key: cord-0295561-2svbjtvv authors: Willett, Brian J.; Kurshan, Ashwini; Thakur, Nazia; Newman, Joseph; Manali, Maria; Tyson, Grace; Logan, Nicola; Murcia, Pablo R.; Snell, Luke B.; Edgeworth, Jonathan D.; Zhou, Jie; Sukhova, Ksenia; Amirthalingam, Gayatri; Brown, Kevin; Charleston, Bryan; Malim, Michael H.; Thomson, Emma C.; Barclay, Wendy S.; Bailey, Dalan; Doores, Katie J.; Peacock, Thomas P. title: Distinct antigenic properties of the SARS-CoV-2 Omicron lineages BA.4 and BA.5 date: 2022-05-25 journal: bioRxiv DOI: 10.1101/2022.05.25.493397 sha: 5ea2a87df43e41b16f0ed43d799e1286a6c5f863 doc_id: 295561 cord_uid: 2svbjtvv Over the course of the pandemic variants have arisen at a steady rate. The most recent variants to emerge, BA.4 and BA.5, form part of the Omicron lineage and were first found in Southern Africa where they are driving the current wave of infection. In this report, we perform an in-depth characterisation of the antigenicity of the BA.4/BA.5 Spike protein by comparing sera collected post-vaccination, post-BA.1 or BA.2 infection, or post breakthrough infection of vaccinated individuals with the Omicron variant. In addition, we assess sensitivity to neutralisation by commonly used therapeutic monoclonal antibodies. We find sera collected post-vaccination have a similar ability to neutralise BA.1, BA.2 and BA.4/BA.5. In contrast, in the absence of vaccination, prior infection with BA.2 or, in particular, BA.1 results in an antibody response that neutralises BA.4/BA.5 poorly. Breakthrough infection with Omicron in vaccinees leads to a broad neutralising response against the new variants. The sensitivity of BA.4/BA.5 to neutralisation by therapeutic monoclonal antibodies was similar to that of BA.2. These data suggest BA.4/BA.5 are antigenically distinct from BA.1 and, to a lesser extent, BA.2. The enhanced breadth of neutralisation observed following breakthrough infection with Omicron suggests that vaccination with heterologous or multivalent antigens may represent viable strategies for the development of cross-neutralising antibody responses. post-BA.1 or BA.2 infection, or post breakthrough infection of vaccinated 31 individuals with the Omicron variant. In addition, we assess sensitivity to 32 neutralisation by commonly used therapeutic monoclonal antibodies. 33 We find sera collected post-vaccination have a similar ability to neutralise In November 2021 a novel SARS-CoV-2 variant of concern, Omicron, was 49 identified in Southern Africa 1 . The Omicron complex is now composed of five 50 related lineages -BA.1 to BA.5, with BA.4 and BA.5 recently being described in 51 Southern Africa 2 . The Omicron lineages BA.1 and BA.2 have been described as 52 having a large antigenic distance from previous variants and current vaccine 53 strains 3-5 , but a more modest antigenic distance between one another 6,7 . Additional funding to D was by The Pirbright Institute's BBSRC institute strategic program 201 grant (BBS/E/I/00007038). The Medical Research Council (MRC) provided 202 funding to E.T. for the COVID-19 DeplOyed VaccinE (DOVE) study 203 (MCUU1201412) and to Health Data Research UK (HDR UK) funded E.T. and B.W. for 205 the Evaluation of Variants Affecting Deployed COVID-19 Vaccine (EVADE) study Huo Family Foundation funding acquisition 213 by Rapid epidemic expansion of the SARS-CoV-2 Omicron 219 variant in southern Africa Continued Emergence and Evolution of Omicron in South 221 Africa: New BA.4 and BA.5 lineages Omicron extensively but incompletely escapes Pfizer 223 BNT162b2 neutralization Neutralising antibody activity against SARS-CoV-2 225 variants, including Omicron Neutralization of the SARS-CoV-2 Omicron BA.1 and BA.2 228 Variants Omicron BA.1 and BA.2 are antigenically distinct 230 SARS-CoV-2 variants Omicron breakthrough infections in vaccinated or 232 previously infected hamsters Comprehensive mapping of mutations in the 234 SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human plasma 235 antibodies Omicron sub-lineages BA.4/BA.5 escape BA.1 infection 237 elicited neutralizing immunity BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by 239 Omicron infection Neutralization Escape by the SARS-CoV-2 Omicron 241 Variants BA Further antibody escape by Omicron BA.4 and BA.5 243 from vaccine and BA.1 serum Sensitivity of novel SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4 and BA.5 to therapeutic monoclonal antibodies Neutralizing antibody activity in convalescent sera from 248 infection in humans with SARS-CoV-2 and variants of concern Longitudinal observation and decline of neutralizing 250 antibody responses in the three months following SARS-CoV-2 infection in humans SARS-CoV-2 Omicron is an immune escape variant 253 with an altered cell entry pathway Development of a Multiplex Tandem PCR (MT-PCR) 255 Assay for the Detection of Emerging SARS-CoV-2 Variants The authors declare funding sources had no role in the design, collection, 191 analysis, interpretation of data, the writing of the report, or in the decision to 192 submit the paper for publication.