SARS-CoV-2 variants in the making: Sequential intrahost evolution and forward transmissions in the context of persistent infections

Gonzalez‐Reiche, Ana S.; Alshammary, Hala; Schaefer, Sarah; Patel, Gopi; Polanco, Jose; Amoako, Angela; Rooker, Aria; Cognigni, Christian; Floda, Daniel; Khalil, Zain; Farrugia, Keith; Assad, Nima; Zhang, Jian; Alburquerque, Bremy; Sominsky, Levy A.; Srivastava, Komal; Sebra, Robert; Ramírez, Juan David; Banu, Radhika; Shrestha, Paras; Paniz‐Mondolfi, Alberto; Sordillo, Emilia Mia; Simon, Viviana; Bakel, Harm van

doi:10.1101/2022.05.25.22275533

Cited by 13 publications

(11 citation statements)

References 48 publications

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“…In contrast, the mutation L455W which reduces ACE2 affinity in Wuhan-Hu-1 is affinityenhancing in Omicron RBDs. While L455W is accessible via single-nucleotide mutation from the position TTG codon present in Wuhan-Hu-1 and Omicron, mutations to site 455 have not yet been important in SARS-CoV-2 variant evolution (but see [29]). This may be because all such mutations previously decreased ACE2 affinity.…”

Section: Epistatic Shifts In the Omicron Mutational Landscapementioning

confidence: 99%

Deep mutational scans for ACE2 binding, RBD expression, and antibody escape in the SARS-CoV-2 Omicron BA.1 and BA.2 receptor-binding domains

Starr

Greaney

Stewart

et al. 2022

Preprint

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SARS-CoV-2 continues to acquire mutations in the spike receptor-binding domain (RBD) that impact ACE2 receptor binding, folding stability, and antibody recognition. Deep mutational scanning prospectively characterizes the impacts of mutations on these biochemical properties, enabling rapid assessment of new mutations seen during viral surveillance. However, the effects of mutations can change as the virus evolves, requiring updated deep mutational scans. We determined the impacts of all amino acid mutations in the Omicron BA.1 and BA.2 RBDs on ACE2-binding affinity, RBD folding, and escape from binding by the LY-CoV1404 (bebtelovimab) monoclonal antibody. The effects of some mutations in Omicron RBDs differ from those measured in the ancestral Wuhan-Hu-1 background. These epistatic shifts largely resemble those previously seen in the Beta variant due to the convergent epistatically modifying N501Y substitution. However, Omicron variants show additional lineage-specific shifts, including examples of the epistatic phenomenon of entrenchment that causes the Q498R and N501Y substitutions present in Omicron to be more favorable in that background than in earlier viral strains. In contrast, the Omicron substitution Q493R exhibits no sign of entrenchment, with the derived state, R493, being as unfavorable for ACE2 binding in Omicron RBDs as in Wuhan-Hu- 1. Likely for this reason, the R493Q reversion has occurred in Omicron sub-variants including BA.4/BA.5 and BA.2.75, where the affinity buffer from R493Q reversion may potentiate concurrent antigenic change. Consistent with prior studies, we find that Omicron RBDs have reduced expression, and identify candidate stabilizing mutations that ameliorate this deficit. Last, our maps highlight a broadening of the sites of escape from LY-CoV1404 antibody binding in BA.1 and BA.2 compared to the ancestral Wuhan-Hu-1 background. These BA.1 and BA.2 deep mutational scanning datasets identify shifts in the RBD mutational landscape and inform ongoing efforts in viral surveillance.

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Section: Epistatic Shifts In the Omicron Mutational Landscapementioning

confidence: 99%

Deep mutational scans for ACE2 binding, RBD expression, and antibody escape in the SARS-CoV-2 Omicron BA.1 and BA.2 receptor-binding domains

Starr

Greaney

Stewart

et al. 2022

Preprint

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“…Unfortunately, in vivo selection evidences are so far available for sotrovimab[40] but not for Evusheld™. It should be anyway noted that R346T[41,42] and R346I[43] have been reported to spontaneously develop and fix in 3 IC patients without any selective pressure.…”

Section: Introductionmentioning

confidence: 99%

Convergent evolution in SARS-CoV-2 Spike creates a variant soup that causes new COVID-19 waves

Focosi¹,

Quiroga

McConnell

et al. 2022

Preprint

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The first 2 years of the COVID-19 pandemic were mainly characterized by convergent evolution of mutations of SARS-CoV-2 Spike protein at residues K417, L452, E484, N501 and P681 across different variants of concern (Alpha, Beta, Gamma, and Delta). Since Spring 2022 and the third year of the pandemic, with the advent of Omicron and its sublineages, convergent evolution has led to the observation of different lineages acquiring an additional group of mutations at different amino acid residues, namely R346, K444, N450, N460, F486, F490, Q493, and S494. Mutations at these residues have become increasingly prevalent during Summer and Autumn 2022, with combinations showing increased fitness. The most likely reason for this convergence is the selective pressure exerted by previous infection- or vaccine-elicited immunity. Such accelerated evolution has caused failure of all anti-Spike monoclonal antibodies, including bebtelovimab and cilgavimab. While we are learning how fast coronaviruses can mutate and recombine, we should reconsider opportunities for economically sustainable escape-proof combination therapies, and reevaluate the potential for polyclonal therapies (such as COVID19 convalescent plasma) in immunocompromised patients.

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“…). Onward transmission from such chronic infections has also been documented (Gonzalez-Reiche et al ., 2022). However, to date there is no direct evidence for the mode of emergence of any variant.…”

mentioning

confidence: 96%

“…The pre-dominant hypothesis for this cryptic emergence of highly mutated, transmissible and immune evasive variants are chronic infections that are common in patients with impaired immune systems, either through HIV-1 infection (Cele et al, 2022) or medical intervention (Choi et al, 2020;Kemp et al, 2021). Onward transmission from such chronic infections has also been documented (Gonzalez-Reiche et al, 2022). However, to date there is no direct evidence for the mode of emergence of any variant.…”

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confidence: 99%

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Contributions of adaptation and purifying selection to SARS-CoV-2 evolution

Neher

2022

Preprint

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Continued evolution and adaptation of SARS-CoV-2 has lead to more transmissible and immune-evasive variants with profound impact on the course of the pandemic. Here I analyze the evolution of the virus over 2.5 years since its emergence and estimate rates of evolution for synonymous and non-synonymous changes separately for evolution within clades -- well defined mono-phyletic groups with gradual evolution -- and for the pandemic overall. The rate of synonymous mutations is found to be around 6 changes per year. Synonymous rates within variants vary little from variant to variant and are compatible with the overall rate. In contrast, the rate at which variants accumulate amino acid changes (non-synonymous mutation) was initially around 12-16 changes per year, but in 2021 and 2022 dropped to 6-9 changes per year. The overall rate of non-synonymous evolution, that is across variants, is estimated to be about 25 amino acid changes per year. This 2-fold higher rate indicates that the evolutionary process that gave rise to the different variants is qualitatively different from that in typical transmission chains and likely dominated by adaptive evolution. I further quantify the spectrum of mutations and purifying selection in different SARS-CoV-2 proteins. Many accessory proteins evolve under limited evolutionary constraint with little short term purifying selection. About half of the mutations in other proteins are strongly deleterious and rarely observed, not even at low frequency.

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SARS-CoV-2 variants in the making: Sequential intrahost evolution and forward transmissions in the context of persistent infections

Cited by 13 publications

References 48 publications

Deep mutational scans for ACE2 binding, RBD expression, and antibody escape in the SARS-CoV-2 Omicron BA.1 and BA.2 receptor-binding domains

Deep mutational scans for ACE2 binding, RBD expression, and antibody escape in the SARS-CoV-2 Omicron BA.1 and BA.2 receptor-binding domains

Convergent evolution in SARS-CoV-2 Spike creates a variant soup that causes new COVID-19 waves

Contributions of adaptation and purifying selection to SARS-CoV-2 evolution

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