After the end of the first epidemic episode of SARS-CoV-2 infections, as cases began to rise again during the summer of 2020, we at IHU Méditerranée Infection in Marseille, France, intensified the genomic surveillance of SARS-CoV-2, and described the first viral variants. In this study, we compared the incidence curves of SARS-CoV-2-associated deaths in different countries and reported the classification of SARS-CoV-2 variants detected in our institute, as well as the kinetics and sources of the infections. We used mortality collected from a COVID-19 data repository for 221 countries. Viral variants were defined based on ≥5 hallmark mutations along the whole genome shared by ≥30 genomes. SARS-CoV-2 genotype was determined for 24,181 patients using next-generation genome and gene sequencing (in 47 and 11% of cases, respectively) or variant-specific qPCR (in 42% of cases). Sixteen variants were identified by analyzing viral genomes from 9,788 SARS-CoV-2-diagnosed patients. Our data show that since the first SARS-CoV-2 epidemic episode in Marseille, importation through travel from abroad was documented for seven of the new variants. In addition, for the B.1.160 variant of Pangolin classification (a.k.a. Marseille-4), we suspect transmission from farm minks. In conclusion, we observed that the successive epidemic peaks of SARS-CoV-2 infections are not linked to rebounds of viral genotypes that are already present but to newly introduced variants. We thus suggest that border control is the best mean of combating this type of introduction, and that intensive control of mink farms is also necessary to prevent the emergence of new variants generated in this animal reservoir.

Introduction In Marseille, France, following a first SARS-CoV-2 outbreak in March-May 2020, a second epidemic phase occurred from June, involving ten new variants. The Marseille-4 variant caused an epidemic that started in August and is still ongoing. Materials and methods The 1,038 SARS-CoV-2 whole genome sequences obtained in our laboratory by next-generation sequencing with Illumina technology were analyzed using Nextclade and nextstrain/ncov pipelines and IQ-TREE. A Marseille-4-specific qPCR assay was implemented. Demographic and clinical features were compared between patients with Marseille-4 and earlier strains. Results Marseille-4 harbors 13 hallmark mutations. One leads to S477 N substitution in the spike receptor binding domain targeted by current vaccines. Using a specific qPCR, we observed that Marseille-4 caused 12-100% of SARS-CoV-2 infections in Marseille from September 2020, being involved in 2,106 diagnoses. This variant was more frequently associated with hypoxemia than clade 20A strains before May 2020. It caused re-infection in eleven patients SARS-CoV-2-diagnosed with different strains before June 2020, suggesting either short-term protective immunity or lack of cross-immunity. Discussion/conclusion Marseille-4 should be considered as a major SARS-CoV-2 variant. Its sudden appearance points toward an animal reservoir, possibly minks. The protective role of past-exposure and current vaccines against this variant should be evaluated.

Multiple SARS‐CoV‐2 variants have successively, or concomitantly spread worldwide since the summer of 2020. A few co‐infections with different variants were reported and genetic recombinations, common among coronaviruses, were reported or suspected based on co‐detection of signature mutations of different variants in a given genome. Here we report three infections in southern France with a Delta 21J_AY.4‐Omicron 21K/BA.1 “Deltamicron” recombinant. The hybrid genome harbors signature mutations of the two lineages, supported by a mean sequencing depth of 1163–1421 reads and a mean nucleotide diversity of 0.1%–0.6%. It is composed of the near full‐length spike gene (from codons 156–179) of an Omicron 21K/BA.1 variant in a Delta 21J/AY.4 lineage backbone. Importantly, we cultured an isolate of this recombinant and sequenced its genome. It was observed by scanning electron microscopy. As it is misidentified with current variant screening quantitative polymerase chain reaction (qPCR), we designed and implemented for routine diagnosis a specific duplex qPCR. Finally, structural analysis of the recombinant spike suggested its hybrid content could optimize viral binding to the host cell membrane. These findings prompt further studies of the virological, epidemiological, and clinical features of this recombinant.

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