During 2021 and 2023, a team of researchers at the Robert Koch Institute (RKI) and partnering institutions conducted two living systematic reviews (LSRs) on the effectiveness of COVID-19 vaccines in different age groups to inform recommendations of the Standing Committee on Vaccination in Germany (Ständige Impfkommission, STIKO). Based on our experience from the realization of these LSRs, we developed certain criteria to assess the needs and feasibility of conducting LSRs. Combining these with previously established criteria, we developed the following set to inform future planning of LSRs for STIKO: Needs criterion (N)1: Relevance of the research question, N2: Certainty of evidence (CoE) at baseline; N3: Expected need for Population-Intervention-Comparator-Outcome (PICO) adaptations; N4: Expected new evidence over time; N5: Expected impact of new evidence on CoE; Feasibility criterion (F)1: Availability of sufficient human resources; F2: Feasibility of timely dissemination of the results to inform decision-making. For each criterion we suggest rating options which may support the decision to conduct an LSR or other forms of evidence synthesis when following the provided flowchart.The suggested criteria were developed on the basis of the experiences from exemplary reviews in a specific research field (i.e., COVID-19 vaccination), and did not follow a formal development or validation process. However, these criteria might also be useful to assess whether questions from other research fields can and should be answered using the LSR approach, or assist in determining whether the use of an LSR is sensible and feasible for specific questions in health policy and practice.

Background The SARS-CoV-2 Omicron variant is currently the dominant variant globally. This 3rd interim analysis of a living systematic review summarizes evidence on COVID-19 vaccine effectiveness (VE) and duration of protection against Omicron.Methods We systematically searched the COVID-19 literature for controlled studies evaluating the effectiveness of COVID-19 vaccines approved in the European Union up to 14/01/2022, complemented by hand-searches of websites and metasearch engines up to 11/02/2022. We considered the following comparisons: full primary immunization vs. no vaccination; booster immunization vs. no vaccination; booster vs. primary immunization. VE against any confirmed SARS-CoV-2 infection, symptomatic, and severe COVID-19 (i.e. COVID-19-related hospitalization, ICU-admission, or death) was indicated providing estimate ranges. Meta-analysis was not performed due to high study heterogeneity. Risk of bias was assessed with ROBINS-I, certainty of evidence evaluated using GRADE.Results We identified 26 studies, including 430 to 2.2 million participants.VE against any confirmed SARS-CoV-2 infection compared to no vaccination ranged between 0-62% after full primary immunization, and between 34-66% after a booster dose. VE-range for booster vs. primary immunization was 34-54.6%.Against symptomatic COVID-19, VE ranged between 6-76% after full primary immunization, and between 19-73.9% after booster immunization, if compared to no vaccination. When comparing booster vs. primary immunization VE ranged between 56-69%.VE against severe COVID-19 compared to no vaccination ranged between 3-84% after full primary immunization, and between 12-100% after a booster dose. One study compared booster vs. primary immunization (VE 100%, 95% CI 71.4-100).VE was characterized by a moderate to strong decline within three to six months for SARS-CoV-2 infections and symptomatic COVID-19. Against severe COVID-19 protection remained robust at least for up to six months. Waning immunity was more profound after primary than booster immunization.Risk of bias was moderate to critical across studies and outcomes. GRADE-certainty was very low for all outcomes.Author’s conclusions Under the Omicron variant, effectiveness of EU-licensed COVID-19 vaccines in preventing any SARS-CoV-2 infection or mild disease is low and only short-lasting after primary immunization, but can be improved by booster vaccination. VE against severe COVID-19 remains high and is long-lasting, especially after receiving the booster vaccination.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementThis study did not receive any funding### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesI confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data produced in the present work are contained in the manuscript

ZusammenfassungDie Ständige Impfkommission (STIKO) ist ein ehrenamtliches Gremium, dessen 18 ExpertInnen vom Bundesministerium für Gesundheit (BMG) berufen werden. Die wissenschaftliche Arbeit der STIKO wird durch eine Geschäftsstelle am Robert Koch-Institut (RKI) unterstützt. Die STIKO erarbeitet unabhängige Impfempfehlungen für Deutschland mit der Methodik der evidenzbasierten Medizin (EBM).Während der COVID-19-Pandemie sah sich die STIKO mit großen Herausforderungen konfrontiert. Innerhalb kürzester Zeit wurden mehrere COVID-19-Impfstoffe z. T. neuer Technologien zugelassen. Die Nutzen-Risiko-Abwägung wurde nach dem jeweils aktuellen Wissensstand durchgeführt. Die Impfempfehlungen mussten fortlaufend angepasst werden an die sich stetig ändernde Epidemiologie von SARS-CoV‑2, zunehmende Impfstoffverfügbarkeiten, neue Zulassungen, Indikationserweiterungen und neue Sicherheitssignale (z. B. Sinusvenenthrombosen nach Vektor-basierten Impfstoffen). Die STIKO hat ihre Arbeitsweise der Situation angepasst und während der Pandemie Beeindruckendes geleistet. Sie hat auch unter Zeitdruck die EBM-Prinzipien beachtet und Impfempfehlungen basierend auf der jeweils verfügbaren Evidenz erarbeitet. Jede Impfempfehlung wurde vor der endgültigen Beschlussfassung in ein Stellungnahmeverfahren mit den betroffenen Fachkreisen (z. B. med. Fachgesellschaften, Gesundheitsbehörden) gegeben. Dabei wurde trotz der kurzen Fristen umfassend und konstruktiv kommentiert und der STIKO die Möglichkeit gegeben, ihre Empfehlungen unter Berücksichtigung der Stellungnahmen zu diskutieren, anzupassen und somit auf breiten Konsens zu bauen.Die zurückliegenden Monate haben gezeigt, dass es möglich und sinnvoll ist, Impfempfehlungen auch während einer Pandemie nach den Prinzipien der EBM zu erarbeiten. Ausreichende personelle Ressourcen in der STIKO-Geschäftsstelle sind dabei essentiell.

Abstract Background Control of the 2019 coronavirus disease (COVID-19) pandemic in Germany and return to pre-pandemic behaviour can only be achieved through natural or vaccine-induced immunity. Sufficient vaccine capacity promotes interest in the necessary and feasible target vaccination coverage. Methods An age and risk group stratified SEIR transmission model was used to assess the impact of vaccination coverage ranging 65%-95% for 12-59-year-olds and 90%-95% for ≥ 60-year-olds on COVID-19 incidence and intensive care unit (ICU) utilization between 01.07.2021-31.03.2022. Separate implementation of licensed vaccines allows to consider different efficacies, delivery rates and age-specific national vaccination recommendations. The analysis was conducted under different assumptions about contact behaviour during summer, reduction of daily contacts with increasing number of cases, daily vaccination uptake and the dominant variant. Data from the COVIMO study (N = 3004, data collection: 17.05.-09.06.2021) were used to define the population percentage willing to be vaccinated. Results The COVIMO study indicates an achievable vaccination compliance rate of 83.9% among 12-59-year-olds and 94.8% among those ≥ 60-year-olds. Maximum incidence or ICU utilization during observation period decreases from 385 to 61 and 6220 to 2800, respectively, with an increase in vaccination coverage from 65% to 95% of 12-59-year-olds, 90% vaccination rate among ≥ 60-year-olds, compared to pre-pandemic reduced contact behaviour in summer and reduction of contacts as case numbers increase. Conclusions The vaccination campaign should be continued at high intensity until at least 85% of 12-59-year-olds or 90% of ≥ 60-year-olds are fully vaccinated against COVID-19. Based on the population's willingness to be vaccinated, this goal seemed feasible. Key messages • Mathematical modeling was used to determine an evidence-based target vaccination coverage of ≥ 85%. • Expertise in modeling should be further strengthened.

BackgroundThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is currently the dominant variant globally. This third interim analysis of a living systematic review summarizes evidence on the effectiveness of the coronavirus disease 2019 (COVID-19) vaccine (vaccine effectiveness, VE) and duration of protection against Omicron.MethodsWe systematically searched literature on COVID-19 for controlled studies, evaluating the effectiveness of COVID-19 vaccines approved in the European Union up to 14/01/2022, complemented by hand searches of websites and metasearch engines up to 11/02/2022. We considered the following comparisons: full primary immunization vs. no vaccination, booster immunization vs. no vaccination, and booster vs. full primary immunization. VE against any confirmed SARS-CoV-2 infection, symptomatic, and severe COVID-19 (i.e., COVID-19-related hospitalization, ICU admission, or death) was indicated, providing estimate ranges. Meta-analysis was not performed due to high study heterogeneity. The risk of bias was assessed with ROBINS-I, and the certainty of the evidence was evaluated using GRADE.ResultsWe identified 26 studies, including 430 to 2.2 million participants, which evaluated VE estimates against infections with the SARS-CoV-2 Omicron variant. VE against any confirmed SARS-CoV-2 infection ranged between 0–62% after full primary immunization and between 34–66% after a booster dose compared to no vaccination. VE range for booster vs. full primary immunization was 34–54.6%. After full primary immunization VE against symptomatic COVID-19 ranged between 6-76%. After booster immunization VE ranged between 3-84% compared to no vaccination and between 56-69% compared to full primary immunization. VE against severe COVID-19 ranged between 3-84% after full primary immunization and between 12-100% after booster immunization compared to no vaccination, and 100% (95% CI 71.4-100) compared to full primary immunization (data from only one study). VE was characterized by a moderate to strong decline within 3–6 months for SARS-CoV-2 infections and symptomatic COVID-19. Against severe COVID-19, protection remained robust for at least up to 6 months. Waning immunity was more profound after primary than booster immunization. The risk of bias was moderate to critical across studies and outcomes. GRADE certainty was very low for all outcomes.ConclusionsUnder the Omicron variant, the effectiveness of EU-licensed COVID-19 vaccines in preventing any SARS-CoV-2 infection is low and only short-lasting after full primary immunization, but can be improved by booster vaccination. VE against severe COVID-19 remains high and is long-lasting, especially after receiving the booster vaccination.

Background: To date, more than 628 million confirmed SARS-CoV-2 infections were recorded globally. Highest incidences were usually observed in school-aged children. Methods: The aim of this living systematic review is to evaluate vaccine efficacy/effectiveness (VE) and safety of COVID-19 vaccines approved in the European Union for children aged 5-11 years. In this version, we included studies of any design identified through searching the COVID-19 L·OVE (Living OVerview of Evidence) platform up to 13 September 2022. We assessed risk of bias and rated the certainty of evidence (CoE) using GRADE. Findings: In total 4,651 records were screened and 30 studies were included. The studies assessed two mRNA vaccines (BNT162b2 or mRNA-1273), with pivotal randomized controlled trials (RCTs) being conducted before and all other studies during the Omicron era.VE against pre-Omicron variant SARS-CoV-2 infections was 73·0% (41%-87%, 1 RCT, CoE: moderate), while VE against Omicron variant SARS-CoV-2 infections was 41·9% (27·4%-53·5%, 6 non-randomized studies of interventions [NRSIs], CoE: moderate). Pre-Omicron VE against symptomatic COVID-19 was 86·7% (58·1-95·8%, 2 RCTs, CoE: moderate) and 38·7% (21·7%-52·1%, 5 NRSIs, CoE: moderate) after Omicron emergence. No cases of severe COVID-19 were reported in RCTs. VE against Omicron-associated COVID-19 hospitalisation was 75·3% (68·0%-81·0%, 6 NRSIs, CoE: moderate).Safety data suggests no increased risk of serious adverse events (RR 0·83 [0·21-3·33], 2 RCTs, CoE: low), with approximately 1·2 events per 100,000 administered vaccines reported in real-life observations. Evidence on the risk of myocarditis was uncertain (RR 4·6 [0·1-156·1], 1 NRSI, CoE: low), with 0·13-1·04 observed events per 100,000 administered vaccines. The risk of AEs (RR 1·21 [1·07-1·38], CoE: moderate) was higher among mRNA-vaccinated children. Interpretation: In 5-11-year-old children mRNA-vaccines are moderately effective against infections with the Omicron variant, but probably still protect well against COVID-19 hospitalisations. Vaccines were reactogenic but generally safe.

The expression of inducible nitric oxide synthase (iNOS) is markedly elevated in rat colon cancers induced by azoxymethane (AOM). In addition, iNOS can be detected in most adenomas and dysplastic aberrant crypt foci (ACF), suggesting that iNOS plays an important role in colon carcinogenesis. In the present study, the effect of an iNOS inhibitor, ONO-1714 ((1S,5S,6R,7R)-7-chloro-3-imino-5-methyl-2-azabicyclo[4.1.0] heptane hydrochloride), on AOM-induced rat colon carcinogenesis was investigated. Male F344 rats were treated with 15 mg/kg body weight of AOM once a week, for 2 weeks. ONO-1714 was given to the rats at doses of 10, 20, 50, and 100 ppm in diet for 4 weeks from the day before the first carcinogen treatment. The number of AOM-induced ACF in the rats receiving 10, 20, 50 and 100 ppm ONO-1714 were 94, 73 (P < 0.05), 71 (P < 0.005), and 53% (P < 0.0005), respectively, of the control value. Moreover, the mean number of aberrant crypts per focus was significantly lowered in 100 ppm ONO-1714 group (P < 0.05). Then, the effects of long-term treatment (32 weeks) with 50 and 100 ppm ONO-1714 on AOM-induced colorectal tumor development were examined. Although incidences and multiplicities of colon tumors did not significantly differ among the groups, number of tumors developing in the middle part of colon were reduced with both 50 and 100 ppm doses (P < 0.05). Furthermore, colon tumor volume tended to be decreased by ONO-1714 treatment, and the number of colon tumors more than 3 mm in diameter was significantly lowered in the 100 ppm ONO-1714 group (P < 0.01). These results suggest that iNOS plays roles in both early and late stages of colon carcinogenesis.

BACKGROUND:The WHO European Region targets the elimination of measles, rubella, and the congenital rubella syndrome and welcomes mumps elimination via the joint MMR vaccine. In a push towards this elimination goal, Germany introduced a recommendation on MMR vaccination for adults in 2010 to prevent increasing numbers of measles cases among adults and to strengthen herd immunity.METHODS:The prevalence of anti-measles, -mumps, and -rubella IgG antibodies was analysed in 7,115 participants between the ages of 18 and 79 years in the German Health Interview and Examination Survey. Risk factors of seronegativity of adults born 1970 or later were determined.FINDINGS:The seroprevalence of anti-measles IgG antibodies was more than 97% in adults born before 1965 and less than 90% in adults born afterwards. Prevalence and GMTs declined with later years of birth. Seronegativity was associated with two-sided migration background and region of residence in East Germany. For anti-mumps IgG antibodies, the seroprevalence was less than 90% in almost all age groups. Prevalence and GMTs declined with later years of birth. Seronegativity was not associated with any socio-demographic factor. Anti-rubella IgG seropositivity was found in more than 90% of adults born before 1985. GMTs declined in younger age groups. Seronegativity was associated with birth between 1980 and 1993 and male gender. High socio-economic status lowered the odds of being seronegative.INTERPRETATION:These data reinforce the implementation of the vaccination recommendation for adults and provide the basis for further evaluation of this measure.FUNDING:The Federal Ministry of Health, Germany.

The Delta variant has become the dominant strain of SARS-CoV-2. We summarised the evidence on COVID-19 vaccine effectiveness (VE) identified in 17 studies that investigated VE against different endpoints. Pooled VE was 63.1% (95% confidence interval (CI): 40.9-76.9) against asymptomatic infection, 75.7% (95% CI: 69.3-80.8) against symptomatic infection and 90.9% (95% CI: 84.5-94.7) against hospitalisation. Compared with the Alpha variant, VE against mild outcomes was reduced by 10-20%, but fully maintained against severe COVID-19.

Evidence on COVID-19 vaccine efficacy/effectiveness (VE) in preventing asymptomatic SARS-CoV-2 infections is needed to guide public health recommendations for vaccinated people. We report interim results of a living systematic review. We identified a total of 30 studies that investigated VE against symptomatic and/or asymptomatic infection. In fully vaccinated individuals, VE against symptomatic and asymptomatic infections was 80–90% in nearly all studies. Fully vaccinated persons are less likely to become infected and contribute to transmission.

Background: Universal mass vaccination (UMV) against rotavirus has been implemented in many but not all European countries. This study investigated the impact of UMV on rotavirus incidence trends by com-paring European countries with UMV: Belgium, England/Wales and Germany versus countries without UMV: Denmark and the Netherlands. Methods: For this observational retrospective cohort study, time series data (2001-2016) on rotavirus detections, meteorological factors and population demographics were collected. For each country, several meteorological and population factors were investigated as possible predictors of rotavirus incidence. The final set of predictors were incorporated in negative binomial models accounting for seasonality and serial autocorrelation, and time-varying incidence rate ratios (IRR) were calculated for each age group and country separately. The overall vaccination impact two years after vaccine implementation was esti-mated by pooling the results using a random effects meta-analyses. Independent t-tests were used to compare annual epidemics in the pre-vaccination and post-vaccination era to explore any changes in the timing of rotavirus epidemics. Results: The population size and several meteorological factors were predictors for the rotavirus epidemi-ology. Overall, we estimated a 42% (95%-CI 23;56%) reduction in rotavirus incidence attributable to UMV. Strongest reductions were observed for age-groups 0-, 1-and 2-years (IRR 0.47, 0.48 and 0.63, respec-tively). No herd effect induced by UMV in neighbouring countries was observed. In all UMV countries, the start and/or stop and corresponding peak of the rotavirus season was delayed by 4-7 weeks. Conclusions: The introduction of rotavirus UMV resulted in an overall reduction of 42% in rotavirus inci-dence in Western European countries two years after vaccine introduction and caused a change in sea-sonal pattern. No herd effect induced by UMV neighbouring countries was observed for Denmark and the Netherlands. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

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In March 2021 several cases of cerebral venous sinus thrombosis (CVST) accompanied by thrombocytopenia were reported that occurred within two weeks after immunization with a viral vector-based COVID-19 vaccine. This study aimed to assess the background incidence of CVST and CVST with concurrent thrombocytopenia in adults using anonymized claims data from 2015-2019 in Germany. The average annual CVST incidence was 1.9 per 100,000 individuals (95%-CI 1.4-2.3). It was higher in women aged 18 to 59 years as compared to same-aged men. In contrast to the currently reported immunization-related cases, CVST was rarely associated with concurrent thrombocytopenia or death.

Background This study applies an umbrella review approach to summarise the global evidence on the risk of severe COVID-19 outcomes in patients with pre-existing health conditions. Methods Systematic reviews (SRs) were identified in PubMed, Embase/Medline and seven pre-print servers until December 11, 2020. Due to the absence of age-adjusted risk effects stratified by geographical regions, a re-analysis of the evidence was conducted. Primary studies were extracted from SRs and evaluated for inclusion in the re-analysis. Studies were included if they reported risk estimates (odds ratio (OR), hazard ratio (HR), relative risk (RR)) for hospitalisation, intensive care unit admission, intubation or death. Estimated associations were extracted from the primary studies for reported pre-existing conditions. Meta-analyses were performed stratified for each outcome by regions of the World Health Organization. The evidence certainty was assessed using GRADE. Registration number CRD42020215846. Results In total, 160 primary studies from 120 SRs contributed 464 estimates for 42 pre-existing conditions. Most studies were conducted in North America, European, and Western Pacific regions. Evidence from Africa, South/Latin America, and the Eastern Mediterranean region was scarce. No evidence was available from the South-East Asia region. Diabetes (HR range 1.2-2.0 (CI range 1.1-2.8)), obesity (OR range 1.5-1.75 (CI range 1.1-2.3)), heart failure (HR range 1.3-3.3 (CI range 0.9-8.2)), COPD (HR range 1.12-2.2 (CI range 1.1-3.2)) and dementia (HR range 1.4-7.7 (CI range 1.2-39.6)) were associated with fatal COVID-19 in different regions, although the estimates varied. Evidence from Europe and North America showed that liver cirrhosis (OR range 3.2-5.9 (CI range 0.9-27.7)) and active cancer (OR range 1.6-4.7 (CI range 0.5-14.9)) were also associated with increased risk of death. Association between HIV and undesirable COVID-19 outcomes showed regional heterogeneity, with an increased risk of death in Africa (HR 1.7 (CI 1.3-2.2)). GRADE certainty was moderate to high for most associations. Conclusion Risk of undesirable COVID-19 health outcomes is consistently increased in certain patient subgroups across geographical regions, showing high variability in others. The results can be used to inform COVID-19 vaccine prioritisation or other intervention strategies.