key: cord-0784544-tdqiuf8e authors: Wang, Xun; Zhao, Xiaoyu; Song, Jieyu; Wu, Jing; Zhu, Yuqi; Li, Minghui; Cui, Yuchen; Chen, Yanjia; Yang, Lulu; Liu, Jun; Zhu, Huanzhang; Jiang, Shibo; Wang, Pengfei title: Homologous or Heterologous Booster of Inactivated Vaccine Reduces SARS-CoV-2 Omicron Variant Escape from Neutralizing Antibodies date: 2021-12-27 journal: bioRxiv DOI: 10.1101/2021.12.24.474138 sha: aaeef6398bc2b57a3ca52ad5ed6d64ce0bbd038e doc_id: 784544 cord_uid: tdqiuf8e The massive and rapid transmission of SARS-CoV-2 has led to the emergence of several viral variants of concern (VOCs), with the most recent one, B.1.1.529 (Omicron), which accumulated a large number of spike mutations, raising the specter that this newly identified variant may escape from the currently available vaccines and therapeutic antibodies. Using VSV-based pseudovirus, we found that Omicron variant is markedly resistant to neutralization of sera form convalescents or individuals vaccinated by two doses of inactivated whole-virion vaccines (BBIBP-CorV). However, a homologous inactivated vaccine booster or a heterologous booster with protein subunit vaccine (ZF2001) significantly increased neutralization titers to both WT and Omicron variant. Moreover, at day 14 post the third dose, neutralizing antibody titer reduction for Omicron was less than that for convalescents or individuals who had only two doses of the vaccine, indicating that a homologous or heterologous booster can reduce the Omicron escape from neutralizing. In addition, we tested a panel of 17 SARS-CoV-2 monoclonal antibodies (mAbs). Omicron resists 7 of 8 authorized/approved mAbs, as well as most of the other mAbs targeting distinct epitopes on RBD and NTD. Taken together, our results suggest the urgency to push forward the booster vaccination to combat the emerging SARS-CoV-2 variants. Coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to disrupt worldwide social and economic equity, and global public health. As of December 2021, more than 278 million confirmed cases of COVID-19, including 5.4 million deaths, have been reported across the world (https://www.worldometers.info/coronavirus). The massive and rapid transmission of SARS-CoV-2 has led to the emergence of several viral variants, some of which have raised high concern due to their impact on transmissibility, mortality and putative capacity to escape from immune responses generated after infection or vaccination 1 . Distributed throughout the world, the previous four SARS-CoV-2 well-characterized SARS-CoV-2 variants of concern (VOCs), including Alpha A key question in the Omicron investigation thus far is its putative ability to escape immune surveillance. Therefore, we took steps to measure and clarify the extent of such immune evasion by this VOC after infection or vaccination. To accomplish this, we first evaluated the neutralizing activity of serum collected from 10 convalescent patients infected with the Delta variant of SARS-CoV-2 (Supplementary Table 1 ). Using VSV-based PsVs, we observed robust titers against WT virus in all 10 sera, with the geometric mean neutralizing titers (GMTs) of about 1,100. However, the Omicron variant was markedly resistant to neutralization by convalescent plasma. Only 3 out of the 10 sera showed ID50 titers above the lower limit of quantification Table 1 ). Here, we found that the GMT against WT was 84 with 80% Figure 2 , the activity against Omicron of the supersite-directed mAbs was totally abolished, but only 5-7 retained its activity partially. The SARS-CoV-2 Omicron variant struck the world soon after its identification. The retrospective analysis of epidemiological surveillance data in South Africa showed that Omicron is associated with a higher rate of reinfection 21 . Besides, the protection against infection of Omicron from symptomatic disease at 25 weeks after 2-dose vaccination was suggested to be less than 10% in the UK 22 . Similar to these preliminary real-world data, here we reported that a markedly reduced neutralizing activity against Omicron variant in the convalescent and two-dose BBIBP-CorV vaccination group, which is also confirmed by others 23, 24 . However, the good news is that after two doses of inactivated vaccines as the "priming" shot, a third homologous Monoclonal antibodies tested in this study were constructed and produced at Fudan University. Plasmids encoding the WT (D614G) SARS-CoV-2 spike and Omicron variant (B.1.1.529) spike were synthesized. Expi293 cells were grown to 3×10 6 /mL before transfection with the spike gene using Polyethylenimine (Polyscience). Cells were cultured overnight at 37°C with 8% CO 2 and VSV-G pseudo-typed Materials used in this study will be made available but may require execution of a materials transfer agreement. All the data are provided in the paper or the Supplementary Information. SARS-CoV-2 Omicron variant: Characteristics and prevention Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7 Effectiveness of the BNT162b2 Covid-19 Vaccine against the B.1.1.7 and B.1.351 Variants Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum Track Omicron's spread with molecular data Heavily mutated Omicron variant puts scientists on alert Recombinant protein subunit vaccine booster following two-dose inactivated vaccines dramatically enhanced anti-RBD responses and neutralizing titers against SARS-CoV-2 and Variants of Concern Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail The neutralizing antibody, LY-CoV555, protects against SARS-CoV-2 infection in nonhuman primates A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2 Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody Potently neutralizing and protective human antibodies against SARS-CoV-2 A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein Broad and potent activity against SARS-like viruses by an engineered human monoclonal antibody A monoclonal antibody that neutralizes SARS-CoV-2 variants, SARS-CoV, and other sarbecoviruses Potent SARS-CoV-2 neutralizing antibodies directed against spike N-terminal domain target a single supersite Neutralizing antibody 5-7 defines a distinct site of vulnerability in SARS-CoV-2 spike N-terminal domain Increased risk of SARS-CoV-2 reinfection associated with emergence of the Omicron variant in South Africa. medRxiv Omicron variant and booster COVID-19 vaccines Omicron variant showed lower neutralizing sensitivity than other SARS-CoV-2 variants to immune sera elicited by vaccines after boost The significant immune escape of pseudotyped SARS-CoV-2 variant Omicron Booster of mRNA-1273 Strengthens SARS-CoV-2 Omicron Neutralization. medRxiv Effectiveness of COVID-19 vaccines against the Omicron (B.1.1.529) variant of concern. medRxiv Striking Antibody Evasion Manifested by the Omicron Variant of SARS-CoV-2 We are grateful Dr. Rong Zhang (Fudan University) for providing Vero E6 cells. This study was supported by funding from the National Natural Science Foundation of China (82041001 to HZ and 82041025 to SJ).