Striking Antibody Evasion Manifested by the Omicron Variant of SARS-CoV-2
Lihong Liu, Sho Iketani, Yicheng Guo, Null- W Chan, Maple Wang, Liyuan Liu, Yang Luo, Hin Chu, Yiming Huang, Manoj S Nair, Jian Yu, Null- H Chik, Null- T Yuen, Chaemin Yoon, Null- W To, Honglin Chen, Michael T Yin, Magdalena E Sobieszczyk, Yaoxing Huang, Harris H Wang, Zizhang Sheng, Kwok-Yung Yuen, David D Ho
doi:10.1101/2021.12.14.472719
The Omicron (B.1.1.529) variant of SARS-CoV-2 was only recently detected in southern Africa, but its subsequent spread has been extensive, both regionally and globally 1 . It is expected to become dominant in the coming weeks 2 , probably due to enhanced transmissibility. A striking feature of this variant is the large number of spike mutations 3 that pose a threat to the efficacy of current COVID-19 vaccines and antibody therapies 4 . This concern is amplified by the findings from our study. We found B.1.1.529 to be markedly resistant to neutralization by serum not only from convalescent patients, but also from individuals vaccinated with one of the four widely used COVID-19 vaccines. Even serum from persons vaccinated and boosted with mRNA-based vaccines exhibited substantially diminished neutralizing activity against B.1.1.529. By evaluating a panel of monoclonal antibodies to all known epitope clusters on the spike protein, we noted that the activity of 18 of the 19 antibodies tested were either abolished or impaired, including ones currently authorized or approved for use in patients. In addition, we also identified four new spike mutations (S371L, N440K, G446S, and Q493R) that confer greater antibody resistance to B.1.1.529. The Omicron variant presents a serious threat to many existing COVID-19 vaccines and therapies, compelling the development of new interventions that anticipate the evolutionary trajectory of SARS-CoV-2.
Methods
Serum samples Convalescent plasma samples were obtained from patients with documented SARS-CoV-2 infection approximately one month after recovery or later. These samples were collected at the beginning of the pandemic in early 2020 at Columbia University Irving Medical Center, and therefore are assumed to be infection by the wild-type strain of SARS-CoV-2 4 . Sera from individuals who received two or three doses of mRNA-1273 or BNT162b2 vaccine were collected at Columbia University Irving Medical Center at least two weeks after the final dose. Sera from individuals who received one dose of Ad26.COV2.S or two doses of ChAdOx1 nCov-19 were obtained from BEI Resources. Some individuals were also infected by SARS-CoV-2 in addition to the vaccinations they received. Note that, whenever possible, we specifically chose samples with high titers against the wild-type strain of SARS-CoV-2 such that the loss in activity against B.1.1.529 could be better quantified, and therefore the titers observed here should be considered in that context. All collections were conducted under protocols reviewed and approved by the Institutional Review Board of Columbia University. Additional information for the vaccinee samples can be found in Extended Data Table 1 .
Monoclonal antibodies Antibodies were expressed as previously described 22 , by synthesis of VH and VL genes (GenScript), transfection of Expi293 cells (Thermo Fisher), and affinity purification from the supernatant by..
References
Abu-Raddad, Chemaitelly, Butt, Study Group For, Effectiveness of the BNT162b2 Covid-19 Vaccine against the B, and B
Banach, Paired heavy-and light-chain signatures contribute to potent SARS-CoV-2 neutralization in public antibody responses, Cell Rep,
doi:10.1016/j.celrep.2021.109771Cerutti, Potent SARS-CoV-2 neutralizing antibodies directed against spike Nterminal domain target a single supersite, Cell Host Microbe,
doi:10.1016/j.chom.2021.03.005Chu, Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: an observational study, Lancet Microbe,
doi:10.1016/S2666-5247(20)30004-5Cromer, Neutralising antibody titres as predictors of protection against SARS-CoV-2 variants and the impact of boosting: a meta-analysis, Lancet Microbe,
doi:10.1016/S2666-5247(21)00267-6Garcia-Beltran, mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant, medRxiv,
doi:10.1101/2021.12.14.21267755Grabowski, Kochańczyk, Lipniacki, Omicron strain spreads with the doubling time of 3.2-3.6 days in South Africa province of Gauteng that achieved herd immunity to Delta variant, medRxiv,
doi:10.1101/2021.12.08.21267494Hansen, Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail, Science
Kuhlmann, Breakthrough Infections with SARS-CoV-2 Omicron Variant Despite Booster Dose of mRNA Vaccine, SSRN,
doi:10.2139/ssrn.3981711Langmead, Salzberg, Fast gapped-read alignment with Bowtie 2, Nat Methods
Martin, Cutadapt Removes Adapter Sequences From High-Throughput Sequencing Reads, EMBnet.journal,
doi:10.14806/ej.17.1.200Pulliam, Increased risk of SARS-CoV-2 reinfection associated with emergence of the Omicron variant in South Africa, medRxiv,
doi:10.1101/2021.11.11.21266068Rappazzo, Broad and potent activity against SARS-like viruses by an engineered human monoclonal antibody, Science,
doi:10.1126/science.abf4830Uriu, Neutralization of the SARS-CoV-2 Mu Variant by Convalescent and Vaccine Serum, N Engl J Med,
doi:10.1056/NEJMc2114706Wroughton, The Washington Post
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'abstract': '<jats:p>The Omicron (B.1.1.529) variant of SARS-CoV-2 was only recently detected in southern '
'Africa, but its subsequent spread has been extensive, both regionally and globally. It is '
'expected to become dominant in the coming weeks, probably due to enhanced transmissibility. '
'A striking feature of this variant is the large number of spike mutations that pose a threat '
'to the efficacy of current COVID-19 vaccines and antibody therapies. This concern is '
'amplified by the findings from our study. We found B.1.1.529 to be markedly resistant to '
'neutralization by serum not only from convalescent patients, but also from individuals '
'vaccinated with one of the four widely used COVID-19 vaccines. Even serum from persons '
'vaccinated and boosted with mRNA-based vaccines exhibited substantially diminished '
'neutralizing activity against B.1.1.529. By evaluating a panel of monoclonal antibodies to '
'all known epitope clusters on the spike protein, we noted that the activity of 18 of the 19 '
'antibodies tested were either abolished or impaired, including ones currently authorized or '
'approved for use in patients. In addition, we also identified four new spike mutations '
'(S371L, N440K, G446S, and Q493R) that confer greater antibody resistance to B.1.1.529. The '
'Omicron variant presents a serious threat to many existing COVID-19 vaccines and therapies, '
'compelling the development of new interventions that anticipate the evolutionary trajectory '
'of SARS-CoV-2.</jats:p>',
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