December 6, 2023

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New Advances in COVID-19 Research by Dr. David Ho

New Advances in COVID-19 Research by Dr. David Ho

New Advances in COVID-19 Research by Dr. David Ho

The SARS-CoV-2 Omicron subvariant, BA.2.86, has emerged and spread to many countries worldwide, causing concerns due to its spike protein featuring two additional mutations compared to its predecessor, BA.2.

On October 23, 2023, Dr. David Ho from Columbia University, in collaboration with Lihong Liu, published a research paper titled “Antigenicity and receptor affinity of SARS-CoV-2 BA.2.86 spike” in the journal Nature. This study sheds light on the antigenicity and receptor affinity of the SARS-CoV-2 BA.2.86 spike.

Furthermore, on September 11, 2023, a team including Yang Haitao and Rao Ziheng from ShanghaiTech University, along with Dr. David Ho from Columbia University, published a research paper in Nature titled “Molecular mechanisms of SARS-CoV-2 resistance to nirmatrelvir.” This research demonstrated that mutations in the Mpro substrate-binding pocket could confer resistance to nirmatrelvir in SARS-CoV-2 in two distinct ways.


New Advances in COVID-19 Research by Dr. David Ho


Despite the official end of the COVID-19 pandemic, SARS-CoV-2 continues to circulate and evolve. Recent infections have been dominated by subvariants XBB.1.5 and EG.5.1. A highly mutated subvariant of SARS-CoV-2 Omicron, BA.2.86, was recently reported, genetically distinct from the popular XBB lineage. Its genetic distance from its precursor, BA.2, is comparable to that between BA.1 and the Delta variant when the first Omicron variant emerged at the end of 2021, raising similar concerns about antibody escape. While current monitoring is limited, over 430 BA.2.86 sequences have been identified in 28 countries. A recent outbreak of the new subvariant in an English care facility had a high incidence among residents and staff, suggesting easy transmissibility. Presently, there is limited clinical evidence regarding its pathogenicity.

Compared to BA.2, BA.2.86 features an additional 34 mutations in the spike protein, with 13 mutations in the N-terminal domain (NTD), 14 in the receptor-binding domain (RBD), 2 in subdomain 1 (SD1), 3 in subdomain 2 (SD2), and 2 in the S2 region. Mutations H69V70 deletion (H69V70∆), Y144 65 deletion (Y144∆), G446S, N460K, F486P, and R493Q had previously been identified, but mutations V445H, N450D, N481K, V483 deletion (V483∆), and E554K are rarely observed in circulating viruses. The extensive spike mutations in BA.2.86, a total of 68, raise concerns about the virus’s potential for immune escape from previous infections, vaccinations, or clinical use of monoclonal antibodies. Current research, using a variety of human sera and monoclonal antibodies, examined its antigenicity.


New Advances in COVID-19 Research by Dr. David Ho

Differentiation of the spike sequence of SARS-CoV-2 major variant BA.2.86 (Figure from Nature )



The study used human sera and monoclonal antibodies (mAbs) to assess its antigenicity and found that BA.2.86 doesn’t exhibit stronger resistance to human sera than the currently dominant XBB.1.5 and EG.5.1, indicating that the new subvariant lacks a growth advantage in this regard. Importantly, sera from breakthrough infection patients from the XBB lineage displayed robust neutralizing activity against all tested viruses, suggesting that the upcoming XBB.1.5 monovalent vaccine may provide additional protection.

Although BA.2.86 demonstrates increased resistance to mAbs against subdomain 1 (SD1) and receptor-binding domain (RBD) class 2 and 3 epitopes, it is more sensitive to mAbs against class 1 and 4/1 epitopes within the RBD “inner surface,” which are only exposed when the domain is in an “up” position. The authors also identified six new spike protein mutations mediating antibody resistance, including E1K in the SD554 monoclonal antibody, which poses a threat to clinical development. BA.2.86 spike protein also exhibits very high receptor affinity. The ultimate trajectory of this new SARS-CoV-2 variant will soon be revealed through ongoing monitoring, but its global spread is a cause for concern.

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New Advances in COVID-19 Research by Dr. David Ho

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Important Note: The information provided is for informational purposes only and should not be considered as medical advice.