Rational identification of potent and broad sarbecovirus-neutralizing antibody cocktails from SARS convalescents

Cao, Yunlong; Jian, Fanchong; Zhang, Zhiying; Yisimayi, Ayijiang; Hao, Xiaohua; Bao, Linlin; Yuan, Fei; Yu, Yuanling; Du, Shuo; Wang, Jing; Xiao, Tianhe; Song, Weiliang; Zhang, Ying; Liu, Pulan; An, Ran; Wang, Peng; Wang, Yao; Yang, Sijie; Xiao, Ning; Zhang, Yuhang; Gu, Qingqing; Shao, Fei; Hu, Yaling; Yin, Weidong; Zheng, Ai; Wang, Youchun; Qin, Chuan; Jin, Ronghua; Xiao, Junyu; Xie, X. Sunney

doi:10.1101/2022.08.03.499114

Cited by 10 publications

(20 citation statements)

References 48 publications

(135 reference statements)

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“…2a and Extended Data Fig. 2a) 13,27-32 . The COV2-2196+COV2-2130 (Evusheld) 28,33 is vulnerable to F486, R346, and K444 mutations, evaded or highly impaired by BA.2.38.1 (K444N), BJ.1 (R346T), BR.1 (L452R+K444M), BA.5.2.7 (K444M), BA.5.6.2 (K444T), and BQ.1.1 (R346T+K444T).…”

Section: Mainmentioning

confidence: 99%

“…2a and Extended Data Fig. 2a) 13,27-32 . The COV2-2196+COV2-2130 (Evusheld) 28,33 is vulnerable to F486, R346, and K444-G446 mutations, evaded or highly impaired by BJ.1 (R346T), XBB (R346T+V445P+F486S), BA.2.75.2/CA.1/BM.1.1/BM.1.1.1 (R346T+F486S), BR.2 (R346T+F486I), BA.4.6.1 (R346T+F486V), BA.5.6.2/BQ.1 (K444T+F486V), BU.1 (K444M+F486V), and BQ.1.1 (R346T+K444T+F486V).…”

Section: Mainmentioning

confidence: 99%

“…First, we tested the antibody evasion capability of these variants. We constructed the VSV-based spike-pseudotyped virus of Omicron BA.2, BA.2.75 and BA.4/5 lineages carrying those convergent mutations and examined the neutralizing activities of therapeutic neutralizing antibodies (NAbs) against them 13,27–32 . The COV2-2196+COV2-2130 (Evusheld) 28,33 are vulnerable to F486, R346, and K444 mutations, evaded or highly impaired by BA.2.38.1 (K444N), BJ.1 (R346T), BR.1 (L452R+K444M), BA.5.2.7 (K444M), BA.5.6.2 (K444T).…”

Section: Convergent Rbd Evolution Causes Further Immune Evasionmentioning

confidence: 99%

“…However, LY-CoV1404 was escaped by BJ.1 and BR.1, and exhibited strongly reduced activity against BA.2.38.1, BA.5.2.7 and BA.5.6.2 due to K444 N/M/T mutations 31 . SA55+SA58 is a pair of broad NAbs isolated from vaccinated SARS convalescents and targeting non-competing conserved epitopes 2,32 . Here SA55 demonstrated high potency against all tested Omicron subvariants, although SA58 was evaded by BA.2.77, and showed reduced neutralization efficacy against BJ.1 and some of the BA.2.75 variants (Fig.…”

Section: Convergent Rbd Evolution Causes Further Immune Evasionmentioning

confidence: 99%

“…2a and Extended Data Fig. 1a) 26–28 . In total, pseudoviruses of 50 convergent variants were constructed and tested.…”

Section: Mainmentioning

confidence: 99%

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

Cao

Jian

Wang

et al. 2022

Preprint

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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: Mainmentioning

confidence: 99%

Section: Mainmentioning

confidence: 99%

Section: Convergent Rbd Evolution Causes Further Immune Evasionmentioning

confidence: 99%

Section: Convergent Rbd Evolution Causes Further Immune Evasionmentioning

confidence: 99%

“…2a and Extended Data Fig. 1a) 26–28 . In total, pseudoviruses of 50 convergent variants were constructed and tested.…”

Section: Mainmentioning

confidence: 99%

See 3 more Smart Citations

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

Cao

Jian

Wang

et al. 2022

Preprint

Self Cite

115

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Characterization of cross‐reactive monoclonal antibodies against SARS‐CoV‐1 and SARS‐CoV‐2: Implication for rational design and development of pan‐sarbecovirus vaccines and neutralizing antibodies

Jiang

et al. 2023

Journal of Medical Virology

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Emergence of various circulating SARS‐CoV‐2 variants of concern (VOCs) promotes the identification of pan‐sarbecovirus vaccines and broadly neutralizing antibodies (bNAbs). Here, to characterize monoclonal antibodies cross‐reactive against both SARS‐CoV‐1 and SARS‐CoV‐2 and to search the criterion for bNAbs against all emerging SARS‐CoV‐2, we isolated several SARS‐CoV‐1‐cross‐reactive monoclonal antibodies (mAbs) from a wildtype SARS‐CoV‐2 convalescent donor. These antibodies showed broad binding capacity and cross‐neutralizing potency against various SARS‐CoV‐2 VOCs, including B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta), but failed to efficiently neutralize Omicron variant and its sublineages. Structural analysis revealed how Omicron sublineages, but not other VOCs, efficiently evade an antibody family cross‐reactive against SARS‐CoV‐1 through their escape mutations. Further evaluation of a series of SARS‐CoV‐1/2‐cross‐reactive bNAbs showed a negative correlation between the neutralizing activities against SARS‐CoV‐1 and SARS‐CoV‐2 Omicron variant. Together, these results suggest the necessity of using cross‐neutralization against SARS‐CoV‐1 and SARS‐CoV‐2 Omicron as criteria for rational design and development of potent pan‐sarbecovirus vaccines and bNAbs.

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Concerns on Bebtelovimab (LY‐CoV1404) used to neutralize Omicron subvariants

Wang

Yang

Song

et al. 2023

Journal of Medical Virology

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Bebtelovimab (LY-CoV1404) is a monoclonal antibody showing remarkable neutralizing capacity against all severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) as of June 2022, including the Omicron variant and its subvariants (BA.1, BA.2, BA.4, and BA.5). 1,2 However, SARS-CoV-2 continues to acquire mutations in the spike that impact antibody recognition and neutralization. 3,4 It is important to evaluate the efficiency of Bebtelovimab against new SARS-CoV-2 variants and provide a reference for the application of Bebtelovimab.

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Rational identification of potent and broad sarbecovirus-neutralizing antibody cocktails from SARS convalescents

Cited by 10 publications

References 48 publications

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

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

Characterization of cross‐reactive monoclonal antibodies against SARS‐CoV‐1 and SARS‐CoV‐2: Implication for rational design and development of pan‐sarbecovirus vaccines and neutralizing antibodies

Concerns on Bebtelovimab (LY‐CoV1404) used to neutralize Omicron subvariants

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