A study posted recently to the bioRxiv* preprint server elucidated the antigenic properties of the sublineages of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron variant.
Since the emergence of the SARS-CoV-2 Omicron variant (B.1.1.529) in November 2021, the coronavirus disease 2019 (COVID-19) health crisis has further exacerbated as the novel variant exhibits additional pathogenic features compared to the wildtype (WT) virus.
Surveillance studies on the evolution of the Omicron variant reveal a declining proportion of BA.1 lineage (the original form of Omicron) in circulation. Concurrently, the prevalence of two Omicron sublineages has increased. One of the sublineages (BA.1 + R346K) carries an extra R346K mutation than the BA.1 lineage, and the other sublineage (BA.2) has eight unique substitutions and lacks 13 spike mutations of the BA.1 lineage. The BA.1 lineage and its sublineages (BA.1 + R346K and BA.2) have 21 common mutations while the BA.1 lineage harbors 13 unique substitutions.
In the present study, a team of researchers investigated the antigenic characteristics of the Omicron sublineages. The neutralization activity of polyclonal sera from individuals infected with WT SARS-CoV-2 and messenger ribonucleic acid (mRNA) vaccine recipients (including boosted individuals) against the sublineages was determined.
Similarly, neutralization activity was determined against the WT (D614G) pseudovirus. Further, around 19 monoclonal antibodies directed at either the receptor-binding domain (RBD) or the N-terminal domain (NTD) of the SARS-CoV-2 spike protein were included as probes to examine their sensitivity to the Omicron sublineages.
Sera from both infected and vaccinated persons showed lower neutralizing potential against the two sublineages, which is consistent with previous reports of reduced neutralization potency of sera against the BA.1 lineage. The authors observed that neutralizing titers for many samples were below the limit of detection (LoD). Sera from individuals who had been administered with a booster dose showed better neutralizing titers against the sublineages than that from doubly vaccinated subjects. The mean neutralization titers of sera against the sublineages were lower than that for D614G or WT SARS-CoV-2.
The researchers observed that 17 MAbs had either lost neutralization activity against the BA.2 sublineage or were severely impaired to neutralize it, which is similar to earlier results for the BA.1 lineage by the same research team. All MAbs from RBD class 4 demonstrated a higher loss of neutralization against BA.2 as compared with the BA.1 + R346K sublineage. Sotrovimab or S309, a MAb approved for clinical use against the Omicron (BA.1) variant, had the most prominent loss of neutralization with a 27-fold decrease against the BA.2 sublineage. One RBD class 3 MAb, Ly-CoV1404 or bamlanivimab, was found to neutralize all Omicron sublineages. COV2-2130, or, cilgavimab was found to neutralize BA.2 and a combination of cilgavimab and tixagevimab (COV2-2196), too, retained neutralization potency against BA.2.
Each of the eight unique mutations observed in BA.2 were introduced into separate pseudoviruses and tested with MAbs. The S371F mutation of BA.2 negatively affected the activity of many RBD MAbs similar to the S371L substitution of the BA.1 lineage. The S371F mutation has been speculated to be responsible for the observed loss of sotrovimab potency against BA.2. The team also observed that another mutation (D405N) in the BA.2 sublineage had adverse effects on the activity of the CB6 antibody.
Overall, the study findings show that polyclonal sera from convalescent and vaccinated people had lower neutralization activity against the sublineages of the Omicron variant comparable to that reported against the BA.1 lineage.
The researchers proposed that all sublineages were antigenically equidistant from WT SARS-CoV-2 and thereby could comparably affect the established efficacies of available vaccines. The present study highlighted important observations and noted that none of the approved therapeutic antibodies could neutralize all Omicron sublineages, raising suspicions over the validity of current therapies.
The MAbs with neutralizing activity against BA.2 are either in development or are approved for preventive use and, therefore, it is essential to develop more novel therapeutic strategies to effectively manage the COVID-19 pandemic.
bioRxiv 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.
- Sho Iketani, Lihong Liu, Yicheng Guo, Liyuan Liu, Yiming Huang, Maple Wang, Yang Luo, Jian Yu, Michael T. Yin, Magdalena E. Sobieszczyk, Yaoxing Huang, Harris H. Wang, Zizhang Sheng, David D. Ho. (2022). Antibody Evasion Properties of SARS-CoV-2 Omicron Sublineages. bioRxiv. doi: 10.1101/2022.02.07.479306 https://www.biorxiv.org/content/10.1101/2022.02.07.479306v1