Omicron BA.1 breakthrough infection drives cross-variant neutralization and memory B cell formation against conserved epitopes

Quandt, Jasmin; Muik, Alexander; Salisch, Nadine; Lui, Bonny Gaby; Lutz, Sebastian; Krüger, Kimberly; Wallisch, Ann-Kathrin; Adams‐Quack, Petra; Bacher, Maren; Finlayson, Andrew; Ozhelvaci, Orkun; Vogler, Isabel; Grikscheit, Katharina; Hoehl, Sebastian; Goetsch, Udo; Ciesek, Sandra; Türeci, Özlem; Şahin, Uğur

doi:10.1126/sciimmunol.abq2427

Cited by 183 publications

(214 citation statements)

References 53 publications

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“…In contrast to when Omicron first appeared, new Omicron sublineages are able to target the humoral immunity induced by Omicron itself, such as by post-vaccination Omicron infection. Omicron breakthrough infections mainly recall WT-induced memory B cells 40 , 41 , which in turn narrow the diversity of elicited antibodies and may further drive the appearance of future mutants. These phenomena pose a challenge to the current herd immunity established through WT-based vaccination and infection by BA.1 and BA.2 variants, which is concordant with recent observations 42 .…”

Section: Ba1-specific Nabs Exhibit Narrow Breadthsmentioning

confidence: 99%

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

Cao

Yisimayi

Jian

et al. 2022

Nature

1,119

937

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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 lineage1. The receptor binding and immune-evasion capability of these recently emerged variants require immediate investigation. Here, coupled with structural comparisons of the spike proteins, we show that BA.2.12.1, BA.4 and BA.5 (BA.4 and BA.5 are hereafter referred collectively to as BA.4/BA.5) exhibit similar binding affinities to BA.2 for the angiotensin-converting enzyme 2 (ACE2) receptor. Of note, BA.2.12.1 and BA.4/BA.5 display increased evasion of neutralizing antibodies compared with BA.2 against plasma from triple-vaccinated individuals or from individuals who developed a BA.1 infection after vaccination. To delineate the underlying antibody-evasion mechanism, we determined the escape mutation profiles2, epitope distribution3 and Omicron-neutralization efficiency of 1,640 neutralizing antibodies directed against the receptor-binding domain of the viral spike protein, including 614 antibodies isolated from people who had recovered from BA.1 infection. BA.1 infection after vaccination predominantly recalls humoral immune memory directed against ancestral (hereafter referred to as wild-type (WT)) SARS-CoV-2 spike protein. The resulting elicited antibodies could neutralize both WT SARS-CoV-2 and BA.1 and are enriched on epitopes on spike that do not bind ACE2. However, most of these cross-reactive neutralizing antibodies are evaded by spike mutants L452Q, L452R and F486V. BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1. Nevertheless, these neutralizing antibodies are largely evaded by BA.2 and BA.4/BA.5 owing to D405N and F486V mutations, and react weakly to pre-Omicron variants, exhibiting narrow neutralization breadths. The therapeutic neutralizing antibodies bebtelovimab4 and cilgavimab5 can effectively neutralize BA.2.12.1 and BA.4/BA.5, whereas the S371F, D405N and R408S mutations undermine most broadly sarbecovirus-neutralizing antibodies. Together, our results indicate that Omicron may evolve mutations to evade the humoral immunity elicited by BA.1 infection, suggesting that BA.1-derived vaccine boosters may not achieve broad-spectrum protection against new Omicron variants.

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Section: Ba1-specific Nabs Exhibit Narrow Breadthsmentioning

confidence: 99%

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

Cao

Yisimayi

Jian

et al. 2022

Nature

1,119

937

View full text Add to dashboard Cite

show abstract

“…Unlike when Omicron first appeared, now Omicron sublineages could target the humoral immunity induced by Omicron itself, such as post-vaccination Omicron infection. The Omicron breakthrough infections mainly recall WT-induced memory B cells 40, 41 , which in turn narrows the diversity of antibodies elicited and may further facilitate the appearance of future mutants. These phenomena pose a great challenge to the currently established herd immunity through WT-based vaccination and BA.1/BA.2 infection.…”

Section: Mainmentioning

confidence: 99%

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

Cao¹,

Yisimayi

Jian

et al. 2022

Preprint

199

294

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Recent emergence of SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.2.13, BA.4 and BA.5 all contain L452 mutations and show potential higher transmissibility over BA.2. The new variants' receptor binding and immune evasion capability require immediate investigation, especially on the role of L452 substitutions. Herein, coupled with structural comparisons, we showed that BA.2 sublineages, including BA.2.12.1 and BA.2.13, exhibit increased ACE2-binding affinities compared to BA.1; while BA.4/BA.5 shows the weakest receptor-binding activity due to F486V and R493Q reversion. Importantly, compared to BA.2, BA.2.12.1 and BA.4/BA.5 exhibit stronger neutralization escape from the plasma of 3-dose vaccinees and, most strikingly, from vaccinated BA.1 convalescents. To delineate the underlying evasion mechanism, we determined the escaping mutation profiles, epitope distribution and Omicron sublineage neutralization efficacy of 1640 RBD-directed neutralizing antibodies (NAbs), including 614 isolated from BA.1 convalescents. Interestingly, post-vaccination BA.1 infection mainly recalls wildtype (WT) induced humoral memory and elicits antibodies that neutralize both WT and BA.1. These cross-reactive NAbs are significantly enriched on non-ACE2-competing epitopes; and surprisingly, the majority are undermined by R346 and L452 substitutions, namely R346K (BA.1.1), L452M (BA.2.13), L452Q (BA.2.12.1) and L452R (BA.4/BA.5), suggesting that R346K and L452 mutations appeared under the immune pressure of Omicron convalescents. Nevertheless, BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1 but do not respond to WT SARS-CoV-2, due to the high susceptibility to N501, N440, K417 and E484. However, these NAbs are largely escaped by BA.2 sublineages and BA.4/BA.5 due to D405N and F486V, exhibiting poor neutralization breadths. As for therapeutic NAbs, LY-CoV1404 (Bebtelovimab) and COV2-2130 (Cilgavimab) can still effectively neutralize BA.2.12.1 and BA.4/BA.5, while the S371F, D405N and R408S mutations carried by BA.2/BA.4/BA.5 sublineages would undermine most broad sarbecovirus NAbs. Together, our results indicate that Omicron can evolve mutations to specifically evade humoral immunity elicited by BA.1 infection. The continuous evolution of Omicron poses great challenges to SARS-CoV-2 herd immunity and suggests that BA.1-derived vaccine boosters may not be ideal for achieving broad-spectrum protection.

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“…However, fourth doses with the ancestral strain only transiently boost neutralizing antibody titers back to the peak observed after three (Bar-On et al, 2022; Magen et al, 2022; Regev-Yochay et al, 2022). In contrast, sequential exposure to the ancestral vaccine followed by Omicron PVI may induce broader neutralizing antibody responses than vaccination with three doses alone (Quandt et al, 2022) although other studies suggest protection against severe disease is similar (Gagne et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Post-vaccination Omicron infections induce broader immunity across antigenic space than prototype mRNA COVID-19 booster vaccination or primary infection

Wang

Lusvarghi

Subramanian

et al. 2022

Preprint

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SummaryThe rapid emergence of new SARS-CoV-2 variants challenges vaccination strategies. Here, we measured antigenic diversity among variants and interpreted neutralizing antibody responses following single and multiple exposures in longitudinal infection and vaccine cohorts. Antigenic cartography using primary infection antisera showed that BA.2, BA.4/BA.5, and BA.2.12.1 are distinct from BA.1 and closer to the Beta cluster. Three doses of an mRNA COVID-19 vaccine increased breadth to BA.1 more than to BA.4/BA.5 or BA.2.12.1. Omicron BA.1 post-vaccination infection elicited antibody landscapes characterized by broader immunity across antigenic space than three doses alone, although with less breadth than expected to BA.2.12.1 and BA.4/BA.5. Those with Omicron BA.1 infection after two or three vaccinations had similar neutralizing titer magnitude and antigenic breadth. Accounting for antigenic differences among variants of concern when interpreting neutralizing antibody titers aids understanding of complex patterns in humoral immunity and informs selection of future COVID-19 vaccine strains.

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Omicron BA.1 breakthrough infection drives cross-variant neutralization and memory B cell formation against conserved epitopes

Cited by 183 publications

References 53 publications

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

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

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

Post-vaccination Omicron infections induce broader immunity across antigenic space than prototype mRNA COVID-19 booster vaccination or primary infection

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