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SARS-CoV-2’s genetic plasticity has led to several variants of concern (VOCs). Here we studied replicative capacity for seven SARS-CoV-2 isolates (B.1, Alpha, Beta, Gamma, Delta, Zeta, and Omicron BA.1) in primary reconstituted airway epithelia (HAE) and lung-derived cell lines. Furthermore, to investigate the host range of Delta and Omicron compared to ancestral SARS-CoV-2, we assessed replication in 17 cell lines from 11 non-primate mammalian species, including bats, rodents, insectivores and carnivores. Only Omicron’s phenotype differedin vitro, with rapid but short replication and efficient production of infectious virus in nasal HAEs, in contrast to other VOCs, but not in lung cell lines. No increased infection efficiency for other species was observed, but Delta and Omicron infection efficiency was increased in A549 cells. Notably replication in A549 and Calu3 cells was lower than in nasal HAE. Our results suggest better adaptation of VOCs towards humans, without an extended host range.

Emerging SARS-CoV-2 variants of concern/interest (VOC/VOI) raise questions about effectiveness of neutralizing antibodies derived from infection or vaccination. As the population immunity to SARS-CoV-2 has become more complex due to prior infection and/or vaccination, understanding the antigenic relationship between variants is needed. Here, we have assessed in total 104 blood specimens from convalescent individuals after infection with early-pandemic SARS-CoV-2 (pre-VOC) or with Alpha, Beta, Gamma or Delta, post-vaccination after double-dose mRNA-vaccination and break through infections due to Delta or Omicron. Neutralization against seven authentic SARS-CoV-2 isolates (B.1, Alpha, Beta, Gamma, Delta, Zeta, Omicron) was assessed by plaque-reduction neutralization assay. We found highest neutralization titers against the homologous (previously infecting) variant, with lower neutralization efficiency against heterologous variants. Significant loss of neutralization for Omicron was observed but to a varying degree depending on previously infecting variant (23.0-fold in Beta-convalescence up to 56.1-fold in Alpha-convalescence), suggesting that infection-derived immunity varies, but independent of the infecting variant is only poorly protective against Omicron. Of note, Zeta VOI showed also pronounced escape from neutralization of up to 28.2-fold in Alpha convalescent samples. Antigenic mapping reveals both Zeta and Omicron as separate antigenic clusters. Double dose vaccination showed robust neutralization for Alpha, Beta, Gamma, Delta and Zeta, with fold-change reduction of only 2.8 (for Alpha) up to 6.9 (for Beta). Escape from neutralization for Zeta was largely restored in vaccinated individuals, while Omicron still showed a loss of neutralization of 85.7-fold compared to pre-VOC SARS-CoV-2. Combined immunity from infection followed by vaccination or vaccine breakthrough infection showed highest titers and most robust neutralization for heterologous variants. Breakthrough infection with Delta showed only 12.5-fold reduced neutralization for Omicron, while breakthrough infection with Omicron showed only a 1.5-fold loss for Delta, suggests that infection with antigenically different variants can boost immunity for antigens closer to the vaccine strain. Antigenic cartography showed also a tendency towards broader neutralizing capacity for heterologous variants. We conclude that the complexity of background immunity needs to be taken into account when assessing new VOCs. Development towards separate serotypes such as Zeta was already observed before Omicron emergence, thus other factors than just immune escape must contribute to Omicrons rapid dominance. However, combined infection/vaccination immunity could ultimately lead to broad neutralizing capacity also against non-homologous variants.

BackgroundThe emergence of each novel SARS-CoV-2 variants of concern (VOCs) requires investigation of its potential impact on the performance of diagnostic tests in use, including Antigen-detecting rapid diagnostic tests (Ag-RDT). Although anecdotal reports have been circulating that the newly emerged Omicron variant is in principle detectable by Ag-RDTs, few data on sensitivity are available.MethodsWe have performed 1) analytical sensitivity testing with cultured virus in eight Ag-RDTs and 2) retrospective testing in duplicates with clinical samples from vaccinated individuals with Omicron (n=18) or Delta (n=17) breakthrough infection on seven Ag-RDTs.FindingsOverall, we have found large heterogenicity between Ag-RDTs for detecting Omicron. When using cultured virus, we observed a trend towards lower sensitivity for Omicron detection compared to earlier circulating SARS-CoV-2 and the other VOCs. When comparing performance for Delta and Omicron in a comparable set of clinical samples in seven Ag-RDTs, 124/252 (49.2%) of all test performed showed a positive result for Omicron compared to 156/238 (65.6%) for Delta samples. Sensitivity for both Omicron and Delta between Ag-RDTs was highly variable. Four out of seven Ag-RDTs showed significantly lower sensitivity (pInterpretationSensitivity for detecting Omicron is highly variable between Ag-RDTs, necessitating a careful consideration when using these tests to guide infection prevention measures. While analytical and retrospective testing may be a proxy and timely solution to generate performance data, it is not a replacement for clinical evaluations which are urgently needed. Biological and technical reasons for detection failure by some Ag-RDTs need to be further investigated.FundingThis work was supported by the Swiss National Science Foundation (grant numbers 196383, 196644 and 198412), the Fondation Ancrage Bienfaisance du Groupe Pictet, the Fondation Privée des Hôpiteaux Universitaires de Genève and FIND, the global alliance for diagnostics.

We report a prospective epidemiological, virological and serological investigation of a SARS-CoV-2 outbreak in a primary school, as part of a longitudinal, prospective, primary school-based surveillance study. It involved repeated testing of pupils and teachers and household members of participants who tested positive, with rapid antigen tests and/or RT-PCR (Day 0-2 and Day 5-7), serologies on dried capillary blood samples (Day 0-2 and Day 30), contact tracing interviews and SARS-CoV-2 whole genome sequencing. This SARS-CoV-2 outbreak caused by the Alpha variant involved 20 children aged 4 to 6 years from 4 classes, 2 teachers and a total of 4 household members. Infection attack rates were between 11.8 and 62.0% among pupils from the 4 classes, 22.2% among teachers and 0% among non-teaching staff. Secondary attack rate among household members was 15.4%. Symptoms were reported by 63% of infected children, 100% of teachers and 50% of household members. All analysed sequences but one showed 100% identity. Serological tests detected 8 seroconversions unidentified by SARS-CoV-2 virological tests. This study confirmed child-to-child and child-to-adult transmission of the infection. Effective measures to limit transmission in schools have the potential to reduce the overall community circulation.

Emerging variants of concern (VOCs) drive the SARS-CoV-2 pandemic. We assessed VOC B.1.1.7, now prevalent in several countries, and VOC B.1.351, representing the greatest threat to populations with immunity to the early SARS-CoV-2 progenitors. B.1.1.7 showed a clear fitness advantage over the progenitor variant (wt-S614G) in ferrets and two mouse models, where the substitutions in the spike glycoprotein were major drivers for fitness advantage. In the “superspreader” hamster model, B.1.1.7 and wt-S614G had comparable fitness, whereas B.1.351 was outcompeted. The VOCs had similar replication kinetics as compared to wt-S614G in human airway epithelial cultures. Our study highlights the importance of using multiple models for complete fitness characterization of VOCs and demonstrates adaptation of B.1.1.7 towards increased upper respiratory tract replication and enhanced transmission in vivo.Summary sentenceB.1.1.7 VOC outcompetes progenitor SARS-CoV-2 in upper respiratory tract replication competition in vivo.

Several SARS-CoV-2 variants of concern/interest (VOC/VOI) emerged recently, with VOCs outcompeting earlier lineages on a global scale. To date, few data on routine diagnostic performance for VOC/VOIs are available. Here, we investigate the analytical performance of nine commercially available antigen-detecting rapid diagnostic tests (Ag-RDTs) for VOC B.1.1.7, B.1.351, P.1 and VOI P.2 with cultured SARS-CoV-2. Comparable or higher sensitivity was observed for VOC/VOI compared to a non-VOC/VOI early-pandemic virus for all Ag-RDTs.