Nanomolar anti-SARS-CoV-2 Omicron activity of the host-directed TMPRSS2 inhibitor N-0385 and synergistic action with direct-acting antivirals DOI Creative Commons
Jimena Pérez‐Vargas, Gabriel Lemieux,

Connor A.H. Thompson

et al.

Antiviral Research, Journal Year: 2024, Volume and Issue: 225, P. 105869 - 105869

Published: March 26, 2024

SARS-CoV-2 Omicron subvariants with increased transmissibility and immune evasion are spreading globally alarming persistence. Whether the mutations evolution of spike (S) alter viral hijacking human TMPRSS2 for entry remains to be elucidated. This is particularly important investigate because large number diversity S reported since emergence BA.1. Here we report that a molecular determinant all clinical isolates tested in lung cells, including ancestral (BA.1, BA.2, BA.5), contemporary (BQ.1.1, XBB.1.5, EG.5.1) currently circulating BA.2.86. First, used co-transfection assay demonstrate endoproteolytic cleavage by subvariants. Second, found N-0385, highly potent inhibitor, robust inhibitor virus-like particles harbouring protein Third, show N-0385 exhibits nanomolar broad-spectrum antiviral activity against live Calu-3 cells primary patient-derived bronchial epithelial cells. Interestingly, 10-20 times more than repositioned camostat, BA.5, EG.5.1, We further shows broad synergistic clinically approved direct-acting antivirals (DAAs), i.e., remdesivir nirmatrelvir, subvariants, demonstrating potential therapeutic benefits multi-targeted treatment based on DAAs.

Language: Английский

Post-pandemic memory T cell response to SARS-CoV-2 is durable, broadly targeted, and cross-reactive to the hypermutated BA.2.86 variant DOI Creative Commons

Rofhiwa Nesamari,

Millicent A. Omondi, Richard Baguma

et al.

Cell Host & Microbe, Journal Year: 2024, Volume and Issue: 32(2), P. 162 - 169.e3

Published: Jan. 10, 2024

Ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has given rise to recombinant Omicron lineages that dominate globally (XBB.1), as well the emergence of hypermutated variants (BA.2.86). In this context, durable and cross-reactive T cell immune memory is critical for continued protection against COVID-19. We examined responses SARS-CoV-2 approximately 1.5 years since first emerged. describe sustained CD4+ CD8+ spike-specific in healthcare workers South Africa (n = 39) who were vaccinated experienced at least one infection. Spike-specific cells are highly with all tested, including BA.2.86. Abundant nucleocapsid membrane-specific detectable most participants. The bulk SARS-CoV-2-specific have an early-differentiated phenotype, explaining their persistent nature. Overall, hybrid immunity leads accumulation spike non-spike evident 3.5 after start pandemic, preserved recognition mutated variants.

Language: Английский

Citations

31
Memory T cells effectively recognize the SARS-CoV-2 hypermutated BA.2.86 variant DOI Creative Commons
Thomas Müller, Yu Gao, Jinghua Wu

et al.

Cell Host & Microbe, Journal Year: 2024, Volume and Issue: 32(2), P. 156 - 161.e3

Published: Jan. 10, 2024

T cells are critical in mediating the early control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection. However, it remains unknown whether memory can effectively cross-recognize new SARS-CoV-2 variants with a broad array mutations, such as emergent hypermutated BA.2.86 variant. Here, we report two separate cohorts, including healthy controls and individuals chronic lymphocytic leukemia, that spike-specific CD4

Language: Английский

Citations

27
Characteristics of JN.1-derived SARS-CoV-2 subvariants SLip, FLiRT, and KP.2 in neutralization escape, infectivity and membrane fusion DOI Creative Commons

Pei Li,

Julia N. Faraone, Cheng Chih Hsu

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 21, 2024

SARS-CoV-2 variants derived from the immune evasive JN.1 are on rise worldwide. Here, we investigated JN.1-derived subvariants SLip, FLiRT, and KP.2 for their ability to be neutralized by antibodies in bivalent-vaccinated human sera, XBB.1.5 monovalent-vaccinated hamster sera people infected during BA.2.86/JN.1 wave, class III monoclonal antibody (Mab) S309. We found that compared parental JN.1, SLip KP.2, especially exhibit increased resistance COVID-19 BA.2.86/JN.1-wave convalescent sera. Interestingly, monovalent vaccinated robustly FLiRT but had reduced efficiency SLip. These were resistant neutralization Mab In addition, aspects of spike protein biology including infectivity, cell-cell fusion processing, these subvariants, a decreased infectivity membrane relative correlating with processing. Homology modeling revealed L455S F456L mutations local hydrophobicity hence its binding ACE2. contrast, additional R346T mutation strengthened conformational support receptor-binding motif, thus counteracting effects F456L. three mutations, alongside D339H, which is present all sublineages, alter epitopes targeted therapeutic Mabs, I S309, explaining sensitivity Together, our findings provide insight into newly emerged suggest future vaccine formulations should consider as immunogen, although current could still offer adequate protection.

Language: Английский

Citations

20
Anticipating the future of the COVID-19 pandemic: insights into the emergence of SARS-CoV-2 variant JN.1 and its projected impact on older adults DOI Open Access
Jorge Quarleri, M. Victoria Delpino, Verónica Galván

et al.

GeroScience, Journal Year: 2024, Volume and Issue: 46(3), P. 2879 - 2883

Published: Jan. 10, 2024

Language: Английский

Citations

19
Neutralization of SARS-CoV-2 Omicron subvariant BA.2.87.1 DOI Creative Commons
Ninaad Lasrado, Annika Rössler, Marjorie Rowe

et al.

Vaccine, Journal Year: 2024, Volume and Issue: 42(9), P. 2117 - 2121

Published: March 7, 2024

A new highly mutated Omicron subvariant BA.2.87.1 has recently been identified with over 30 amino acid mutations in the Spike protein compared BA.2, BA.5, XBB.1.5, and JN.1 variants. Mutiple are located N-terminal domain (NTD) rather than receptor binding (RBD) of protein. We evaluated neutralizing antibody (NAb) responses to because its sequence unique NTD region. Our data show that NAb were lower BA.2 but higher JN.1, suggesting is not a further escape variant other currently circulating Moreover, XBB.1.5 mRNA boosting increased titers all variants tested including BA.2.87.1.

Language: Английский

Citations

16
Distinct evolution of SARS-CoV-2 Omicron XBB and BA.2.86/JN.1 lineages combining increased fitness and antibody evasion DOI Creative Commons
Delphine Planas, Isabelle Staropoli, Vincent Michel

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 21, 2023

The unceasing circulation of SARS-CoV-2 leads to the continuous emergence novel viral sublineages. Here, we isolated and characterized XBB.1, XBB.1.5, XBB.1.9.1, XBB.1.16.1, EG.5.1.1, EG.5.1.3, XBF, BA.2.86.1 JN.1 variants, representing >80% circulating variants in January 2024. XBB subvariants carry few but recurrent mutations spike, whereas harbor >30 additional changes. These replicated IGROV-1 no longer Vero E6 were not markedly fusogenic. They potently infected nasal epithelial cells, with EG.5.1.3 exhibiting highest fitness. Antivirals remained active. Neutralizing antibody (NAb) responses from vaccinees BA.1/BA.2-infected individuals lower compared BA.1, without major differences between variants. An breakthrough infection enhanced NAb against both BA.2.86 displayed affinity ACE2 higher immune evasion properties BA.2.86.1. Thus, while distinct, evolutionary trajectory these combines increased fitness evasion.

Language: Английский

Citations

32
Deep mutational scans of XBB.1.5 and BQ.1.1 reveal ongoing epistatic drift during SARS-CoV-2 evolution DOI Creative Commons
Ashley L. Taylor, Tyler N. Starr

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(12), P. e1011901 - e1011901

Published: Dec. 29, 2023

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

Language: Английский

Citations

32
Virological characteristics of the SARS-CoV-2 BA.2.86 variant DOI Creative Commons
Tomokazu Tamura,

Keita Mizuma,

Hesham Nasser

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 3, 2023

Abstract In late 2023, a lineage of SARS-CoV-2 emerged and was named the BA.2.86 variant. is phylogenetically distinct from other Omicron sublineages identified so far, displaying an accumulation over 30 amino acid mutations in its spike protein. Here, we performed multiscale investigations to reveal virological characteristics Our epidemic dynamics modeling suggested that relative reproduction number significantly higher than EG.5.1. Experimental studies showed four clinically-available antivirals were effective against BA.2.86. Although fusogenicity similar parental BA.2 spike, intrinsic pathogenicity hamsters lower BA.2. Since growth kinetics both vitro cell cultures vivo , it attenuated due decreased replication capacity.

Language: Английский

Citations

27
Neutralizing antibody response to XBB.1.5, BA.2.86, FL.1.5.1, and JN.1 six months after the BNT162b2 bivalent booster DOI Creative Commons
Julien Favresse, Constant Gillot, Julien Cabo

et al.

International Journal of Infectious Diseases, Journal Year: 2024, Volume and Issue: 143, P. 107028 - 107028

Published: April 5, 2024

IntroductionAn increase evasion of the SARS-CoV-2 virus towards vaccination strategies and natural immunity has been rapidly described notably due to mutations in spike receptor binding domain N-terminal domain.Material methodsParticipants CRO-VAX HCP study who received bivalent booster were followed at 6 months. A pseudovirus‐neutralization test was used assess neutralization potency antibodies against D614G, Delta, BA.1, BA.5, XBB.1.5, BA.2.86, FL.1.5.1, JN-1.ResultsThe neutralizing capacity Omicron variant or subvariants significantly reduced compared D614G Delta (p<0.0001). The lowest response that observed with JN-1 (GMT=22.1) also lower XBB.1.5 (GMT=29.5, p<0.0001), BA.2.86 (GMT=29.6, FL.1.5.1 (GMT=25.2, p<0.0001). Participants contracted a breakthrough infection had higher all variants uninfected participants, especially subvariants.ConclusionOur results confirm JN.1 is one most immune evading date subvariant did not show an increased escape XBB.1.5. stronger BKI supports need use vaccine antigens target circulating variants.

Language: Английский

Citations

15
Lineage-specific pathogenicity, immune evasion, and virological features of SARS-CoV-2 BA.2.86/JN.1 and EG.5.1/HK.3 DOI Creative Commons

Yuanchen Liu,

Xiaoyu Zhao,

Jialu Shi

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Oct. 9, 2024

SARS-CoV-2 JN.1 with an additional L455S mutation on spike when compared its parental variant BA.2.86 has outcompeted all earlier variants to become the dominant circulating variant. Recent studies investigated immune resistance of but factors are speculated contribute global dominance, which remain elusive until today. Here, we find that a higher infectivity than in differentiated primary human nasal epithelial cells (hNECs). Mechanistically, demonstrate gained over associates increased entry efficiency conferred by and better cleavage hNECs. Structurally, S455 altered mode binding protein ACE2 at

Language: Английский

Citations

13