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

Nature, Год журнала: 2022, Номер unknown

Опубликована: Дек. 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.

Язык: Английский

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

Nature, Год журнала: 2023, Номер 625(7993), С. 148 - 156

Опубликована: Ноя. 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.

Язык: Английский

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Molecular fate-mapping of serum antibody responses to repeat immunization

Nature, Год журнала: 2023, Номер 615(7952), С. 482 - 489

Опубликована: Янв. 16, 2023

Язык: Английский

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Immunological imprinting: Understanding COVID-19

Immunity, Год журнала: 2023, Номер 56(5), С. 909 - 913

Опубликована: Апрель 19, 2023

Язык: Английский

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Persistent immune imprinting occurs after vaccination with the COVID-19 XBB.1.5 mRNA booster in humans

Immunity, Год журнала: 2024, Номер 57(4), С. 904 - 911.e4

Опубликована: Март 14, 2024

Immune imprinting describes how the first exposure to a virus shapes immunological outcomes of subsequent exposures antigenically related strains. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron breakthrough infections and bivalent COVID-19 vaccination primarily recall cross-reactive memory B cells induced by prior Wuhan-Hu-1 spike mRNA rather than priming Omicron-specific naive cells. These findings indicate that immune occurs after repeated exposures, but whether it can be overcome remains unclear. To understand persistence imprinting, we investigated plasma antibody responses administration updated XBB.1.5 vaccine booster. We showed booster elicited neutralizing against current variants were dominated pre-existing previously spike. Therefore, persists multiple spikes through infection, including post vaccination, which will need considered guide future vaccination.

Язык: Английский

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Deep immunological imprinting due to the ancestral spike in the current bivalent COVID-19 vaccine

Cell Reports Medicine, Год журнала: 2023, Номер 4(11), С. 101258 - 101258

Опубликована: Окт. 30, 2023

To combat the evolving SARS-CoV-2 Omicron variants, bivalent COVID-19 mRNA vaccines, encoding both ancestral and BA.5 spikes, have replaced monovalent vaccines in numerous countries. However, fourth doses of either vaccine result similar neutralizing antibody titers against subvariants, raising possibility immunological imprinting. address this, we investigate responses 72 participants given three a vaccine, followed by or booster, those with breakthrough infections BQ. Bivalent boosters do not show notably higher binding virus-neutralizing various variants compared to ones. lead significantly better neutralization subvariants. Multiple analyses, including antigenic mapping, suggest that spike is causing deep imprinting, preventing broadening antibodies component, thereby defeating its intended goal. Its removal from future compositions therefore strongly recommended.

Язык: Английский

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Original SARS-CoV-2 monovalent and Omicron BA.4/BA.5 bivalent COVID-19 mRNA vaccines: phase 2/3 trial interim results

Nature Medicine, Год журнала: 2023, Номер 29(9), С. 2325 - 2333

Опубликована: Авг. 31, 2023

This ongoing, open-label, phase 2/3 trial compared the safety and immunogenicity of Omicron BA.4/BA.5-containing bivalent mRNA-1273.222 vaccine with ancestral Wuhan-Hu-1 mRNA-1273 as booster doses. Two groups adults who previously received primary vaccination series doses were enrolled in a sequential, nonrandomized manner single-second boosters (n = 376) or 511). Primary objectives noninferiority superiority neutralizing antibody (nAb) responses against BA.4/BA.5 SARS-CoV-2 D614G mutation (ancestral (D614G)), 28 days post boost. Superiority based on prespecified success criteria (lower bounds 95% CI > 1 < 0.677, respectively) mRNA-1273.222:mRNA-1273 geometric mean ratios. Bivalent elicited superior nAb versus noninferior (D614G) at day 29 boost participants without detectable prior infection. Day seroresponses higher for than similar (D614G), both meeting criterion. The profile was to that reported no new concerns identified. Continued monitoring neutralization real-world effectiveness are needed additional divergent-virus variants emerge. ClinicalTrials.gov registration: NCT04927065.

Язык: Английский

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Interim Report of the Reactogenicity and Immunogenicity of Severe Acute Respiratory Syndrome Coronavirus 2 XBB–Containing Vaccines

The Journal of Infectious Diseases, Год журнала: 2024, Номер 230(2), С. e279 - e286

Опубликована: Фев. 13, 2024

Monovalent Omicron XBB.1.5-containing vaccines were approved for coronavirus disease 2019 (COVID-19) 2023-2024 immunizations.

Язык: Английский

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Evolution of antibody immunity following Omicron BA.1 breakthrough infection

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Май 12, 2023

Understanding the longitudinal dynamics of antibody immunity following heterologous SAR-CoV-2 breakthrough infection will inform development next-generation vaccines. Here, we track SARS-CoV-2 receptor binding domain (RBD)-specific responses up to six months Omicron BA.1 in mRNA-vaccinated individuals. Cross-reactive serum neutralizing and memory B cell (MBC) decline by two- four-fold through study period. Breakthrough elicits minimal de novo BA.1-specific but drives affinity maturation pre-existing cross-reactive MBCs toward BA.1, which translates into enhanced breadth activity across other variants. Public clones dominate response at both early late time points breakthough infection, their escape mutation profiles predict newly emergent sublineages, suggesting that convergent continue shape evolution. While is limited our relatively small cohort size, these results suggest variant exposure evolution memory, supporting continued variant-based

Язык: Английский

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

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Май 2, 2023

Abstract The continuous emergence of highly immune evasive SARS-CoV-2 variants, like XBB.1.5 1,2 and XBB.1.16 3,4 , highlights the need to update COVID-19 vaccine compositions. However, imprinting induced by wildtype (WT)-based vaccination would compromise antibody response Omicron-based boosters 5-9 . Vaccination strategies that can counter are critically needed. In this study, we investigated degree dynamics in mouse models human cohorts, especially focusing on role repeated Omicron stimulation. Our results show mice, efficacy single Omicron-boosting is heavily limited imprinting, when using variants antigenically distinct from WT, XBB, while concerning situation could be largely mitigated a second booster. Similarly, humans, found infections also alleviate WT-vaccination-induced generate high neutralizing titers against both plasma nasal mucosa. By isolating 781 RBD-targeting mAbs infection revealed double exposure alleviates generating large proportion matured potent Omicron-specific antibodies. Importantly, epitope characterization deep mutational scanning (DMS) showed these antibodies target RBD epitopes compared WT-induced antibodies, bias towards non-neutralizing observed exposures due was restored after stimulation, together leading substantial shift. Based DMS profiles, identified evolution hotspots demonstrated combinations mutations further boost XBB.1.5’s immune-evasion capability maintaining ACE2 binding affinity. findings suggest WT component should abandoned updating antigen compositions XBB lineages, those who haven’t been exposed yet receive two updated boosters.

Язык: Английский

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