Emergence and antibody evasion of BQ, BA.2.75 and SARS-CoV-2 recombinant sublineages in the face of maturing antibody breadth at the population level

The Omicron era of the COVID-19 pandemic commenced at the beginning of 2022 and whilst it started with primarily BA.1, it was latter dominated by BA.2 and related sub-lineages. Over the course of 2022, we monitored the potency and breadth of antibody neutralization responses to many emerging variants at two levels: (i) we tracked over 420,000 U.S. plasma donors over time through various vaccine booster roll outs and Omicron waves using sequentially collected IgG pools; (ii) we mapped the antibody response in individuals using blood from strigently curated vaccine and convalescent cohorts. In pooled IgG samples, we observed the maturation of neutralization breadth to Omicron variants over time through continuing vaccine and infection waves. Importantly, in many cases we observed increased antibody breadth to variants that were yet to be in circulation. Determination of viral neutralization at the cohort level supported equivalent coverage across prior and emerging variants with emerging isolates BQ.1.1, XBB.1, BR.2.1 and XBF the most evasive. Further, these emerging variants were resistant to Evusheld, whilst neutralization resistance to Sotrovimab was restricted to BQ.1.1 and XBF. We conclude at this current point in time that dominant variants can evade antibodies at levels equivalent to their most evasive lineage counterparts but sustain an entry phenotype that continues to promote an additional outgrowth advantage. In Australia, BR2.1 and XBF share this phenotype and are dominating across NSW and Victoria. Evidence before this study Up until the BA.5 wave in mid 2022, many global waves were seeded by dominant variants such as Delta, Omicron BA.1 and Omicron BA.2. Following resolution of the BA.5, was the emergence of a pool of BA.4/5 and BA.2.75 sub-lineages accumulating clusters of similar polymorphisms located with the Receptor Binding Domain (RBD) of the Spike glycoprotein. Although iterative changes in the Spike increased the ability of each variant to navigate existing neutralising antibodies, it was unclear if this alone was sufficient to provide an outgrowth advantage to any one variant to fuel major case waves in global communities with high vaccine uptake and/or infection. Added value of this study Prior studies on incoming variants in Australian quarantine, highlighted the potential for Australia to represent a unique mix of cocirculating variants. Following the resolution of the BA.5 Omicron wave, many globally circulating variants appeared early on and ranged from BA.2.75 lineages, recombinants XBB.1, and XBC.1 in addition to many BA.5 derived BQ.1 lineages. Two additional lineages, the recombinant XBF and the BA.2.75 derived BR.2.1 also appeared and were uniquely enriched in Australia. Using 14 primary clinical isolates covering a continuum of circulating variants in Australia, we resolved neutralisation responses of 110 donors stringently documented for their vaccine and infection status over time. In addition, we also tested the well clinical utilised clinical monoclonals Evusheld and Sotrovimab. In addition to tracking donors, we also tracked immunity at the population level, using pooled IgG samples over time. The latter samples were the sum of 420,000 US plasma donors covering time periods of high-booster uptake alongside and in addition to large case waves. Whilst the above resolved the impact of Spike changes in neutralisations, we also tested each variant with respect to the efficiency of TMPRSS2 use, as this significantly influences viral tropism across the respiratory tract. Implications of all the available evidence All variants analysed herein have undertaken a convergent trajectory in accumulating a similar cluster of Spike polymorphisms. Many variants, including BQ.1.1, XBB.1, XBF and BR.2.1 have accumulated key changes that now render neutralisation responses lower in all cohorts and are neutralisation resistant to Evusheld. Whilst sotrovimab retained neutralisation capacity of many variants, there was significant reduction for variants BQ.1.1 and XBF. Impact of Spike changes on TMPRSS2 use were mixed and only one variant, BQ.1.2, had equal to increased usage relative to its parent BA.5. Analysis of neutralisation at the population level over time revealed two key observations. Firstly, whilst variants converged and lowered neutralisation responses, this reduction was negated over time with increasing neutralisation breadth. Secondly, responses to a variant proceeded its appearance and global circulation. In conclusion, whilst many variants are appearing and iterative changes in the spike will challenge antibody responses, increasing breadth in the community over time has enabled sufficient coverage to presently emerging variants. Furthermore, with the exception of BQ.1.2, viral use of TMPRSS2 has not increased and as such viral tropism towards epithelial cells of the upper respiratory tract we predict will be maintained. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was primarily supported by Australian Medical Foundation research grants MRF2005760 (ST, GM & WDR), MRF2001684 (ADK and ST) and Medical Research Future Fund Antiviral Development Call grant (WDR), Medical Research Future Fund COVID-19 grant (MRFF2001684, ADK & SGT) and the New South Wales Health COVID-19 Research Grants Round 2 (SGT) and the NSW Vaccine Infection and immunology Collaborative (VIIM). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All human serum samples were obtained with written informed consent from the participants and have been approved under Ethics review at St Vincents Hospital, Darlinghurst Sydney Australia (ADAPT Cohort) and Ethics review at the Western Sydney Local Health (WSLHD) District (VIIM cohort)(2020/ETH00964; 2020/ETH02068; 2019/ETH03336; 2021/ETH00180; 2021/ETH0042). All primary isolates used herein were obtained from de-identified remnant diagnostic swabs that had completed all diagnostic testing under approval by the New South Wales Chief Health Officer following independent scientific review and as outlined in the ADAPT ethics protocol 2020/ETH00964. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Source data for generating the figures are available in the online version of the paper in the supplmentary tables. Any other data are available on request