BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection

Nature, Journal Year: 2022, Volume and Issue: 608(7923), P. 593 - 602

Published: June 17, 2022

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages BA.2.12.1, BA.4 and BA.5 exhibit higher transmissibility than the BA.2 lineage 1 . The receptor binding immune-evasion capability of these recently emerged variants require immediate investigation. Here, coupled with structural comparisons spike proteins, we show that (BA.4 are hereafter referred collectively to as BA.4/BA.5) similar affinities for angiotensin-converting enzyme (ACE2) receptor. Of note, BA.2.12.1 BA.4/BA.5 display increased evasion neutralizing antibodies compared against plasma from triple-vaccinated individuals or who developed a BA.1 infection after vaccination. To delineate underlying antibody-evasion mechanism, determined escape mutation profiles , epitope distribution 3 Omicron-neutralization efficiency 1,640 directed receptor-binding domain viral protein, including 614 isolated people had recovered infection. vaccination predominantly recalls humoral immune memory ancestral (hereafter wild-type (WT)) SARS-CoV-2 protein. resulting elicited could neutralize both WT enriched on epitopes do not bind ACE2. However, most cross-reactive evaded by mutants L452Q, L452R F486V. can also induce new clones BA.1-specific potently BA.1. Nevertheless, largely owing D405N F486V mutations, react weakly pre-Omicron variants, exhibiting narrow neutralization breadths. therapeutic bebtelovimab 4 cilgavimab 5 effectively BA.4/BA.5, whereas S371F, R408S mutations undermine broadly sarbecovirus-neutralizing antibodies. Together, our results indicate may evolve evade immunity infection, suggesting BA.1-derived vaccine boosters achieve broad-spectrum protection variants.

Language: Английский

---

Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution

Nature, Journal Year: 2022, Volume and Issue: unknown

Published: Dec. 19, 2022

Abstract Continuous evolution of Omicron has led to a rapid and simultaneous emergence numerous variants that display growth advantages over BA.5 (ref. 1 ). Despite their divergent evolutionary courses, mutations on receptor-binding domain (RBD) converge several hotspots. The driving force destination such sudden convergent its effect humoral immunity remain unclear. Here we demonstrate these can cause evasion neutralizing antibody drugs convalescent plasma, including those from breakthrough infection, while maintaining sufficient ACE2-binding capability. BQ.1.1.10 (BQ.1.1 + Y144del), BA.4.6.3, XBB CH.1.1 are the most antibody-evasive strains tested. To delineate origin evolution, determined escape mutation profiles neutralization activity monoclonal antibodies isolated individuals who had BA.2 infections 2,3 . Owing immune imprinting, especially infection reduced diversity binding sites increased proportions non-neutralizing clones, which, in turn, focused pressure promoted RBD. Moreover, show RBD could be accurately inferred by deep mutational scanning 4,5 , trends BA.2.75 subvariants well foreseen through constructed pseudovirus mutants. These results suggest current herd vaccine boosters may not efficiently prevent variants.

Language: Английский

---

Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Sept. 16, 2022

Abstract Continuous evolution of Omicron has led to a rapid and simultaneous emergence numerous variants that display growth advantages over BA. 5. Despite their divergent evolutionary courses, mutations on receptor-binding domain (RBD) converge several hotspots. The driving force destination such convergent its impact humoral immunity remain unclear. Here, we demonstrate these can cause striking evasion neutralizing antibody (NAb) drugs convalescent plasma, including those from BA.5 breakthrough infection, while maintaining sufficient ACE2 binding capability. BQ.1.1.10, BA.4.6.3, XBB, CH. 1.1 are the most antibody-evasive strain tested, even exceeding SARS-CoV-1 level. To delineate origin evolution, determined escape mutation profiles neutralization activity monoclonal antibodies (mAbs) isolated BA.2 breakthrough-infection convalescents. Importantly, due immune imprinting, especially infection caused significant reductions in epitope diversity NAbs increased proportion non-neutralizing mAbs, which turn concentrated pressure promoted evolution. Moreover, showed RBD could be accurately inferred by integrated deep mutational scanning (DMS) profiles, trends BA.2.75/BA.5 subvariants well-simulated through constructed pseudovirus mutants. Together, our results suggest current herd vaccine boosters may not provide good protection against infection. Broad-spectrum SARS-CoV-2 vaccines NAb development should highly prioritized, mutants help examine effectiveness advance.

Language: Английский

---

Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

Science, Journal Year: 2022, Volume and Issue: 378(6620), P. 619 - 627

Published: Oct. 20, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages carry distinct spike mutations resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity vaccine boosters elicit plasma-neutralizing against BA.1, BA.2, BA.2.12.1, and BA.4/5, breakthrough infections, but not vaccination alone, induce neutralizing the nasal mucosa. Consistent with immunological imprinting, most derived memory B cells plasma of cases cross-react Wuhan-Hu-1, BA.4/5 receptor-binding domains, whereas primary infections narrow specificity up to 6 months after infection. Although clinical have reduced neutralization Omicron, we identified an ultrapotent pan-variant–neutralizing antibody is a strong candidate for development.

Language: Английский

---

Characterization of the enhanced infectivity and antibody evasion of Omicron BA.2.75

Cell Host & Microbe, Journal Year: 2022, Volume and Issue: 30(11), P. 1527 - 1539.e5

Published: Oct. 4, 2022

Recently emerged SARS-CoV-2 Omicron subvariant, BA.2.75, displayed a growth advantage over circulating BA.2.38, BA.2.76, and BA.5 in India. However, the underlying mechanisms for enhanced infectivity, especially compared with BA.5, remain unclear. Here, we show that BA.2.75 exhibits substantially higher affinity host receptor angiotensin-converting enzyme 2 (ACE2) than other variants. Structural analyses of spike shows its decreased thermostability increased frequency binding domain (RBD) "up" conformation under acidic conditions, suggesting low-pH-endosomal cell entry. Relative to BA.4/BA.5, reduced evasion humoral immunity from BA.1/BA.2 breakthrough-infection convalescent plasma but greater Delta plasma. also weaker neutralization against mainly due BA.2.75's distinct neutralizing antibody (NAb) escape pattern. Antibody therapeutics Evusheld Bebtelovimab effective BA.2.75. These results suggest may prevail after receptor-binding capability could support further immune-evasive mutations.

Language: Английский

---

Repeated Omicron exposures override ancestral SARS-CoV-2 immune imprinting

Nature, Journal Year: 2023, Volume and Issue: 625(7993), P. 148 - 156

Published: Nov. 22, 2023

Abstract The continuing emergence of SARS-CoV-2 variants highlights the need to update COVID-19 vaccine compositions. However, immune imprinting induced by vaccination based on ancestral (hereafter referred as WT) strain would compromise antibody response Omicron-based boosters 1–5 . Vaccination strategies counter are critically needed. Here we investigated degree and dynamics in mouse models human cohorts, especially focusing role repeated Omicron stimulation. In mice, efficacy single boosting is heavily limited when using that antigenically distinct from WT—such XBB variant—and this concerning situation could be mitigated a second booster. Similarly, humans, infections alleviate WT vaccination-induced generate broad neutralization responses both plasma nasal mucosa. Notably, deep mutational scanning-based epitope characterization 781 receptor-binding domain (RBD)-targeting monoclonal antibodies isolated infection revealed double exposure induce large proportion matured Omicron-specific have RBD epitopes WT-induced antibodies. Consequently, was largely mitigated, bias towards non-neutralizing observed exposures restored. On basis scanning profiles, identified evolution hotspots XBB.1.5 demonstrated these mutations further boost immune-evasion capability while maintaining high ACE2-binding affinity. Our findings suggest component should abandoned updating vaccines, individuals without prior receive two updated boosters.

Language: Английский

---

Neutralization, effector function and immune imprinting of Omicron variants

Nature, Journal Year: 2023, Volume and Issue: 621(7979), P. 592 - 601

Published: Aug. 30, 2023

Abstract Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain 1 (RBD) of spike protein. The effects these on viral infection and transmission efficacy vaccines therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 XBB.1.5 bind host ACE2 with high affinity promote membrane fusion more efficiently than earlier Omicron variants. Structures BQ.1.1, XBB.1 BN.1 RBDs bound to fragment antigen-binding region S309 antibody (the parent for sotrovimab) human explain preservation binding through conformational selection, altered recognition immune evasion. We show sotrovimab binds avidly all variants, promotes Fc-dependent effector functions protects mice challenged hamsters XBB.1.5. Vaccine-elicited plasma antibodies cross-react trigger against current despite a reduced neutralizing activity, suggesting mechanism protection disease, exemplified by S309. Cross-reactive RBD-directed memory B cells remained dominant even after two exposures spikes, underscoring role persistent imprinting.

Language: Английский

---

Bivalent Omicron BA.1–Adapted BNT162b2 Booster in Adults Older than 55 Years

New England Journal of Medicine, Journal Year: 2023, Volume and Issue: 388(3), P. 214 - 227

Published: Jan. 18, 2023

The emergence of immune-escape variants severe acute respiratory syndrome coronavirus 2 warrants the use sequence-adapted vaccines to provide protection against disease 2019.

Language: Английский

---

Mapping SARS-CoV-2 antigenic relationships and serological responses

Science, Journal Year: 2023, Volume and Issue: 382(6666)

Published: Oct. 6, 2023

During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, multiple variants escaping preexisting immunity emerged, causing reinfections of previously exposed individuals. Here, we used antigenic cartography to analyze patterns cross-reactivity among 21 and 15 groups human sera obtained after primary infection with 10 different or messenger RNA (mRNA)–1273 mRNA-1273.351 vaccination. We found differences pre-Omicron caused by substitutions at spike-protein positions 417, 452, 484, 501. Quantifying changes in response breadth over time additional vaccine doses, our results show largest increase between 4 weeks >3 months a second dose. immunodominance spike regions, depending on variant an individual was first to, implications for risk assessment vaccine-strain selection.

Language: Английский

---

Omicron variant (B.1.1.529) and its sublineages: What do we know so far amid the emergence of recombinant variants of SARS-CoV-2?

Biomedicine & Pharmacotherapy, Journal Year: 2022, Volume and Issue: 154, P. 113522 - 113522

Published: Aug. 15, 2022

Since the start of COVID-19 pandemic, numerous variants SARS-CoV-2 have been reported worldwide. The advent concern (VOCs) raises severe concerns amid serious containment efforts against that include physical measures, pharmacological repurposing, immunization, and genomic/community surveillance. Omicron variant (B.1.1.529) has identified as a highly modified, contagious, crucial among five VOCs SARS-CoV-2. increased affinity spike protein (S-protein), host receptor, angiotensin converting enzyme-2 (ACE-2), due to higher number mutations in receptor-binding domain (RBD) S-protein proposed primary reason for decreased efficacy majorly available vaccines transmissible nature variant. Because its significant competitive advantage, sublineages swiftly surpassed other become dominant circulating lineages nations. prevalent strain United Kingdom South Africa. Furthermore, emergence recombinant through conjunction with or by mixing variant's sublineages/subvariants poses major threat humanity. This various issues hazards regarding sublineages, such an breakout susceptible populations fully vaccinated persons. As result, understanding features genetic implications this is crucial. Hence, we explained depth evolution analyzed repercussions on infectiousness, dissemination ability, viral entry mechanism, immune evasion. We also presented viewpoint feasible strategies precluding counteracting any future catastrophic spread omicron could result detrimental wave cases.

Language: Английский

---