Omicron BA.2 breakthrough infection enhances cross-neutralization of BA.2.12.1 and BA.4/BA.5

Muik, Alexander; Lui, Bonny Gaby; Bacher, Maren; Wallisch, Ann-Kathrin; Toker, Aras; Finlayson, Andrew; Krueger, Kimberly; Ozhelvaci, Orkun; Grikscheit, Katharina; Hoehl, Sebastian; Ciesek, Sandra; Tuereci, Oezlem; Şahin, Uğur

doi:10.1101/2022.08.02.502461

Cited by 21 publications

(37 citation statements)

References 36 publications

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“…5g). More NTD mutations does not contribute to stronger evasion in BA.2.75-based mutants, but we observed significant reduction in NT50 of BA.2/BA.5 convalescents against BA.5-based mutants with K147E+W152R, suggesting BA.2/BA.5 convalescent plasma contains large proportion of NTD-targeting antibodies 43 . As the NTD of BA.1 is quite different from that of BA.2 and BA.5, we did not observe significant effects of NTD mutations on the efficacy of BA.1 convalescent plasma.…”

Section: Convergent Evolution Could Eventually Nullify Plasma Neutral...contrasting

confidence: 50%

“…We then evaluated the potency of NTD-targeting NAbs against BA.2.75, BA.5 and BA.2 with selected NTD mutations using a panel of 14 mAbs, as it is reported that NTD-targeting antibodies are abundant in plasma from BA.2 breakthrough infection 43 . The selected mutations are most from BA.2.75, except for R237T which was designed to escape mAbs targeting a certain epitope reported recently 20 .…”

Section: Convergent Evolution Could Eventually Nullify Plasma Neutral...mentioning

confidence: 99%

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

Cao

Jian

Wang

et al. 2022

Preprint

115

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Continuous evolution of Omicron has led to numerous subvariants that exhibits growth advantage over BA.5. Such rapid and simultaneous emergence of variants with enormous advantages is unprecedented. Despite their rapidly divergent evolutionary courses, mutations on their receptor-binding domain (RBD) converge on several hotspots, including R346, R356, K444, L452, N460K and F486. The driving force and destination of such convergent evolution and its impact on humoral immunity established by vaccination and infection remain unclear. Here we demonstrate that these convergent mutations can cause striking evasion of convalescent plasma, including those from BA.5 breakthrough infection, and existing antibody drugs, including Evusheld and Bebtelovimab. BA.2.75.2 is the most evasive strain tested, and only BQ.1.1 could compare. To clarify the origin of the convergent evolution, we determined the escape mutation profiles and neutralization activity of monoclonal antibodies (mAbs) isolated from convalescents of BA.2 and BA.5 breakthrough infection. Importantly, due to humoral immune imprinting, BA.2 and especially BA.5 breakthrough infection caused significant reductions of neutralizing antibody epitope diversity and increased proportion of non-neutralizing mAbs, which in turn concentrated humoral immune pressure and promoted the convergent RBD evolution. Additionally, the precise convergent RBD mutations and evolution trends of BA.2.75/BA.5 subvariants could be inferred by integrating the neutralization-weighted DMS profiles of mAbs from various immune histories (3051 mAbs in total). Moreover, we demonstrated that as few as five additional convergent mutations based on BA.5 or BA.2.75 could completely evade most plasma samples, including those from BA.5 breakthrough infections, while remaining sufficient hACE2-binding affinity. These results suggest herd immunity established by natural infection could hardly stop RBD evolution, and vaccine boosters using BA.5 may not provide sufficiently broad protection. Broad-spectrum SARS-CoV-2 vaccines and NAb drugs development should be in high priority and the constructed convergent mutants could serve to examine their effectiveness in advance.

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Section: Convergent Evolution Could Eventually Nullify Plasma Neutral...contrasting

confidence: 50%

Section: Convergent Evolution Could Eventually Nullify Plasma Neutral...mentioning

confidence: 99%

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

Cao

Jian

Wang

et al. 2022

Preprint

115

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“…Sera were obtained from a non-interventional study researching vaccinated patients that had experienced Omicron breakthrough infection, and from the biosample collections of BNT162b2 vaccine trials. Data for the reference cohorts were previously published and are used here for benchmarking ( 17, 21 ).…”

Section: Resultsmentioning

confidence: 99%

“…Serum neutralizing activity was tested in a well-characterized pseudovirus neutralization test (pVNT) ( 21, 25, 26 ) by determining 50% pseudovirus neutralization (pVN 50 ) geometric mean titers (GMTs) with pseudoviruses bearing the S glycoproteins of the SARS-CoV-2 wild-type strain or Omicron BA.1, BA.2, and the BA.2-derived sublineages BA.2.12.1, and BA.4/BA.5 (BA.4 and BA.5 are identical in their S glycoprotein sequence). In addition, we assayed SARS-CoV (herein referred to as SARS-CoV-1) to detect potential pan-Sarbecovirus neutralizing activity ( 27 ).…”

Section: Resultsmentioning

confidence: 99%

“…We and others have previously reported that Omicron BA.1 and BA.2 breakthrough infection of individuals previously immunized with wild-type strain-based mRNA vaccines or an inactivated virus vaccine was associated with potent neutralizing activity against Omicron BA.1, BA.2 and previous VOCs (16)(17)(18)(19)(20)(21). A considerable boost of Omicron BA.2.12.1 and BA.4/BA.5 neutralization was only evident in BA.2 breakthrough cases, albeit with titers against BA.4/BA.5 remaining lower than titers against previous Omicron VOCs ( 16,[20][21][22].…”

Section: Introductionmentioning

confidence: 97%

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Exposure to BA.4/BA.5 Spike glycoprotein drives pan-Omicron neutralization in vaccine-experienced humans and mice

Muik

Lui

Bacher

et al. 2022

Preprint

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The SARS-CoV-2 Omicron variant and its sublineages show pronounced viral escape from neutralizing antibodies elicited by vaccination or prior SARS-CoV-2 variant infection owing to over 30 amino acid alterations within the spike (S) glycoprotein. We and others have recently reported that breakthrough infection of vaccinated individuals with Omicron sublineages BA.1 and BA.2 are associated with distinct patterns of cross-neutralizing activity against SARS-CoV-2 variants of concern (VOCs). BA.2 breakthrough infection mediated overall stronger cross-neutralization of BA.2 and its descendants (BA.2.12.1, BA.4, and BA.5) compared to BA.1 breakthrough infection. Here we characterized the effect of Omicron BA.4/BA.5 S glycoprotein exposure on the magnitude and breadth of the neutralizing antibody response upon breakthrough infection in vaccinated individuals and in mice upon booster vaccination. We show that immune sera from triple mRNA-vaccinated individuals with subsequent Omicron BA.4/BA.5 breakthrough infection display broad and robust neutralizing activity against Omicron BA.1, BA.2, BA.2.12.1, and BA.4/BA.5. Administration of a prototypic BA.4/BA.5-adapted mRNA booster vaccine to mice following SARS-CoV-2 wild-type strain-based primary immunization is associated with similarly broad neutralizing activity. Immunization of naive mice with a bivalent mRNA vaccine (wild-type + Omicron BA.4/BA.5) induces strong and broad neutralizing activity against Omicron VOCs and previous variants. These findings suggest that when administered as boosters, mono- and bivalent Omicron BA.4/BA.5-adapted vaccines may enhance neutralization breadth, and in a bivalent format may also have the potential to confer protection to individuals with no pre-existing immunity against SARS-CoV-2.

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Analysis of anti-Omicron neutralizing antibody titers in different vaccinated and unvaccinated convalescent plasma sources

Focosi

Franchini

Joyner

et al. 2021

Preprint

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The novel SARS-CoV-2 Omicron variant of concern (VOCs), with its escape from unboosted vaccines and monoclonal antibodies, is demanding for a return to COVID19 convalescent plasma therapies. Lessons learnt from previous usage of CCP suggests focusing on outpatients and using high nAb-titer units in early disease stages. In this systematic analysis, we show that CCP from unvaccinated donors is not effective against Omicron, while CCP from vaccinees convalescents from previous VOCs or third-dose uninfected vaccinees is likely to remain effective against Omicron. countries. CCP remains the only antibody-based therapy that keeps up with the variants and provides an effective tool to combat the emergence of variants that defeat monoclonal antibodies. Consequently, there is a need for continue study of the variables that determine CCP efficacy.

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Omicron BA.2 breakthrough infection enhances cross-neutralization of BA.2.12.1 and BA.4/BA.5

Cited by 21 publications

References 36 publications

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

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

Exposure to BA.4/BA.5 Spike glycoprotein drives pan-Omicron neutralization in vaccine-experienced humans and mice

Analysis of anti-Omicron neutralizing antibody titers in different vaccinated and unvaccinated convalescent plasma sources

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