Needs and feasibility of living systematic reviews (LSRs): Experience from LSRs on COVID-19 vaccine effectiveness.

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.

Recovery and sequelae in 523 adults and children with tick-borne encephalitis in Germany.

PURPOSE: Despite being vaccine-preventable, tick-borne encephalitis (TBE) continues to cause considerable morbidity in Germany. Limited insight into potentially debilitating consequences of TBE may partially underly low (~ 20%) TBE vaccine uptake. We aimed to systematically assess TBE sequelae and other consequences. METHODS: Routinely notified TBE patients from 2018 to 2020 from Southern Germany were invited to telephone interviews acutely and again after 18 months. Duration of acute symptoms was prospectively assessed. Recovery was defined as score 0 on the modified RANKIN scale. Determinants of time to recovery were analysed with cox regression, adjusted for covariates identified using directed acyclic graphs, yielding hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Of 558 cases, 523 (93.7%) completed follow-up. Full recovery was reported by 67.3% (children: 94.9%, adults: 63.8%). Sequelae included fatigue (17.0%), weakness (13.4%), concentration deficit (13.0%), and impaired balance (12.0%). Compared with 18-39-year-olds, recovery rates were 44% lower in ≥ 50-year-olds (HR: 0.56, 95%CI 0.42-0.75) and 79% higher in children (HR: 1.79, 95%CI 1.25-2.56). The recovery rate was 64% lower after severe TBE (compared to mild; HR: 0.36, 95%CI 0.25-0.52) and 22% lower with comorbidities (HR: 0.78, 95%CI 0.62-0.99). Substantial health-care use was reported (90.1% hospitalisation, 39.8% rehabilitation). Of employed cases, 88.4% required sick leave; 10.3% planned/reported premature retirement due to sequelae. CONCLUSION: Half the adult and 5% of paediatric patients reported persisting sequelae after 18 months. Improved prevention could alleviate both individual (morbidity) and societal TBE burden (health-care costs, productivity losses). Insights into sequelae can help guide at-risk populations towards tick-avoidant strategies and encourage TBE vaccination.

Use of existing systematic reviews for the development of evidence-based vaccination recommendations: Guidance from the SYSVAC expert panel.

National immunization technical advisory groups (NITAGs) develop immunization-related recommendations and assist policy-makers in making evidence informed decisions. Systematic reviews (SRs) that summarize the available evidence on a specific topic are a valuable source of evidence in the development of such recommendations. However, conducting SRs requires significant human, time, and financial resources, which many NITAGs lack. Given that SRs already exist for many immunization-related topics, and to prevent duplication and overlap of reviews, a more practical approach may be for NITAGs to use existing SRs. Nevertheless, it can be challenging to identify relevant SRs, to select one SR from among multiple SRs, or to critically assess and effectively use them. To support NITAGs, the London School of Hygiene and Tropical Medicine, Robert Koch Institute and collaborators developed the SYSVAC project, which consists of an online registry of systematic reviews on immunization-related topics and an e-learning course, that supports the use of them (both freely accessible at https://www.nitag-resource.org/sysvac-systematic-reviews). Drawing from the e-learning course and recommendations from an expert panel, this paper outlines methods for using existing systematic reviews when making immunization-related recommendations. With specific examples and reference to the SYSVAC registry and other resources, it offers guidance on locating existing systematic reviews; assessing their relevance to a research question, up-to-dateness, and methodological quality and/or risk of bias; and considering the transferability and applicability of their findings to other populations or settings.

Tick-borne encephalitis: Acute clinical manifestations and severity in 581 cases from Germany, 2018-2020.

OBJECTIVES: Tick-borne encephalitis (TBE) is a growing public health problem with an average of 361 cases notified annually to Germany's passive surveillance system since 2001. We aimed to assess clinical manifestations and identify covariates associated with severity. METHODS: We included cases notified 2018-2020 in a prospective cohort study and collected data with telephone interviews, questionnaires to general practitioners, and hospital discharge summaries. Covariates' causal associations with severity were evaluated with multivariable logistic regression, adjusted for variables identified via directed acyclic graphs. RESULTS: Of 1220 eligible cases, 581 (48%) participated. Of these, 97.1% were not (fully) vaccinated. TBE was severe in 20.3% of cases (children: 9.1%, ≥70-year-olds: 48.6%). Routine surveillance data underreported the proportion of cases with central nervous system involvement (56% vs. 84%). Ninety percent required hospitalization, 13.8% intensive care, and 33.4% rehabilitation. Severity was most notably associated with age (odds ratio (OR): 1.04, 95% confidence interval (CI): 1.02-1.05), hypertension (OR: 2.27, 95%CI: 1.37-3.75), and monophasic disease course (OR: 1.67, 95%CI: 1.08-2.58). CONCLUSIONS: We observed substantial TBE burden and health service utilization, suggesting that awareness of TBE severity and vaccine preventability should be increased. Knowledge of severity-associated factors may help inform patients' decision to get vaccinated.

Facing the Omicron variant-how well do vaccines protect against mild and severe COVID-19? Third interim analysis of a living systematic review.

Background: The 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. Methods: We 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. Results: We 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. Conclusions: Under 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.

Tick-borne encephalitis vaccine effectiveness and barriers to vaccination in Germany.

Tick-borne encephalitis (TBE) vaccination coverage remains low in Germany. Our case-control study (2018-2020) aimed to examine reasons for low vaccine uptake, vaccine effectiveness (VE), and vaccine breakthrough infections (VBIs). Telephone interviews (581 cases, 975 matched controls) covered vaccinations, vaccination barriers, and confounders identified with directed acyclic graphs. Multivariable logistic regression determined VE as 1-odds ratio with 95% confidence intervals (CI). We additionally calculated VE with the Screening method using routine surveillance and vaccination coverage data. Main vaccination barriers were poor risk perception and fear of adverse events. VE was 96.6% (95% CI 93.7-98.2) for ≥ 3 doses and manufacturer-recommended dosing intervals. Without boosters, VE after ≥ 3 doses at ≤ 10 years was 91.2% (95% CI 82.7-95.6). VE was similar for homologous/heterologous vaccination. Utilising routine surveillance data, VE was comparable (≥ 3 doses: 92.8%). VBIs (n = 17, 2.9% of cases) were older, had more comorbidities and higher severity than unvaccinated cases. However, only few VBIs were diagnostically confirmed; 57% of re-tested vaccinated cases (≥ 1 dose, n = 54) proved false positive. To increase TBE vaccine uptake, communication efforts should address complacency and increase confidence in the vaccines' safety. The observed duration of high VE may inform decision-makers to consider extending booster intervals to 10 years.

Tick-Borne Encephalitis Risk Increases with Dog Ownership, Frequent Walks, and Gardening: A Case-Control Study in Germany 2018-2020.

In Germany, tick-borne encephalitis (TBE) infections mainly occur in southern regions. Despite recent increases in incidence, TBE vaccination coverage remains low, necessitating additional preventive strategies against TBE. Our case-control study in Southern Germany from 2018 to 2020 mapped knowledge/application of tick-protective strategies and identified TBE risk factors. We calculated odds ratios (OR), with 95% confidence intervals (CI). We interviewed 581 cases and 975 matched controls. Most participants recalled lifetime tick bites, mainly while walking, gardening, or hiking. However, only 45% of cases noticed ticks during exposure time; another 12% reported unpasteurized milk intake. While tick-protection knowledge was satisfactory, application lagged behind. Risk factors included dog ownership (OR = 2.45, 95% CI: 1.85−3.24), walks ≥ 4×/week (OR = 2.11, 95% CI: 1.42−3.12), gardening ≥ 4×/week (OR = 1.83, 95% CI: 1.11−3.02), and garden proximity < 250 m of forests (OR = 2.54, 95% CI: 1.82−3.56). Applying ≥2 tick-protective strategies (OR = 0.52, 95% CI: 0.40−0.68) and keeping lawns mowed (OR = 0.63, 95% CI: 0.43−0.91) were inversely associated with TBE. In 2020 (likely pandemic-related), cases reported significantly more walks than previously, potentially explaining the record high case numbers. Our findings provide guidance on targets for TBE prevention. Persons with gardens near forests, frequent outdoor activities, or dogs could particularly benefit from targeted information, including on vaccination and preventing tick bites.

Geo-Spatial Characteristics of 567 Places of Tick-Borne Encephalitis Infection in Southern Germany, 2018-2020.

Tick-borne encephalitis (TBE) is a growing public health problem with increasing incidence and expanding risk areas. Improved prevention requires better understanding of the spatial distribution and ecological determinants of TBE transmission. However, a TBE risk map at sub-district level is still missing for Germany. We investigated the distribution and geo-spatial characteristics of 567 self-reported places of probable TBE infection (POI) from 359 cases notified in 2018-2020 in the study area of Bavaria and Baden-Wuerttemberg, compared to 41 confirmed TBE foci and 1701 random comparator places. We built an ecological niche model to interpolate TBE risk to the entire study area. POI were distributed heterogeneously at sub-district level, as predicted probabilities varied markedly across regions (range 0-93%). POI were spatially associated with abiotic, biotic, and anthropogenic geo-spatial characteristics, including summer precipitation, population density, and annual frost days. The model performed with 69% sensitivity and 63% specificity at an optimised probability threshold (0.28) and an area under the curve of 0.73. We observed high predictive probabilities in small-scale areas, consistent with the known circulation of the TBE virus in spatially restricted microfoci. Supported by further field work, our findings may help identify new TBE foci. Our fine-grained risk map could supplement targeted prevention in risk areas.

Pre-existing health conditions and severe COVID-19 outcomes: an umbrella review approach and meta-analysis of global evidence.

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.

Efficacy and effectiveness of COVID-19 vaccines against SARS-CoV-2 infection: interim results of a living systematic review, 1 January to 14 May 2021.

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.