Clinical characteristics of 310 SARS-CoV-2 Omicron variant patients and comparison with Delta and Beta variant patients in China

Although the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has spread, data on the clinical characteristics of infected patients are limited. In this study, the demographic, clinical characteristics, and laboratory data of 310 SARS-CoV-2 Omicron variant patients treated at Haihe Hospital of Tianjin were collected and analyzed. Information on these patients was compared to 96 patients with the Delta variant of concern (VOC) and 326 patients with the Beta VOC during the previous coronavirus disease 2019 (COVID-19) outbreak in Harbin. Of the 310 patients infected with the Omicron variant, the median age was 35 years. Most patients were clinically classified as mild (57.74%), and the most common symptoms were cough (48.71%), fever (39.35%), and sore throat (38.26%). The results for different vaccination groups in the Omicron group showed that the median of “SARS-CoV-2 specific IgG” after 2 or 3 doses of vaccination was higher than the unvaccinated group (all Ps < 0.05). Older age was associated with a higher proportion of moderate cases and lower asymptomatic and mild cases based on clinical classifications. Compared to the Delta and Beta groups, the median age of the Omicron group was younger. The total number of asymptomatic patients and mild patients in the Omicron virus group was higher than the Delta and Beta groups (60.97% vs. 54.17% vs. 47.55%). This study presented the clinical characteristics of the first group of patients infected with the Omicron variant in Tianjin, China, and compared their clinical features with patients infected by the Delta and Beta variants, which would increase our understanding of the characteristics of SARS-CoV-2 Omicron variant.     

Genomic Perspectives on the Emerging SARS-CoV-2 Omicron Variant

A new variant of concern for SARS-CoV-2, Omicron (B.1.1.529), was designated by the World Health Organization on November 26, 2021. This study analyzed the viral genome sequencing data of 108 samples collected from patients infected with Omicron. First, we found that the enrichment efficiency of viral nucleic acids was reduced due to mutations in the region where the primers anneal to. Second, the Omicron variant possesses an excessive number of mutations compared to other variants circulating at the same time (median: 62 vs. 45), especially in the Spike gene. Mutations in the Spike gene confer alterations in 32 amino acid residues, more than those observed in other SARS-CoV-2 variants. Moreover, a large number of nonsynonymous mutations occur in the codons for the amino acid residues located on the surface of the Spike protein, which could potentially affect the replication, infectivity, and antigenicity of SARS-CoV-2. Third, there are 53 mutations between the Omicron variant and its closest sequences available in public databases. Many of these mutations were rarely observed in public databases and had a low mutation rate. In addition, the linkage disequilibrium between these mutations was low, with a limited number of mutations concurrently observed in the same genome, suggesting that the Omicron variant would be in a different evolutionary branch from the currently prevalent variants. To improve our ability to detect and track the source of new variants rapidly, it is imperative to further strengthen genomic surveillance and data sharing globally in a timely manner.     

Evidence for a mouse origin of the SARS-CoV-2 Omicron variant

The rapid accumulation of mutations in the SARS-CoV-2 Omicron variant that enabled its outbreak raises questions as to whether its proximal origin occurred in humans or another mammalian host. Here, we identified 45 point mutations that Omicron acquired since divergence from the B.1.1 lineage. We found that the Omicron spike protein sequence was subjected to stronger positive selection than that of any reported SARS-CoV-2 variants known to evolve persistently in human hosts, suggesting a possibility of host-jumping. The molecular spectrum of mutations (i.e., the relative frequency of the 12 types of base substitutions) acquired by the progenitor of Omicron was significantly different from the spectrum for viruses that evolved in human patients but resembled the spectra associated with virus evolution in a mouse cellular environment. Furthermore, mutations in the Omicron spike protein significantly overlapped with SARS-CoV-2 mutations known to promote adaptation to mouse hosts, particularly through enhanced spike protein binding affinity for the mouse cell entry receptor. Collectively, our results suggest that the progenitor of Omicron jumped from humans to mice, rapidly accumulated mutations conducive to infecting that host, then jumped back into humans, indicating an inter-species evolutionary trajectory for the Omicron outbreak.     

The humoral and cellular immune evasion of SARS-CoV-2 Omicron and sub-lineages

The recently discovered SARS-CoV-2 variant Omicron (B.1.1.529) has rapidly become a global public health issue. The substantial mutations in the spike protein in this new variant have raised concerns about its ability to escape from pre-existing immunity established by natural infection or vaccination. In this review, we give a summary of current knowledge concerning the antibody evasion properties of Omicron and its subvariants (BA.2, BA.2.12.1, BA.4/5, and BA.2.75) from therapeutic monoclonal antibodies and the sera of SARS-CoV-2 vaccine recipients or convalescent patients. We also summarize whether vaccine-induced cellular immunity (memory B cell and T cell response) can recognize Omicron specifically. In brief, the Omicron variants demonstrated remarkable antibody evasion, with even more striking antibody escape seen in the Omicron BA.4 and BA.5 sub-lineages. Luckily, the third booster vaccine dose significantly increased the neutralizing antibodies titers, and the vaccine-induced cellular response remains conserved and provides second-line defense against the Omicron.     

COVID-19: Omicron – the latest,the least virulent,but probably not the last variant of concern of SARS-CoV-2

The Omicron variant rapidly became the dominant SARS-CoV-2 strain in South Africa and elsewhere. This review explores whether this rise was due to an increased transmission of the variant or its escape from population immunity by an extensively mutated spike protein. The mutations affected the structure of the spike protein leading to the loss of neutralization by most, but not all, therapeutic monoclonal antibodies. Omicron also shows substantial immune escape from serum antibodies in convalescent patients and vaccinees. A booster immunization increased, however, the titre and breadth of antiviral antibody response. The cellular immune response against Omicron was largely preserved explaining a satisfying protection of boosted vaccinees against severe infections. Clinicians observed less severe infection with Omicron, but other scientists warned that this must not necessarily reflect less intrinsic virulence. However, in animal experiments with mice and hamsters, Omicron infections also displayed a lesser virulence than previous VOCs and lung functions were less compromised. Cell biologists demonstrated that Omicron differs from Delta by preferring the endocytic pathway for cell entry over fusion with the plasma membrane which might explain Omicron’s distinct replication along the respiratory tract compared with Delta. Omicron represents a distinct evolutionary lineage that deviated from the mainstream of evolving SARS-CoV-2 already in mid-2020 raising questions about where it circulated before getting widespread in December 2021. The role of Omicron for the future trajectory of the COVID-19 pandemic is discussed.     

Structural topological analysis of spike proteins of SARS-CoV-2 variants of concern highlight distinctive amino acid substitution patterns

Since the onset of pandemic in 2019, SARS-CoV-2 has diverged into numerous variants driven by antigenic and infectivity-oriented selection. Some variants have accumulated fitness-enhancing mutations, evaded immunity and spread despite global vaccination campaigns. The spike (S) glycoprotein of SARS-CoV-2 demonstrated the greatest immunogenicity and amino acid substitution diversity owing to its importance in the interaction with human angiotensin receptor 2 (hACE2). The S protein consistently emerges as an amino acid substitution (AAS) hotspot in all six lineages, however, in Omicron this enrichment is significantly higher. This study attempts to design and validate a method of mapping S-protein substitution profile across variants to identify the conserved and AAS regions. A substitution matrix was created based on publicly available databases, and the substitution localization was illustrated on a cryo-electron microscopy generated S-protein model. Our analyses indicated that the diversity of N-terminal (NTD) and receptor-binding (RBD) domains exceeded that of any other regions but still contained extended low substitution density regions particularly considering significantly broader substitution profiles of Omicron BA.2 and BA.4/5. Finally, the substitution matrix was compared to a random sample alignment of variant sequences, revealing discrepancies. Therefore, it was suggested to improve matrix accuracy by processing a large number of S-protein sequences using an automated algorithm. Several critical immunogenic and receptor-interacting residues were identified in the conserved regions within NTD and RBD. In conclusion, the structural and topological analysis of S proteins of SARS-CoV-2 variants highlight distinctive amino acid substitution patterns which may be foundational in predicting future variants.     

Characteristics of replication and pathogenicity of SARS-CoV-2 Alpha and Delta isolates

The continuously arising of SARS-CoV-2 variants has been posting a great threat to public health safety globally, from B.1.17 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta) to B.1.1.529 (Omicron). The emerging or reemerging of the SARS-CoV-2 variants of concern is calling for the constant monitoring of their epidemics, pathogenicity and immune escape. In this study, we aimed to characterize replication and pathogenicity of the Alpha and Delta variant strains isolated from patients infected in Laos. The amino acid mutations within the spike fragment of the isolates were determined via sequencing. The more efficient replication of the Alpha and Delta isolates was documented than the prototyped SARS-CoV-2 in Calu-3 and Caco-2 cells, while such features were not observed in Huh-7, Vero E6 and HPA-3 cells. We utilized both animal models of human ACE2 (hACE2) transgenic mice and hamsters to evaluate the pathogenesis of the isolates. The Alpha and Delta can replicate well in multiple organs and cause moderate to severe lung pathology in these animals. In conclusion, the spike protein of the isolated Alpha and Delta variant strains was characterized, and the replication and pathogenicity of the strains in the cells and animal models were also evaluated.     

严重急性呼吸综合征冠状病毒2 Omicron变异株研究进展

世界卫生组织(World Health Organization, WHO)于2021年11月26日将首次在南非报告的新型冠状病毒 B．1.1.529 变异株列为受关注变种(variant of concern, VOC),并将其命名为奥密克戎(Omicron)。该变异株存在约50个突变,仅在刺突蛋白区域就有至少30个突变,远远超过其他流行株的突变位点数量。根据对突变位点的分析以及初步实验证实,该毒株可能具有极强的传染性以及免疫逃逸能力。Omicron变异株会怎样影响新冠疫情的走向引起了各国的广泛关注,本文将从Omicron变异株的基本特征、检测、致病性、传染性、免疫逃逸等方面进行综述。     

SARS-CoV-2 VOCs,Mutational diversity and clinical outcome: Are they modulating drug efficacy by altered binding strength?

The global COVID-19 pandemic continues due to emerging Severe Acute Respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC). Here, we performed comprehensive analysis of in-house sequenced SARS-CoV-2 genome mutations dynamics in the patients infected with the VOCs - Delta and Omicron, within Recovered and Mortality patients. Statistical analysis highlighted significant mutations - T4685A, N4992N, and G5063S in RdRp; T19R in NTD spike; K444N and N532H in RBD spike, associated with Delta mortality. Mutations, T19I in NTD spike, Q493R and N440K in the RBD spike were significantly associated with Omicron mortality. We performed molecular docking for possible effect of significant mutations on the binding of Remdesivir. We found that Remdesivir showed less binding efficacy with the mutant Spike protein of both Delta and Omicron mortality compared to recovered patients. This indicates that mortality associated mutations could have a modulatory effect on drug binding which could be associated with disease outcome.     

Clinical and immunological features of convalescent pediatric patients infected with the SARS-CoV-2 Omicron variant in Tianjin,China

COVID-19 has spread surprisingly fast worldwide, and new variants continue to emerge. Recently, the World Health Organization acknowledged a new mutant strain “Omicron”, with children were accounting for a growing share of COVID-19 cases compared with other mutant strains. However, the clinical and immunological characteristics of convalescent pediatric patients after Omicron infection were lacking. In this study, we comparatively analyzed the clinical data from pediatric patients with adult patients or healthy children and the effects of SARSCoV-2 vaccine on the clinical and immune characteristics in convalescent pediatric patients. Our results indicated that convalescent pediatric patients had unique clinical and immune characteristics different from those of adult patients or healthy children, and SARS-CoV-2 vaccination significantly affected on the clinical and immune characteristics and the prevention of nucleic acid re-detectable positive (RP) in convalescent patients. Our study further deepens the understanding of the impact of Omicron on the long-term health of pediatric patients and provides a valuable reference for the prevention and treatment of children infected with Omicron.     

High-resolution melting analysis to discriminate between the SARS-CoV-2 Omicron variants BA.1 and BA.2

High-resolution melting (HRM) analysis was conducted to discriminate between SARS-CoV-2 Omicron variant BA.1 (B.1.1.529.1) and subvariant BA.2 (B.1.1.529.2). We performed two-step PCR consisting of the first PCR and the second nested PCR to prepare the amplicon for HRM analysis, which detected G339D, N440K, G446S and D796Y variations in the SARS-CoV-2 spike protein. The melting temperatures (Tms) of the amplicons from the cDNA of the Omicron variant BA.1 and subvariant BA.2 receptor binding domain (RBD) in spike protein were the same: 75.2 °C (G339D variation) and 73.4 °C (D796Y variation). These Tms were distinct from those of SARS-CoV-2 isolate Wuhan-Hu-1, and were specific to the Omicron variant. In HRM analyses that detected the N440K and G446S variations, the Tms of amplicons from the cDNA of the Omicron variant BA.1 and subvariant BA.2 RBDs were 73.0 °C (N440K and G446S variations) and 73.5 °C (G446S variation). This difference indicates that the SARS-CoV-2 Omicron variants BA.1 and BA.2 can be clearly discriminated. Our study demonstrates the usefulness of HRM analysis after two-step PCR for the discrimination of SARS-CoV-2 variants.     

Mutations in spike protein T cell epitopes of SARS-COV-2 variants: Plausible influence on vaccine efficacy

With emerging SARS-CoV-2 variants, vaccines approved so far are under scrutiny for long term effectiveness against the circulating strains. There is a prevalent obsession with humoral immunity as in vitro studies have indicated diminished effects of vaccine-induced neutralizing antibodies. However, this need not clinically translate to vaccine resistance as immune response against all forms of present vaccine preparations is T dependent unlike that against native viral particles which can induce T independent immune responses. Thus, we focused on this major correlate of protection against infections, T cell response. Using bioinformatics tools, we analyzed SARS-CoV-2 Spike protein T cell epitopes and their diversity across Delta plus/B.1.617.2.1, Gamma/P.1 (variant of concern), B.1.1.429, Zeta/P.2 and Mink cluster 5/B.1.1.298 variants as well as Omicron/B.1.1.529 (variant of concern). We also compared HLA restriction profiles of the mutant epitopes with that of the native epitopes (from Wuhan_hu_1 strain, used in vaccine formulations). Our observations show ~90% conservation of CD4+ and CD8+ epitopes across Delta plus/B.1.617.2.1, Gamma/P.1 (variant of concern), B.1.1.429, Zeta/P.2 and Mink cluster 5/B.1.1.298. For the Omicron/B.1.1.529 variant, ~75% of CD4+ and ~ 87% CD8+ epitopes were conserved. Majority of the mutated CD4+ and CD8+ epitopes of this variant were predicted to retain the HLA restriction pattern as their native epitopes. The results of our bioinformatics analysis suggest largely conserved T cell responses across the studied variants, ability of T cells to tackle new SARS-CoV-2 variants and aid in protection from COVID-19 post vaccination. In conclusion, the results suggest that current vaccines may not be rendered completely ineffective against new variants.     

SARS-CoV-2 variants: A double-edged sword?

Since the worldwide emergence of the COVID-19 outbreak, there have been international concerns about the possible viral evolution into variants with underlying mutations that may contribute to their increased transmissibility, disease severity, risk of death, and their potential escape from the immune response or may even lead to its extinction. Rigorous surveillance has revealed the variants harboring mutations in the spike protein, the main target of neutralizing antibodies generated through vaccination or herd immunity. In this review, we have highlighted major SARS-CoV-2 variants as well as other local strains along with their specific mutations, suspected changes in their characteristics, and their impact on the current pandemic and vaccine efficacy. We have also emphasized the need to develop widely protective interventions to curb further transmission of variants.     

新型冠状病毒及泛β冠状病毒广谱中和单抗的研究进展

新型冠状病毒的全球大流行,给人类的生命健康和社会秩序带来了巨大的危害。疫苗、小分子药物及各类抗体药物的研发在遏制新型冠状病毒感染传播、降低重症率和死亡风险上发挥了积极的作用。然而,由于新冠病毒庞大的感染基数及自身易突变的特征,当前已经演化出多种能逃逸疫苗及中和抗体的变异株,显著削弱了抗体的保护效果。研发新型冠状病毒广谱甚至泛β冠状病毒广谱的中和抗体对于未来新冠变异株及其他高致病性β冠状病毒的防治具有重要意义。本文从新型冠状病毒中和抗体的筛选制备策略、作用机制、中和效果及广谱性等方面进行了系统综述,并对当前面临的挑战和未来的发展方向进行了讨论和展望,以期为后续相关研究提供参考。     

A comprehensive review on Covid-19 Omicron (B.1.1.529) variant

The world has been combating different variants of SARS-COV-19 since its first outbreak in Wuhan city. SARS-COV-19 is caused by the coronavirus. The corona virus mutates and becomes more transmissible than earlier variants as the day passes. Till 24 November 2021, SARS-COV-19 has four variants Alpha, Beta, Gamma, and Delta, respectively. Among them, the delta variant caused severe havoc across the world. South Africa registered a new variant with the World Health Organization (WHO) on 24 November 2021, which is much more transmissible than previous variants. The WHO classified it as a variant of concern (VOC) on 26 November 2021 and called it the Greek letter Omicron (B.1.1.529), the fifteenth letter in the alphabet. Here a serious attempt was made to comprehend the omicron variant’s origin, nomenclature, characteristics, mutations, the difference between delta and omicron variant, epidemiology, transmission, clinical features, impact on immunity, immune evasion, vaccines efficacy, etc.     

Omicron Spike Protein is Vulnerable to Reduction

SARS-CoV-2 virus spike (S) protein is an envelope protein responsible for binding to the ACE2 receptor, driving subsequent entry into host cells. The existence of multiple disulfide bonds in the S protein makes it potentially susceptible to reductive cleavage. Using a tri-part split luciferase-based binding assay, we evaluated the impacts of chemical reduction on S proteins from different virus variants and found that those from the Omicron family are highly vulnerable to reduction. Through manipulation of different Omicron mutations, we found that alterations in the receptor binding module (RBM) are the major determinants of this vulnerability. Specifically we discovered that Omicron mutations facilitate the cleavage of C480-C488 and C379-C432 disulfides, which consequently impairs binding activity and protein stability. The vulnerability of Omicron S proteins suggests a mechanism that can be harnessed to treat specific SARS-CoV-2 strains.     

The Genetic Variant of SARS-CoV-2: would It Matter for Controlling the Devastating Pandemic?

The pandemic of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is far from being controlled despite the great effort that have been taken throughout the world. Herd immunity through vaccination is our major expectation to rein the virus. However, the emergence of widespread genetic variants could potentially undermine the vaccines. The evidence that some variants could evade immune responses elicited by vaccines and previous infection is growing. In this review, we summarized the current understanding on five notable genetic variants, i.e., D614G, Cluster 5, VOC 202012/01, 501Y.V2 and P.1, and discussed the potential impact of these variants on the virus transmission, pathogenesis and vaccine efficacy. We also highlight that mutations in the N-terminal domain of spike protein should be considered when evaluating the antibody neutralization abilities. Among these genetic variants, a concern of genetic variant 501Y.V2 to escape the protection by vaccines was raised. We therefore call for new vaccines targeting this variant to be developed.     

Longitudinal neutralization activities on authentic Omicron variant provided by three doses of BBIBP-CorV vaccination during one year

The majority of people in China have been immunized with the inactivated viral vaccine BBIBP-CorV. The emergence of the Omicron variant raised the concerns about protection efficacy of the inactivated viral vaccine in China. However, longitudinal neutralization data describing protection efficacy against Omicron variant is still lacking. Here we present one-year longitudinal neutralization data of BBIBP-CorV on authentic Omicron, Delta, and wild-type strains using 224 sera collected from 14 volunteers who have finished three doses BBIBP-CorV. The sera were also subjected for monitoring the SARS-CoV-2 specific IgG, IgA, and IgM responses on protein and peptide microarrays. The neutralization titers showed different protection efficacies against the three strains. By incorporating IgG and IgA signals of proteins and Spike protein derived peptide on microarray, panels as potential surrogate biomarkers for rapid estimation of neutralization titers were established. These data support the necessity of the 3^rd dose of BBIBP-CorV vaccination. After further validation and assay development, the panels could be used for reliable, convenient and fast evaluation of the efficacy of vaccination.     

A systematic review of Vaccine Breakthrough Infections by SARS-CoV-2 Delta Variant

Vaccines are proving to be highly effective in controlling hospitalization and deaths associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as shown by clinical trials and real-world evidence. However, a deadly second wave of coronavirus disease 2019 (COVID-19), infected by SARS-CoV-2 variants, especially the Delta (B.1.617.2) variant, with an increased number of post-vaccination breakthrough infections were reported in the world recently. Actually, Delta variant not only resulted in a severe surge of vaccine breakthrough infections which was accompanied with high viral load and transmissibility, but also challenged the development of effective vaccines. Therefore, the biological characteristics and epidemiological profile of Delta variant, the current status of Delta variant vaccine breakthrough infections and the mechanism of vaccine breakthrough infections were discussed in this article. In addition, the significant role of the Delta variant spike (S) protein in the mechanism of immune escape of SARS-CoV-2 was highlighted in this article. In particular, we further discussed key points on the future SARS-CoV-2 vaccine research and development, hoping to make a contribution to the early, accurate and rapid control of the COVID-19 epidemic.