Prevalence of vaccine-derived hepatitis B surface antibodies in children and adolescents in Germany: results from a population-based survey, 2014-2017.

INTRODUCTION: Childhood vaccination against hepatitis B has been recommended in Germany since 1995. WHO defines a primary vaccination series as successful if the initial hepatitis B surface antibody (anti-HBs) level is ≥ 10 IU/L directly after vaccination. Anti-HBs levels vary depending on the number of doses, type of vaccine, and time interval between the last two doses. In 2021, Germany began to recommend three instead of four doses of polyvalent hepatitis-B-containing vaccines. Our aim was to estimate the proportion of vaccinated children in Germany with anti-HBs levels < 10 IU/L, 10-99 IU/L, and ≥ 100 IU/L by number and type of vaccine, and assess if number of doses and compliance with recommended time interval between the last two doses are associated with an anti-HBs level ≥ 10 IU/L when considering type of vaccine and time since last dose. METHODS: We used data from a national cross-sectional study (2014-2017) of children (3-17 years). We excluded participants with unknown vaccination dates, unreadable or incomplete vaccination cards, and hepatitis B virus (HBV)-positive participants. We defined a recommended schedule as a vaccination series with at least six months between the two last doses and having three doses or more. We calculated weighted anti-HBs sero-prevalence for three anti-HBs levels: < 10 IU/L, 10-99 IU/L and ≥ 100 IU/L. We fitted two logistic regression models to examine the relationship between number of doses and recommended schedule on anti-HBs levels (≥ 10 IU/L and ≥ 100 IU/L) considering time since last dose and type of vaccine (Infanrix, Hexavac, Monovalent). RESULTS: We included 2,489 participants. The weighted proportion of vaccinated children per anti-HBs level was < 10 IU/L: 36.3% [95%CI 34.0-38.7%], 10-99 IU/L: 35.7% [33.2-38.2%] and ≥ 100 IU/L: 28.0% [25.9-30.2%]. We did not find an association between a recommended schedule of three versus four doses and anti-HBs ≥ 10 IU/L or ≥ 100 IU/L. CONCLUSIONS: Anti-HBs levels in later childhood were about equal, whether children received three or four doses. This implies that the change in the recommendations does not affect the anti-HBs level among children in Germany. Future studies are needed on the association of anti-HBs levels and adequate sustained protection against HBV.

COVID-19 cross-border case and contact tracing activities - experiences and lessons learnt, Germany, April-December 2020.

BACKGROUND: Interruption of transmission chains has been crucial in the COVID-19 response. The Emergency Operations Centre (EOC) at the Robert Koch Institute (RKI) coordinated cross-border case and contact tracing activities at the national level by sharing data with German public health authorities (PHA) and other countries. Data on these activities were not collected in the national surveillance system, and thus were challenging to quantify. Our aim was to describe cross-border COVID-19 case and contact tracing activities including lessons learnt by PHA to adapt the procedures accordingly. METHODS: Case and contact tracing events were recorded using unique identifiers. We collected data on cases, contacts, dates of exposure and/or SARS-CoV-2 positive test results and exposure setting. We performed descriptive analyses of events from 06.04.-31.12.2020. We conducted interviews with PHA to understand experiences and lessons learnt, applying a thematic approach for qualitative analysis. RESULTS: From 06.04.-31.12.2020 data on 7,527 cross-border COVID-19 case and contact tracing activities were collected. Germany initiated communication 5,200 times, and other countries 2,327 times. Communication from other countries was most frequently initiated by Austria (n = 1,184, 50.9%), Switzerland (n = 338, 14.5%), and the Netherlands (n = 168, 7.2%). Overall, 3,719 events (49.4%) included information on 5,757 cases (median 1, range: 1-42), and 4,114 events (54.7%) included information on 13,737 contacts (median: 1, range: 1-1,872). The setting of exposure was communicated for 2,247 of the events (54.6%), and most frequently included private gatherings (35.2%), flights (24.1%) and work-related meetings (20.3%). The median time delay between exposure date and contact information receipt at RKI was five days. Delay between positive test result and case information receipt was three days. Main challenges identified through five interviews were missing data or delayed accessibility particularly from flights, and lack of clear and easy to use communication channels. More and better trained staff were mentioned as ideas for improving future pandemic response preparedness. CONCLUSION: Cross-border case and contact tracing data can supplement routine surveillance but are challenging to measure. We need improved systems for cross-border event management, by improving training and communication channels, that will help strengthen monitoring activities to better guide public health decision-making and secure a good future pandemic response.

Large Multicountry Outbreak of Invasive Listeriosis by a Listeria monocytogenes ST394 Clone Linked to Smoked Rainbow Trout, 2020 to 2021.

Whole-genome sequencing (WGS) has revolutionized surveillance of infectious diseases. Disease outbreaks can now be detected with high precision, and correct attribution of infection sources has been improved. Listeriosis, caused by the bacterium Listeria monocytogenes, is a foodborne disease with a high case fatality rate and a large proportion of outbreak-related cases. Timely recognition of listeriosis outbreaks and precise allocation of food sources are important to prevent further infections and to promote public health. We report the WGS-based identification of a large multinational listeriosis outbreak with 55 cases that affected Germany, Austria, Denmark, and Switzerland during 2020 and 2021. Clinical isolates formed a highly clonal cluster (called Ny9) based on core genome multilocus sequence typing (cgMLST). Routine and ad hoc investigations of food samples identified L. monocytogenes isolates from smoked rainbow trout filets from a Danish producer grouping with the Ny9 cluster. Patient interviews confirmed consumption of rainbow trout as the most likely infection source. The Ny9 cluster was caused by a MLST sequence type (ST) ST394 clone belonging to molecular serogroup IIa, forming a distinct clade within molecular serogroup IIa strains. Analysis of the Ny9 genome revealed clpY, dgcB, and recQ inactivating mutations, but phenotypic characterization of several virulence-associated traits of a representative Ny9 isolate showed that the outbreak strain had the same pathogenic potential as other serogroup IIa strains. Our report demonstrates that international food trade can cause multicountry outbreaks that necessitate cross-border outbreak collaboration. It also corroborates the relevance of ready-to-eat smoked fish products as causes for listeriosis. IMPORTANCE Listeriosis is a severe infectious disease in humans and characterized by an exceptionally high case fatality rate. The disease is transmitted through consumption of food contaminated by the bacterium Listeria monocytogenes. Outbreaks of listeriosis often occur but can be recognized and stopped through implementation of whole-genome sequencing-based pathogen surveillance systems. We here describe the detection and management of a large listeriosis outbreak in Germany and three neighboring countries. This outbreak was caused by rainbow trout filet, which was contaminated by a L. monocytogenes clone belonging to sequence type ST394. This work further expands our knowledge on the genetic diversity and transmission routes of an important foodborne pathogen.

Hepatitis B vaccination coverage in Germany: systematic review.

BACKGROUND: Despite being considered as a low prevalence country for hepatitis B (HBV), some populations in Germany are at higher risk of infection. In the context of the World Health Organization's (WHO) viral hepatitis elimination goals, a valid epidemiological data base is needed to plan and monitor the national response. Prevention strategies include general and targeted HBV vaccination programmes. OBJECTIVE: The aim of this work was to estimate the HBV vaccination coverage (VC) in the general population (GP) and different population groups in Germany from available evidence and to identify current evidence gaps for future research. METHODS: We conducted a systematic review on HBV VC in the general population and populations at high risk of HBV exposure or severe infection in Germany. We included eligible publications (01/01/2017 to 06/06/2020) from databases Embase, Pubmed and Livivo, from a previous scoping review (including data published 01/01/2005-17/03/2017), from the national surveillance system and screened the reference lists of all publications at full text level. Risk of bias was assessed using the Hoy et al. tool. RESULTS: We included 68 publications of 67 studies and assigned them to one or more suitable population groups. Twenty-one studies contained data among children/adolescents and three among adults from the GP (VC 65.8-90.5% and 22.9-52.1%, respectively), one among travelers (VC 89.0%), 13 among immunocompromised populations (VC 7.8-89.0%), 16 among populations with occupational risk and 16 with non-occupational risk of HBV exposure (VC 63.6-96.5% and 4.4-84.5%, respectively). CONCLUSION: Comprehensive evidence at low risk of bias was identified for children/adolescents. However, 25 years after including HBV in the national immunisation schedule, VC in Germany is still below the 95%-goal defined by WHO. For people at occupational risk of HBV exposure, VC was mostly reported to be over the WHO goal of 80%, but quality of evidence was heterogenous and should be improved. For people at non-occupational risk of HBV exposure, evidence was sparse and of low quality. The low VC highlights the need for future research to plan vaccination programmes targeting these populations.

Developing and Piloting a Standardized European Protocol for Hepatitis C Prevalence Surveys in the General Population (2016-2019).

Background: A robust estimate of the number of people with chronic hepatitis C virus (HCV) infection is essential for an appropriate public health response and for monitoring progress toward the WHO goal of eliminating viral hepatitis. Existing HCV prevalence studies in the European Union (EU)/European Economic Area (EEA) countries are heterogeneous and often of poor quality due to non-probability based sampling methods, small sample sizes and lack of standardization, leading to poor national representativeness. This project aimed to develop and pilot standardized protocols for undertaking nationally representative HCV prevalence surveys in the general adult population. Methods: From 2016 to 2019 a team from the Robert Koch-Institute contracted by the European Centre for Disease Prevention and Control synthesized evidence on existing HCV prevalence surveys and survey methodology and drafted a protocol. The methodological elements of the protocol were piloted and evaluated in Bulgaria, Finland and Italy, and lessons learnt from the pilots were integrated in the final protocol. An international multidisciplinary expert group was consulted regularly. Results: The protocol includes three alternative study approaches: a stand-alone survey; a "nested" survey within an existing health survey; and a retrospective testing survey approach. A decision algorithm advising which approach to use was developed. The protocol was piloted and finalized covering minimum and gold standards for all steps to be implemented from sampling, data protection and ethical issues, recruitment, specimen collection and laboratory testing options, staff training, data management and analysis and budget considerations. Through piloting, the survey approaches were effectively implemented to produce HCV prevalence estimates and the pilots highlighted the strengths and limitations of each approach and key lessons learnt were used to improve the protocol. Conclusions: An evidence-based protocol for undertaking HCV prevalence serosurveys in the general population reflecting the different needs, resources and epidemiological situations has been developed, effectively implemented and refined through piloting. This technical guidance supports EU/EEA countries in their efforts to estimate their national hepatitis C burden as part of monitoring progress toward the elimination targets.

Prevalence of Hepatitis B, C, and D in Germany: Results From a Scoping Review.

Background: One of the five strategic directions in the World Health Organization global health sector strategy on viral hepatitis 2016-2021 is to generate strong strategic information for focused action to understand the viral hepatitis epidemic and focus the response. Knowledge of national prevalence is a cornerstone of strategic information. Germany is considered to be a low prevalence country for viral hepatitis B, C, and D, however the prevalence is likely to be higher among at-risk groups. Methods: The aim of this work was to give a detailed overview of the prevalence of viral hepatitis B (HBsAg, anti-HBc), C (anti-HCV, HCV RNA), and D (anti-HDV, HDV RNA) in different population groups in Germany. Therefore, we analyzed the results of a comprehensive literature search on various aspects of the epidemiological situation of hepatitis B, C, and D in Germany. Eligible publications including information on hepatitis B, C, and D prevalence were extracted from the overall spreadsheet table and summarized and analyzed based on virus and different population groups. A quality appraisal was performed using a checklist developed by Hoy et al. to assess risk of bias in prevalence studies. Results: Overall, 51 publications were identified through the literature search. The overall prevalence of HBsAg in the general (and proxy) population ranged from 0.3 to 1.6%. Among at-risk groups, including clinical populations and health care workers, the HBsAg prevalence ranged from 0.2% (among rheumatic patients) to 4.5% among HIV positive patients. The overall prevalence of anti-HCV in the general (and proxy) population ranged from 0.2 to 1.9%. Among at-risk groups, including clinical populations and health care workers, the anti-HCV prevalence ranged from 0.04% (among health care workers) to 68.0% among people who inject drugs. Conclusions: The hepatitis B and C prevalence in the general population in Germany is low. Prevalence is high to very high among at-risk populations, however for some groups evidence was incomplete or missing completely. To reach the elimination goals in Germany and implement a targeted response, more research among at-risk groups is needed.

Prevalence of hepatitis C in the adult population of Bulgaria: a pilot study.

OBJECTIVE: This study piloted a European technical protocol for conducting chronic hepatitis C prevalence surveys in the general population. The pilot study took place in the Bulgarian city of Stara Zagora in 2018, and results of setting up, conducting and evaluating the survey are presented. RESULTS: A probability-based sample of the general adult population was drawn from the local population registry, stratified by age and sex. A sample size of 999 was calculated, and accounting for 50% non-response, 1998 registered invitation letters were sent. Venous blood samples and questionnaire data were collected by the Regional Health Inspectorate in Stara Zagora. Blood samples were tested for anti-HCV, and if reactive for RNA. 252 (21.6%) of the participants were included in the study. Mean age and sex distribution differed between the participants (55.9 years, 60.3% females) and the total sample (48.9 years, 53.4%). The weighted chronic HCV prevalence among participants was 0.9% [95% CI 0.2-4.2%]. The approach of only sending registered letters contributed to a low response rate, and more efforts are needed to reduce non-response, especially among men and younger age groups. Results of the evaluation were integrated in the final technical protocol.

The epidemiology of Hepatitis B, C and D in Germany: A scoping review.

BACKGROUND: Germany is considered to be a low prevalence country for viral Hepatitis B, C and D (HBV, HCV, HDV). However, the burden of disease can be high among subpopulations. To meet the world Health Organization (WHO) viral hepatitis (VH) elimination goals, a national strategy was developed by the German government in 2016. We performed a scoping review to understand the baseline epidemiological situation in Germany regarding burden of disease, sequelae and care of HBV, HCV and HDV as a reference to monitor the progress of the national VH elimination and to identify further knowledge gaps and research needs. METHODS: The protocol of the systematic review was prepared following the PRISMA statement guidelines for scoping reviews. Relevant search terms were used to identify eligible studies according to the research questions. We searched six online databases for original work published between January 2005 and March 2017. Based on the identified references, a matrix was developed presenting the eligible literature by targeted population group and outcome category. RESULTS: 104 publications were eligible for extraction covering 299 outcome results. The population groups targeted in the identified studies included the general population and proxy populations, a range of clinical populations, people who inject drugs, men who have sex with men, healthcare workers, people in prisons and different migrant/mobile populations. Other vulnerable populations (e.g. sex workers) were not targeted. Overall, good evidence was found for HBV and HCV prevalence and HBV vaccination coverage in the GP and proxy populations. Evidence for these outcomes was weaker in populations at risk for VH. For HBV and HCV incidence and mortality, we identified large evidence gaps in all population groups. Outcomes on VH sequelae and care were mainly covered by studies in clinical populations of people living with viral hepatitis. For HDV the overall evidence available was scarce. CONCLUSIONS: We created a comprehensive evidence-based overview on the current epidemiological situation of viral hepatitis in Germany. We identified knowledge gaps for further research and established a baseline for future monitoring of viral hepatitis elimination goals in Germany.

HIV testing in Europe: Evaluating the impact, added value, relevance and usability of the European Centre for Disease Prevention and Control (ECDC)'s 2010 HIV testing guidance.

BACKGROUND: An evaluation of the 2010 ECDC guidance on HIV testing, conducted in October 2015-January 2016, assessed its impact, added value, relevance and usability and the need for updated guidance. METHODS: Data sources were two surveys: one for the primary target audience (health policymakers and decision makers, national programme managers and ECDC official contact points in the European Union/European Economic Area (EU/EEA) countries and one for a broader target audience (clinicians, civil society organisations and international public health agencies); two moderated focus group discussions (17 participants each); webpage access data; a literature citation review; and an expert consultation (18 participants) to discuss the evaluation findings. RESULTS: Twenty-three of 28 primary target audience and 31 of 51 broader target audience respondents indicated the guidance was the most relevant when compared with other international guidance. Primary target audience respondents in 11 of 23 countries reported that they had used the guidance in development, monitoring and/or evaluation of their national HIV testing policy, guidelines, programme and/or strategy, and 29 of 51 of the broader target audience respondents reported having used the guidance in their work. Both the primary and broader target audience considered it important or very important to have an EU/EEA-level HIV testing guidance (23/28 and 46/51, respectively). CONCLUSION: The guidance has been widely used to develop policies, guidelines, programmes and strategies in the EU/EEA and should be regularly updated due to continuous developments in the field in order to continue to serve as an important reference guidance in the region.

Associations between national viral hepatitis policies/programmes and country-level socioeconomic factors: a sub-analysis of data from the 2013 WHO viral hepatitis policy report.

BACKGROUND: As more countries worldwide develop national viral hepatitis strategies, it is important to ask whether context-specific factors affect their decision-making. This study aimed to determine whether country-level socioeconomic factors are associated with viral hepatitis programmes and policy responses across WHO Member States (MS). METHODS: WHO MS focal points completed a questionnaire on national viral hepatitis policies. This secondary analysis of data reported in the 2013 Global Policy Report on the Prevention and Control of Viral Hepatitis in WHO Member States used logistic regression to examine associations between four survey questions and four socioeconomic factors: country income level, Human Development Index (HDI), health expenditure and physician density. RESULTS: This analysis included 119 MS. MS were more likely to have routine viral hepatitis surveillance and to have a national strategy and/or policy/guidelines for preventing infection in healthcare settings if they were in the higher binary categories for income level, HDI, health expenditure and physician density. In multivariable analyses, the only significant finding was a positive association between having routine surveillance and being in the higher binary HDI category (adjusted odds ratio 26; 95% confidence interval 2.0-340). CONCLUSION: Countries with differing socioeconomic status indicators did not appear to differ greatly regarding the existence of key national policies and programmes. A more nuanced understanding of the multifaceted interactions of socioeconomic factors, health policy, service delivery and health outcomes is needed to support country-level efforts to eliminate viral hepatitis.

Are the testing needs of key European populations affected by hepatitis B and hepatitis C being addressed? A scoping review of testing studies in Europe.

AIM: To investigate whether or not key populations affected by hepatitis B and hepatitis C are being tested sufficiently for these diseases throughout the European region. METHODS: We searched MEDLINE and EMBASE for studies on HBV and HCV testing in the 53 Member States of the World Health Organization European Region following PRISMA criteria. RESULTS: 136 English-language studies from 24 countries published between January 2007 and June 2013 were found. Most studies took place in 6 countries: France, Germany, Italy, the Netherlands, Turkey, and the United Kingdom. 37 studies (27%) addressed HBV, 46 (34%) HCV, and 53 (39%) both diseases. The largest categories of study populations were people who use drugs (18%) and health care patient populations (17%). Far fewer studies focused on migrants, prison inmates, or men who have sex with men. CONCLUSIONS: The overall evidence base on HBV and HCV testing has considerable gaps in terms of the countries and populations represented and validity of testing uptake data. More research is needed throughout Europe to guide efforts to provide testing to certain key populations.

A systematic review of Hepatitis C virus treatment uptake among people who inject drugs in the European Region.

BACKGROUND: Fifteen million adults in the World Health Organization European Region are estimated to have active hepatitis C infection. Intravenous drug use is a major hepatitis C transmission route in this region, and people who inject drugs (PWID) constitute a high-risk and high-prevalence population. A systematic review was conducted to assess levels of hepatitis C treatment uptake among PWID in Europe. METHODS: Searches in MEDLINE and EMBASE were carried out for articles in any language published between 1 January 2000 and 31 December 2012. Articles were included in the review if they presented original research findings about hepatitis C treatment uptake levels among people who reported injecting drugs currently or formerly, as well as those who reported using drugs currently or formerly (mode of consumption not specified). Treatment uptake data were extracted if uptake was measurable in relation to the number of patients who either: (a) tested HCV antibody-positive; (b) tested positive for HCV-RNA; or (c) tested positive for HCV-RNA and met additional treatment criteria. RESULTS: Twenty-five articles from 12 countries were included in the review. Among groups of drug-using study participants who were hepatitis C antibody-positive, the median treatment uptake level was 17%, and among those who were hepatitis C RNA-positive, the median was 30%. In the 11 studies reporting specifically on treatment uptake among current and former injecting drug users, hepatitis C RNA-positive study populations had a median treatment uptake level of 32%. Only one study reported on treatment uptake for current drug users. CONCLUSIONS: This systematic review indicates that hepatitis C treatment uptake is relatively low among drug users in several European countries, and also points to considerable knowledge gaps regarding treatment uptake levels in this population. There was large variability in treatment uptake levels, suggesting that there may be major differences between and within countries in relation to treatment availability, drug-using populations in need of treatment, and the existence of integrated health care services targeting drug users. Stronger national hepatitis C treatment policies are needed, along with efforts to increase knowledge and reduce misconceptions among physicians regarding the feasibility and importance of treating drug users who have hepatitis C.

Hepatitis C virus infection epidemiology among people who inject drugs in Europe: a systematic review of data for scaling up treatment and prevention.

BACKGROUND: People who inject drugs (PWID) are a key population affected by hepatitis C virus (HCV). Treatment options are improving and may enhance prevention; however access for PWID may be poor. The availability in the literature of information on seven main topic areas (incidence, chronicity, genotypes, HIV co-infection, diagnosis and treatment uptake, and burden of disease) to guide HCV treatment and prevention scale-up for PWID in the 27 countries of the European Union is systematically reviewed. METHODS AND FINDINGS: We searched MEDLINE, EMBASE and Cochrane Library for publications between 1 January 2000 and 31 December 2012, with a search strategy of general keywords regarding viral hepatitis, substance abuse and geographic scope, as well as topic-specific keywords. Additional articles were found through structured email consultations with a large European expert network. Data availability was highly variable and important limitations existed in comparability and representativeness. Nine of 27 countries had data on HCV incidence among PWID, which was often high (2.7-66/100 person-years, median 13, Interquartile range (IQR) 8.7-28). Most common HCV genotypes were G1 and G3; however, G4 may be increasing, while the proportion of traditionally 'difficult to treat' genotypes (G1+G4) showed large variation (median 53, IQR 43-62). Twelve countries reported on HCV chronicity (median 72, IQR 64-81) and 22 on HIV prevalence in HCV-infected PWID (median 3.9%, IQR 0.2-28). Undiagnosed infection, assessed in five countries, was high (median 49%, IQR 38-64), while of those diagnosed, the proportion entering treatment was low (median 9.5%, IQR 3.5-15). Burden of disease, where assessed, was high and will rise in the next decade. CONCLUSION: Key data on HCV epidemiology, care and disease burden among PWID in Europe are sparse but suggest many undiagnosed infections and poor treatment uptake. Stronger efforts are needed to improve data availability to guide an increase in HCV treatment among PWID.