Bridging the gap - estimation of 2022/2023 SARS-CoV-2 healthcare burden in Germany based on multidimensional data from a rapid epidemic panel.

OBJECTIVES: Throughout the SARS-CoV-2 pandemic, Germany like other countries lacked adaptive population-based panels to monitor the spread of epidemic diseases. METHODS: To fill a gap in population-based estimates needed for winter 2022/23 we resampled in the German SARS-CoV-2 cohort study MuSPAD in mid-2022, including characterization of systemic cellular and humoral immune responses by interferon-γ-release assay (IGRA) and CLIA/IVN assay. We were able to confirm categorization of our study population into four groups with differing protection levels against severe COVID-19 courses based on literature synthesis. Using these estimates, we assessed potential healthcare burden for winter 2022/23 in different scenarios with varying assumptions on transmissibility, pathogenicity, new variants, and vaccine booster campaigns in ordinary differential equation models. RESULTS: We included 9921 participants from eight German regions. While 85% of individuals were located in one of the two highest protection categories, hospitalization estimates from scenario modeling were highly dependent on viral variant characteristics ranging from 30-300% compared to the 02/2021 peak. Our results were openly communicated and published to an epidemic panel network and a newly established modeling network. CONCLUSIONS: We demonstrate feasibility of a rapid epidemic panel to provide complex immune protection levels for inclusion in dynamic disease burden modeling scenarios.

Humoral immune response to SARS-CoV-2 and endemic coronaviruses in urban and indigenous children in Colombia.

BACKGROUND: Although anti-SARS-CoV-2 humoral immune responses and epidemiology have been extensively studied, data gaps remain for certain populations such as indigenous people or children especially in low- and middle-income countries. To address this gap, we evaluated SARS-CoV-2 seroprevalence and humoral immunity towards the parental B.1 strain, local SARS-CoV-2 variants, and endemic coronaviruses in children from Colombia from March to April 2021. METHODS: We performed a cross-sectional seroprevalence study with 80 children from Bogotá and expanded our analysis by comparing results with an independent observational study of 82 children from the Wiwa community living in the north-eastern Colombian territories. Antibody IgG titers towards SARS-CoV-2 and the endemic coronaviruses as well as ACE2 binding inhibition as a proxy for neutralization towards several SARS-CoV-2 variants were analyzed using two multiplex-based immunoassays. RESULTS: While we find seroprevalence estimates of 21.3% in children from Bogotá, seroprevalence is higher with 34.1% in Wiwa children. We observe a robust induction of antibodies towards the surface-exposed spike protein, its S1-, S2- and receptor-binding-subdomains in all SARS-CoV-2 seropositive children. Only nucleocapsid-specific IgG is significantly lower in the indigenous participants. ACE2 binding inhibition is low for all SARS-CoV-2 variants examined. We observe a dominance of NL63 S1 IgG levels in urban and indigenous children which suggests an early exposure to this respiratory virus independent of living conditions and geographic location. SARS-CoV-2 seropositivity does not correlate with antibody levels towards any of the four endemic coronaviruses indicating the absence of cross-protective immunity. CONCLUSIONS: Overall, antibody titers, but in particular ACE2 binding inhibition are low within Colombian samples, requiring further investigation to determine any potential clinical significance.

Our knowledge of SARS-CoV-2, the virus causing COVID-19 remains incomplete for certain populations including indigenous people and younger age groups. Here, we aim to understand the extent to which children from urban and indigenous populations of Colombia were previously infected with SARS-CoV-2 and the related common cold coronaviruses. By measuring antibodies, protective proteins produced by the immune system, we find higher levels of previous SARS-CoV-2 infections in indigenous children of the Wiwa community (34.1%) compared to children from urbanized Bogotá (21.3%). Antibody levels towards the common cold coronaviruses were similar in SARS-CoV-2 infected and uninfected children suggesting immune responses to one coronavirus do not automatically protect against closely-related viruses. Further, we find low levels of protective immunity against SARS-CoV-2 in both populations. This finding warrants further investigation as it relates to reinfection risk and future vaccination strategies in these populations.

Facilitators and Barriers in the Implementation of a Digital Surveillance and Outbreak Response System in Ghana Before and During the COVID-19 Pandemic: Qualitative Analysis of Stakeholder Interviews.

BACKGROUND: In the past 2 decades, many countries have recognized the use of electronic systems for disease surveillance and outbreak response as an important strategy for disease control and prevention. In low- and middle-income countries, the adoption of these electronic systems remains a priority and has attracted the support of global health players. However, the successful implementation and institutionalization of electronic systems in low- and middle-income countries have been challenged by the local capacity to absorb technologies, decisiveness and strength of leadership, implementation costs, workforce attitudes toward innovation, and organizational factors. In November 2019, Ghana piloted the Surveillance Outbreak Response Management and Analysis System (SORMAS) for routine surveillance and subsequently used it for the national COVID-19 response. OBJECTIVE: This study aims to identify the facilitators of and barriers to the sustainable implementation and operation of SORMAS in Ghana. METHODS: Between November 2021 and March 2022, we conducted a qualitative study among 22 resource persons representing different stakeholders involved in the implementation of SORMAS in Ghana. We interviewed study participants via telephone using in-depth interview guides developed consistent with the model of diffusion of innovations in health service organizations. We transcribed the interviews verbatim and performed independent validation of transcripts and pseudonymization. We performed deductive coding using 7 a priori categories: innovation, adopting health system, adoption and assimilation, diffusion and dissemination, outer context, institutionalization, and linkages among the aspects of implementation. We used MAXQDA Analytics Pro for transcription, coding, and analysis. RESULTS: The facilitators of SORMAS implementation included its coherent design consistent with the Integrated Disease Surveillance and Response system, adaptability to evolving local needs, relative advantages for task performance (eg, real-time reporting, generation of case-base data, improved data quality, mobile offline capability, and integration of laboratory procedures), intrinsic motivation of users, and a smartphone-savvy workforce. Other facilitators were its alignment with health system goals, dedicated national leadership, political endorsement, availability of in-country IT capacities, and financial and technical support from inventors and international development partners. The main barriers were unstable technical interoperability between SORMAS and existing health information systems, reliance on a private IT company for data hosting, unreliable internet connectivity, unstable national power supply, inadequate numbers and poor quality of data collection devices, and substantial dependence on external funding. CONCLUSIONS: The facilitators of and barriers to SORMAS implementation are multiple and interdependent. Important success conditions for implementation include enhanced scope and efficiency of task performance, strong technical and political stewardship, and a self-motivated workforce. Inadequate funding, limited IT infrastructure, and lack of software development expertise are mutually reinforcing barriers to implementation and progress to country ownership. Some barriers are external, relate to the overall national infrastructural development, and are not amenable even to unlimited project funding.

Prostration and the prognosis of death in African children with severe malaria.

OBJECTIVES: Malaria is still one of the main reasons for hospitalization in children living in sub-Saharan Africa. Rapid risk stratification at admission is essential for optimal medical care and improved prognosis. Whereas coma, deep breathing, and, to a lesser degree, severe anemia are established predictors of malaria-related death, the value of assessing prostration for risk stratification is less certain. METHODS: Here we used a retrospective multi-center analysis comprising over 33,000 hospitalized children from four large studies, including two observational studies from the Severe Malaria in African Children network, a randomized controlled treatment study, and the phase-3-clinical RTS,S-malaria vaccine trial, to evaluate known risk factors of mortality and with a specific emphasis on the role of prostration. RESULTS: Despite comparable age profiles of the participants, we found significant inter- and intra-study variation in the incidence of fatal malaria as well as in the derived risk ratios associated with the four risk factors: coma, deep breathing, anemia, and prostration. Despite pronounced variations, prostration was significantly associated with an increased risk of mortality (P <0.001) and its consideration resulted in improved predictive performance, both in a multivariate model and a univariate model based on the Lambaréné Organ Dysfunction Score. CONCLUSION: Prostration is an important clinical criterion to determine severe pediatric malaria with possible fatal outcomes.

Simultaneous Detection of Different Antibody Classes in a Multiplexed Serological Test.

To monitor the progression of infectious diseases, it is useful to assess immunoreactivity against various antigenic determinants, and measure different antibody isotypes because they appear at different stages of the host immune response. With Lyme borreliosis, the pathogenic agent can be one of the multiple members of the Borrelia species. Therefore, correct sample classification requires evaluating the immunoreactivity against different antigens of different Borrelia species. Additionally, anti-pathogen IgG and IgM responses can have different elicitation time courses during disease progression. Here we demonstrate the development of a two-reporter multiplex immunoassay that has utility in identifying Borrelia-specific immune response in human serum samples by simultaneously evaluating both IgG and IgM immunoreactivity against different bacterial antigens in the same reaction well. This dual-reporter approach retains the analytical performance of single-reporter methods while conserving time and resources and reducing sample size requirements. This assay allows essentially double the serological information to be generated from a blood sample in half the time.

Seroprevalence of Hepatitis E virus in children and adolescents living in urban Bogotá: An explorative cross-sectional study.

The majority of Hepatitis E Virus (HEV)-related studies are carried out in adults whereas information about HEV seroprevalence, clinical disease manifestation, molecular epidemiology, and transmission patterns in children is limited. To estimate HEV seroprevalence among scholar children living in an urban setting and to analyze risk factors for an infection, we invited children aged 5-18 years from Bogotá (Colombia) for a cross-sectional survey. We collected self-reported data on demographics, social, clinical, and exposure variables in a structured interview. Venous blood samples were analyzed with two commercially available ELISAs for HEV-specific IgG antibodies. Among the 263 participants, we found three HEV IgG-reactive samples (1.1%) using both assays. We additionally characterized the samples for HEV IgM using a commercially available IgM ELISA and for HEV RNA. Here, we found one IgM-reactive sample, which was also reactive for IgG. In contrast, none of the IgM- and IgG-reactive sera samples showed detectable RNA levels indicating HEV exposure had not been recently. All participants reported access to drinking water and sanitary systems in their households and frequent hand washing routines (76-88%). Eighty percent of children reported no direct contact with pigs, but occasional pork consumption was common (90%). In contrast to the majority of studies performed in Colombian adults, we found a low unadjusted HEV seroprevalence of 1.1% (95% CI: 0.3-3.6%) for both HEV IgG ELISAs in our study population. While the majority of participants reported pork consumption, we speculate in the absence of viral RNA for genotyping in the affected individuals, that existing access to drinking water and sanitary systems within our study group contribute to the low HEV seroprevalence.

The challenge of estimating the direct and indirect effects of COVID-19 interventions - Toward an integrated economic and epidemiological approach.

Decisions on public health measures to contain a pandemic are often based on parameters such as expected disease burden and additional mortality due to the pandemic. Both pandemics and non-pharmaceutical interventions to fight pandemics, however, produce economic, social, and medical costs. The costs are, for example, caused by changes in access to healthcare, social distancing, and restrictions on economic activity. These factors indirectly influence health outcomes in the short- and long-term perspective. In a narrative review based on targeted literature searches, we develop a comprehensive perspective on the concepts available as well as the challenges of estimating the overall disease burden and the direct and indirect effects of COVID-19 interventions from both epidemiological and economic perspectives, particularly during the early part of a pandemic. We review the literature and discuss relevant components that need to be included when estimating the direct and indirect effects of the COVID-19 pandemic. The review presents data sources and different forms of death counts, and discusses empirical findings on direct and indirect effects of the pandemic and interventions on disease burden as well as the distribution of health risks.

Age-specific contribution of contacts to transmission of SARS-CoV-2 in Germany.

Current estimates of pandemic SARS-CoV-2 spread in Germany using infectious disease models often do not use age-specific infection parameters and are not always based on age-specific contact matrices of the population. They also do usually not include setting- or pandemic phase-based information from epidemiological studies of reported cases and do not account for age-specific underdetection of reported cases. Here, we report likely pandemic spread using an age-structured model to understand the age- and setting-specific contribution of contacts to transmission during different phases of the COVID-19 pandemic in Germany. We developed a deterministic SEIRS model using a pre-pandemic contact matrix. The model was optimized to fit age-specific SARS-CoV-2 incidences reported by the German National Public Health Institute (Robert Koch Institute), includes information on setting-specific reported cases in schools and integrates age- and pandemic period-specific parameters for underdetection of reported cases deduced from a large population-based seroprevalence studies. Taking age-specific underreporting into account, younger adults and teenagers were identified in the modeling study as relevant contributors to infections during the first three pandemic waves in Germany. For the fifth wave, the Delta to Omicron transition, only age-specific parametrization reproduces the observed relative and absolute increase in pediatric hospitalizations in Germany. Taking into account age-specific underdetection did not change considerably how much contacts in schools contributed to the total burden of infection in the population (up to 12% with open schools under hygiene measures in the third wave). Accounting for the pandemic phase and age-specific underreporting is important to correctly identify those groups of the population in which quarantine, testing, vaccination, and contact-reduction measures are likely to be most effective and efficient. Age-specific parametrization is also highly relevant to generate informative age-specific output for decision makers and resource planers.

Antibody Binding and Angiotensin-Converting Enzyme 2 Binding Inhibition Is Significantly Reduced for Both the BA.1 and BA.2 Omicron Variants.

BACKGROUND: The rapid emergence of the Omicron variant and its large number of mutations led to its classification as a variant of concern (VOC) by the World Health Organization. Subsequently, Omicron evolved into distinct sublineages (eg, BA.1 and BA.2), which currently represent the majority of global infections. Initial studies of the neutralizing response toward BA.1 in convalescent and vaccinated individuals showed a substantial reduction. METHODS: We assessed antibody (immunoglobulin G [IgG]) binding, ACE2 (angiotensin-converting enzyme 2) binding inhibition, and IgG binding dynamics for the Omicron BA.1 and BA.2 variants compared to a panel of VOCs/variants of interest, in a large cohort (N = 352) of convalescent, vaccinated, and infected and subsequently vaccinated individuals. RESULTS: While Omicron was capable of efficiently binding to ACE2, antibodies elicited by infection or immunization showed reduced binding capacities and ACE2 binding inhibition compared to wild type. Whereas BA.1 exhibited less IgG binding compared to BA.2, BA.2 showed reduced inhibition of ACE2 binding. Among vaccinated samples, antibody binding to Omicron only improved after administration of a third dose. CONCLUSIONS: Omicron BA.1 and BA.2 can still efficiently bind to ACE2, while vaccine/infection-derived antibodies can bind to Omicron. The extent of the mutations within both variants prevents a strong inhibitory binding response. As a result, both Omicron variants are able to evade control by preexisting antibodies.

Infection and transmission risks of COVID-19 in schools and their contribution to population infections in Germany: A retrospective observational study using nationwide and regional health and education agency notification data.

BACKGROUND: School-level infection control measures in Germany during the early Coronavirus Disease 2019 (COVID-19) pandemic differed across the 16 federal states and lacked a dependable evidence base, with available evidence limited to regional data restricted to short phases of the pandemic. This study aimed to assess the (a) infection risks in students and staff; (b) transmission risks and routes in schools; (c) effects of school-level infection control measures on school and population infection dynamics; and (d) contribution of contacts in schools to population cases. METHODS AND FINDINGS: For this retrospective observational study, we used German federal state (NUTS-2) and county (NUTS-3) data from public health and education agencies from March 2020 to April 2022. We assessed (a) infection risk as cumulative risk and crude risk ratios and (b) secondary attack rates (SARs) with 95% confidence interval (CI). We used (c) multiple regression analysis for the effects of infection control measures such as reduced attendance, mask mandates, and vaccination coverage as absolute reduction in case incidence per 100,000 inhabitants per 14 days and in percentage relative to the population, and (d) infection dynamic modelling to determine the percentage contribution of school contacts to population cases. We included (a) nationwide NUTS-2 data from calendar weeks (W) 46-50/2020 and W08/2021-W15/2022 with 3,521,964 cases in students and 329,283 in teachers; (b) NUTS-3 data from W09-25/2021 with 85,788 student and 9,427 teacher cases; and (c) detailed data from 5 NUTS-3 regions from W09/2020 to W27/2021 with 12,814 cases (39% male, 37% female; median age 14, range 5 to 63), 43,238 contacts and 4,165 secondary cases for students (for teachers, 14,801 [22% male, 50% female; median age 39, range 16 to 75], 5,893 and 472). Infection risk (a) for students and teachers was higher than the population risk in all phases of normal presence class and highest in the early 2022 omicron wave with 30.6% (95% CI 30.5% to 32.6%) of students and 32.7% (95% CI 32.6% to 32.8%) of teachers infected in Germany. SARs (b) for students and staff were below 5% in schools throughout the study period, while SARs in households more than doubled from 13.8% (95% CI 10.6% to 17.6%) W21-39/2020 to 28.7% (95% CI 27% to 30.4%) in W08-23/2021 for students and 10.9% (95% CI 7% to 16.5%) to 32.7% (95% CI 28.2% to 37.6%) for staff. Most contacts were reported for schools, yet most secondary cases originated in households. In schools, staff predominantly infected staff. Mandatory surgical mask wearing during class in all schools was associated with a reduction in the case incidence of students and teachers (c), by 56/100,000 persons per 14 days (students: 95% CI 47.7 to 63.4; teachers: 95% CI 39.6 to 71.6; p < 0.001) and by 29.8% (95% CI 25% to 35%, p < 0.001) and 24.3% (95% CI 13% to 36%, p < 0.001) relative to the population, respectively, as were reduced attendance and higher vaccination coverage. The contribution of contacts in schools to population cases (d) was 2% to 20%, lowest during school closures/vacation and peaked during normal presence class intervals, with the overall peak early during the omicron wave. Limitations include underdetection, misclassification of contacts, interviewer/interviewee dependence of contact-tracing, and lack of individual-level confounding factors in aggregate data regression analysis. CONCLUSION: In this study, we observed that open schools under hygiene measures and testing strategies contributed up to 20% of population infections during the omicron wave early 2022, and as little as 2% during vacations/school closures; about a third of students and teachers were infected during the omicron wave in early 2022 in Germany. Mandatory mask wearing during class in all school types and reduced attendance models were associated with a reduced infection risk in schools.

Seroepidemiology of Borrelia burgdorferi s.l. among German National Cohort (NAKO) Participants, Hanover.

Lyme borreliosis is the leading tick-related illness in Europe, caused by Borrelia Burgdorferi s.l. Lower Saxony, Germany, including its capital, Hanover, has a higher proportion of infected ticks than central European countries, justifying a research focus on the potential human consequences. The current knowledge gap on human incident infections, particularly in Western Germany, demands serological insights, especially regarding a potentially changing climate-related tick abundance and activity. We determined the immunoglobulin G (IgG) and immunoglobulin M (IgM) serostatuses for 8009 German National Cohort (NAKO) participants from Hanover, examined in 2014-2018. We used an enzyme-linked immunosorbent assay (ELISA) as the screening and a line immunoblot as confirmation for the Borrelia Burgdorferi s.l. antibodies. We weighted the seropositivity proportions to estimate general population seropositivity and estimated the force of infection (FOI). Using logistic regression, we investigated risk factors for seropositivity. Seropositivity was 3.0% (IgG) and 2.1% (IgM). The FOI varied with age, sharply increasing in participants aged ≥40 years. We confirmed advancing age and male sex as risk factors. We reported reduced odds for seropositivity with increasing body mass index and depressive symptomatology, respectively, pointing to an impact of lifestyle-related behaviors. The local proportion of seropositive individuals is comparable to previous estimates for northern Germany, indicating a steady seroprevalence.

Borrelia multiplex: a bead-based multiplex assay for the simultaneous detection of Borrelia specific IgG/IgM class antibodies.

BACKGROUND: Lyme borreliosis (LB) is the most common tick-borne infectious disease in the northern hemisphere. The diagnosis of LB is usually made by clinical symptoms and subsequently supported by serology. In Europe, a two-step testing consisting of an enzyme-linked immunosorbent assay (ELISA) and an immunoblot is recommended. However, due to the low sensitivity of the currently available tests, antibody detection is sometimes inaccurate, especially in the early phase of infection, leading to underdiagnoses. METHODS: To improve upon Borrelia diagnostics, we developed a multiplex Borrelia immunoassay (Borrelia multiplex), which utilizes the new INTELLIFLEX platform, enabling the simultaneous dual detection of IgG and IgM antibodies, saving further time and reducing the biosample material requirement. In order to enable correct classification, the Borrelia multiplex contains eight antigens from the five human pathogenic Borrelia species known in Europe. Six antigens are known to mainly induce an IgG response and two antigens are predominant for an IgM response. RESULTS: To validate the assay, we compared the Borrelia multiplex to a commercial bead-based immunoassay resulting in an overall assay sensitivity of 93.7% (95% CI 84.8-97.5%) and a specificity of 96.5% (95%CI 93.5-98.1%). To confirm the calculated sensitivity and specificity, a comparison with a conventional 2-step diagnostics was performed. With this comparison, we obtained a sensitivity of 95.2% (95% CI 84.2-99.2%) and a specificity of 93.0% (95% CI 90.6-94.7%). CONCLUSION: Borrelia multiplex is a highly reproducible cost- and time-effective assay that enables the profiling of antibodies against several individual antigens simultaneously.

Diminished neutralization responses towards SARS-CoV-2 Omicron VoC after mRNA or vector-based COVID-19 vaccinations.

SARS-CoV-2 variants accumulating immune escape mutations provide a significant risk to vaccine-induced protection against infection. The novel variant of concern (VoC) Omicron BA.1 and its sub-lineages have the largest number of amino acid alterations in its Spike protein to date. Thus, they may efficiently escape recognition by neutralizing antibodies, allowing breakthrough infections in convalescent and vaccinated individuals in particular in those who have only received a primary immunization scheme. We analyzed neutralization activity of sera from individuals after vaccination with all mRNA-, vector- or heterologous immunization schemes currently available in Europe by in vitro neutralization assay at peak response towards SARS-CoV-2 B.1, Omicron sub-lineages BA.1, BA.2, BA.2.12.1, BA.3, BA.4/5, Beta and Delta pseudotypes and also provide longitudinal follow-up data from BNT162b2 vaccinees. All vaccines apart from Ad26.CoV2.S showed high levels of responder rates (96-100%) towards the SARS-CoV-2 B.1 isolate, and minor to moderate reductions in neutralizing Beta and Delta VoC pseudotypes. The novel Omicron variant and its sub-lineages had the biggest impact, both in terms of response rates and neutralization titers. Only mRNA-1273 showed a 100% response rate to Omicron BA.1 and induced the highest level of neutralizing antibody titers, followed by heterologous prime-boost approaches. Homologous BNT162b2 vaccination, vector-based AZD1222 and Ad26.CoV2.S performed less well with peak responder rates of 48%, 56% and 9%, respectively. However, Omicron responder rates in BNT162b2 recipients were maintained in our six month longitudinal follow-up indicating that individuals with cross-protection against Omicron maintain it over time. Overall, our data strongly argue for booster doses in individuals who were previously vaccinated with BNT162b2, or a vector-based primary immunization scheme.

Longitudinal cellular and humoral immune responses after triple BNT162b2 and fourth full-dose mRNA-1273 vaccination in haemodialysis patients.

Haemodialysis patients respond poorly to vaccination and continue to be at-risk for severe COVID-19. Therefore, dialysis patients were among the first for which a fourth COVID-19 vaccination was recommended. However, targeted information on how to best maintain immune protection after SARS-CoV-2 vaccinations in at-risk groups for severe COVID-19 remains limited. We provide, to the best of our knowledge, for the first time longitudinal vaccination response data in dialysis patients and controls after a triple BNT162b2 vaccination and in the latter after a subsequent fourth full-dose of mRNA-1273. We analysed systemic and mucosal humoral IgG responses against the receptor-binding domain (RBD) and ACE2-binding inhibition towards variants of concern including Omicron and Delta with multiplex-based immunoassays. In addition, we assessed Spike S1-specific T-cell responses by interferon γ release assay. After triple BNT162b2 vaccination, anti-RBD B.1 IgG and ACE2 binding inhibition reached peak levels in dialysis patients, but remained inferior compared to controls. Whilst we detected B.1-specific ACE2 binding inhibition in 84% of dialysis patients after three BNT162b2 doses, binding inhibition towards the Omicron variant was only detectable in 38% of samples and declining to 16% before the fourth vaccination. By using mRNA-1273 as fourth dose, humoral immunity against all SARS-CoV-2 variants tested was strongly augmented with 80% of dialysis patients having Omicron-specific ACE2 binding inhibition. Modest declines in T-cell responses in dialysis patients and controls after the second vaccination were restored by the third BNT162b2 dose and significantly increased by the fourth vaccination. Our data support current advice for a four-dose COVID-19 immunisation scheme for at-risk individuals such as haemodialysis patients. We conclude that administration of a fourth full-dose of mRNA-1273 as part of a mixed mRNA vaccination scheme to boost immunity and to prevent severe COVID-19 could also be beneficial in other immune impaired individuals. Additionally, strategic application of such mixed vaccine regimens may be an immediate response against SARS-CoV-2 variants with increased immune evasion potential.

Authors' response: Occupation and SARS-CoV-2 infection risk among workers during the first pandemic wave in Germany: potential for bias.

We thank van Tongeren et al for responding to our study on occupational disparities in SARS-CoV-2 infection risks during the first pandemic wave in Germany (1). The authors address the potential for bias resulting from differential testing between occupational groups and propose an alternative analytical strategy for dealing with selective testing. In the following, we want to discuss two aspects of this issue, namely (i) the extent and reasons of differential testing in our cohort and (ii) the advantages and disadvantages of different analytical approaches to study risk factors for SARS-CoV-2 infection. Our study relied on nationwide prospective cohort data including more than 100 000 workers in order to compare the incidence of infections between different occupations and occupational status positions. We found elevated infection risks in personal services and business administration, in essential occupations (including health care) and among people in higher occupational status positions (ie, managers and highly skilled workers) during the first pandemic wave in Germany (2). Van Tongeren's et al main concern is that the correlations found could be affected by a systematic bias because people in healthcare professions get tested more often than employees in other professions. A second argument is that better-off people could be more likely to use testing as they are less affected by direct costs (prices for testing) and the economic hardship associated with a positive test result (eg, loss of earnings in the event of sick leave). We share the authors' view that differential testing must be considered when analysing and interpreting the data. Thus, in our study, we examined the proportion of tests conducted in each occupational group as part of the sensitivity analyses (see supplementary figure S1, accessible at www.sjweh.fi/article/4037). As expected, testing proportions were exceptionally high in medical occupations (due to employer requirements). However, we did not observe systematic differences among non-medical occupations or when categorising by skill-level or managerial responsibility. This might be explained by several reasons. First, SARS-CoV-2 testing was free of charge during the first pandemic wave in Germany, but reporting a risk contact or having symptoms was a necessary condition for testing ( https://www.bundesgesundheitsministerium.de/coronavirus/chronik-coronavirus.html (accessed 5 September 2022). The newspaper article cited by van Tongeren et al is misleading as it refers to a calendar date after our study period. Second, different motivation for testing due to economic hardship in case of a positive test result is an unlikely explanation, because Germany has a universal healthcare system, including paid sick leave and sickness benefits for all workers (3). Self-employed people carry greater financial risks in case of sickness. We therefore included self-employment in the multivariable analyses to address this potential source of bias. While the observed inverse social gradient may be surprising, it actually matches with findings of ecological studies from Germany (4, 5), the United States (6, 7) as well as Spain, Portugal, Sweden, The Netherlands, Israel, and Hong Kong (8), all of which observed higher infection rates in wealthier neighbourhoods during the initial outbreak phase of the pandemic. One possible explanation is the higher mobility of managers and better educated workers, who are more likely to participate in meetings and engage in business travel and holiday trips like skiing. Given the increasing number of studies providing evidence for this hypothesis, we conclude that the inverse social gradient in our study likely reflects different exposure probabilities and is not a result of systematic bias. This also holds true for the elevated infection risks in essential workers, which is actually corroborated by a large body of research (9-11). Regarding differential likelihood of testing, van Tongeren et al state that "[i]t is relatively simple to address this problem by using a test-negative design" (1). As van Tongeren et al describe, this is a case-control approach only including individuals who were tested (without considering those who were not tested). However, the proposed analytical strategy can lead to another (more serious) selection bias if testing proportions and/or testing criteria differ between groups (12). This can be easily illustrated when comparing the results based on a time-incidence design with those obtained by a test-negative design as shown in table 1 (see PDF). Both approaches show similar results in terms of vertical occupational differences. Infection was more common if individuals had a high skill level or had a managerial position, but associations were stronger in the time-incidence design and did not reach statistical significance in the test-negative design (as indicated by the confidence intervals overlapping "1"). Unfortunately, the test-negative approach relies on a strongly reduced sample size and thus results in greater statistical uncertainty and loss of statistical power (13). In contrast, the test-negative design yields a different picture when estimating the association between essential occupation and infection risk: In this analysis, essential workers did not differ from non-essential workers in their chance of being infected with SARS-CoV-2 (the test-negative design even exhibits a lower chance for essential workers). This is rather counter-intuitive and is not in accordance with what we know about the occupational hazards of healthcare workers during the pandemic (14). The main problem is that proportions of positive tests are highly unreliable when testing proportions and/or testing criteria differ between groups. As essential workers were tested more often without being symptomatic (due to employer requirements), a lower proportion of positive tests in this group does not necessarily correspond to a lower risk of infection. Consequently, we are not convinced that the test-negative design should be the 'gold standard' for studying risk factors for SARS-CoV-2 infections (15). Especially problematic is the loss of statistical power (increasing the probability of a type II error) and the low validity of the test-positivity when test criteria and/or test proportions differ between groups. References 1. van Tongeren M, Rhodes S, Pearce N. Occupation and SARS-CoV-2 infection risk among workers during the first pandemic wave in Germany: potential for bias. Scand J Work Environ Health 2022;48(7):586-587. https://doi.org/10.5271/sjweh.4052. 2. Reuter M, Rigó M, Formazin M, Liebers F, Latza U, Castell S, et al. Occupation and SARS-CoV-2 infection risk among 108 960 workers during the first pandemic wave in Germany. Scand J Work Environ Health 2022;48:446-56. https://doi.org/10.5271/sjweh.4037. 3. Busse R, Blümel M, Knieps F, Bärnighausen T. Statutory health insurance in Germany: a health system shaped by 135 years of solidarity, self-governance, and competition. Lancet 2017;390:882-97. https://doi.org/10.1016/S0140-6736(17)31280-1. 4. Wachtler B, Michalski N, Nowossadeck E, Diercke M, Wahrendorf M, Santos-Hövener C, et al. Socioeconomic inequalities in the risk of SARS-CoV-2 infection - First results from an analysis of surveillance data from Germany. J Heal Monit 2020;5:18-29. https://doi.org/10.25646/7057. 5. Plümper T, Neumayer E. The pandemic predominantly hits poor neighbourhoods? SARS-CoV-2 infections and COVID-19 fatalities in German districts. Eur J Public Health 2020;30:1176-80. https://doi.org/10.1093/eurpub/ckaa168. 6. Abedi V, Olulana O, Avula V, Chaudhary D, Khan A, Shahjouei S, et al. Racial, Economic, and Health Inequality and COVID-19 Infection in the United States. J Racial Ethn Heal Disparities 2021;8:732-42. https://doi.org/10.1007/s40615-020-00833-4. 7. Mukherji N. The Social and Economic Factors Underlying the Incidence of COVID-19 Cases and Deaths in US Counties During the Initial Outbreak Phase. Rev Reg Stud 2022;52. https://doi.org/10.52324/001c.35255. 8. Beese F, Waldhauer J, Wollgast L, Pförtner T, Wahrendorf M, Haller S, et al. Temporal Dynamics of Socioeconomic Inequalities in COVID-19 Outcomes Over the Course of the Pandemic-A Scoping Review. Int J Public Health 2022;67:1-14. https://doi.org/10.3389/ijph.2022.1605128. 9. Nguyen LH, Drew DA, Graham MS, Joshi AD, Guo C-G, Ma W, et al. Risk of COVID-19 among front-line health-care workers and the general community: a prospective cohort study. Lancet Public Heal 2020;5:e475-83. https://doi.org/10.1016/S2468-2667(20)30164-X. 10. Chou R, Dana T, Buckley DI, Selph S, Fu R, Totten AM. Epidemiology of and Risk Factors for Coronavirus Infection in Health Care Workers. Ann Intern Med 2020;173:120-36. https://doi.org/10.7326/M20-1632. 11. Stringhini S, Zaballa M-E, Pullen N, de Mestral C, Perez-Saez J, Dumont R, et al. Large variation in anti-SARS-CoV-2 antibody prevalence among essential workers in Geneva, Switzerland. Nat Commun 2021;12:3455. https://doi.org/10.1038/s41467-021-23796-4. 12. Accorsi EK, Qiu X, Rumpler E, Kennedy-Shaffer L, Kahn R, Joshi K, et al. How to detect and reduce potential sources of biases in studies of SARS-CoV-2 and COVID-19. Eur J Epidemiol 2021;36:179-96. https://doi.org/10.1007/s10654-021-00727-7. 13. Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd Editio. New York: Routledge; 2013. https://doi.org/10.4324/9780203771587. 14. The Lancet. The plight of essential workers during the COVID-19 pandemic. Lancet 2020;395:1587. https://doi.org/10.1016/S0140-6736(20)31200-9. 15. Vandenbroucke JP, Brickley EB, Pearce N, Vandenbroucke-Grauls CMJE. The Evolving Usefulness of the Test-negative Design in Studying Risk Factors for COVID-19. 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Regional seropositivity for Borrelia burgdorferi and associated risk factors: findings from the Rhineland Study, Germany.

BACKGROUND: Lyme borreliosis is the most prevalent vector-borne disease in Europe, and numbers might increase due to climate change. However, borreliosis is not notifiable in North Rhine-Westphalia (NRW), Germany. Hence, little is known about the current human seroprevalence in NRW. However, the proportion of Borrelia burgdorferi sensu lato-infected ticks has increased in a NRW nature reserve. The literature suggests increasing age and male sex as risk factors for seropositivity, whereas the influence of socioeconomic status is controversial. Thus, we aimed to determine regional seropositivity for Borrelia burgdorferi sensu lato (B. burgdorferi s.l.) and its risk factors in the Rhineland Study population in Bonn, NRW, and to compare it with previous surveys to evaluate potential effects of climate change. METHODS: We assessed seropositivity in 2865 Rhineland Study participants by determining immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies for B. burgdorferi s.l. using a two-step algorithm combining enzyme-linked immunosorbent assay tests and line immunoblots. We calculated the odds of being classified as IgG or IgM positive as a function of age, sex, and educational level using binomial logistic regression models. We applied varying seropositivity classifications and weights considering age, sex and education to compensate for differences between the sample and regional population characteristics. RESULTS: IgG antibodies for B. burgdorferi s.l. were present in 2.4% and IgM antibodies in 0.6% of the participants (weighted: 2.2% [IgG], 0.6% [IgM]). The likelihood of IgG seropositivity increased by 3.0% (95% confidence interval [CI] 1.5-5.2%) per 1 year increase in age. Men had 1.65 times the odds for IgG seropositivity as women (95% CI 1.01-2.73), and highly educated participants had 1.83 times the odds (95% CI 1.10-3.14) as participants with an intermediate level of education. We found no statistically significant link between age, sex, or education and IgM seropositivity. Our weighted and age-standardized IgG seroprevalence was comparable to the preceding serosurvey German Health Interview and Examination Survey for Adults (DEGS) for NRW. CONCLUSIONS: We confirmed that increasing age and male sex are associated with increased odds for IgG seropositivity and provide evidence for increased seropositivity in the highly educated group. B. burgdorferi s.l. seropositivity remained constant over the past decade in this regional German population.

Seroprevalence of hepatitis E virus infection in the Americas: Estimates from a systematic review and meta-analysis.

BACKGROUND: Hepatitis E virus (HEV) infection is responsible for inflammatory liver disease and can cause severe health problems. Because the seroprevalence of HEV varies within different population groups and between regions of the continent, we conducted a systematic review on the topic in order to provide evidence for targeted prevention strategies. METHODS: We performed a systematic review in PubMed, SCIELO, LILACS, EBSCO, and Cochrane Library and included reports up to 25 May 2021 (PROSPERO registration number: CRD42020173934). We assessed the risk of bias, publication bias, and heterogeneity between studies and conducted a random-effect meta-analysis for proportions using a (binomial-normal) generalized linear mixed model (GLMM) fitted by Maximum Likelihood (ML). We also reported other characteristics like genotype and risk factors. RESULTS: Of 1212 identified records, 142 fulfilled the inclusion criteria and were included in the qualitative analysis and 132 in the quantitative analysis. Our random-effects GLMM pooled overall estimate for past infection (IgG) was 7.7% (95% CI 6.4%-9.2%) with high heterogeneity (I2 = 97%). We found higher seroprevalence in certain population groups, for example in people with pig related exposure for IgG (ranges from 6.2%-28% and pooled estimate of 13.8%, 95% CI: 7.6%-23.6%), or with diagnosed or suspected acute viral hepatitis for IgM (ranges from 0.3%-23.9% and pooled estimate of 5.5%, 95% CI: 2.0%-14.1%). Increasing age, contact with pigs and meat products, and low socioeconomic conditions are the main risk factors for HEV infection. Genotype 1 and 3 were documented across the region. CONCLUSION: HEV seroprevalence estimates demonstrated high variability within the Americas. There are population groups with higher seroprevalence and reported risk factors for HEV infection that need to be prioritized for further research. Due to human transmission and zoonotic infections in the region, preventive strategies should include water sanitation, occupational health, and food safety.

Occupation and SARS-CoV-2 infection risk among 108 960 workers during the first pandemic wave in Germany.

OBJECTIVE: The aim of this study was to identify the occupational risk for a SARS-CoV-2 infection in a nationwide sample of German workers during the first wave of the COVID-19 pandemic (1 February-31 August 2020). METHODS: We used the data of 108 960 workers who participated in a COVID follow-up survey of the German National Cohort (NAKO). Occupational characteristics were derived from the German Classification of Occupations 2010 (Klassifikation der Berufe 2010). PCR-confirmed SARS-CoV-2 infections were assessed from self-reports. Incidence rates (IR) and incidence rate ratios (IRR) were estimated using robust Poisson regression, adjusted for person-time at risk, age, sex, migration background, study center, working hours, and employment relationship. RESULTS: The IR was 3.7 infections per 1000 workers [95% confidence interval (CI) 3.3-4.1]. IR differed by occupational sector, with the highest rates observed in personal (IR 4.8, 95% CI 4.0-5.6) and business administration (IR 3.4, 95% CI 2.8-3.9) services and the lowest rates in occupations related to the production of goods (IR 2.0, 95% CI 1.5-2.6). Infections were more frequent among essential workers compared with workers in non-essential occupations (IRR 1.95, 95% CI 1.59-2.40) and among highly skilled compared with skilled professions (IRR 1.36, 95% CI 1.07-1.72). CONCLUSIONS: The results emphasize higher infection risks in essential occupations and personal-related services, especially in the healthcare sector. Additionally, we found evidence that infections were more common in higher occupational status positions at the beginning of the pandemic.

Long-term effect of chronic hepatitis B on mortality in HIV-infected persons in a differential HBV transmission setting.

BACKGROUND: There remain gaps in quantifying mortality risk among individuals co-infected with chronic hepatitis B (HBV) and human immunodeficiency virus (HIV) in sub-Saharan African contexts. Among a cohort of HIV-positive individuals in Rwanda, we estimate the difference in time-to mortality between HBV-positive (HIV/HBV co-infected) and HBV-negative (HIV mono-infected) individuals. METHODS: Using a dataset of HIV-infected adults screened for hepatitis B surface antigen (HBsAg) from January to June 2016 in Rwanda, we performed time-to-event analysis from the date of HBsAg results until death or end of study (31 December 2019). We used the Kaplan-Meier method to estimate probability of survival over time and Cox proportional hazard models to adjust for other factors associated with mortality. RESULTS: Of 21,105 available entries, 18,459 (87.5%) met the inclusion criteria. Mean age was 42.3 years (SD = 11.4) and 394 (2.1%) died during follow-up (mortality rate = 45.7 per 100,000 person-months, 95% confidence interval (CI) 41.4-50.4) Mortality rate ratio for co-infection was 1.7, 95% CI 1.1-2.6, however, Cox regression analysis did not show any association with mortality between compared groups. The adjusted analysis of covariates stratified by co-infection status showed that males, residing outside of the capital Kigali, drinking alcohol, WHO-HIV-clinical stage 3 and 4 were associated with increased mortality in this HIV cohort. CONCLUSIONS: HBV infection does not significantly influence mortality among HIV-infected individuals in Rwanda. The current cohort is likely to have survived a period of high-risk exposure to HBV and HIV mortality and limited health care until their diagnosis.