Molecular Epidemiology of Omicron CH.1.1 Lineage: Genomic and Phenotypic Data Perspective.

BACKGROUND: The Omicron variant (B.1.1.529 lineage) of SARS-CoV-2 represents a substantial global health challenge due to its high transmissibility and potential resistance to immunity from vaccines or previous infections. Among the rapidly evolving Omicron lineages, the BA.2.75 and the emerging CH.1.1 have garnered attention. While BA.2.75 is marked by mutations that may enhance immune evasion, CH.1.1 is distinguished by the S: L452R mutation, linked to increased pathogenicity and transmission. Initially identified in India by the end of 2021, these variants have exhibited global dissemination, signaling an urgent need to track and analyze their progression. METHODS: In this study, the genomic and geographical distribution data of CH.1.1 were collected from the Global Initiative on Sharing Avian Influenza Data (GISAID), PANGOLIN, CoV-Spectrum, and NextStrain databases. Due to the unavailability of epidemiological and genomic data of the CH.1.1 lineage, PubMed and ScienceDirect were used as sources of the phenotypic data of the lineage variations. Amino acid variations utilized in the data mining included S: R346T, S: K444T, S: L452R, and S: F486S. RESULTS: The current epidemiological data indicate that CH.1.1 is more likely to become one of the dominant spreading lineages in the United Kingdom, New Zealand, Australia, and the United States based on a 32% growth advantage, present CH.1.1 lineage cases number, and the amino acid variation's impact. CONCLUSION: A significant increase in the newly detected lineage CH.1.1 is highly anticipated. The rise in the detected sequences number from 13,231 on January 21, 2023, to 23,181 on February 6, 2023, supports the prediction and growth advantage of the lineage detected cases. Increases in viral transmissibility caused by higher affinity to ACE2 receptors and immune evasion are deduced from amino acid variations analyzed in the study.

Differential pathogenic and molecular features in neurological infection of SARS-CoV-2 Omicron BA.5.2 and BA.2.75 and Delta.

The Coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global threat, exacerbated by the emergence of viral variants. Two variants of SARS-CoV-2, Omicron BA.2.75 and BA.5, led to global infection peaks between May 2022 and May 2023, yet their precise characteristics in pathogenesis are not well understood. In this study, we compared these two Omicron sublineages with the previously dominant Delta variant using a human angiotensin-converting enzyme 2 knock-in mouse model. As expected, Delta exhibited higher viral replication in the lung and brain than both Omicron sublineages which induced less severe lung damage and immune activation. In contrast, the Omicron variants especially BA.5.2 showed a propensity for cellular proliferation and developmental pathways. Both Delta and BA.5.2 variants, but not BA.2.75, led to decreased pulmonary lymphocytes, indicating differential adaptive immune response. Neuroinvasiveness was shared with all strains, accompanied by vascular abnormalities, synaptic injury, and loss of astrocytes. However, Immunostaining assays and transcriptomic analysis showed that BA.5.2 displayed stronger immune suppression and neurodegeneration, while BA.2.75 exhibited more similar characteristics to Delta in the cortex. Such differentially infectious features could be partially attributed to the weakened interaction between Omicron Spike protein and host proteomes decoded via co-immunoprecipitation followed by mass spectrometry in neuronal cells. Our present study supports attenuated replication and pathogenicity of Omicron variants but also highlights their newly infectious characteristics in the lung and brain, especially with BA.5.2 demonstrating enhanced immune evasion and neural damage that could exacerbate neurological sequelae.

Evolving antibody evasion and receptor affinity of the Omicron BA.2.75 sublineage of SARS-CoV-2.

SARS-CoV-2 Omicron BA.2.75 has diversified into multiple subvariants with additional spike mutations and several are expanding in prevalence, particularly CH.1.1 and BN.1. Here, we investigated the viral receptor affinities and neutralization evasion properties of major BA.2.75 subvariants actively circulating in different regions worldwide. We found two distinct evolutionary pathways and three newly identified mutations that shaped the virological features of these subvariants. One phenotypic group exhibited a discernible decrease in viral receptor affinities, but a noteworthy increase in resistance to antibody neutralization, as exemplified by CH.1.1, which is apparently as resistant as XBB.1.5. In contrast, a second group demonstrated a substantial increase in viral receptor affinity but only a moderate increase in antibody evasion, as exemplified by BN.1. We also observed that all prevalent SARS-CoV-2 variants in the circulation presently, except for BN.1, exhibit profound levels of antibody evasion, suggesting this is the dominant determinant of virus transmissibility today.

Clinical virology and effect of Covid-19 vaccination and monoclonal antibodies against highly infectious SARS- CoV-2 omicron sub variant BF.7 (BA.5.2.1.7): A systematic review.

Over time, the SARS-CoV-2 virus has acquired several genetic mutations, particularly on the receptor-binding domain (RBD) spike glycoprotein. The Omicron variant is highly infectious, with enhanced immune escape activity, and has given rise to various sub-lineages due to mutations. However, there has been a sudden increase in COVID-19 reports of the Omicron subvariant BF.7 (BA.2.75.2), which has the highest number of reported cases, accounting for 76.2% of all cases worldwide. Hence, the present systematic review aimed to understand the viral mutations and factors associated with the increase in the reports of COVID-19 cases and to assess the effectiveness of vaccines and mAbs against the novel Omicron variant BF.7. The R346T mutation on the spike glycoprotein RBD might be associated with increased infection rates, severity, and resistance to vaccines and mAbs. Booster doses of COVID-19 vaccination with bivalent mRNA booster vaccine shots are effective in curtailing infections and decreasing the severity and mortality by enhancing the neutralizing antibodies (Abs) against the emerging Omicron subvariants of SARS-CoV-2, including BF.7 and future VOCs.

Novel pro-and eukaryotic expression plasmid expressing omicron antigens delivered via Salmonella elicited MHC class I and II based protective immunity.

The latest omicron variants are emerging with mutations in the receptor binding domain (RBD) that confer immune evasion and resistance against current vaccines. Such variants have raised the peril of future vaccine effectiveness, as leading vaccines target the spike protein. Type-IV hypersensitivity, and other ailments due to the dominant Th1 response by leading vaccines, is also to be resolved. Therefore, vaccine that target diverse SARS-CoV-2 proteins and provide broad-spectrum protection and a balanced Th1 and Th2 response is an indispensable armament against the pandemic. In that prospect, a novel dual expression plasmid pJHL270 was developed and demonstrated the expression of omicron antigens exogenously from Salmonella and endogenously in the host cells. The simultaneous activation of MHC class I and II molecules culminated in a balanced Th1 and Th2 response, which was evident through the upsurge of IgG, IgA antibodies, IgG2a/IgG1 ratio, cytokine responses and CD4+, CD8+ T-lymphocytes. The level of CD44+ cells showed the trigger for Th1 and Th2 balance and memory-cell activation for long-lasting immunity. The level of IFN-γ + cells and neutralizing antibodies signifies the anti-viral response. The vaccine protected the hamsters from BA.5 and BA.2.75 omicron viral-challenge, exhibited a significant reduction in lung viral-load and histopathological lesions. In addition to two-way antigen expression and bilateral immune elicitation, this Salmonella-based vaccine delivery system can be prospectively applied to humans and a broad range of animals as a convenient alternative to viral and chemical vaccine delivery approaches.

An updated atlas of antibody evasion by SARS-CoV-2 Omicron sub-variants including BQ.1.1 and XBB.

Emerging Omicron sub-variants are causing global concerns, and their immune evasion should be monitored continuously. We previously evaluated the escape of Omicron BA.1, BA.1.1, BA.2, and BA.3 from an atlas of 50 monoclonal antibodies (mAbs), covering seven epitope classes of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD). Here, we update the atlas of totally 77 mAbs against emerging sub-variants including BQ.1.1 and XBB and find that BA.4/5, BQ.1.1, and XBB display further evasion. Besides, investigation into the correlation of binding and neutralization of mAbs reveals the important role of antigenic conformation in mAb functioning. Moreover, the complex structures of BA.2 RBD/BD-604/S304 and BA.4/5 RBD/BD-604/S304/S309 further elucidate the molecular mechanism of antibody evasion by these sub-variants. By focusing on the identified broadly potent mAbs, we find a general hotspot epitope on the RBD, which could guide the design of vaccines and calls for new broad-spectrum countermeasures against COVID-19.

Can the New BA.2.75 Sub-variant Lead To One More COVID-19 Wave?

The highly transmissible variation of COVID-19 has a new sub-variant known as a variant BA.2.75, which was initially discovered in India and is now found in at least 10 more countries. The World Health Organization (WHO) officials said that the new variant is actively being monitored. It has yet to be determined if the new variation is more clinically severe than its predecessors. It is known that the Omicron strain sub-variants are responsible for this rise in the worldwide COVID tally. It is too early to know if this sub-variant exhibits additional immune evasion characteristics, or is more clinically severe. The extremely contagious BA.2.75 sub-variant of Omicron has been documented in India, but there is no evidence yet that it has increased disease severity or dissemination. Many of the BA.2 lineage's sublineages form a unique collection of mutations as it evolves. A related branch of the BA.2 lineage is B.2.75. The size of genomic sequencing must be increased and maintained for the early detection of the variant strains of SARS-CoV-2. BA.2.75 is the second generation of BA.2 variations and has a high transmissibility level.

Clinical Characteristics and Outcomes of Laboratory-Confirmed SARS-CoV-2 Cases Infected With Omicron Subvariants and the XBB Recombinant Variant.

Background SARS-CoV-2 has evolved to produce new variants causing successive waves of infection. Currently, six variants are being monitored by the World Health Organization that are replacing BA.5. These include BF.7 (BA.5 + R346T in spike), BQ.1 (and BQ.1.1, with BA.5 + R346T, K444T, N460K mutations in spike), BA.2.75 (including BA.2.75.2 and CH.1.1), and XBB (including XBB.1.5). BQ.1 and XBB variants are more immune evasive and have spread quickly throughout the world. Concerning the potential severity of infections caused by these variants, the present study describes the clinical characteristics and outcomes of these major variants in Maharashtra. Methodology A total of 1,141 reverse transcriptase-polymerase chain reaction (RT-PCR)-positive SARS-CoV-2 samples, with a cycle threshold (Ct) value of less than 25, were processed for SARS-CoV-2 whole genome sequencing between July 10, 2022, and January 12, 2023. All corresponding demographic and clinical data were recorded and analyzed using Microsoft® Excel and Epi Info™. Results Out of the 1,141 samples sequenced, BA.2.75* (63.78%) was the predominant Omicron variant, followed by the XBB* (18.88%), BA.2.38* (4.94%), BA.5* (4.06%), BA.2.10* (3.51%), and BQ.1* (1.65%). A total of 540 cases were contacted telephonically, of whom 494 (91.48%) were symptomatic with mild symptoms. Fever (77.73%) was the most common symptom, followed by cold (47.98%), cough (42.31%), and myalgia and fatigue (18.83%). Of the 540 cases, 414 (76.67%) cases recovered at home, and 126 (23.33%) were institutionally quarantined/hospitalized. Among the home-isolated and hospitalized cases, 416 (99.76%) and 108 (87.80%), respectively, recovered with symptomatic treatment, while one (0.24%) and 15 (12.20%), respectively, succumbed to the disease. Out of the 540 cases, 491 (90.93%) were vaccinated with at least one dose of the COVID-19 vaccine, 41 (7.59%) were unvaccinated, and for eight (1.48%) cases, vaccination data was not available. Conclusions The current study indicates that the XBB* variant is causing mild disease in India. However, as XBB* possesses both immune-escape and infectivity-enhancing mutations, it has the potential to spread to other parts of the world rapidly. Further, anti-SARS-CoV-2 vaccination improves survival rates in COVID-19.

Wastewater surveillance of SARS-CoV-2 variants in October-November 2022 in Italy: detection of XBB.1, BA.2.75 and rapid spread of the BQ.1 lineage.

This study adds insight regarding the occurrence and spread of SARS-CoV-2 Variants of Concern (VOCs) and Variants of Interest (VOIs) in Italy in October and November 2022, by testing urban wastewater collected throughout the country. A total of 332 wastewater samples were collected from 20 Italian Regions/Autonomous Provinces (APs) within the framework of national SARS-CoV-2 environmental surveillance. Of these, 164 were collected in the first week of October and 168 in the first week of November. A ∼1600 bp fragment of the spike protein was sequenced by Sanger (for individual samples) and long-read nanopore sequencing (for pooled Region/AP samples). In October, mutations characteristic of Omicron BA.4/BA.5 were detected in the vast majority (91 %) of the samples amplified by Sanger sequencing. A fraction of these sequences (9 %) also displayed the R346T mutation. Despite the low prevalence documented in clinical cases at the time of sampling, amino acid substitutions characteristic of sublineages BQ.1 or BQ.1.1 were detected in 5 % of sequenced samples from four Regions/APs. A significantly higher variability of sequences and variants was documented in November 2022, when the rate of sequences harbouring mutations of lineages BQ.1 and BQ1.1 increased to 43 %, and the number of Regions/APs positive for the new Omicron subvariant more than tripled (n = 13) compared to October. Moreover, an increase in the number of sequences with the mutation package BA.4/BA.5 + R346T (18 %), as well as the detection of variants never observed before in wastewater in Italy, such as BA.2.75 and XBB.1 (the latter in a Region where no clinical cases associated with this variant had ever been documented) was recorded. The results suggest that, as predicted by the ECDC, BQ.1/BQ.1.1 is rapidly becoming dominant in late 2022. Environmental surveillance proves to be a powerful tool for tracking the spread of SARS-CoV-2 variants/subvariants in the population.

SpikeSeq: A rapid, cost efficient and simple method to identify SARS-CoV-2 variants of concern by Sanger sequencing part of the spike protein gene.

In 2020, the novel coronavirus, SARS-CoV-2, caused a pandemic, which is still raging at the time of writing this. Here, we present results from SpikeSeq, the first published Sanger sequencing-based method for the detection of Variants of Concern (VOC) and key mutations, using a 1 kb amplicon from the recognized ARTIC Network primers. The proposed setup relies entirely on materials and methods already in use in diagnostic RT-qPCR labs and on existing commercial infrastructure offering sequencing services. For data analysis, we provide an automated, open source, and browser-based mutation calling software (https://github.com/kblin/covid-spike-classification, https://ssi.biolib.com/covid-spike-classification). We validated the setup on 195 SARS-CoV-2 positive samples, and we were able to profile 85% of RT-qPCR positive samples, where the last 15% largely stemmed from samples with low viral count. We compared the SpikeSeq results to WGS results. SpikeSeq has been used as the primary variant identification tool on > 10.000 SARS-CoV-2 positive clinical samples during 2021. At approximately 4€ per sample in material cost, minimal hands-on time, little data handling, and a short turnaround time, the setup is simple enough to be implemented in any SARS-CoV-2 RT-qPCR diagnostic lab. Our protocol provides results that can be used to choose antibodies in a clinical setting and for the tracking and surveillance of all positive samples for new variants and known ones such as Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1) Delta (B.1.617.2), Omicron BA.1(B.1.1.529), BA.2, BA.4/5, BA.2.75.x, and many more, as of October 2022.

Further quantitative in silico analysis of SARS-CoV-2 S-RBD Omicron BA.4, BA.5, BA.2.75, BQ.1, and BQ.1.1 transmissibility.

The Covid-19 variants' transmissibility was further quantitatively analyzed in silico to study the binding strength with ACE-2 and find the binding inhibitors. The molecular interaction energy values of their optimized complex structures (MIFS) demonstrated that Omicron BA.4 and 5's MIFS value (344.6 kcal mol-1) was equivalent to wild-type MIFS (346.1 kcal mol-1), that of Omicron BQ.1 and BQ. 1.1's MIFS value (309.9 and 364.6 kcal mol-1). Furthermore, the MIFS value of Omicron BA.2.75 (515.1 kcal mol-1) was about Delta-plus (511.3 kcal mol-1). The binding strength of Omicron BA.4, BA. 5, and BQ.1.1 may be neglectable, but that of Omicron BA.2.75 was urging. Furthermore, the 79 medicine candidates were analyzed as the binding inhibitors from binding strength with ACE-2. Only carboxy compounds were repulsed from the ACE-2 binding site indicating that further modification of medical treatment candidates may produce an effective binding inhibitor.

A delicate balance between antibody evasion and ACE2 affinity for Omicron BA.2.75.

Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have caused successive global waves of infection. These variants, with multiple mutations in the spike protein, are thought to facilitate escape from natural and vaccine-induced immunity and often increase in affinity for ACE2. The latest variant to cause concern is BA.2.75, identified in India where it is now the dominant strain, with evidence of wider dissemination. BA.2.75 is derived from BA.2 and contains four additional mutations in the receptor-binding domain (RBD). Here, we perform an antigenic and biophysical characterization of BA.2.75, revealing an interesting balance between humoral evasion and ACE2 receptor affinity. ACE2 affinity for BA.2.75 is increased 9-fold compared with BA.2; there is also evidence of escape of BA.2.75 from immune serum, particularly that induced by Delta infection, which may explain the rapid spread in India, where where there is a high background of Delta infection. ACE2 affinity appears to be prioritized over greater escape.

An Early and Preliminary Assessment of the Clinical Severity of the Emerging SARS-CoV-2 Omicron Variants in Maharashtra, India.

BACKGROUND: The SARS-CoV-2 Omicron variants BA.2.74, BA.2.75, and BA.2.76 have appeared recently in India and have already spread to over 40 countries. They have acquired additional mutations in their spike protein compared to BA.2, branching away on the SARS-CoV-2 phylogenetic tree. These added mutations have raised concerns about the impact on viral pathogenicity, transmissibility, and immune evasion properties of the new variants. MATERIAL AND METHODS: A total of 990 Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) positive SARS-CoV-2 samples, with a cycle threshold value (Ct) less than 25, were processed for SARS-CoV-2 whole genome sequencing between June 3, 2022 to August 7, 2022. All corresponding demographic and clinical data were recorded and analyzed using Microsoft® Excel. RESULTS: Out of 990 samples sequenced, BA.2.75 (23.03%) was the predominant Omicron sublineage, followed by BA.2.38 (21.01%), BA.5 (9.70%), BA.2 (9.09%), BA.2.74 (8.89%) and BA.2.76 (5.56%). A total of 228 cases of BA.2.74, BA.2.75, and BA.2.76 were contacted by telephone, of which 215 (94.30%) were symptomatic with mild symptoms, and 13 (5.70%) had no symptoms. Fever (82.02%) was the most common symptom, followed by cough (49.12%), cold (35.97%), fatigue (27.19%), headache (21.05%), and myalgia (20.61%). Of the 228 cases, 195 (85.53%) cases recovered at home, and 33 (14.47%) required institutional quarantine. Recovery with conservative treatment was observed in 92.98% of cases, while 4.83% required additional oxygen therapy. Only three (1.32%) cases had poor outcomes resulting in death, and the remaining 225 (98.68%) survived. Among the 228 cases, 219 (96.05%) cases were vaccinated with the COVID-19 vaccine; of these, 72.60% had received both doses, 26.03% had also received the precautionary booster dose, while 1.37% were incompletely vaccinated with a single dose of vaccine. CONCLUSION: The current study indicates that the three BA.2 sublineages are causing mild disease in India. However, BA.2.75 has key mutations that are notable for accelerated growth and transmission and require close and effective monitoring.

Could the New BA.2.75 Sub-Variant Cause the Emergence of a Global Epidemic of COVID-19? A Scoping Review.

With over 58 million cases and 6 million deaths by August 2022, the Coronavirus disease 2019 (COVID-19), causing severe acute respiratory syndrome coronavirus 2 (SARs-CoV-2), has had an insurmountable impact on the world's population. This is one of the worst health crises since 1918's influenza pandemic. There are four subvariants of Omicron; BA.1, BA.1.1, BA.2 and BA.3. As a result of new mutations in its spike protein, most of which occur in its receptor binding site, the Omicron variant appears to be more transmissible and less resistant to vaccination and antibody response. Understanding Omicron's virology and mutations is essential to developing diagnostic and therapeutic methods. A thorough assessment of control measures, as well as timely adjustment of control measures, requires addressing such issues as re-infection risk, vaccine response, booster vaccine doses, and the increased rate of Omicron infections. This review article aims to look at the current information about the different types of SARs-CoV-2, focusing on the new subtype BA.2.75.

Evasion of neutralizing antibody responses by the SARS-CoV-2 BA.2.75 variant.

The newly emerged BA.2.75 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant contains 9 additional mutations in its spike (S) protein compared to the ancestral BA.2 variant. Here, we examine the neutralizing antibody escape of BA.2.75 in mRNA-vaccinated and BA.1-infected individuals, as well as the molecular basis underlying functional changes in S. Notably, BA.2.75 exhibits enhanced neutralization resistance over BA.2 but less than the BA.4/5 variant. The G446S and N460K mutations of BA.2.75 are primarily responsible for its enhanced resistance to neutralizing antibodies. The R493Q mutation, a reversion to the prototype sequence, reduces BA.2.75 neutralization resistance. The impact of these mutations is consistent with their locations in common neutralizing antibody epitopes. Further, BA.2.75 shows enhanced cell-cell fusion over BA.2, driven largely by the N460K mutation, which enhances S processing. Structural modeling reveals enhanced receptor contacts introduced by N460K, suggesting a mechanism of potentiated receptor utilization and syncytia formation.

Omicron BA.2.75 Subvariant of SARS-CoV-2 Is Expected to Have the Greatest Infectivity Compared with the Competing BA.2 and BA.5, Due to Most Negative Gibbs Energy of Binding.

Omicron BA.2.75 may become the next globally dominant strain of COVID-19 in 2022. The BA.2.75 sub-variant has acquired more mutations (9) in spike protein and other genes of SARS-CoV-2 than any other variant. Thus, its chemical composition and thermodynamic properties have changed compared with earlier variants. In this paper, the Gibbs energy of the binding and antigen-receptor binding rate was reported for the BA.2.75 variant. Gibbs energy of the binding of the Omicron BA.2.75 variant is more negative than that of the competing variants BA.2 and BA.5.

The Omicron variant of concern: Diversification and convergent evolution in spike protein, and escape from anti-Spike monoclonal antibodies.

WHO-defined SARS-CoV-2 variants of concern (VOC) drive therapeutics and vaccine development. The Omicron VOC is dominating the arena since November 2021, but the number of its sublineages is growing in complexity. Omicron represent a galaxy with a myriad of stars that suddenly rise and expand before collapsing into apparent extinction when a more fit sublineage appears. This has already happened with BA.1, BA.2, and BA.4/5 and is happening with BA.2.75. We review here the current PANGO phylogeny, focusing on sublineages with Spike mutations, and show how frequently xxxxxxxx convergent evolution has occurred in these sublineages. We finally summarize how Omicron evolution has progressively defeated the anti-Spike monoclonal antibodies authorized so far, leaving clinicians to again fall back on COVID19 convalescent plasma from vaccinated donors as the only antibody-based therapy available.

Characterization of the enhanced infectivity and antibody evasion of Omicron BA.2.75.

Recently emerged SARS-CoV-2 Omicron subvariant, BA.2.75, displayed a growth advantage over circulating BA.2.38, BA.2.76, and BA.5 in India. However, the underlying mechanisms for enhanced infectivity, especially compared with BA.5, remain unclear. Here, we show that BA.2.75 exhibits substantially higher affinity for host receptor angiotensin-converting enzyme 2 (ACE2) than BA.5 and other variants. Structural analyses of BA.2.75 spike shows its decreased thermostability and increased frequency of the receptor binding domain (RBD) in the "up" conformation under acidic conditions, suggesting enhanced low-pH-endosomal cell entry. Relative to BA.4/BA.5, BA.2.75 exhibits reduced evasion of humoral immunity from BA.1/BA.2 breakthrough-infection convalescent plasma but greater evasion of Delta breakthrough-infection convalescent plasma. BA.5 breakthrough-infection plasma also exhibits weaker neutralization against BA.2.75 than BA.5, mainly due to BA.2.75's distinct neutralizing antibody (NAb) escape pattern. Antibody therapeutics Evusheld and Bebtelovimab remain effective against BA.2.75. These results suggest BA.2.75 may prevail after BA.4/BA.5, and its increased receptor-binding capability could support further immune-evasive mutations.

Virological characteristics of the SARS-CoV-2 Omicron BA.2.75 variant.

The SARS-CoV-2 Omicron BA.2.75 variant emerged in May 2022. BA.2.75 is a BA.2 descendant but is phylogenetically distinct from BA.5, the currently predominant BA.2 descendant. Here, we show that BA.2.75 has a greater effective reproduction number and different immunogenicity profile than BA.5. We determined the sensitivity of BA.2.75 to vaccinee and convalescent sera as well as a panel of clinically available antiviral drugs and antibodies. Antiviral drugs largely retained potency, but antibody sensitivity varied depending on several key BA.2.75-specific substitutions. The BA.2.75 spike exhibited a profoundly higher affinity for its human receptor, ACE2. Additionally, the fusogenicity, growth efficiency in human alveolar epithelial cells, and intrinsic pathogenicity in hamsters of BA.2.75 were greater than those of BA.2. Our multilevel investigations suggest that BA.2.75 acquired virological properties independent of BA.5, and the potential risk of BA.2.75 to global health is greater than that of BA.5.

Antigenic characterization of the SARS-CoV-2 Omicron subvariant BA.2.75.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariant BA.2.75 emerged recently and appears to be spreading. It has nine mutations in spike compared with the currently circulating BA.2, raising concerns that it may further evade vaccine-elicited and therapeutic antibodies. We found BA.2.75 to be moderately more neutralization resistant to sera from vaccinated/boosted individuals than BA.2 (1.8-fold), similar to BA.2.12.1 (1.1-fold), but more neutralization sensitive than BA.4/5 (0.6-fold). Relative to BA.2, BA.2.75 showed heightened resistance to class 1 and class 3 monoclonal antibodies targeting the spike-receptor-binding domain while gaining sensitivity to class 2 antibodies. Resistance was largely conferred by G446S and R460K mutations. BA.2.75 was slightly resistant (3.7-fold) to bebtelovimab, a therapeutic antibody with potent activity against all Omicron subvariants. BA.2.75 also exhibited a higher binding affinity to host receptor ACE2 than other Omicron subvariants. BA.2.75 provides further insight into SARS-CoV-2 evolution as it gains transmissibility while incrementally evading antibody neutralization.