Sequential intrahost evolution and onward transmission of SARS-CoV-2 variants

Gonzalez‐Reiche, Ana S.; Alshammary, Hala; Schaefer, Sarah; Patel, Gopi; Polanco, Jose; Carreño, Juan Manuel; Amoako, Angela; Rooker, Aria; Cognigni, Christian; Floda, Daniel; Khalil, Zain; Farrugia, Keith; Assad, Nima; Zhang, Jian; Alburquerque, Bremy; Kleiner, Giulio; Andre, Dalles; Beach, Katherine F.; Bermudez-Gonzalez, Maria; Cai, Gianna; Lyttle, Neko; Mulder, Lubbertus C. F.; Oostenink, Annika; Salimbangon, Ashley Beathrese T.; Singh, Gagandeep; Kesteren, Morgan van; Monahan, Brian; Mauldin, Jacob; Awawda, Mahmoud H.; Sominsky, Levy A.; Gleason, Charles; Srivastava, Komal; Sebra, Robert; Ramírez, Juan David; Banu, Radhika; Shrestha, Paras; Krammer, Florian; Paniz‐Mondolfi, Alberto; Sordillo, Emilia Mia; Simon, Viviana; Bakel, Harm van

doi:10.1038/s41467-023-38867-x

Cited by 40 publications

(26 citation statements)

References 58 publications

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“…Each of these sites exhibits potential for evolution. For example, residues 455 and 456 show substantial amino acid variation across the sarbecovirus alignment, the Y453F mutation occurred independently in multiple outbreaks of SARS-CoV-2 in farms of American mink (Oude Munnink et al 2021; Ren et al 2021), and the mutation L455W has been observed in a chronic human SARS-CoV-2 infection (Gonzalez-Reiche et al 2023). At the time of writing, XBB.1.5 descendants such as EG.5 and XBB.1.16.6 (each containing F456L) and an EG.5 derivative that combines F456L with L455F (Pango lineage HK.3) have been detected, and in the case of EG.5.1 (containing F456L), begun to rise substantially in global frequency consistent with a selective advantage.…”

Section: Resultsmentioning

confidence: 99%

Deep mutational scans of XBB.1.5 and BQ.1.1 reveal ongoing epistatic drift during SARS-CoV-2 evolution

Taylor,

Starr

2023

Preprint

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Substitutions that fix between SARS-CoV-2 variants can transform the mutational landscape of future evolution via epistasis. For example, large epistatic shifts in mutational effects caused by N501Y underlied the original emergence of Omicron variants, but whether such large epistatic saltations continue to define ongoing SARS-CoV-2 evolution remains unclear. We conducted deep mutational scans to measure the impacts of all single amino acid mutations and single-codon deletions in the spike receptor-binding domain (RBD) on ACE2-binding affinity and protein expression in the recent Omicron BQ.1.1 and XBB.1.5 variants, and we compared mutational patterns to earlier viral strains that we have previously profiled. As with previous RBD deep mutational scans, we find many mutations that are tolerated or even enhance binding to ACE2 receptor. The tolerance of sites to single-codon deletion largely conforms with tolerance to amino acid mutation. Though deletions in the RBD have not yet been seen in dominant lineages, we observe many tolerated deletions including at positions that exhibit indel variation across broader sarbecovirus evolution and in emerging SARS-CoV-2 variants of interest, most notably the well-tolerated Δ483 deletion in BA.2.86. The substitutions that distinguish recent viral variants have not induced as dramatic of epistatic perturbations as N501Y, but we identify ongoing epistatic drift in SARS-CoV-2 variants, including interaction between R493Q reversions and mutations at positions 453, 455, and 456, including mutations like F456L that define the newly emerging EG.5 lineage. Our results highlight ongoing drift in the effects of mutations due to epistasis, which may continue to direct SARS-CoV-2 evolution into new regions of sequence space.

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Section: Resultsmentioning

confidence: 99%

Deep mutational scans of XBB.1.5 and BQ.1.1 reveal ongoing epistatic drift during SARS-CoV-2 evolution

Taylor,

Starr

2023

Preprint

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“…In contrast, insufficient polyclonal antibody reactivities have been described to induce the emergence of variants carrying multiple escape mutations [22, 27, 37], resulting in transmission [38]. Accordingly, the onset of the IgM antibody response in our patient six to seven weeks after infection was associated with the emergence of virus variants harbouring various additional mutations within the NTD and RBD of S. Of note, variants carrying substitutions and deletions at positions 140-4 and 241-3 of the NTD and substitution E484K within the RBD appeared, of which the triple mutant S:Delta141-4 E484K S494P became stably established until virus elimination.…”

Section: Discussionmentioning

confidence: 99%

Variant-specific humoral immune response to SARS-CoV-2 escape mutants arising in clinically severe, prolonged infection

Günther,

Schöfbänker,

Lorentzen

et al. 2024

Preprint

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Neutralising antibodies against the SARS-CoV-2 spike (S) protein are major determinants of protective immunity, though insufficient antibody responses may cause the emergence of escape mutants. We studied the intra-host evolution and the humoral immune response in a B-cell depleted, haemato-oncologic patient experiencing clinically severe, prolonged SARS-CoV-2 infection with a virus of lineage B.1.177.81.Bamlanivimab treatment early in infection was associated with the emergence of the bamlanivimab escape mutation S:S494P. Ten days before virus elimination, additional mutations within the N-terminal domain (NTD) and the receptor binding domain (RBD) of S were observed, of which the triple mutant S:Delta141-4 E484K S494P became dominant. Routine serology revealed no evidence of an antibody response in the patient. A detailed analysis of the variant-specific immune response by pseudotyped virus neutralisation test (pVNT), surrogate VNT (sVNT), and immunoglobulin-capture EIA showed that the onset of an IgM-dominated antibody response coincided with the appearance of escape mutations. The formation of neutralising antibodies against S:Delta141-4 E484K S494P correlated with virus elimination. One year later, the patient experienced clinically mild re-infection with Omicron BA.1.18, which was treated with sotrovimab and resulted in a massive increase of Omicron-reactive antibodies.In conclusion, the onset of an IgM-dominated endogenous immune response in an immunocompromised patient coincided with the appearance of additional mutations in the NTD and RBD of S in a bamlanivimab-resistant virus. Although virus elimination was ultimately achieved, this humoral immune response escaped detection by routine diagnosis and created a situation temporarily favouring the emergence of escape variants with known epidemiological relevance.

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“…Therefore the strongest selective filter may occur upon transmission to new hosts (Xue et al, 2020, N’Guessan et al, 2023). In some cases, such as chronically infected patients, viral lineages that are selectively favored within a host can be transmitted to other hosts (Gonzalez-Reiche et al, 2023). As a result, within-host viral diversity may foreshadow the success of viral mutations and lineages at a global scale (Xue et al, 2017, Harari et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have quantified and analyzed the level of intra-host diversity of SARS-CoV-2 in humans. Intra-host diversity of SARS-CoV-2 is generally low in acute human infections (Valesano et al, 2021, Lythgoe et al, 2021, Braun and Moreno et al, 2021), but much higher in chronic infections, during which mutations can be selected within a host and potentially transmitted to new hosts (Gonzalez-Reiche et al, 2023). In acute infections, the median number of intrahost single nucleotide variants (iSNVs) at measurable frequency has been estimated to be between one and eight (Lythgoe et al, 2021, Valesano et al, 2021), with most samples having fewer than three (Lythgoe et al, 2021) iSNVs.…”

Section: Introductionmentioning

confidence: 99%

Within-host genetic diversity of SARS-CoV-2 across animal species

Naderi,

Sagan,

Shapiro

2024

Preprint

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Infectious disease transmission to different host species makes eradication very challenging and expands the diversity of evolutionary trajectories taken by the pathogen. Since the beginning of the ongoing COVID-19 pandemic, SARS-CoV-2 has been transmitted from humans to many different animal species, and viral variants of concern could potentially evolve in a non-human animal. Previously, using available whole genome consensus sequences of SARS-CoV-2 from four commonly sampled animals (mink, deer, cat, and dog) we inferred similar numbers of transmission events from humans to each animal species but a relatively high number of transmission events from mink back to humans (Naderi et al., 2023). Using a genome-wide association study (GWAS), we identified 26 single nucleotide variants (SNVs) that tend to occur in deer -- more than any other animal -- suggesting a high rate of viral adaptation to deer. Here we quantify intra-host SARS-CoV-2 across animal species and show that deer harbor more intra-host SNVs (iSNVs) than other animals, providing a larger pool of genetic diversity for natural selection to act upon. Within-host diversity is particularly high in deer lymph nodes compared to nasopharyngeal samples, suggesting tissue-specific differences in viral population sizes or selective pressures. Neither mixed infections involving more than one viral lineage nor large changes in the strength of selection are likely to explain the higher intra-host diversity within deer. Rather, deer are more likely to contain larger viral population sizes, to be infected for longer periods of time, or to be systematically sampled at later stages of infections. Combined with extensive deer-to-deer transmission, the high levels of within-deer viral diversity help explain the apparent rapid adaptation of SARS-CoV-2 to deer.

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Sequential intrahost evolution and onward transmission of SARS-CoV-2 variants

Cited by 40 publications

References 58 publications

Deep mutational scans of XBB.1.5 and BQ.1.1 reveal ongoing epistatic drift during SARS-CoV-2 evolution

Deep mutational scans of XBB.1.5 and BQ.1.1 reveal ongoing epistatic drift during SARS-CoV-2 evolution

Variant-specific humoral immune response to SARS-CoV-2 escape mutants arising in clinically severe, prolonged infection

Within-host genetic diversity of SARS-CoV-2 across animal species

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