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PubMed2023

Phylogeny and evolution of SARS-CoV-2 during Delta and Omicron variant waves in India.

SARS-CoV-2 evolution has continued to generate variants, responsible for new pandemic waves locally and globally. Varying disease presentation and severity has been ascribed to inherent variant characteristics and vaccine immunity. This study analyzed genomic data from 305 whole genome sequences from SARS-CoV-2 patients before and through the third wave in India. Delta variant was reported in patients without comorbidity (97%), while Omicron BA.2 was reported in patients with comorbidity (77%). Tissue adaptation studies brought forth higher propensity of Omicron variants to bronchial tissue than lung, contrary to observation in Delta variants from Delhi. Study of codon usage pattern distinguished the prevalent variants, clustering them separately, Omicron BA.2 isolated in February grouped away from December strains, and all BA.2 after December acquired a new mutation S959P in ORF1b (44.3% of BA.2 in the study) indicating ongoing evolution. Loss of critical spike mutations in Omicron BA.2 and gain of immune evasion mutations including G142D, reported in Delta but absent in BA.1, and S371F instead of S371L in BA.1 could explain very brief period of BA.1 in December 2021, followed by complete replacement by BA.2. Higher propensity of Omicron variants to bronchial tissue, probably ensured increased transmission while Omicron BA.2 became the prevalent variant possibly due to evolutionary trade-off. Virus evolution continues to shape the epidemic and its culmination.Communicated by Ramaswamy H. Sarma.

SARS-CoV-2↗

PubMed2025

Proteomics and Phosphoproteomics Characteristics of the Rhesus Macaque Lung Infected With Original SARS-CoV-2, Delta, and Omicron Variants.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains mutate rapidly, making it crucial to study their molecular mechanisms for swift vaccine and drug development. Here, we utilized host lung proteomic and phosphoproteomic profiling to investigate the underlying pathology caused by the variants. Lung tissues infected with wild-type GD108, Delta, or Omicron BA.1 variants showed overexpression of proteins and phosphoproteins linked to the innate immune pathway, particularly in the Omicron group, with high activation of NOD-receptor and RIG-I like receptor signaling pathways. Protein-protein interaction (PPI) analysis revealed six key proteins, including antiviral innate immune response receptor RIG-I (DDX58), and five interferon-related proteins (IFIT2, ISG15, MX1, STAT1, and EIF2AK2), highlighting the importance of the innate immune response in combating all three variants. Kinase prediction analysis suggested that six kinases (DAPK1, DAPK2, DAPK3, PRACK, TTK, and MAP2K2), potentially inhibited by Fostamatinib, were activated across all three variants, and might be potential drug targets, pending further verification. Omicron infection, compared to other mutants, significantly disrupted proteins related to pulmonary structural support, like integrin and collagens, and inhibited efferocytosis, reducing the host's ability to eliminate the pathogen. These findings suggest that innate immune activation and structural disruption may contribute to Omicron-related pathology, potentially being useful for research into the molecular mechanisms underlying lung injury from SARS-CoV-2 variants.

Animals↗

PubMed2025

Deep Sequencing Reveals Dual Evolution of SARS-CoV-2: Insights Into Defective Genomes From Wuhan-Hu-1 Variants to Omicron Subvariants.

SARS-CoV-2 has evolved from early variants dominating the first (B.1.5, B.1.1) and second (B.1.177) pandemic waves, which exhibited a higher frequency of minority mutants with deletions leading to Defective Viral Genomes (DVGs) in the spike region near the S1/S2 cleavage site than the Alpha, Beta, and Delta variants. The emergence of Omicron has significantly altered the dominant variant profile, with Omicron subvariants now representing 100% of circulating viruses. To monitor the evolution and adaptation of Omicron in the human population, a deep-sequencing study was performed in RNA samples of BA.1, BA.1.1, BA.2, BA.5, BQ.1.1, XBB.1.5 and BA.2.86 Omicron subvariants. The findings reveal two occurrences of similar evolutionary patterns within SARS-CoV-2 characterized by a shift from a significant to a very low production of DVGs. This event suggests that DVGs might play a role in the virus's spread and adaptation for persistence in infected humans.

SARS-CoV-2↗

PubMed2025

Genomic Epidemiology of the Main SARS-CoV-2 Variants Circulating in Italy During the Omicron Era.

Since early 2022 the Omicron variant has rapidly spread worldwide, becoming the dominant variant to date. The study aimed to investigate the clinical and epidemiological characteristics of COVID-19 patients and reconstruct the genomic epidemiology of main SARS-CoV-2 Omicron sublineages in Italy in 2022. A total of 8970 SARS-CoV-2 samples were studied, and phylogenetic analyses were focused on BA.1, BA.2, and BA.5 subvariants. More than half of subjects received three doses of vaccine and experienced a reinfection. A significant larger proportion of unvaccinated subjects presented reinfection compared with vaccinated. Clusters presented a tMRCA between September-November 2021 (BA.1), November 2021-January 2022 (BA.2), and October 2021-May 2022 (BA.5). Re values showed the highest level between September-October, January-February 2022, and May 2022 for BA.1, BA.2 and BA.5, respectively. Limited number of studied variant sequences are included in clusters. The spread rate of the studied variant exceeded its evolutionary rate. No single sublineage had sufficient time to differentiate into large clusters, but only into small and fragmented groups sharing the same recent ancestor. These analyses dissect the epidemiological dynamics of Omicron sublineages in Italy over a period of great epidemiological changes in the COVID-19 epidemic.

Humans↗

PubMed2025

Cycle threshold values and SARS-CoV-2 variant associations with breakthrough infections: a retrospective study in Accra, Ghana.

BACKGROUND: Breakthrough infections are defined as SARS-CoV-2 infections occurring ≥ 14 days after completing the primary COVID-19 vaccination series and remain a public health challenge, particularly in regions where immune-evasive variants are circulating. However, data on their virological and clinical profiles in low-resource settings are limited. METHODS: This retrospective study was conducted from July to December 2022 in Accra, Ghana, among individuals testing positive for SARS-CoV-2. Real-time Reverse Transcription Polymerase Chain Reaction (RT-PCR) was performed using the Allplex™ 2019-nCoV Assay. Cycle threshold (Ct) values for the nucleocapsid (N), RNA-dependent RNA polymerase (RdRP), and envelope (E) genes, categorised as < 25, 25–30, or > 30. Variant identification targeted Alpha, Delta, and Omicron mutations using mutation-specific RT-PCR. Logistic regression was used to assess associations between vaccination status and demographic, clinical, and virological factors. RESULTS: Of the 268 samples analysed, 81 tested positive; 43.20% [n = 35] were vaccinated individuals. Median Ct-values for the N [27.13, IQR: 21.59–31.96] and E [24.57, IQR: 19.43–29.43] genes were significantly higher among vaccinated cases, indicating lower viral loads. Breakthrough infections were strongly associated with the Omicron variant [aOR = 4.38, p = 0.034]. Diarrhoea [aOR = 9.67, p = 0.022], sore throat [aOR = 8.99, p = 0.038], headache [aOR = 10.156, p = 0.039] and chills [aOR = 3.316, p = 0.046] were mostly associated with breakthrough infections. Ct-values of 25–30 [aOR = 11.33, p = 0.012] and > 30 [aOR = 4.01, p = 0.047] were significantly associated with breakthrough infection compared to Ct < 25 in breakthrough infections. CONCLUSION: Vaccinated individuals with SARS-CoV-2 infection had lower viral loads and were more likely to be infected with the Omicron variant. These findings reinforce the role of vaccination in reducing viral load and support the adoption of practical surveillance strategies, such as Ct value-based surveillance and variant screening in low middle-income countries facing similar constraints in genomic capacity and vaccine deployment.

Humans↗

PubMed2025

Enhanced RNA replication and pathogenesis in recent SARS-CoV-2 variants harboring the L260F mutation in NSP6.

The COVID-19 pandemic has been driven by SARS-CoV-2 variants with enhanced transmission and immune escape. Apart from extensive evolution in the Spike protein, non-Spike mutations are accumulating across the entire viral genome and their functional impact is not well understood. To address the contribution of these mutations, we reconstructed genomes of recent Omicron variants with disabled Spike expression (replicons) to systematically compare their RNA replication capabilities independently from Spike. We also used a single reference replicon and complemented it with various Omicron variant Spike proteins to quantify viral entry capabilities in single-round infection assays. Viral entry and RNA replication were negatively correlated, suggesting that as variants evolve reduced entry functions under growing immune pressure on Spike, RNA replication increases as a compensatory mechanism. We identified multiple mutations across the viral genome that enhanced viral RNA replication. NSP6 emerged as a hotspot with a distinct L260F mutation independently arising in the BQ.1.1 and XBB.1.16 variants. Using mutant and revertant NSP6 viral clones, the L260F mutation was validated to enhance viral replication in cells and increase pathogenesis in mice. Notably, this mutation reduced host lipid droplet content by NSP6. Collectively, a systematic analysis of RNA replication of recent Omicron variants defined NSP6's key role in viral RNA replication that provides insight into evolutionary trajectories of recent variants with possible therapeutic implications.

SARS-CoV-2↗

PubMed2025

Dissecting Sex-Specific Pathology in K18-hACE2 Transgenic Mice Infected With Different SARS-CoV-2 Variants.

Sex-biased differences in COVID-19 outcomes in relation to individual SARS-CoV-2 variants are not well understood. In this study, lungs and nasal cavities of age-matched female and male K18-hACE2 transgenic mice were collected for dissecting sex-specific differences in pathology after infection of SARS-CoV-2 614 G, Delta, or Omicron variant. Overall, Delta infection induced the most severe inflammation and pathology in nasal cavity and lung followed by the 614 G, then Omicron variant. Sex differences in host responses to SARS-CoV-2 infection were variant-specific. Delta-infected males showed increased pulmonary infiltration of CD163+ "M2" macrophages, Ly6G+ neutrophils, and NKR-P1C + NK cells during early onset of infection, and elevated lung inflammatory cytokines such as IL-10, IL-6, and IP-10 than Delta-infected females. Conversely, females had increased lung CD4 + T cell recruitment after Omicron infection and significantly elevated lung MCP-1 secretion after Delta infection than males. Lung spatial transcriptomics data revealed that Delta-infected females had enriched gene pathways related to humoral immune response and interferon signaling, while males had enriched pathways associated with extracellular matrix production, chemokine signaling, and cell chemotaxis. Taken together, this study highlights the complex infection dynamics with respect to individual SARS-CoV-2 variants and underscores the importance of sex as a confounding factor for COVID-19 pathology.

Animals↗

PubMed2026

Correction to "Deep Sequencing Reveals Dual Evolution of SARS-CoV-2: Insights Into Defective Genomes From Wuhan-Hu-1 Variants to Omicron Subvariants".

Explore the source record for details and available documents.

Published Erratum↗

PubMed2026

Dynamic case-control sampling for rapid estimation of vaccine effectiveness against an emerging infectious disease variant.

New SARS-CoV-2 variants arise frequently with different viral properties that can impact the effectiveness of the vaccines. Updating estimates of vaccine effectiveness (VE) in public health surveillance can be limited by the necessity of conducting a distinct study that entails analysis of prospective cohort data or using a test-negative design. We introduce a method for dynamically updating estimates of VE using data that accumulate in real time. Our method uses dynamic case-control sampling to estimate VE against a newly emerging variant relative to a previous variant. Dynamic case-control sampling is a technique that continuously updates VE estimates by comparing individuals infected with a newly emerging variant (defined as "cases") to those infected with a previously circulating variant (defined as "controls"). We use this estimate in combination with information about VE from the previous variant (these estimates are typically available from larger, traditional studies) to infer VE against the emerging variant. We demonstrate the utility of this method on the BA.1 and BA.2 sub-lineages of the Omicron variant. The method produces estimates of VE comparable to those produced using traditional methods, although with increased SE. The increase in error, however, is reasonable given a much smaller sample size than other studies, and error ranges of the estimates could be significantly improved by sequencing a larger proportion of identified cases. Our method, which assumes only a fraction of the new cases are being sequenced, can be applied by health departments using routinely collected data to produce timely, rigorous VE estimates to rapidly identify potential changes in VE.

Humans↗

PubMed2026

Tracking the shifting landscape of SARS-CoV-2 variants in Lebanon among healthcare workers and hospitalized patients.

UNLABELLED: Genomic surveillance of SARS-CoV-2 is critical for tracking viral evolution and informing public health responses. This study characterized variants circulating among healthcare workers (HCWs) and hospitalized patients in Lebanon between January 2022 and September 2024. A total of 530 SARS-CoV-2-positive nasopharyngeal swabs were collected from five Lebanese governorates and subjected to whole-genome sequencing. Correlations between variant circulation and a number of demographic and clinical variables were assessed. Most HCWs were female (64%), young adults (20-30 years, 39%), and had no comorbidities (97%). In contrast, hospitalized patients were mostly older adults (>60 years, 55.6%) with underlying conditions (77%). Early 2022 was marked by BA.1- and BA.2-like Omicron variants, followed by the predominance of BA.5-like lineages. In 2023, recombinant XBB sublineages became widespread. By 2024, these were largely replaced by next-generation variants, including JN.1 and KP.3.1.1. Despite differences in demographics and exposure risk, both groups showed parallel variant evolution. These findings reflect global and regional patterns and highlight the dynamic nature of SARS-CoV-2 circulation in Lebanon. IMPORTANCE: This study provides a comprehensive snapshot of SARS-CoV-2 variant evolution in Lebanon between 2022 and 2024, focusing on healthcare workers and hospitalized patients. By combining genomic and clinical data, it reveals how successive Omicron subvariants emerged and spread within key population groups. The detection of diverse and evolving lineages, including XBB recombinants and next-generation variants such as JN.1, underscores the ongoing antigenic drift of SARS-CoV-2. These insights reinforce the value of continued genomic surveillance for pandemic preparedness, especially in regions where data remain limited. Understanding local variant dynamics can guide targeted vaccination strategies and health policy decisions.

Humans↗

PubMed2024

RNA editing in host lncRNAs as potential modulator in SARS-CoV-2 variants-host immune response dynamics.

Both host and viral RNA editing plays a crucial role in host's response to infection, yet our understanding of host RNA editing remains limited. In this study of in-house generated RNA sequencing (RNA-seq) data of 211 hospitalized COVID-19 patients with PreVOC, Delta, and Omicron variants, we observed a significant differential editing frequency and patterns in long non-coding RNAs (lncRNAs), with Delta group displaying lower RNA editing compared to PreVOC/Omicron patients. Notably, multiple transcripts of UGDH-AS1 and NEAT1 exhibited high editing frequencies. Expression of ADAR1/APOBEC3A/APOBEC3G and differential abundance of repeats were possible modulators of differential editing across patient groups. We observed a shift in crucial infection-related pathways wherein the pathways were downregulated in Delta compared to PreVOC and Omicron. Our genomics-based evidence suggests that lncRNA editing influences stability, miRNA binding, and expression of both lncRNA and target genes. Overall, the study highlights the role of lncRNAs and how editing within host lncRNAs modulates the disease severity.

Biological sciences↗

PubMed2024

Diagnosis with Metagenomic Next-Generation Sequencing (mNGS) technology and real-time PCR for SARS-CoV-2 Omicron detection using various nasopharyngeal swabs in SARS-CoV-2 Omicron.

BACKGROUND: The SARS-CoV-2 Omicron variant, with the main subtypes BA.5.2 and BF.7 in China, led to off-target effects on the S and N genes from December 1, 2022, to January 31, 2023. The kits used for studying and developing these agents were not adequately and independently evaluated. It is important to verify the performance of commercial Real-Time quantitative PCR (RT-qPCR) tests. OBJECTIVE: We conducted a clinical evaluation of two Real Time SARS-CoV-2 Omicron assays to verify their performance using various detection reagents and clinical specimens. METHODS: We performed clinical evaluations of two existing Chinese SARS-CoV-2 Omicron RT-qPCR kits 2019-nCoV nucleic acid diagnostic kits (Fosun Biotechnology, National instrument registration 20203400299, Shanghai, China) and COVID-19 nucleic acid detection kits (eDiagnosis Biomedicine, National instrument registration 20203400212, Wuhan, China) and using BSD (Bondson) (Guangzhou Bondson Biotechnology Co. Ltd, batch number 2022101), quality controls provided by the inspection center and a large number of clinically confirmed specimens. RESULTS: The concordance rates for the Fosun and eDiagnosis kits were 95% and 100%, respectively. The detection limit for the Fosun and eDiagnosis kits was verified to be 300 copies/mL and 500 copies/mL. The Fosun assay exhibited the largest coefficient of variation (CV) for ORF1ab and N gene at the detection limit concentration (4.80%, 3.49%), whereas eDiagnosis showed a smaller CV (0.93%, 1.10%). In the reference product from the Hangzhou Clinical Laboratory Center test, it was found that Fosun had the lowest sensitivity of 93.47% and a specificity of 100%, while eDiagnosis exhibited 100% for both sensitivity and specificity. The lowest single target gene detection rate of Fosun reagents was 68.7% for the ORF1ab gene and 87.5% for the N gene, while eDiagnosis detection rate was 100%. Among the clinical group S specimens, the missed detection rate of the Fosun reagent was 10.9%, which was higher than the 3.9% of eDiagnosis. However, there was no significant difference in the clinical diagnostic efficiency of the two reagents. CONCLUSIONS: The ORF1ab and N assays of SARS-CoV-2 Omicron on the eDiagnosis platform yielded higher values compared to those on the Fosun platform. Consequently, the eDiagnosis kit has also been used as standard detection reagents. Considering that the Fosun reagent has a relatively low detection limit and targets three single genes, it is more advantageous as a confirmatory reagent for the new museum.

Humans↗

PubMed2026

Global disparities in COVID-19 vaccine coverage associated with trajectories of SARS-CoV-2 adaptation.

BACKGROUND: Vaccination serves as an effective intervention for health promotion and disease prevention across the socioecological systems and has played an important role during the COVID-19 pandemic. However, global disparities in vaccine coverage have increased uncertainty about the trajectories of viral adaptation, and the potential interplay between SARS-CoV-2 adaptation and vaccine rollout warrants further quantification. METHODS: Using over 13 million SARS-CoV-2 genomes across 86 countries from March 2020 to September 2022, we analyzed nonlinear associations between SARS-CoV-2 adaptation and vaccination coverage, considering public health and social measures, international travel, and infection dynamics, before and after the emergence of Omicron. Additionally, we examined the relationship between SARS-CoV-2 adaptation and COVID-19 mortality. RESULTS: During the pre-Omicron period, we found positive associations between nonsynonymous to synonymous divergence (dN/dS) ratios in the S1 subunit and medium levels of adjusted vaccine coverage (effect size: 0.96 [95% CI 0.47, 1.45]), while the association became insignificant at high levels (effect size: -1.89 [95% CI -4.20, 0.43]). However, no significant associations were found when Omicron dominated, possibly due to the immune escape ability of Omicron variants and the complex immune landscape shaped by mass hybrid immunity. Moreover, we observed evidence of dynamic interdependence and positive correlations between COVID-19 mortality and SARS-CoV-2 adaptation, with COVID-19 mortality interpreted as a proxy for uncontrolled viral spread. CONCLUSIONS: Our findings suggest a complex nonlinear relationship between vaccine-induced immunity and SARS-CoV-2 adaptation, with high vaccine coverage potentially linked to lower positive selection. We also observed directional coupling between COVID-19 mortality and SARS-CoV-2 adaptation. This may have implications for fair and fast vaccination in pandemic preparedness and response. CLINICAL TRIAL NUMBER: Not applicable.

Humans↗

PubMed2025

A pan-beta-coronavirus vaccine bearing conserved and asymptomatic B- and T-cell epitopes protects against highly pathogenic Delta and highly transmissible Omicron SARS-CoV-2 variants.

Over the last five years of the COVID-19 pandemic, the repetitive mutations and deletions in the SARS-CoV-2 genome, primarily targeting the Spike gene, resulted in the emergence of multiple viral variants and sub-variants. The non-updated mismatched Spike-based sub-unit vaccines are less effective due to the ability of these SARS-CoV-2 variants and sub-variants to evade vaccine-induced humoral immunity. To reduce reliance on neutralizing antibodies and prevent potential mismatches between circulating variants, sub-variants, and the vaccines, we have identified highly conserved Spike and non-Spike viral epitopes associated with protective asymptomatic B- and T-cell immune responses, respectively. We demonstrated that unvaccinated asymptomatic patients with COVID-19 recognized these conserved B- and T-cell epitopes. Using the mRNA-LNP-based antigen delivery system, we developed a multi-epitope vaccine that incorporates the conserved B-cell epitopes, CD4+ T-cell epitopes, and CD8+ T-cell epitopes. To assess the efficacy of this "asymptomatic" multi-epitope vaccine, we used the HLA-A*02:01/HLA-DRB1* 01:01-hACE-2 triple transgenic mouse model. We demonstrated that this "asymptomatic" multi-epitope vaccine conferred robust protection against infection and disease caused by the SARS-CoV-2 Delta (B.1.617.2) and Omicron (XBB.1.5) variants as assessed by: (i) prevention of weight loss, (ii) reduction of virus replication, and (iii) lung pathology. This protection was associated with: (i) strong antibody responses; and (ii) high frequency of anti-viral IFN-γ-producing CD4+ and CD8+ T-cells. These findings illustrate the possibility of developing a pan-beta-coronavirus vaccine to induce broad-spectrum protective immunity against SARS-CoV-2 variants and sub-variants by targeting highly conserved "asymptomatic" B- and T-cell epitopes identified from both structural and non-structural viral proteins.

Epitopes, T-Lymphocyte↗

PubMed2025

Genetic Conservation and Diversity of SARS-CoV-2 Envelope Gene Across Variants of Concern.

SARS-CoV-2 Envelope (E) protein is critical in viral assembly, release, and virulence. E gene was considered highly conserved and evolving slowly. Pan-sarbecoviruses-conserved regions in the E gene have been used as targets for various RT-PCR assays to detect SARS-CoV-2. It remains elusive whether SARS-CoV-2 variants of concern (VOCs) have accumulated significant E mutations that may affect protein stability and diagnostic RT-PCR assays. Herein we aimed to perform a comprehensive genetic analysis on the conservation and diversity of the E gene of SARS-CoV-2 and its VOCs in comparison with other human coronaviruses (HCoVs). In silico analysis of 20 326 HCoV E gene sequences retrieved from GenBank and GISAID suggests that SARS-CoV-2 E gene has multiple pan-HCoVs- and pan-SARS-CoV-2-conserved positions but accumulates significant mutations in VOC B.1.351 and Omicron strains. Mutations were often found in the 5' and 3' variable regions, whereas the central region is conserved. Nucleotide changes C109U and A114G may lead to potential failure of first-line SARS-CoV-2 diagnostic/screening assays. Nucleotide change C212U and its concomitant amino acid substitution Pro71Leu (i.e., C212U/Pro71Leu) is a hallmark mutation of B.1.351 variants, while C26U/Thr9Ile is characteristic of all Omicron variants. Later Omicron subvariants, such as XBB.1.5 and EG.5, additionally acquired the A31G/Thr11Ala mutation, as was confirmed by whole genome sequencing of SARS-CoV-2 in 118 pediatric cases. Wild-type E protein exhibits cytotoxicity to cells, but the mutations Thr9Ile, Thr11Ala, Thr9Ile + Thr11Ala, or Pro71Leu reduces its cytotoxicity. The Thr9Ile + Thr11Ala mutation stabilizes the E proteins of Omicron variants, while Pro71Leu alters the cellular distribution of the E protein, reducing its colocalization with the Golgi body. Altogether, this study not only sheds light on the conservation and diversity of the E gene in SARS-CoV-2 and its VOCs but also informs the improvement and development of SARS-CoV-2 or pan-HCoVs screening and diagnostic assays.

SARS-CoV-2↗

PubMed2024

Infection kinetics, syncytia formation, and inflammatory biomarkers as predictive indicators for the pathogenicity of SARS-CoV-2 Variants of Concern in Calu-3 cells.

The ongoing COVID-19 pandemic has led to the emergence of new SARS-CoV-2 variants as a result of continued host-virus interaction and viral genome mutations. These variants have been associated with varying levels of transmissibility and disease severity. We investigated the phenotypic profiles of six SARS-CoV-2 variants (WT, D614G, Alpha, Beta, Delta, and Omicron) in Calu-3 cells, a human lung epithelial cell line. In our model demonstrated that all variants, except for Omicron, had higher efficiency in virus entry compared to the wild-type. The Delta variant had the greatest phenotypic advantage in terms of early infection kinetics and marked syncytia formation, which could facilitate cell-to-cell spreading, while the Omicron variant displayed slower replication and fewer syncytia formation. We also identified the Delta variant as the strongest inducer of inflammatory biomarkers, including pro-inflammatory cytokines/chemokines (IP-10/CXCL10, TNF-α, and IL-6), anti-inflammatory cytokine (IL-1RA), and growth factors (FGF-2 and VEGF-A), while these inflammatory mediators were not significantly elevated with Omicron infection. These findings are consistent with the observations that there was a generally more pronounced inflammatory response and angiogenesis activity within the lungs of COVID-19 patients as well as more severe symptoms and higher mortality rate during the Delta wave, as compared to less severe symptoms and lower mortality observed during the current Omicron wave in Thailand. Our findings suggest that early infectivity kinetics, enhanced syncytia formation, and specific inflammatory mediator production may serve as predictive indicators for the virulence potential of future SARS-CoV-2 variants.

Humans↗

PubMed2026

A Multiepitope Intranasal Adenoviral Vaccine Induces Robust Mucosal Immunity and Protection against SARS‑CoV‑2.

BACKGROUND: Vaccination has been central to mitigating the COVID-19 pandemic; however, the continual emergence of SARS-CoV-2 variants of concern (VOCs) has reduced the effectiveness of current intramuscular vaccines that primarily target the Spike (S) protein. Although updated formulations are periodically introduced, there remains a critical need for next-generation vaccine platforms capable of inducing broad, variant-independent protection. Here we evaluate a heterologous intranasal (i.n.) prime-boost vaccination strategy using bovine adenoviral (BAd) and chimpanzee adenoviral (ChAd) vectors expressing the S1 subunit in combination with either full-length membrane (M) and nucleocapsid (N) proteins (Ad-S1 + N + M) or multiepitope constructs derived from M and N (Ad-S1 + Epi/N + Epi/M). The constructs were incorporated with the autophagy-inducing peptide C5 (AIP-C5) to enhance antigen-specific T-cell responses. RESULTS: In BALB/c mice, Ad-S1 + Epi/N + Epi/M vaccination induced robust S1-specific immunity while simultaneously inducing strong N- and M-specific humoral and cellular responses that were comparable to or greater than those induced by Ad-S1 + N + M. All S1-containing formulations generated high neutralizing antibody titers (~ 3.8 log₁₀) against Omicron B.1.1.529 and BA.2.86 variants, although titers against the ancestral Wuhan strain were approximately one log₁₀ lower. In K18-hACE2 mice, i.n. immunization with S1-expressing vectors provided near-complete protection against BA.2.86 challenge, with undetectable lung viral titers and viral genome copies. CONCLUSION: An i.n. multiepitope adenoviral vaccine incorporating conserved SARS-CoV-2 antigens induces robust mucosal, humoral, and cellular immune responses and confers significant protection following SARS-CoV-2 challenge.

Animals↗

PubMed2026

A bireporter recombinant SARS-CoV-2 Omicron BA.5 for in vitro and in vivo studies.

The continuous emergence of variants of concern (VoCs) represents a significant challenge to effectively control severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although FDA-approved vaccines and antivirals have been successfully developed and implemented for the prophylactic and therapeutic intervention of SARS-CoV-2 infection, recent VoCs could escape protection garnered by previous vaccine and antiviral approaches. Determining the efficacy of prophylactics and/or therapeutics against recent VoCs will assist in efficiently controlling currently circulating SARS-CoV-2 strains. We used our previously described bacterial artificial chromosome-based reverse genetics approach for Omicron BA.5 to generate a recombinant SARS-CoV-2 BA.5 encoding a fusion of ZsGreen to Nanoluciferase (rBA.5 ZsG-Nluc) from the locus of the viral nucleocapsid (N) protein separated by the porcine teschovirus-1 2A proteolytic cleavage site. The rBA.5 ZsG-Nluc replicates to levels comparable to recombinant BA.5 wild type (rBA.5 WT) and expresses high levels of ZsG and Nluc in cultured cells. This facilitates tracking viral infection and the identification of antivirals and neutralizing antibodies with EC50 and NT50 values, respectively, similar to those obtained with rBA.5 WT. Importantly, in Keratin-18 human angiotensin-converting enzyme-2 mice, rBA.5 ZsG-Nluc retains the same pathogenicity and ability to replicate in the lungs of infected mice as rBA.5 WT. Using rBA.5 ZsG-Nluc, we detected Nluc activity systemically and Nluc and ZsG expression in the lungs of infected mice using an in vivo imaging system. Our results demonstrate the feasibility of using rBA.5 ZsG-Nluc to track viral infections and identify prophylactics and therapeutics against recent SARS-CoV-2 VoCs in vitro, ex vivo, and in vivo.IMPORTANCESevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of the coronavirus disease 2019 pandemic, is continually evolving to escape immunity acquired by previous natural infections or vaccinations. Moreover, recent SARS-CoV-2 variants of concern (VoCs) have acquired antiviral-resistant mutations to FDA-approved drugs. The emergence of these VoCs highlights the importance of identifying new prophylactics and therapeutics against currently circulating SARS-CoV-2 strains. We generated a recombinant bireporter Omicron BA.5 SARS-CoV-2 (rBA.5 ZsG-Nluc) that expresses reporter proteins, which are useful for cellular and whole animal studies, and has similar viral replication and pathogenicity to a wild-type recombinant Omicron BA.5 SARS-CoV-2. In Keratin-18 human angiotensin-converting enzyme-2 mice, rBA.5 ZsG-Nluc infection can be tracked systemically or in the lungs of infected mice using an in vivo imaging system. We establish a proof-of-concept platform of rBA.5 ZsG-Nluc in combination with an ancestral SARS-CoV-2 strain expressing mCherry to simultaneously identify antivirals and neutralizing antibodies against original and recent SARS-CoV-2 strains.

SARS-CoV-2↗