Systematic genomic analysis of SARS-CoV-2 co-infections throughout the pandemic and segregation of the strains involved

Abstract

Background SARS-CoV-2 recombinants involving the divergent Delta and Omicron lineages have been described, and one of them, “Kraken” (XBB.1.5), has recently been a matter of concern. Recombination requires the coexistence of two SARS-CoV-2 strains in the same individual. Only a limited number of studies have focused on the identification of co-infections and are restricted to co-infections involving the Delta/Omicron lineages. Methods We performed a systematic identification of SARS-CoV-2 co-infections throughout the pandemic (7609 different patients sequenced), not biassed towards the involvement of highly divergent lineages. Through a comprehensive set of validations based on the distribution of allelic frequencies, phylogenetic consistency, re-sequencing, host genetic analysis and contextual epidemiological analysis, these co-infections were robustly assigned. Results Fourteen (0.18%) co-infections with ≥ 8 heterozygous calls (8–85 HZs) were identified. Co-infections were identified throughout the pandemic and involved an equal proportion of strains from different lineages/sublineages (including pre-Alpha variants, Delta and Omicron) or strains from the same lineage. Co-infected cases were mainly unvaccinated, with mild or asymptomatic clinical presentation, and most were at risk of overexposure associated with the healthcare environment. Strain segregation enabled integration of sequences to clarify nosocomial outbreaks where analysis had been impaired due to co-infection. Conclusions Co-infection cases were identified throughout the pandemic, not just in the time periods when highly divergent lineages were co-circulating. Co-infections involving different lineages or strains from the same lineage were occurring in the same proportion. Most cases were mild, did not require medical assistance and were not vaccinated, and a large proportion were associated with the hospital environment.

Mining genomic repositories to further our knowledge of the extent of SARS-CoV-2 co-infections

“…The co-infection frequency was higher than reported elsewhere [8, 9], although the frequencies of individual projects ranged widely (0.15–2.03) (). Moreover, higher co-infection rates were found in the Spanish and South African projects (1.04 and 2.03 %, respectively).…”

“…In our previous study performed in Madrid [9], we identified a proportion of co-infection candidates that were likely due to co-existence of variants emerging in immunosuppressed patients or to laboratory contaminations. However, in this current study, Continued the unavailability of comprehensive epidemiological, laboratory and clinical data and the constraints of sample resequencing hinder the replication of some of the validation procedures applied in our prior work.…”

“…In the population covered by our hospital in Madrid, Spain, our group found comparable co-infection frequencies throughout the entire pandemic. For that study [ 9 ], we applied a pipeline that we had recently designed, which enabled us not only to identify co-infection regardless of the strains/lineages involved (>7 SNP differences between them), but also to segregate the sequences involved for individual analysis.…”

A program for real-time surveillance of SARS-CoV-2 genetics

“…Our targeted long-read sequencing approach is also equipped for recovery of haplotype-resolved viral genomes. To our knowledge, our study is the first to provide a pandemic-wide, high-resolution evaluation of co-infections at this scale, though there have been other systematic efforts that are smaller 40 or target specific types of co-infections, e.g. Omicron/Delta 37 .…”

COVID -19: On the threshold of the fifth year. The situation in Spain

“…During the year 2023, a new phenomenon has occurred in the evolution of SARS-CoV-2 lineages with the emergence of recombinant variants, resulting from the existence of patients coinfected with more than one strain. Systems have been developed for the optimized identification of these coinfections from whole genome sequences, which allow determining that these recombinant variants have existed throughout the pandemic, contributing to the evolutionary acquisition of diversity in this virus, together with the accumulation of sequential mutations [ 19 ]. However, the evolutionary advantages of recombination arise especially when the co-infecting strains are markedly different; hence, attention began to be paid to the recombination phenomenon when the genomic diversity of circulating SARS-CoV-2 was highest, during the Omicron waves, when the BA.1, BA,2 , BA.5 lineages, among others, were prevalent [ 20 ].…”