Immune Escape Associated with RBD Omicron Mutations and SARS-CoV-2 Evolution Dynamics

Kudriavtsev, Aleksandr V.; Vakhrusheva, Anna; Novoseletsky, Valery; Bozdaganyan, Marine E.; Шайтан, К. В.; Kirpichnikov, Mikhaǐl P.; Sokolova, Olga S.

doi:10.20944/preprints202206.0022.v1

Cited by 12 publications

(4 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Due to the high selective pressure against the spike protein, new variants of the SARS-CoV-2 that escape current vaccines continue to emerge. Among the new strains, multiple versions of Omicron have been reported with more than 500 Omicron sublineages in existence [49][50][51][52][53][61]. Antiviral therapies are essential for treatment of those who are not vaccinated or cases of breakthrough infection.…”

Section: Discussionmentioning

confidence: 99%

Nirmatrelvir Resistance in SARS-CoV-2 Omicron_BA.1 and WA1 Replicons and Escape Strategies

Lan

Neilsen

Slack

et al. 2023

Preprint

View full text Add to dashboard Cite

The antiviral component of Paxlovid, nirmatrelvir (NIR), forms a covalent bond with Cys145 of SARS-CoV-2 nsp5. To explore NIR resistance we designed mutations to impair binding of NIR over substrate. Using 12 Omicron (BA.1) and WA.1 SARS-CoV-2 replicons, cell-based complementation and enzymatic assays, we showed that in both strains, E166V imparted high NIR resistance (~55-fold), with major decrease in WA1 replicon fitness (~20-fold), but not BA.1 (~2-fold). WA1 replicon fitness was restored by L50F. These differences may contribute to a potentially lower barrier to resistance in Omicron than WA1. E166V is rare in untreated patients, albeit more prevalent in paxlovid-treated EPIC-HR clinical trial patients. Importantly, NIR-resistant replicons with E166V or E166V/L50F remained susceptible to a) the flexible GC376, and b) PF-00835231, which forms additional interactions. Molecular dynamics simulations show steric clashes between the rigid and bulky NIR t-butyl and β-branched V166 distancing the NIR warhead from its Cys145 target. In contrast, GC376, through-wiggling and jiggling- accommodates V166 and still covalently binds Cys145. PF-00835231 uses its strategically positioned methoxy-indole to form a beta-sheet and overcome E166V. Drug design based on strategic flexibility and main chain-targeting may help develop second-generation nsp5-targeting antivirals efficient against NIR-resistant viruses.

show abstract

Section: Discussionmentioning

confidence: 99%

Nirmatrelvir Resistance in SARS-CoV-2 Omicron_BA.1 and WA1 Replicons and Escape Strategies

Lan

Neilsen

Slack

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Omicron and its sublineages, with an unprecedented mutation burden focused in the Spike protein, have rapidly displaced previous circulating variants since late 2021. Antigenic changes leading to significant evasion from humoral immunity induced either by infection with other SARS-CoV-2 variants or by vaccination, together with functional and structural modifications affecting transmissibility and pathogenicity (3, 4) call for considering omicron a distinct SARS-CoV-2 serotype that needs vaccine adaptation (5, 6). However, such an approach may be practically unfeasible given the speed at which novel variants have emerged and then disappeared and if the future variants will not linearly evolve from the latest circulating variants.…”

Section: Introductionmentioning

confidence: 99%

GRAd-COV2 vaccine provides potent and durable immunity in randomised placebo-controlled phase 2 trial (COVITAR)

Capone¹,

Fusco

Milleri

et al. 2022

Preprint

View full text Add to dashboard Cite

Background. SARS-CoV-2 ongoing pandemic and heterologous immunization approaches implemented worldwide for booster doses call for diversified vaccines portfolio. We report safety and immunogenicity of GRAd-COV2, a novel gorilla adenovirus-based COVID-19 vaccine, in a phase 2 trial aimed at identifying the appropriate dose and schedule. Method. 917 eligible adults aged 18 years or older, including participants with co-morbidities, were randomised to receive, 21 days apart, a single vaccine administration at 2x1011 viral particles (vp) followed by placebo, or repeated vaccine administration at 1x1011 vp, or two doses of placebo. Primary endpoints were the incidence of local and systemic solicited AEs for 7 days post each dose and the post-treatment (35 days after the first dose), geometric mean titers (GMTs) and geometric mean fold rise (GMFRs) of ELISA antibody responses to Spike protein. Additional humoral and cellular immune response parameters were monitored for up to six months. Results. The safety profile of GRAd-COV2 was characterized by short-term, mild-to-moderate pain and tenderness at injection site, fatigue, headache, malaise, and myalgia. Neither related SAEs nor deaths were reported. Humoral (binding and neutralizing) Ab responses peaked at day 35 after a single administration, were boosted by a second vaccination, were sustained until day 57 to then decline at day 180. Potent, VOC cross-reactive T cell responses peaked already after first dose with high frequencies of long-lived CD8 T cells. Conclusion. GRAd-COV2 was safe, and induced robust immune responses after a single immunization; the second administration increased humoral but not cellular immune responses.

show abstract

“…Therefore, foresighted expansion of our antiviral arsenal appears warranted. Fortunately, novel therapeutic approaches as reviewed in section 2.3 offer high versatility enabling rapid adaption to essentially any coding or non-coding, viral or host cell, molecular target [171][172][173][174][175][176][177][178][179]. Further, their large-scale production will follow similar (i.e.…”

Section: Need For Highly Versatile Antiviral Toolsmentioning

confidence: 99%

Innate Immunity in Cardiovascular Diseases – Identification of Novel Molecular Players and Targets

Poller¹,

Heidecker²,

Ammirati³

et al. 2022

Preprint

View full text Add to dashboard Cite

During the past few years unexpected developments have driven studies in the field of clinical immunology. One driver of immense impact was the outbreak of a pandemic caused by the novel virus SARS-CoV-2. Excellent recent reviews address diverse aspects of immunological re-search into cardiovascular diseases. Here, we specifically focus on selected studies taking ad-vantage of advanced state-of-the-art molecular genetic methods ranging from genome-wide epi/transcriptome mapping and variant scanning to optogenetics and chemogenetics. First, we discuss emerging clinical relevance of advanced diagnostics for cardiovascular diseases - includ-ing those associated with COVID-19 - with a focus on the role of inflammation in cardiomyopa-thies and arrhythmias. Second, we consider newly identified immunological interactions at or-gan and systems level which affect cardiovascular pathogenesis. Thus, studies into immune in-fluences arising from the intestinal system are moving towards therapeutic exploitation. Fur-ther, powerful new research tools have enabled novel insight into brain – immune system inter-actions at unprecedented resolution. This latter line of investigation emphasizes the strength of influence of emotional stress - acting through defined brain regions - upon viral and cardiovas-cular disorders. Several challenges need to be overcome before the full impact of these far-reaching new findings will hit the clinical arena.

show abstract

Immune Escape Associated with RBD Omicron Mutations and SARS-CoV-2 Evolution Dynamics

Cited by 12 publications

References 0 publications

Nirmatrelvir Resistance in SARS-CoV-2 Omicron_BA.1 and WA1 Replicons and Escape Strategies

Nirmatrelvir Resistance in SARS-CoV-2 Omicron_BA.1 and WA1 Replicons and Escape Strategies

GRAd-COV2 vaccine provides potent and durable immunity in randomised placebo-controlled phase 2 trial (COVITAR)

Innate Immunity in Cardiovascular Diseases – Identification of Novel Molecular Players and Targets

Contact Info

Product

Resources

About