A recent article posted to the Research Square* preprint server, whilst under consideration at a Nature Portfolio journal, presented the rapid profiling of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta-Omicron recombinant sequence from Europe.
Recombination is responsible for the evolution of various organisms. However, evolutionary reasons for the presence of recombination in ribonucleic acid (RNA) viruses are unknown. Yet, it has been linked to key epidemiological events in RNA viruses like antigenic shift, variation in virulence, or virus-host range expansion. Recombination is a common occurrence in positive-strand RNA viruses like coronaviruses.
The reason for the ongoing coronavirus disease 2019 (COVID-19) pandemic is the subsequent emergence of SARS-CoV-2 variants of concern (VOCs) with higher immune escape, transmissibility, or disease severity properties.
The previously global dominant SARS-CoV-2 Delta VOC has now been replaced by the emergence of Omicron BA.1 and BA.2 lineages since November 2021. This has established conditions for the genetic swap between SARS-CoV-2 viruses with both phenotypic specificities and genetic diversity.
About the study
In the current work, the researchers identified a SARS-CoV-2 Delta-Omicron recombinant strain in Europe and characterized them both in vivo and in vitro.
The scientists analyzed epidemiological data of 32 Delta-Omicron recombinant-infected patients and six recombinant suspected SARS-CoV-2 cases between January 3 and March 9, 2022, from France. The team compared this with recently procured epidemiological data of Omicron cases. The authors conducted similarity searches on the Global Initiative on Sharing All Influenza Data (GISAID) EpiCoV database to discover the parent sequences of the identified SARS-CoV-2 recombinant.
The immune escape properties of the recombinant in vaccinated serum samples were assessed using pseudoviruses with the recombinant's spike (S) and SARS-CoV-2 BA.1, AY.4, and ancestral strains for reference. Additionally, the sensitivity of the recombinant strain to therapeutic SARS-CoV-2 human monoclonal antibodies (mAbs) was determined. Moreover, the authors profiled the recombinant viral load in nasal turbinates and the lungs of the highly susceptible model of human angiotensin-converting enzyme 2 (ACE2) transgenic (K18-hACE2) mice.
The in-depth analysis of the Nextclade-classified and Pangolin-classified SARS-CoV-2 Delta 21J and AY.4 sequences, respectively, in Europe and France at the beginning of 2021 revealed that they have characteristic mutations of the BA.1 lineage in some portion of their genome. This is indicative of the possibility of a SARS-CoV-2 Delta-Omicron recombinant. Further, the authors confirmed that the SARS-CoV-2 sequences were not because of laboratory contamination or co-infection. The SARS-CoV-2 Delta-Omicron recombinant lineage was initially classified as GKA clade by GISAID, and then XD by Pango lineage, whereas the European Center for Disease Prevention and Control (ECDC) designated it as the SARS-CoV-2 variant under monitoring (VUM) on March 17, 2022.
The authors discovered two break points in the genomic structure of the Delta-Omicron recombinant, 1) at the initiation of the S and 2) within the Open Reading Frame 3a (ORF 3a). According to the scientists, the initial sequence of this Delta-Omicron recombinant was sampled in Northern France on January 3, 2022. By March 18, 2022, the XD lineage was discovered in numerous parts of France, Netherlands, Denmark, Germany, and Belgium via cluster examinations and random sampling. Except for one case, most cases did not present a history of travel, implying widespread yet infrequent circulation. The team identified a signal of diversity within the Delta-Omicron recombinant lineage comprising geographical clustering within both Europe and France.
The median age of XD patients was 32.5 years parallel to 35 years in Omicron cases in France. Yet, the XD was more prevalent in people younger than 20 years versus Omicron cases. Only two XD patients had prior COVID-19 history, less than Omicron. None of the reported XD patients were older than 70 years, and no risk factor was documented. Overall, COVID-19 vaccination coverage of the XD cases was distinct from the Omicron patients.
The analyzed XD patients from France were symptomatic, and the most frequent symptoms included headache, fatigue, and fever. The rates of anosmia and ageusia were hiked in XD cases relative to Omicron. Among the only two XD patients who were admitted to the hospital, one was admitted for unrelated reasons and the other for less than 24 hours and without requiring intensive care unit (ICU) admission.
The Delta- and Omicron-like portion of the analyzed recombinant XD sequence had 100% similarity with the selected AY.4 and BA.1 viruses. The immune evasion characteristics of the XD virus was similar to the Omicron VOC. The mAbs such as sotrovimab, tixagevimab, cilgavimab, and tixagevimab/cilgavimab cocktail had less efficiency in neutralizing the recombinant XD strain and BA.2 variant compared to the AY.4 parental strain.
The clinical features associated with the recombinant XD infection in K18-hACE2 mice was diverse from the BA.1 infection. The XD RNA levels in the lungs of the mice were similar to BA.1 and lower than AY.4. On the contrary, XD RNA in nasal turbinates was higher than BA.1 and slightly lower than AY.4. Competition assays of XD and BA.1 together infected K18-hACE2 mice illustrated that while Omicron surpassed the XD levels in the lungs, the opposite was observed in nasal turbinates.
XD and BA.1 did not cause weight loss in mice, unlike Delta. Yet, comparable to AY.4 infection, the clinical condition of XD-infected mice worsened within seven to eight days of infection and subsequently, the mice died or were euthanized.
The study findings depicted that although SARS-CoV-2 Delta-Omicron recombinant has immune evasion capacities comparable to the Omicron VOC, it behaves more like the Delta VOC in mice encoding human ACE2 receptors. In addition, the Delta-Omicron recombinant identified in this study offers a rare and natural chance to learn more about the genotype-phenotype relationships in SARS-CoV-2.
The authors believe that the persistent diversification of SARS-CoV-2 observed during the ongoing COVID-19 pandemic will probably present more potential for recombination. Hence, continued global surveillance and rapid risk analysis will be critical for determining the long-lasting response to SARS-CoV-2 circulation and comprehending its biology.
Additional research is required to understand the reason for the intermediate phenotype of the Delta-Omicron XD recombinant and its impact on humans.
Research Square publish preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.