Characterization of immune evasion and cell entry for new variants: BQ.1.1, XBB.1, and BR.2.1
In a recent study posted to the medRxiv* preprint server, researchers in Australia and Switzerland evaluated the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) in community-based settings of the United States (US).
The continual emergence of SARS-CoV-2 VOCs has increased coronavirus 2019 (COVID-19) mitigation difficulties. Omicron sub-VOC BA.1 emergence was followed by the circulation of Omicron sub-VOCs BA.2, BA.5, and BA.2.75. In addition, BA.5 is reported to have greater immune-evasiveness than its parent (BA.2) VOC due to spike (S) protein receptor-binding domain (RBD) mutations and greater TMPRSS2 use.
Study: Emergence and antibody evasion of BQ and BA.2.75 SARS-CoV-2 sublineages in the face of maturing antibody breadth at the population level. Image Credit: NIAID
About the study
In the present study, researchers evaluated SARS-CoV-2 VOC prevalence in US communities.
The team monitored the potency and breadth of antibody neutralization responses to several emerging VOCs at two levels. Blood samples were obtained from COVID-19 vaccinees and convalescents to map VOC responses to monoclonal antibodies such as Evusheld (cilgavimab and tixagevimab combination) and Sotrovimab. To assess neutralization response maturation, 37 sequential immunoglobulin G (IgG)-derived serum pool batches of >420,000 individuals were analyzed between August 2021 and June 2022.
VOC isolation (including BQ.1.1, XBB.1, and BR.2.1 (+R346T), BL.1 BR.2.1 (346R), BA.4.6 and BA.5) and ex vivo whole genome sequencing of SARS-CoV-2 obtained from nasopharyngeal swabs were performed throughout 2022. Transmembrane serine protease 2 (TMPRSS2) use by VOCs was evaluated using HAT-24 cells, and the consequences of S protein mutations on TMPRSS2 use were evaluated. SARS-CoV-2 titers were evaluated by quantitative polymerase chain reaction (qPCR) analysis. To determine whether the changes in breadth and potency were associated with vaccination versus BA.1 infection, the team plotted mean neutralization titers and breadth with three key comparators: month of plasma collection, VOC breadth, and reported SARS-CoV-2 infection cases.
Further, anti-nucleocapsid (N) protein IgG titers were determined. The team tested neutralizing responses of sera from the VIIM (vaccine, infection, and immunology collaborative research) cohort and the ADAPT (Australians’ drug use: adapting to pandemic threats) cohort of Australian individuals. VIIM cohort samples were obtained in September 2022, and ADAPT cohort samples were obtained between March and September 2022. Whole S protein live cell assays were performed, and the phenotypes of antibody evasion and SARS-CoV-2 entry MODES were characterized. To determine BA.5 phenotype tropism, the team compared Delta, BA.2, and BA.5 infections in primary human bronchial- and alveolar epithelial cultures differentiated at the air-liquid interface (ALI).
To monitor the phenotype of emerging VOCs beyond antibody evasion, endpoint titers of 188 primary swabs were determined between October and November 2022. Donor individuals were grouped as follows (i) 3.0-dose Pfizer messenger ribonucleic acid (mRNA) vaccinees with a 6.0 month-post-vaccination period; (ii) 3.0-dose Pfizer mRNA vaccinees with breakthrough BA.2/BA.5 infections (between June and August 2022); (iii) 4.0-dose Pfizer vaccinees, with the most recent dose in the last 3.0 months; and (iv) donors infected between March and August 2020 who received 3.0 vaccinations late 2021 onward and a Pfizer vaccine booster in the initial days of 2022.
Results
The team isolated A.2.2 clade (ancestral) VOC, Delta VOC, emerged Omicron BA.1 sub-VOC, BA.2 sub-VOC and Omicron BA.5 sub-VOC, and the yet-to-emerge Omicron BL.1 sub-VOC, BQ.1.1 sub-VOC, BQ.1.2 sub-VOC, XXB.1 sub-VOC, and Omicron BR.2.1 sub-VOC. Elevated antibody breadth was observed in emerging VOCs. BQ.1.1, XBB.1, and BR.2.1 were highly immune-evasive (with the highest number of RBD mutations and 18-fold to 20-fold lower neutralization than A.2.2 neutralization across all study cohorts). The three immune-evasive VOCs were resistant to Evusheld; however, only BQ.1.1 showed Sotrovimab resistance, with 58-fold lower binding antibody titers than the ancestral clade).
The convergence of S protein polymorphisms across emerging lineages significantly decreased the potency and breadth of neutralization responses across all cohorts. Samples obtained in October were enriched for BA.5-derived lineages, and those in mid-November were enriched by BA.5 parent (e.g., BQ.1)- or BA.2.75 parent-derived lineages (especially BR.2.1 VOC with characteristic S67F mutation in the open reading frame 8 (ORF8). BA.2.75- and BA.5-derived lineages showed mutations in class I, II, and III antibody sites across the RBD, such as L452R/M, R346T, N460K, F486V/I, F490S, and K444R/T.
Lowered anti-N IgG levels compared to neutralization titers were observed, indicating that COVID-19 vaccination and no infection contributed to enhanced breadth and neutralization. Contrastingly, A.2.2 neutralization titers and anti-N IgG titers peaked in February, associated with BA.1 sub-VOC peak resolution during January of 2022. Concomitant uptake of vaccines and BA.1 infections led to increased BA.1 sub-VOC, BA.2 sub-VOC, BA.5 sub-VOC, and Omicron BL.1 sub-VOC neutralization.
Anti-N titers increased after the BA.2 peak, and thus, the increasing breadth of neutralization responses across the study period may represent two predominant immune events in late 2021-early 2022, i.e., third-dose vaccinations and Omicron BA.1 infections. BQ lineages (with high infectivity to particle ratios and higher fusogenicity) utilized TMPRSS2 more than BA.2.75-derived lineages, BA.1 and BA.2. BA.5 showed high TMPRSS2 use (but less than Delta), resulting in a growth advantage across pulmonary epithelial cells. Delta showed higher reductions in titers in the presence of Nafamostat.
Overall, the study findings showed that BQ-derived sub-lineages efficiently evade neutralization responses and sustain an outgrowth advantage of TMPRSS2 usage at levels comparable to BA.5.
*Important notice
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
