disease- and exposure misclassification. All bias parameters were evidence-based to the extent possible. Results: Given the assumptions used for confounding, selection bias and misclassification, the Finnish rate ratio of 13.78 (95% CI: 5.72–28.11) reduced to a median value of 6.06 (2.5th- 97.5th percentile: 2.49–15.1) and the French odds ratio of 5.43 (95% CI: 2.6–10.08) to 1.85 (2.5th—97.5th percentile: 0.85–4.08). Conclusion: We illustrate multiple-bias analyses using two studies on the Pandemrix™-narcolepsy association and advocate their use to better understand the robustness of study findings. Based on our multiple-bias models, the observed Pandemrix™-narcolepsy association consistently persists in the Finnish study. For the French study, the results of our multiple-bias models were inconclusive. [ABSTRACT FROM AUTHOR]

Introduction New adjuvants such as the AS- or the MF59-adjuvants improve vaccine efficacy and facilitate dose-sparing. Their use in influenza and malaria vaccines has resulted in a large body of evidence on their clinical safety in children. Methods We carried out a systematic search for safety data from published clinical trials on newly adjuvanted vaccines in children ≤10 years of age. Serious adverse events (SAEs), solicited AEs, unsolicited AEs and AEs of special interest were evaluated for four new adjuvants: the immuno-stimulants containing adjuvant systems AS01 and AS02, and the squalene containing oil-in-water emulsions AS03 and MF59. Relative risks (RR) were calculated, comparing children receiving newly adjuvanted vaccines to children receiving other vaccines with a variety of antigens, both adjuvanted and unadjuvanted. Results Twenty-nine trials were included in the meta-analysis, encompassing 25,056 children who received at least one dose of the newly adjuvanted vaccines. SAEs did not occur more frequently in adjuvanted groups (RR 0.85, 95%CI 0.75–0.96). Our meta-analyses showed higher reactogenicity following administration of newly adjuvanted vaccines, however, no consistent pattern of solicited AEs was observed across adjuvant systems. Pain was the most prevalent AE, but often mild and of short duration. No increased risks were found for unsolicited AEs, febrile convulsions, potential immune mediated diseases and new onset of chronic diseases. Conclusions Our meta-analysis did not show any safety concerns in clinical trials of the newly adjuvanted vaccines in children ≤10 years of age. An unexplained increase of meningitis in one Phase III AS01-adjuvanted malaria trial and the link between narcolepsy and the AS03-adjuvanted pandemic vaccine illustrate that continued safety monitoring is warranted. [ABSTRACT FROM AUTHOR]

With the availability of the nonavalent human papillomavirus (HPV) vaccine, vaccinees, parents and healthcare providers need guidance on how to complete an immunization course started with the bi- or quadrivalent vaccine and whether to revaccinate individuals who have completed a full immunization course with the bi- or quadrivalent vaccine. To answer these questions three parameters should be considered: age at the start of vaccination (9 to 14 years of age versus 15 years and older, the cut-off for 2 or 3 doses schedule), the number of doses already received and the time interval between doses. Based on a number of scenarios, we propose that the 9-valent vaccine can be used to complete an incomplete vaccination regimen or might be added to a previous completed schedule to extend protection. [ABSTRACT FROM AUTHOR]

Background: Noroviruses (NoVs) are the most common cause of acute gastroenteritis (AGE) causing both sporadic and outbreak-associated illness. Norovirus (NoV) infections occur across all ages but certain sub-groups are considered at increased risk due to heightened transmission and/or symptom severity. Older adults are potentially at high risk of NoV-associated illness due to frequent outbreaks in long-term care facilities (LTCFs) and severe health outcomes following infection. Elucidation of NoV risk among older adults will support prevention, treatment and control efforts.Methods: We conducted a systematic literature review to summarize the published risk estimates of NoV-associated illness, hospitalization and death among individuals aged 65 years and older. A structured search using defined NoV and gastroenteritis (GE) terms was performed in the PubMed and EMBASE databases of human studies published between January 1, 2003 and May 16, 2013.Results: We identified 39 studies from high income (HI) and upper-middle income (UMI) countries. Thirty-six percent of publications provided risk estimates based on laboratory-confirmed or epidemiologically-linked population-based surveillance data using molecular diagnostic methods. Over the study period, estimated annual NoV rates and extrapolated number of cases among older adults in HI and UMI countries were: 29-120/10,000 or 1.2-4.8 million NoV-associated illnesses; 18-54/10,000 or 723,000-2.2 million NoV-associated outpatient visits; 1-19/10,000 or 40,00-763,000 NoV-associated inpatient visits; 0.04-0.32/10,000 or 2000-13,000 NoV-associated deaths. NoV was responsible for approximately 10-20 % of GE hospitalizations and 10-15 % of all-cause GE deaths among older adults. Older adults experienced a heightened risk of nosocomial infections. Those in LTCFs experience frequent NoV outbreaks and the range in attack rates was 3-45 %, case hospitalization rates 0.5-6 % and case fatality rates 0.3-1.6 %.Conclusions: Older adults are at increased risk of severe NoV-associated health outcomes. NoV-associated hospitalization rates were higher, more severe, resulted in longer stays and incurred greater costs than for younger patients. NoV-associated mortality rates were approximately 200 % higher among individuals 65 years and older compared to <5 years. The burden of NoV among older adults is expected to rise along with societal aging and increased need for institutionalized care. NoV prevention in older adults, including potential vaccination, may significantly impact risk of severe illness. [ABSTRACT FROM AUTHOR]

Abstract: Infection with influenza virus during pregnancy poses a significant risk of complications for both mother and fetus. During the H1N1 2009 pandemic, pregnant women constituted one of the priority groups for vaccination in many countries, creating a need for close monitoring of the safety of the vaccine in pregnant women. We present findings from an analysis of a cohort of pregnant women (N =267) from a prospective, observational, post-authorization safety study of the AS03-adjuvanted split virion H1N1 (2009) pandemic vaccine. There were 265 known pregnancy outcomes with 261 live births, four spontaneous abortions with no congenital anomalies, and no stillbirths. There were six live births with congenital anomalies, of which one was diagnosed before vaccination. A total of 247 women (94.6%), of whom four had twin pregnancies, delivered at term, and 14 women (5.4%), of whom two had twin pregnancies, delivered preterm (between Weeks 24 and 36 of gestation), with three of them (1.1%) occurring before 32 weeks (very preterm). Twenty-one neonates (8.1%) had a low birth weight (<2.5kg), of whom nine (3.5%) were term neonates. The prevalence of all outcomes was in line with the expected rates. The adverse events reported were consistent with the events anticipated to be reported by this study population. No adverse events of special interest were reported. The results of this analysis suggest that exposure to the AS03 adjuvanted H1N1 (2009) vaccine during pregnancy does not increase the risk of adverse pregnancy outcomes including spontaneous abortion, congenital anomalies, preterm delivery, low birth weight neonates, or maternal complications. Although limited in size, the fully prospective nature of the safety follow-up of these women vaccinated during pregnancy is unique and offers an important degree of reassurance for the use of the AS03 adjuvanted H1N1 (2009) vaccine in this high risk group for H1N1 infection. [Copyright &y& Elsevier]

Abstract: Ladino and native Indian Guatemalan infants developed high rates (96–100%) of protective antibodies after receiving conjugate Haemophilus influenzae type b and hepatitis B vaccines at 2, 4 and 6 months of age. Native Indian infants developed significantly (p <0.01) higher geometric mean anti-PRP (polyribose-ribitol-phosphate) and anti-HBs (anti-hepatitis b surface) antibody concentrations than Ladino infants. Malnourished infants generally responded as well as healthy infants. Unvaccinated native Indian infants had higher rates of developing anti-PRP antibodies than Ladino infants by seven months of age. [Copyright &y& Elsevier]