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Background. The COVID-19 pandemic has demonstrated the importance of pathogen genomic surveillance. At RKI, the German National Institute of Public Health, we established the Integrated Molecular Surveillance for SARS-CoV-2 (IMS-SC2) network to perform SARS-CoV-2 genomic surveillance. Methods. SARS-CoV-2 positive samples from laboratories distributed across Germany regularly undergo whole-genome sequencing at RKI. This surveillance instrument enables (i) almost-real-time monitoring of SARS-CoV-2 genomic diversity and evolution, (ii) in vitro assessment of vaccine coverage against emerging variants and (iii) genome-based estimates of SARS-CoV-2-incidences. Results. We report the results of our analyses of 3623 SARS-CoV-2 genomes collected between 12/1/2020 and 12/31/2021. All variants of concern were identified, at ratios equivalent to those in the 100-fold larger German GISAID sequence dataset from the same time period. Lineage distributions fluctuated over time, covering the rise of the Alpha and Delta, as well as the emergence of Omicron. Phylogenetic analysis confirmed variant assignments. Multiple mutations of concern emerged during the observation period. To model vaccine effectiveness in vitro, we employed authentic-virus neutralization assays, confirming that both the Beta and Zeta variants are capable of immune evasion. The IMS-SC2 sequence dataset facilitated an estimate of the SARS-CoV-2 incidence based on genetic evolution rates. Together with modelled vaccine efficacies, Delta-specific incidence estimation indicated that the German vaccination campaign contributed substantially to a deceleration of the nascent German Delta wave. Conclusion. This example illustrates that pathogen genomics enables a proactive approach to controlling a pandemic as the virus evolves. Molecular and genomic SARS-CoV-2 surveillance will be crucial during the post-pandemic future, informing public health policies including vaccination strategies. Of note, the IMS-SC2 infrastructure can be adapted to many other pathogens, serving as a blueprint for future efforts to increase genomic pathogen surveillance.
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Recent research has shown that Coronavirus (CoV) replication depends on active immunophilin pathways. Here we demonstrate that the drug FK506 (Tacrolimus) inhibited strongly the growth of human coronaviruses SARS-CoV, HCoV-NL63 and HCoV-229E at low, non-cytotoxic concentrations in cell culture. As shown by plaque titration, qPCR, Luciferase- and green fluorescent protein (GFP) reporter gene expression, replication was diminished by several orders of magnitude. Knockdown of the cellular FK506-binding proteins FKBP1A and FKBP1B in CaCo2 cells prevented replication of HCoV-NL63, suggesting the requirement of these members of the immunophilin family for virus growth. © 2012 Elsevier B.V.
ABSTRACT
Background: Several research groups have recently described a reduced vaccination response to COVID-19 vaccination under methotrexate (MTX) (1,2). The increase in humoral immune response when pausing MTX two weeks after vaccination has already been described for infuenza vaccination (3). However, data regarding MTX-hold during COVID-19 vaccination are still lacking. Objectives: To study the effect of MTX and its discontinuation on the humoral immune response after COVID-19 vaccination in patients with autoimmune rheumatic diseases (AIRD). Methods: In this retrospective study, neutralising SARS-CoV-2 antibodies were measured after second vaccination in 64 rheumatic patients on methotrexate therapy, 31 of whom temporarily paused medication without a fxed regimen. The control group consisted of 21 AIRD patients without immunosuppressive medication. Results: MTX patients showed a signifcantly lower mean antibody response compared to AIRD patients without immunosuppressive therapy (71.8 % vs 92.4 %, p<0.001). For patients taking MTX, age correlated negatively with immune response (r=-0.49;p<0.001). All nine patients with antibody levels below the cutoff were older than 60 years. Patients who held MTX during at least one vaccination showed signifcantly higher mean neutralising antibody levels after second vaccination, compared to patients who continued MTX therapy during both vaccinations (83.1 % vs 61.2 %, p=0.001). This effect was particularly pronounced in patients older than 60 years (80.8 % vs 51.9 %, p=0.001). The impact of the time period after vaccination was greater than of the time before vaccination with the critical cut-off being 10 days. Conclusion: MTX reduces the immunogenicity of SARS-CoV-2 vaccination in an age-dependent manner. Our data further suggest that holding MTX for at least 10 days after vaccination signifcantly improves the antibody response in patients over 60 years of age.
ABSTRACT
Latin America has been severely affected by the COVID-19 pandemic. The COVID-19 burden in rural settings in Latin America is unclear. We performed a cross-sectional, population-based, random-selection SARS-CoV-2 serologic study during March 2021 in the rural population of San Martin region, northern Peru. In total, 563 persons from 288 houses across 10 provinces were enrolled, reaching 0.2% of the total rural population of San Martin. Screening for SARS-CoV-2 IgG antibodies was done using a chemiluminescence immunoassay (CLIA), and reactive sera were confirmed using a SARS-CoV-2 surrogate virus neutralization test (sVNT). Validation of the testing algorithm using prepandemic sera from two regions of Peru showed false-positive results in the CLIA (23/84 sera;27%) but not in the sVNT, highlighting the pitfalls of SARS-CoV-2 antibody testing in tropical regions and the high specificity of the two-step algorithm used in this study. An overall 59.0% seroprevalence (95% confidence interval [CI], 55 to 63%) corroborated intense SARS-CoV-2 spread in San Martin. Seroprevalence rates between the 10 provinces varied from 41.3 to 74.0% (95% CI, 30 to 84%). Higher seroprevalence was not associated with population size, population density, surface area, mean altitude, or poverty index in Spearman correlations. Seroprevalence and reported incidence diverged substantially between provinces, suggesting regional biases of COVID-19 surveillance data. Potentially, limited health care access due to environmental, economic, and cultural factors might lead to undetected infections in rural populations. Additionally, test avoidance to evade mandatory quarantine might affect rural regions more than urban regions. Serologic diagnostics should be pursued in resource-limited settings to inform country-level surveillance and vaccination strategies and to support control measures for COVID-19. IMPORTANCE Latin America is a global hot spot of the COVID-19 pandemic. Serologic studies in Latin America have been mostly performed in urban settings. Rural populations comprise 20% of the total Latin American population. Nevertheless, information on COVID-19 spread in rural settings is scarce. Using a representative population-based seroprevalence study, we detected a high seroprevalence in rural populations in San Martin, northern Peru, in 2021, reaching 41 to 74%. However, seroprevalence and reported incidence diverged substantially between regions, potentially due to limited health care access or test avoidance due to mandatory quarantine. Our results suggest that rural populations are highly affected by SARS-CoV-2 even though they are sociodemographically distinct from urban populations and that highly specific serological diagnostics should be performed in resource-limited settings to support public health strategies of COVID-19 control.
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Background: Several observational studies suggested efficacy of COVID-19 convalescent plasma (CCP) but the results of several randomized clinical trials of CCP are not consistent. The trials differ in treatment schedules in terms of timing, volume and antibody content of CCP as well as enrolled patient populations and endpoints. The CAPSID was designed at the beginning of the pandemic and assessed the efficacy of neutralizing antibody containing high-dose COVID-19 convalescent plasma (CCP) in hospitalized patients with severe COVID-19. Methods: Patients (n=105) in 13 hospitals in Germany were randomized to either receive standard treatment and three units of CCP on days 1, 3 and 5 (total dose 846 ml) (n=53) or standard treatment alone (n=52). Patients in the control group with progress on day 14 could receive CCP (crossover group;n=7) on days 15, 17 and 19. The primary outcome was a dichotomous composite outcome of survival and no longer fulfilling criteria of severe COVID-19 on day 21. For Cross over patients a propensity matching with patients of the plasma group was performed. Results: Neutralizing antibodies were present at baseline in 18.2% of CCP and 19.2% of control group patients. In the ITT analysis the primary outcome occurred in 43.4% of patients in the CCP and 32.7% in the control group (p=0.32). The CCP group showed a trend for shorter times to clinical improvement (40 days, p=0.27) and discharge from hospital (20 days, p=0.24). Among those in the CCP group who received a higher or lower cumulative amount of neutralizing antibodies the primary outcome occurred in 56.0% and 32.1% of patients The high titer group showed significantly shorter intervals to clinical improvement or hospital discharge and a better overall survival (p=0.02). None of the patients in the crossover group (CG) achieved clinical improvement and survived. Comparing the CG to 14 CCP patients matched by baseline characteristics resulted in worse OS in the CG group (p=0.02) while comparison with 6 day 14 matched patients showed equal OS. Interpretation: CCP added to standard treatment did not result in a significant difference in the primary and secondary outcomes. A pre-defined subgroup analysis showed a signal of benefit for CCP among those who received a larger amount of neutralizing antibodies. A progress on day 14 is an indicator for poor outcome in COVID-19. Late administration of CCP is not supported by our results.
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Late in 2020, two genetically-distinct clusters of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with mutations of biological concern were reported, one in the United Kingdom and one in South Africa. Using a combination of data from routine surveillance, genomic sequencing and international travel we track the international dispersal of lineages B.1.1.7 and B.1.351 (variant 501Y-V2). We account for potential biases in genomic surveillance efforts by including passenger volumes from location of where the lineage was first reported, London and South Africa respectively. Using the software tool grinch (global report investigating novel coronavirus haplotypes), we track the international spread of lineages of concern with automated daily reports, Further, we have built a custom tracking website (cov-lineages.org/global_report.html) which hosts this daily report and will continue to include novel SARS-CoV-2 lineages of concern as they are detected.