Minimizing school disruption under high incidence conditions due to the Omicron variant in early 2022 (preprint)

As record cases due to the Omicron variant are currently registered in Europe, schools remain a vulnerable setting suffering large disruption. Extending previous modeling of SARS-CoV-2 transmission in schools in France, we estimate that at high incidence rates reactive screening protocols (as currently applied in France) require comparable test resources as weekly screening (as currently applied in some Swiss cantons), for considerably lower control. Our findings can be used to define incidence levels triggering school protocols and optimizing their cost-effectiveness.

SARS-CoV-2 in schools: genome analysis shows that concurrent cases in the second and third wave were often unconnected (preprint)

Background. The risk of SARS-CoV-2 (SCoV2) infection in schools and student households is typically assessed using classical epidemiology whereby transmission is based on time of symptom onset and contact tracing data. Using such methodologies may be imprecise regarding transmission events of different, simultaneous SCoV2 variants spreading with different rates and directions in a given population. We analysed with high resolution the transmission among different communities, social networks, and educational institutions and the extent of outbreaks using whole genome sequencing (WGS). Methods and Findings. We combined WGS and contact tracing spanning two pandemic waves from October 2020 to May 2021 in the Canton of Basel-City, Switzerland and performed an in-depth analysis of 235 cases relating to 22 educational institutions. We describe the caseload in educational institutions and the public health measures taken and delineate the WGS-supported outbreak surveillance. During the study period, 1,573 of 24,557 (6.4%) children and 410 of 3,726 (11%) staff members from educational institutions were reported SCoV2 positive. Thereof, WGS data from 83 children, 35 adult staff in 22 educational institutions and their 117 contacts (social network, families) was available and analysed. 353 contextual sequences from residents of the Canton of Basel-City sequenced through surveillance were identified to be related to cases in the educational institutions. In total, we identified 55 clusters and found that coinciding SCoV2-cases in individual educational institutions were mostly introduced from different sources such as social networks or the larger community. More transmission chains started in the community and were brought into the educational institutions than vice versa (31 vs. 13). Adolescents (12-19 years old) had the highest case prevalence over both waves compared to younger children or adults, especially for the emerging Alpha variant. Conclusions. Introduction of SCoV2 into schools accounts for most events and reflects transmission closely related to social activity, whereby teenagers and young adults contribute to significant parallel activity. Combining WGS with contact tracing is pivotal to properly inform authorities about SCoV2 infection clusters and transmission directions in educational settings and the effectiveness of enacted public health measures. The gathered data showing more clusters to seed in the community than vice versa as well as few subsequent in-school transmissions indicate that the agilely employed health measures for educational institutions helped to prevent outbreaks among staff and children. The clinical trial accession number is NCT04351503 (clinicaltrials.gov).

Transmission of SARS-CoV-2 within households: a prospective cohort study in the Netherlands and Belgium - Interim results (preprint)

Background: Household transmission studies are useful to obtain granular data on SARS-CoV-2 transmission dynamics and to gain insight into the main determinants. In this interim report we investigated secondary attack rates (SAR) by household and subject characteristics in the Netherlands and Belgium. Methods: Households with a real-time reverse transcription polymerase chain reaction (RT-PCR) confirmed SARS-CoV-2 index case were enrolled <48 hours following report of the positive test result. Daily symptom follow-up, standardized nose-throat sampling at enrollment and at new-onset acute respiratory illness (ARI) and paired dried blood spots (DBS) were collected from each participant. Children 0-2 years of age were additionally requested to collect a stool sample 7 days after enrollment and at new-onset of ARI. Swabs and stool samples were tested by RT-PCR for virus detection and DBS by multiplex protein microarray for detection of SARS-CoV-2 antibodies. The SAR was calculated 1) per-household as the proportion of households with [≥]1 secondary SARS-CoV-2 case and 2) per-person as the probability of infection in household members at risk. We explored differences in SARs by household and subject characteristics. Results: This analysis includes 117 households that completed follow-up between April-December 2020. Among 382 subjects, 74 secondary infections were detected, of which 13 (17.6%) were asymptomatic and 20 (27.0%) infections were detected by seroconversion only. Of cases detected by RT-PCR, 50 (67.6%) were found at enrollment. The household SAR was 44.4% (95%-CI: 35.4-53.9%) and was higher for index cases meeting the ARI case definition (52.3%; 95%-CI 41.4-62.9%) compared to mildly symptomatic (22.2%; 95%-CI: 9.4-42.7%) and asymptomatic index cases (0.0%; 95%-CI: 0.0-80.2%). The per-person SAR was 27.9% (95%-CI: 22.7-33.8%). Transmission was lowest from child to parent (9.1%; 95%-CI: 2.4-25.5%) and highest from parent to child (28.1%; 95%-CI: 19.7-38.4%) and in children 6-12 years (34.2%; 95%-CI: 20.1-51.4%). Among 141 subjects with RT-PCR confirmed SARS-CoV-2 infections, seroconversion was detected in 111 (78.7%). Conclusion: We found a high household SAR, with the large majority of transmissions detected early after identification of the index case. Our findings confirm differential SAR by symptom status of the index. In almost a quarter of RT-PCR positive cases, no antibodies were detected. Other factors influencing transmission will be further explored as more data accumulate.

Global surveillance of potential antiviral drug resistance in SARS-CoV-2: proof of concept focussing on the RNA-dependent RNA polymerase (preprint)

Antiviral treatments for COVID-19 have involved many repurposed drugs. Currently, SARS-CoV-2 RNA-dependent RNA polymerase (RdRp, encoded by nsp12-nsp7-nsp8) has been targeted by numerous inhibitors with debated clinical impact. Among these, remdesivir has been conditionally approved for the treatment of COVID-19 patients. Although the emergence of antiviral resistance, an indirect proxy for antiviral efficacy, poses a considerable healthcare threat, an evolutionary perspective on emerging resistant mutants is still lacking. Here we show that SARS-CoV-2 RdRp is under purifying selection, that potential escape mutations are rare, and unlikely to lead to viral fitness loss. In more than 56,000 viral genomes from 105 countries dating from December 2019 to July 2020 we found negative selective pressure affecting nsp12 (Tajimas D = -2.62), with potential antiviral escape mutations in only 0.3% of sequenced genomes. Those affected known key residues, such as Nsp12:Val473 and Nsp12:Arg555. Of the potential escape mutations found globally, in silico structural models show that this rarely implies loss of stability in RdRp. No potential escape mutation were found in our local cohort of remdesivir treated patients from the first wave (n=8). Our results indicate that RdRp is a suitable drug target, and that remdesivir does not seem to exert high selective pressure. Our study could be the starting point of a larger monitoring effort of drug resistance throughout the COVID-19 pandemic. We recommend the application of repetitive genome sequencing of SARS-CoV-2 from patients treated with antivirals to provide early insights into the evolution or antiviral resistance.

Determinants of SARS-CoV-2 transmission to guide vaccination strategy in a city (preprint)

Transmission chains within cities provide an important contribution to case burden and economic impact during the ongoing COVID-19 pandemic, and should be a major focus for preventive measures to achieve containment. Here, at very high spatio-temporal resolution, we analysed determinants of SARS-CoV-2 transmission in a medium-sized European city. We combined detailed epidemiological, mobility, and socioeconomic data-sets with whole genome sequencing during the first SARS-CoV-2 wave. Both phylogenetic clustering and compartmental modelling analysis were performed based on the dominating viral variant (B.1-C15324T; 60% of all cases). Here we show that transmissions on the city population level are driven by the socioeconomically weaker and highly mobile groups. Simulated vaccination scenarios showed that vaccination of a third of the population at 90% efficacy prioritising the latter groups would induce a stronger preventive effect compared to vaccinating exclusively senior population groups first. Our analysis accounts for both social interaction and mobility on the basis of molecularly related cases, thereby providing high confidence estimates of the underlying epidemic dynamics that may readily be translatable to other municipal areas.

Epidemiology and precision of SARS-CoV-2 detection following lockdown and relaxation measures (preprint)

Introduction: SARS-CoV-2-detection is critical for clinical and epidemiological assessment of the ongoing CoVID-19 pandemic. Aim: To cross-validate manual and automated high-throughput (Roche-cobas6800-Target1/Target2) testing for SARS-CoV-2-RNA, to describe detection rates following lockdown and relaxation, and to evaluate SARS-CoV-2-loads in different specimens. Method: The validation cohort prospectively compared Basel-S-gene, Roche-E-gene, and Roche-cobas6800-Target1/Target2 in 1344 naso-oropharyngeal swabs (NOPS) taken in calendar week 13 using Basel-ORF8-gene-assay for confirmation. Follow-up-cohort-1 and -2 comprised 12363 and 10207 NOPS taken over 10 weeks until calendar week 24 and 34, respectively. SARS-CoV-2-loads were compared in follow-up NOPS, lower respiratory fluids, and plasma. Results: Concordant results were obtained in 1308 cases (97%) including 97 (9%) SARS-CoV-2-positives showing high quantitative correlations (Spearman r>0.95; p<0.001) for all assays. Discordant samples (N=36) had significantly lower SARS-CoV-2-loads (p<0.001). Following lockdown, weekly detection rates declined to <1% reducing single-test positive predictive values from 99.3% to 85.1%. Following relaxation, rates flared up to 4% with similarly high SARS-CoV-2-loads, but patients were significantly younger than during lockdown (34 vs 52 years, p<0.001). SARS-CoV-2-loads in follow-up NOPS declined by 3log10 copies/mL within 10 days post-diagnosis (p<0.001). SARS-CoV-2-loads in NOPS correlated weakly with those in time-matched lower respiratory fluids and plasma, but remained detectable in 14 and 7 cases of NOPS with undetectable SARS-CoV-2, respectively. Conclusion: Evaluated manual and automated assays are highly concordant and correlate quantitatively. Following successful lockdown, declining positive predictive values require dual-target-assays for clinical and epidemiologic assessment. Confirmatory and quantitative follow-up testing should be considered within <5 days, using lower respiratory fluids in symptomatic patients with SARS-CoV-2-negative NOPS.