CDC study reveals hybrid SARS-CoV-2 spike from Delta/Omicron recombination event

The United States Centers for Disease Control and Prevention (CDC) conducted nationwide genomic surveillance to identify and characterize the delta-omicron recombinant genomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A total of nine genomes with a hybrid delta-omicron spike protein have been identified. The study is published in the journal Emerging infectious diseases.

CDC Dispatch – SARS-CoV-2 Delta–Omicron Recombinant Viruses, USA. Image Credit: Design_Cells / Shutterstock

Background

The US CDC has launched the National SARS-CoV-2 Strain Surveillance Program to identify, characterize, and monitor emerging variants of SARS-CoV-2. The program has so far identified 1.8 million SARS-CoV-2 genomes in the United States and submitted them to public databases.

Coronaviruses frequently undergo genomic recombination, an evolutionary process of generating new viral variants with increased transmissibility and pathogenicity. The process is defined as an exchange of genetic material between two distinct viral variants, leading to the generation of a new variant with new traits.

During the ongoing coronavirus disease 2019 (COVID-19) pandemic, recombination events have been documented between alpha and delta variants and delta and omicron variants. A recombinant delta-omicron variant is expected to have a significant impact on the efficacy of vaccines and therapeutics due to genomic variations between variants and the potent immune evasion ability of the omicron.

In the current study, scientists sought to identify and characterize recombinant delta-omicron genomes in the United States.

Recombinant delta-omicron genomes

The scientists identified a total of nine delta-omicron recombination sequences from the CDC’s national genomic surveillance dataset using a rapid interclade recombination detection method. The method detects a single breakpoint in a specific nucleotide range where no differentiating mutations between delta and omicron-linked clades are present.

The results revealed that the recombinant sequences contain signature mutations of the delta and omicron variants, changing from delta-linked mutations to omicron-linked mutations between amino acids 158 and 339 of the spike protein.

Previously, delta-omicron recombination events have been identified in the UK and France. However, evidence suggests that these recombinant variants could result from laboratory contaminations, sequencing errors or co-infections.

To rule out these possibilities, the scientists in the present study used various sequencing strategies to examine the raw read data of the identified recombinant sequences that were created by molecular loop and amplicon-based sequencing strategies. The results revealed that the consensus sequences generated from the newly applied confirmatory sequencing strategies are functionally identical to the corresponding original sequences.

Additionally, the scientists fragmented the recombinant sequences at a specific position within the predicted recombination site. By aligning fragmented sequences with reference sequences of the delta and omicron variants, the scientists observed that the first fragment belongs to the delta clade and the rest belong to the omicron clades.

Further sequencing analysis confirmed that characteristic delta mutations coexist with distinct omicron mutations in the recombinant variant. In addition, the translated spike protein showed a hybrid sequence containing amino acids characteristic of the delta and omicron variants with a breakpoint between the N-terminal domain (NTD) and the receptor binding domain (RBD) of the sub. -peak unit S1.

Composition of candidate recombinant SARS-CoV-2 genomes

Composition of candidate recombinant SARS-CoV-2 genomes. A) Amino acid profiles of putative recombinants in the US and UK. Amino acid substitutions associated with the Delta variant are shown in orange and substitutions associated with the Omicron variant are shown in purple; the hues correspond to the proportion of sequences classified Omicron or Delta which contain this substitution (Appendix, https://wwwnc.cdc.gov/EID/article/28/7/22-0526-App1.pdf). Gray boxes indicate an amino acid substitution common to the Omicron and Delta sequences. White boxes indicate no change from Wuhan-Hu-1 virus, and black boxes indicate substitutions that are not common to Delta or Omicron sequences overall. Separate groups are displayed; sequences from the US appear to have recombination in the spike gene, and samples from 2 groups from the UK show recombination upstream of the spike gene (group 1 from the UK represents https://github. com/cov-lineages/pango-designation/issues/445, UK group 2 represents https://github.com/cov-lineages/pango-designation/issues/441). The BA.1.1 (Omicron) deletion associated with spike gene target failure (Δ69–70), receptor binding domain, and range containing recombination location are noted. B) Proportion of reads supporting each variation and deletion of a single nucleotide around the recombination site from Illumina datasets (IDT xGen amplicons) generated at the Centers for Disease Control and Prevention. Shown are 2 recombinants (EPI_ISL_8981459, EPI_ISL_8981824), next to a representative genome AY.119.2 (Delta) ((EPI_ISL_6811176) and a representative genome BA.1.1 (Omicron) (EPI_ISL_9351600). Each bar indicates the proportion of reads containing the given allele (stained by nucleotides A, C, T and G) at each position for each sample. Asterisks indicate deletions. Variants are relative to the Wuhan-Hu-1 virus.

Significance of the study

The study identifies and characterizes delta-omicron recombinant genomes containing a hybrid spike protein. Despite the presence of recombinant variants in the United States over the course of six weeks, the number of resulting cases remains low. The majority of cases have been detected in the mid-Atlantic region of the United States. However, scientists could not determine the epidemiological link due to the lack of identifying information for specimens containing these recombinant genomes.

Scientists recommend continuous genome monitoring for rapid detection and monitoring of new recombinant variants due to the powerful impact of recombinant variants on public health.[if–>

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