key: cord-0872927-puukh1mv authors: Gruell, Henning; Vanshylla, Kanika; Korenkov, Michael; Tober-Lau, Pinkus; Zehner, Matthias; Münn, Friederike; Janicki, Hanna; Augustin, Max; Schommers, Philipp; Sander, Leif Erik; Kurth, Florian; Kreer, Christoph; Klein, Florian title: Delineating antibody escape from Omicron variants date: 2022-04-06 journal: bioRxiv DOI: 10.1101/2022.04.06.487257 sha: ce9fa3dfa9a1199eaf3ae958678badf0a654c0b8 doc_id: 872927 cord_uid: puukh1mv SARS-CoV-2-neutralizing antibodies play a critical role for protection and treatment of COVID-19. Viral antibody evasion therefore threatens essential prophylactic and therapeutic measures. The high number of mutations in the Omicron BA.1 sublineage results in markedly reduced neutralization susceptibility. Consistently, Omicron is associated with lower vaccine effectiveness and a high re-infection rate. Notably, newly emerging Omicron sublineages (BA.1.1, BA.2) have rapidly become dominant. Here, we determine polyclonal serum activity against BA.1, BA.1.1 and BA.2 in 50 convalescent or vaccinated individuals as well as delineate antibody sensitivities on a monoclonal level using 163 antibodies. Our study reveals a significant but comparable reduction of serum activity against Omicron sublineages which markedly increases after booster immunization. However, notable differences in sensitivity to individual antibodies demonstrate distinct escape patterns of BA.1 and BA.2 that also affect antibodies in clinical use. The results have strong implications for vaccination strategies and antibody use in prophylaxis and therapy. Following its emergence two years into the COVID-19 pandemic, the Omicron variant of 38 SARS-CoV-2 has resulted in a global surge of infections (Viana et al., 2022) . Although 39 Omicron is associated with reduced pathogenicity, its high transmissibility poses a 40 considerable threat to individuals at risk and the public health system (Madhi et 0.008 µg/ml) that was similar to its activity against Wu01 and >800-fold higher than 202 against BA.1 and BA.1.1 (Figures 4A and 4B ). In addition, while antibody imdevimab 203 showed no appreciable activity against BA.1 and BA.1.1, neutralization of BA.2 was 204 detectable at low levels ( Figures 4A and 4B) . Out of all clinical antibodies tested, the 205 recently authorized LY-CoV1404 (bebtelovimab) showed the highest levels of 206 neutralizing activity against all Omicron sublineages (Figures 4A and 4B) . We are grateful to all study participants for their dedication to our research. We thank F. to the emergence of variants of concern, as designated by the World Health Organization), 413 most individuals are likely to have been infected with an early viral strain similar to Wu01. 414 Participants were followed longitudinally to analyze long-term immunity to SARS-CoV-2. Serum samples were heat-inactivated at 56°C for 45 min before use. Three-fold 500 serial dilutions of serum (starting at 1:10) and monoclonal antibodies (starting at 10 501 µg/ml) were prepared in culture medium and co-incubated with pseudovirus 502 supernatants for one hour at 37°C and 5% CO2 prior to addition of 293T-ACE2 cells. 503 Following a 48-hour incubation at 37°C and 5% CO2, luciferase activity was determined 504 T 1 9 I Δ 2 4 -2 6 A 2 7 S A 6 7 V Δ 6 9 / 7 0 T 9 5 I G 1 4 2 D Δ 1 4 3 -1 4 5 N 2 1 1 I Δ 2 1 2 V 2 1 3 G i n s 2 1 4 E P E G 3 3 9 D R 3 4 6 K S 3 7 1 L S 3 7 1 F S 3 7 3 P S 3 7 5 F T 3 7 6 A D 4 0 5 N R 4 0 8 S K 4 1 7 N N 4 4 0 K S 4 7 7 N T 4 7 8 K E 4 8 4 A Q 4 9 3 R G 4 9 6 S Q 4 9 8 R N 5 0 1 Y Y 5 0 5 H T 5 4 7 K D 6 1 4 G H 6 5 5 Y N 6 7 9 K P 6 8 1 H N 7 6 4 K D 7 9 6 Y N 8 5 6 K Q 9 5 4 H N 9 6 9 K L 9 8 1 F Activity of convalescent and 593 vaccine serum against SARS-CoV-2 Omicron Omicron extensively but incompletely escapes 596 Pfizer BNT162b2 neutralization Neutralizing antibodies against the SARS-CoV-2 599 Omicron variant BA.1 following homologous and heterologous CoronaVac or BNT162b2 600 vaccination Effect of Bamlanivimab vs Placebo on Incidence of 603 COVID-19 Among Residents and Staff of Skilled Nursing and Assisted Living Facilities: A 604 Randomized Clinical Trial Tackling COVID-19 with 606 neutralizing monoclonal antibodies Protocol and Reagents for 609 Pseudotyping Lentiviral Particles with SARS-CoV-2 Spike Protein for Neutralization 610 Assays Bamlanivimab plus Etesevimab in Mild or Moderate 613 Covid-19 Data, disease and diplomacy: GISAID's 615 innovative contribution to global health Correlates of protection against symptomatic and 618 asymptomatic SARS-CoV-2 infection mRNA-based COVID-19 621 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant UCSF ChimeraX: Meeting modern challenges in visualization and analysis Mapping mutations to the SARS-CoV-2 RBD 628 that escape binding by different classes of antibodies Casirivimab and imdevimab in patients admitted to hospital with 630 COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial mRNA booster immunization elicits potent neutralizing 634 serum activity against the SARS-CoV-2 Omicron variant Early Treatment for Covid-19 with SARS-CoV-2 SARS-CoV-2 variants, 640 spike mutations and immune escape Safety, reactogenicity, and 643 immunogenicity of homologous and heterologous prime-boost immunisation with 644 ChAdOx1 nCoV-19 and BNT162b2: a prospective cohort study The Omicron variant is highly 648 resistant against antibody-mediated neutralization: Implications for control of the COVID-649 19 pandemic Antibody evasion properties of SARS-CoV-2 Omicron sublineages MAFFT: a novel method for rapid 653 multiple sequence alignment based on fast Fourier transform GISAID's Role in Pandemic Response Neutralizing antibody levels are highly 659 predictive of immune protection from symptomatic SARS-CoV-2 infection Longitudinal Isolation of Potent 663 Near-Germline SARS-CoV-2-Neutralizing Antibodies from COVID-19 Patients Breakthrough infections with SARS-667 CoV-2 omicron despite mRNA vaccine booster dose IMGT, the International ImMunoGeneTics Information System. 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