Selection analysis identifies unusual clustered mutational changes in Omicron lineage BA.1 that likely impact Spike function

Martin, Darren P.; Lytras, S; Lucaci, Alexander G; Maier, Wolfgang; Grüning, Björn; Shank, Stephen D; Weaver, Steven; MacLean, Oscar S; Orton, Richard; Lemey, Philippe; Boni, Maciej F.; Tegally, Houriiyah; Harkins, Gordon William; Scheepers, Cathrine; Bhiman, Jinal N.; Everatt, Josie; Amoako, Daniel G.; San, James Emmanuel; Giandhari, Jennifer; Sigal, Alex; Williamson, Carolyn; Hsiao, Nei-yuan; Gottberg, Anne von; Klerk, Arné de; Shafer, Robert W.; Robertson, David L.; Wilkinson, Robert J.; Sewell, B. Trevor; Lessells, Richard; Nekrutenko, Anton; Greaney, Allison J; Starr, Tyler N; Bloom, Jesse D; Murrell, Ben; Wilkinson, Eduan; Gupta, Ravindra; Oliveira, Túlio de; Pond, Sergei L. Kosakovsky

doi:10.1101/2022.01.14.476382

Cited by 45 publications

(56 citation statements)

References 59 publications

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“…The predicted stronger escapers (scores > 0.5) are G446S, T478K, E484A, Q493R, G496S, Q498R, N501Y and Y505H and the weaker escapers (scores < 0.5) are G339D, S371L, S373P, S375F, K417N and N440K. Some novel Omicron mutations (G339D, S371L, S373P, S375F, Q493R, G496S, Q498R, and Y505H) are thought to have either a neutral or negative selective advantage 2 . Our modeling indicates that these mutations induce a range of positive antibody escape scores, implying they contribute to the overall fitness of the Omicron variant.…”

Section: Resultsmentioning

confidence: 99%

“…The rise of the Omicron family of variants indicates that mutational changes occur in clusters. Analysis of individual mutations may not provide a complete understanding of the biological properties of the new variants 2 . To meet the new challenge, approaches that can probe the collective physical and functional properties are needed.…”

Section: Discussionmentioning

confidence: 99%

“…The occurrence of mutation clusters challenges our understanding about their influence on the biological properties of Omicron such as antibody resistance [4][5][6] , mode of host cell entry 7 , viral evolution 2 , virulence 8 , and transmission. Several large-scale experimental studies have demonstrated that Omicron S RBD can evade most neutralizing antibodies, especially those targeting S RBM including some therapeutic monoclonal antibodies 4,5 .…”

Section: Introductionmentioning

confidence: 99%

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Omicron Spike protein has a positive electrostatic surface that promotes ACE2 recognition and antibody escape

Gan

Zinno

Piano

et al. 2022

Preprint

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High transmissibility is a hallmark of the Omicron variant of SARS-CoV-2. Understanding the molecular determinants of Omicron transmissibility will impact development of intervention strategies. Here we map the electrostatic potential surface of the Spike protein to show that major SARS-CoV-2 variants have accumulated positive charges in solvent-exposed regions of the Spike protein, especially its ACE2-binding interface. Significantly, the Omicron Spike-ACE2 complex has complementary electrostatic surfaces. In contrast, interfaces between Omicron and neutralizing antibodies tend to have similar positively charged surfaces. Structural modeling demonstrates that the electrostatic property of Omicron Spike receptor binding domain (S RBD) plays a role in enhancing ACE2 recognition and destabilizing Spike-antibody complexes. Collectively, our structural analysis implies that Omicron S RBD interaction interfaces have been optimized to simultaneously promote access to human ACE2 receptors and evade antibodies. These findings suggest that electrostatic interactions are a major contributing factor for increased Omicron transmissibility relative to other variants.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Omicron Spike protein has a positive electrostatic surface that promotes ACE2 recognition and antibody escape

Gan

Zinno

Piano

et al. 2022

Preprint

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“…The variant has many new mutations compared to previous variants of concern (VOCs), which has enabled an escape from neutralizing antibodies and added to its transmission efficiency in communities 2 . Many of the mutations are located in spike protein that is needed for the virus entry to human cells and is targeted by most of the currently available vaccines 3 .…”

Section: Introductionmentioning

confidence: 99%

Protective antibodies and T cell responses to Omicron variant three months after the booster dose of BNT162b2 vaccine

Naaber

Tserel

Kangro

et al. 2022

Preprint

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The high number of mutations in the Omicron variant of SARS-CoV-2 cause its immune escape when compared to the earlier variants of concern (VOC). At least three vaccine doses are required for the induction of Omicron neutralizing antibodies and further reducing the risk for hospitalization. However, most of the studies have focused on the immediate response after the booster vaccination while the duration of immune response is less known. We here studied longitudinal serum samples from the vaccinated individuals up to three months after their third dose of the BNT162b2 vaccine for their capacity to produce protective antibodies and T cell responses to Wuhan and Omicron variants. After the second dose, the antibody levels to the unmutated spike protein were significantly decreased at three months, and only 4% of the individuals were able to inhibit Omicron spike interaction compared to 47%, 38%, and 14% of individuals inhibiting wild-type, delta, and beta variants spike protein. Nine months after the second vaccination, the antibody levels were similar to the levels before the first dose and none of the sera inhibited SARS-CoV-2 wild-type or any of the three VOCs. The booster dose remarkably increased antibody levels and their ability to inhibit all variants. Three months after the booster the antibody levels and the inhibition activity were trending lower but still up and not significantly different from their peak values at two weeks after the third dose. Although responsiveness towards mutated spike peptides was lost in less than 20 % of vaccinated individuals, the wild-type spike-specific CD4+ and CD8+ memory T cells were still present at three months after the booster vaccination in the majority of studied individuals. Our data show that two doses of the BNT62b2 vaccine are not sufficient to protect against the Omicron variant, however, the spike-specific antibodies and T cell responses are strongly elicited and well maintained three months after the third vaccination dose.

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“…By 2021, several variants of the virus had been discovered and contributed to repeated cycles of infection in different parts of the world. In late November 2021, South Africa reported the detection of a new variant of SARS-CoV-2, B.1.1.529, characterized by more than 50 mutations compared to the reference strain, with at least 30 occurring in the spike (S) protein alone (Martin et al ., 2022; World Health Organization, 2021). The World Health Organization soon after named the variant Omicron and classified it as a variant of concern due to its potential detrimental effect on the ongoing COVID-19 pandemic (World Health Organization, 2021(a)).…”

Section: Introductionmentioning

confidence: 99%

Comparative infection and pathogenesis of SARS-CoV-2 Omicron and Delta variants in aged and young Syrian hamsters

Storm

Crossland

McKay

et al. 2022

Preprint

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Coronavirus disease 2019 continues to batter the world with the unceasing introduction of new variants of the causative virus, SARS-CoV-2. In order to understand differences in disease caused by variants of concern and to develop variant-specific vaccines, suitable small animal models are required that mimic disease progression in humans at various stages of life. In this study, we compared the dynamics of infection with two SARS-CoV-2 variants of concern (Delta and Omicron) in aged (>1 year 3 months old) and young (<5 weeks old) Syrian hamsters (Mesocricetus auratus). We show that no weight loss occurred in Omicron infected groups regardless of age, while infection with the Delta variant caused weight loss of up to 10% by day 7 post-infection with slower and incomplete recovery in the aged group. Omicron replicated to similar levels as Delta in the lungs, trachea and nasal turbinates, with no significant differences in the tissue viral loads of aged versus young animals for either variant. In contrast to rare necrosis observed in Omicron-infected animals regardless of age, severe necrosis was observed in the olfactory epithelium in Delta-infected animals. Omicron infection also resulted in mild pulmonary disease in both young and aged animals compared to the moderate acute necrotizing bronchointerstitial pneumonia seen in Delta-infected animals. These results suggest that Omicron infection results in an attenuated clinical disease outlook in Syrian hamsters compared to infection with the Delta variant irrespective of age.

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Selection analysis identifies unusual clustered mutational changes in Omicron lineage BA.1 that likely impact Spike function

Cited by 45 publications

References 59 publications

Omicron Spike protein has a positive electrostatic surface that promotes ACE2 recognition and antibody escape

Omicron Spike protein has a positive electrostatic surface that promotes ACE2 recognition and antibody escape

Protective antibodies and T cell responses to Omicron variant three months after the booster dose of BNT162b2 vaccine

Comparative infection and pathogenesis of SARS-CoV-2 Omicron and Delta variants in aged and young Syrian hamsters

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