Aug 2026· Virology· Vol 624, pp.
111036
· 0 citations· 41 references
Medicine
TL;DR
The findings demonstrate that the pathogenicity of the Omicron subvariants has not been fully attenuated in the absence of pre-existing immunity, since they caused severe lung disease in immunologically naïve macaques and their enhanced propagation in the upper airway likely facilitates efficient transmission among humans.
Abstract
Since the emergence of the SARS-CoV-2 Omicron variant, decreased morbidity and mortality relative to early strains have been widely reported. However, the virological characteristics of recent subvariants dominating the post-pandemic era remain to be fully elucidated. In the present study, the intrinsic pathogenicities of the Omicron subvariants JN.1, EG.5.1, and BA.2.86.1 were investigated using an immunologically naïve cynomolgus macaque model. All three variants exhibited robust replication in the upper respiratory tract, surpassing the viral titers observed with the early Wuhan strain. Omicron subvariant infection caused prolonged fever and sustained viral shedding in the nasal mucosa for at least seven days, indicating enhanced adaptation to upper airway tissues. Despite this shift in viral replication tropism, histological analysis showed that these variants retained the characteristics to induce lower respiratory tract disease. All infected macaques developed bronchopneumonia characterized by cellular exudates in the alveolar spaces. The histological scores were comparable to those observed with the early strain. These findings demonstrate that the pathogenicity of the Omicron subvariants has not been fully attenuated in the absence of pre-existing immunity, since they caused severe lung disease in immunologically naïve macaques. Furthermore, their enhanced propagation in the upper airway likely facilitates efficient transmission among humans. The continuous circulation of SARS-CoV-2 variants underscores the necessity of ongoing surveillance of viral gene variations and the maintenance of protective immunity in vulnerable populations.
Introduction SARS-CoV-2 undergoes persistent genomic evolution, yet prevalent circulating variants tend to evolve toward reduced pathogenicity. However, direct comparative pathogenesis data involving contemporary, immune-evasive strains—such as the Omicron EG.5 subvariant (a descendant of the globally dominant XBB lineage)—relative to ancestral strains remain scarce. Methods To clarify the evolutionary trajectory of viral virulence, we conducted a systematic, head-to-head comparison of the in vivo pathogenicity of three pivotal strains: the ancestral Wild-type (Wuhan lineage), Delta, and the currently circulating Omicron EG.5. We utilized the highly susceptible K18-hACE2 transgenic mouse model to assess disease progression, viral burden, and histopathology. Results Despite uniformly progressing to lethality in this model, the strains exhibited a distinct gradient in the kinetics and severity of disease. The Wild-type strain demonstrated the most rapid disease progression, highest viral loads across multiple organs (notably liver, brain, lung, and intestine), and most severe histopathological damage. The Delta variant showed an intermediate phenotype. Strikingly, the Omicron EG.5 variant displayed significantly attenuated pathogenicity, characterized by markedly delayed mortality, milder clinical presentation, and reduced tissue viral burden, yet it retained a capacity for multi-organ infection. Discussion Our study provides direct experimental evidence for a pronounced attenuation in pathogenicity along the evolutionary trajectory from Wild-type through Delta to Omicron EG.5. These findings offer crucial insights for risk assessment of emerging variants and underscore the need for ongoing surveillance.
Xiaofang Peng, Qi Zhang, Pingping Zhou et al.· Frontiers in Immunology· 0 citations
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve through mutations in the spike (S) protein, leading to antigenically divergent variants such as the Omicron sublineage JN.1 that markedly reduce vaccine-induced neutralizing antibody activity. These limitations highlight the need for vaccine strategies that can induce multilayered protective immunity rather than relying solely on S protein-targeted immunity. Here, we developed a Wuhan-lineage-based multi-antigen virus-like particle (VLP) vaccine incorporating S, envelope (E), membrane (M), and nucleocapsid (N) proteins using a baculovirus dual-expression system. Mice were primed intramuscularly and boosted via either the intramuscular or intranasal route, and humoral, mucosal, and cellular immune responses were evaluated. Both vaccination regimens induced robust systemic IgG responses, whereas mucosal IgA responses were selectively enhanced following intranasal boosting. Sera from VLP-immunized mice efficiently neutralized the homologous Wuhan-lineage strain but showed no detectable neutralizing activity against the JN.1 variant. Despite this, VLP immunization elicited antigen-specific CD4+ and CD8+ T cell responses in both pulmonary and systemic compartments. In a highly susceptible K18-hACE2 mouse model, VLP immunization completely prevented mortality following challenge with both the ancestral Wuhan-lineage strain and the JN.1 variant and markedly suppressed viral replication in respiratory tissues. Histopathological analysis further showed minimal interstitial lung lesions with organized perivascular lymphocytic infiltration in vaccinated mice, while pulmonary cytokine analysis revealed qualitatively distinct immune response patterns depending on the challenge strain and vaccination status. Our findings show that a Wuhan-lineage-based multi-antigen VLP vaccine can provide cross-protection against an antigenically divergent SARS-CoV-2 variant that is not fully explained by detectable serum neutralizing activity alone, suggesting the importance of integrated immune responses involving humoral, cellular, and local immune mechanisms.
Seung-Ji Kim, Howon Kim, Seung-Eun Son et al.· Vaccine· 0 citations
Introduction: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) shows continuous genetic variation, resulting in the emergence of multiple viral lineages worldwide. These mutations can influence viral transmissibility, pathogenic potential, and immune escape, resulting in changed disease pattern. Genomic surveillance allows systematic tracking of viral evolution and circulating variants; thus, monitoring is essential for informed public health planning and clinical preparedness.
Aim: To detect the emergence of variants of Omicron lineage in the hilly state of Himachal Pradesh, India.
Materials and Methods: This cross-sectional study was conducted at the Shri Lal Bahadur Shastri Medical College, Mandi, Himachal Pradesh, India from January 2024 to June 2024. All the SARS-CoV-2 positive samples with Ct value ≤30 received across the state from the four Virus Research and Diagnostic Laboratories (VRDLs) of the state were included. Ribonucleic acid (RNA) extraction was performed using the Q-Line Molecular Viral RNA Extraction Kit, and Whole Genome Sequencing (WGS) was carried out on the Oxford Nanopore MinION platform. Consensus sequences were generated using Medaka and Nanopolish for variant identification and phylogenetic analysis. All demographic and clinical data, like age, sex, clinical presentation, and vaccination status, were recorded and tabulated in Microsoft Excel 2021. The study focused on genomic sequences generated, and the data were presented as numbers and percentages.
Results: A total of 30 SARS-CoV-2 positive samples were received. Among SARS-CoV-2 positive cases, adult females constituted the highest proportion, 17 (56.7%), with most patients aged 19-60 years, 17 (56.7%), and the majority of samples originating from Shimla, 11 (36.7%). The study identified JN.1 sublineages in 19 (63.3%) as the predominant cause of infection. Most cases, 20 (66.7%) reported to the outpatient department. Mild symptoms such as fever and cough were seen in 7 (35%) cases. Even though 23 (76.7%) of cases were vaccinated with the COVID-19 vaccine, 10 (33.3%) required admissions. However, no mortality was reported.
Conclusion: Tracking SARS-CoV-2 variants revealed the predominance of the JN.1 sublineage of Omicron with generally mild symptoms. Continuous genetic evolution of SARS CoV-2 highlights the need for robust, ongoing genomic surveillance integrated with epidemiological data to enable early detection of emerging variants and strengthen control strategies.
Priyanka Rao, S. Ganju, Lata R. Chandel· Journal of Clinical and Diag...· 0 citations
Highly pathogenic avian influenza H5NX clade 2.3.4.4b viruses continue to circulate globally. Reintroduction of Eurasian lineage viruses into North America and reassortment with endemic low pathogenicity strains have resulted in new genotypes, including D1.2. To assess pathogenicity and cellular tropism, we intranasally inoculated genotype D1.2 virus into pigs. We isolated virus from nasal secretions from most inoculated animals for multiple days. At 5 days postinoculation, PCR and immunohistochemistry detected virus in musculoskeletal, respiratory, digestive, lymphatic, and nervous systems, and virus was isolated from meat juice. At 35 days postinoculation, we detected viral antigen and low levels of RNA in the brain of an animal with lesions consistent with a viral etiology and found viral antigen in the ethmoid of 2 animals. Consistent detection in nasal swab specimens, combined with subclinical respiratory infection, suggest that identifying infection in commercial swine without overt respiratory signs could be difficult.
Hannah Seger, Amy L. Baker, Alexandra C. Buckley et al.· Emerging Infectious Diseases· 0 citations
Higher order protein structural predictions suggested that the putative epistatic interactions among E180V, G184V, and G252V, D253G may be associated with S protein folding and structural stability.
M. Jogi, Sristy Shikha, Pushpendra Singh et al.· Frontiers in Immunology· 0 citations
The ability of respiratory viruses to exploit host immune responses to promote transmission is a defining feature of pandemics. SARS-CoV-2 remains a major global public health threat because of its persistent evolution and capacity to counteract evolving immune defenses. Although the immune evasion properties of the SARS-CoV-2 Spike protein are well characterized, the contributions of other viral proteins to transmission remain poorly understood. Here, we used the infant mouse model to define the role of the accessory protein ORF8 in SARS-CoV-2 spread. We demonstrate that ORF8 supports efficient upper respiratory tract (URT) infection, infectious virus shedding, and host-to-host transmission. Mice infected with a recombinant SARS-CoV-2 strain lacking ORF8 (rΔORF8) had less infectious virus recovered from URT tissues and nasal secretions and transmitted less efficiently than mice infected with the isogenic ancestral strain rWA-1, which contains an intact ORF8. Recombinant viruses encoding naturally occurring ORF8 mutations exhibited distinct transmission phenotypes, with ORF8-deficient viruses resembling rΔORF8. Infection with ORF8-sufficient viruses induced greater macrophage recruitment, inflammatory cytokine production, and type-I interferon (IFN-I) signaling programs than ORF8-deficient viruses. Intranasal IFNβ supplementation partially restored URT shedding by rΔORF8-infected mice and rescued transmission to contacts, whereas blockade of the type I interferon receptor (IFNAR) in rWA-1-infected index mice reduced contact infection and transmission. Together, these findings demonstrate that ORF8 promotes SARS-CoV-2 transmission by engaging an IFN-I-associated inflammatory and secretory program in the URT that supports virus shedding from the infected host. These data identify ORF8 as a viral determinant of host mucosal responses that promote contagiousness. Importance Efficient host-to-host transmission underlies the success of respiratory viruses. Although SARS-CoV-2 research has largely focused on the Spike protein, accessory proteins can also shape viral fitness and spread. We previously identified ORF8 as a determinant of SARS-CoV-2 transmission. Here we show that ORF8 promotes SARS-CoV-2 infectious viral shedding and transmission by engaging IFN-I-associated inflammatory and secretory responses in the URT. These findings reveal how a SARS-CoV-2 accessory protein can exploit mucosal antiviral responses to increase host contagiousness.
G. Ciabattoni, Stacey Bartlett, M. McGrath et al.· bioRxiv· 0 citations