Delta-Omicron recombinant escapes therapeutic antibody neutralization

Duerr, Ralf; Dimartino, Dacia; Marier, Christian; Zappile, Paul; Wang, Guiqing; Plitnick, Jonathan; Griesemer, Sara B.; Lasek‐Nesselquist, Erica; Dittmann, Meike; Ortigoza, Mila B.; Prasad, Prithiv; George, Kirsten St.; Heguy, Adriana

doi:10.1101/2022.04.06.487325

Cited by 11 publications

(9 citation statements)

References 37 publications

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“…Amino acid exchanges E340A/K/G/Q and P337L/R/K were reported to be accompanied by a pronounced increase in IC50 against S309 in WT SARS-CoV-2 (10) as well as in VOC Delta (42,43) and Omicron (44,45). In our S309 selection experiment, SARS-CoV-2 first developed amino acid exchange R346S, which was described as 'immune-escape enabling' amino acid exchange for S309 (46).…”

Section: Discussionmentioning

confidence: 78%

Targeted escape of SARS-CoV-2 in vitro from monoclonal antibody S309, the precursor of sotrovimab

et al. 2022

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Class 1 and 2 monoclonal antibodies inhibit SARS-CoV-2 entry by blocking the interaction of the viral receptor-binding domain with angiotensin-converting enzyme 2 (ACE2), while class 3 antibodies target a highly conserved epitope outside the ACE2 binding site. We aimed to investigate the plasticity of the spike protein by propagating wild-type SARS-CoV-2 in the presence of class 3 antibody S309. After 12 weeks, we obtained a viral strain that was completely resistant to inhibition by S309, due to successively evolving amino acid exchanges R346S and P337L located in the paratope of S309. The antibody lost affinity to receptor-binding domains carrying P337L or both amino acid exchanges, while ACE2 binding was not affected. The resistant strain replicated efficiently in human CaCo-2 cells and was more susceptible to inhibition of fusion than the original strain. Overall, SARS-CoV-2 escaped inhibition by class 3 antibody S309 through a slow, but targeted evolution enabling immune escape and altering cell entry. This immune-driven enhancement of infectivity and pathogenicity could play an important role in the future evolution of SARS-CoV-2, which is under increasing immunological pressure from vaccination and previous infections.

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Section: Discussionmentioning

confidence: 78%

Targeted escape of SARS-CoV-2 in vitro from monoclonal antibody S309, the precursor of sotrovimab

et al. 2022

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“…Evidence from different laboratories indicates that SARS-CoV-2 isolates from infected patients exhibit complex, dynamic, and compartmentalized mutant spectra and that minority mutations in individual isolates, including vaccine-breakthrough cases, can be represented in the consensus sequence of isolates of later epidemic waves [32,33,40,42,43,46,47,[85][86][87][88]. Mutant spectra include many low-frequency point mutations and a remarkable number of deletions, presumably generated through recombination events favored by the limited processivity of the coronavirus polymerases [89][90][91][92]. In terms of variation in the course of the epidemiological expansion of the virus, a current estimate of the rate of evolution of SARS-CoV-2 is (1.2 ± 0.6) × 10 −3 mutations per nucleotide and year (m/n/y), which has been calculated as an average of ten independent measurements (ranging from the following: 9.9 × 10 −4 to 2.2 × 10 −3 m/n/y) [93][94][95][96][97][98][99][100][101][102].…”

Section: Discussionmentioning

confidence: 99%

“…If this were the case, their frequency would fluctuate, and the carrying genomes would be more prone to becoming dominant as a result of selection or random drift [80]. If, on the contrary, the mutations are present in defective genomes, they may be maintained by complementation [112], and eventually they may become part of viable genomes by recombination [91,92]. The epidemiological data suggest that the same mutations that have low frequency in mutant spectra can be found as dominant in independent isolates.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Mutant Spectra at Different Depth Levels Reveal an Overwhelming Abundance of Low Frequency Mutations

et al. 2022

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Populations of RNA viruses are composed of complex and dynamic mixtures of variant genomes that are termed mutant spectra or mutant clouds. This applies also to SARS-CoV-2, and mutations that are detected at low frequency in an infected individual can be dominant (represented in the consensus sequence) in subsequent variants of interest or variants of concern. Here we briefly review the main conclusions of our work on mutant spectrum characterization of hepatitis C virus (HCV) and SARS-CoV-2 at the nucleotide and amino acid levels and address the following two new questions derived from previous results: (i) how is the SARS-CoV-2 mutant and deletion spectrum composition in diagnostic samples, when examined at progressively lower cut-off mutant frequency values in ultra-deep sequencing; (ii) how the frequency distribution of minority amino acid substitutions in SARS-CoV-2 compares with that of HCV sampled also from infected patients. The main conclusions are the following: (i) the number of different mutations found at low frequency in SARS-CoV-2 mutant spectra increases dramatically (50- to 100-fold) as the cut-off frequency for mutation detection is lowered from 0.5% to 0.1%, and (ii) that, contrary to HCV, SARS-CoV-2 mutant spectra exhibit a deficit of intermediate frequency amino acid substitutions. The possible origin and implications of mutant spectrum differences among RNA viruses are discussed.

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“…Moreover, the United Kingdom Health Security Agency (UKHSA) has reported 30 cases of Deltacron in the United Kingdom ( https://www.theguardian.com/world/2022/mar/11/what-is-deltacron-covid-variant-uk ). Deltacron comprise a backbone of Delta variant as well as Omicron spike protein (Omicron-spike/Delta-backbone; the new virus is able to induce both Delta variant (large syncytia cell) and Omicron variant (cell rounding/detachment) features [ 4 , 6 ].…”

mentioning

confidence: 99%

“…Duerr et al reported an infection with Deltacron in an immunosuppressed patient treated with Sotrovimab. The results of whole genome sequencing (WGS) of the new variant showed a recombination in its spike N-terminal domain (a 5′ Delta AY.45 portion and a 3′ Omicron BA.1 portion); In this study, they hypothesized that the use of antiviral monoclonal antibodies in immunocompromised individuals could not effectively eradicate the virus, which in turn provided an opportunity for the emergence of new variants of SARS-CoV-2 in mixed-infections [ 6 ]. After identifying Omicron in different parts of Africa, Gao et al announced that Omicron may have evolved within immunocompromised community with a poorer vaccination rate in South Africa [ 8 ].…”

mentioning

confidence: 99%