Aug 2026· Frontiers in Immunology· 0 citations· 38 references
TL;DR
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.
Abstract
The SARS-CoV-2 XBB variants have been proposed to evolve towards immune evasion against vaccination or natural infection, which may contribute to higher transmissibility. The XBB.1.16 independently emerged due to accumulation of two important substitutions, E180V and T478R in the spike protein. Its pseudoviral infectivity and evasion of humoral immunity were similar to XBB.1 and XBB.1.5. In March 2023, XBB.1.16 had outcompeted other dominant XBB variants in India, which indicate a potential growth advantage. Here, intra-host single nucleotide variations (iSNV) and mutations were screened in SARS-CoV-2 genomes in closely related individuals at two time points: at symptoms onset, and during recovery. The prominence of putative epistatic iSNVs (E180V, G184V, G252V, D253G, and P521S/T) in XBB.1.16 variants were detected during the recovery phase. E180V exhibits mutational constellations with the G252V and P521T in a subset of samples, and this pattern was also detected in contemporary SARS-CoV-2 genomes. 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. This study involving genomics and computational analyses highlights the potential role of these putative epistatic interactions in immune evasion, which may have contributed to dominance of XBB variants.
Background Progressive waves of coronavirus disease 2019 (COVID-19) have been driven by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants carrying mutations in the spike glycoprotein, particularly in immunodominant regions such as the receptor-binding domain (RBD) and the N-terminal domain (NTD). These mutations can alter antigenic surfaces and are associated with changes in antibody recognition and vaccine-induced protection. Integrating experimental neutralisation data with computational analyses may contextualise variant-associated differences in antibody responses. Methods Neutralisation responses were evaluated using a pseudovirus-based luciferase reporter assay including SARS-CoV-2 spike proteins from B.1 (Wuhan), B.1.617.2, AY.2 (Delta), and B.1.1.529 (Omicron). Plasma samples from three cohorts: naturally infected (I), vaccinated (V), and vaccinated-infected individuals (V+I), along with RBD-directed monoclonal antibody CR3022, were assessed to determine neutralizing titres (NT50). In parallel, spike sequences were analysed using epitope prediction, antigenicity profiling, and structural modelling. Docking simulations of CR3022 with variant RBDs were performed using HADDOCK, and binding parameters were estimated using PRODIGY. Results Neutralisation responses varied across cohorts and viral variants, reflecting differences in immune exposure history. Plasma from V group individuals showed comparatively higher neutralisation titre, whereas B.1.617.2 and B.1.1.529 exhibited reduced susceptibility to neutralisation by infection-elicited antibodies. Computational analyses indicated variant-associated differences in predicted antigenicity and epitope landscapes within the RBD and NTD. Structural modelling and docking suggested that spike mutations may influence the CR3022-RBD interaction interface, with corresponding changes in predicted binding affinity across variants. These computational observations provide structural context for experimentally observed trends in reduced neutralisation but do not establish a direct mechanistic relationship. Conclusion This study provides a combined experimental and computational characterization of SARS-CoV-2 variant-specific neutralisation across infection, vaccination and hybrid immunity-driven cohorts. The integration of pseudovirus neutralisation data with structural and in silico analyses offers a hypothesis-generating framework to contextualize observed differences in antibody responses and epitope recognition across variants.
Jyoti Sawant, Ajit Patil, Madhuri Thakar et al.· Frontiers in Immunology· 0 citations
What is already known about this topic? The A28L protein is involved in mpox virus (MPXV) attachment and fusion, is a major target of neutralizing antibodies, and contains regions prone to genetic variation. What is added by this report? Analysis of 6,834 global and 260 Shenzhen MPXV genomes identified lineage-specific length polymorphisms in the A28L low-complexity region (LCR7). Emerging E.4 viruses exhibited complex deletion patterns and a characteristic OPG153_E293Q substitution, indicating ongoing structural diversification. What are the implications for public health practice? Structural variation in A28L provides additional insight into MPXV evolution beyond conventional single-nucleotide analyses. Continued surveillance of these genomic features may improve monitoring of viral transmission and the emergence of new variants.
Bo Peng, Z. Lyu, Wenxiao Gong et al.· China CDC Weekly· 0 citations
BACKGROUND
First identified in late 2021, the Omicron variant of SARS-CoV-2 accumulated substantially more mutations than previously circulating variants. This study investigated the genomic characteristics and structural consequences of mutations in the membrane (M) and envelope (E) proteins of dominant Omicron lineages circulating in southern Iran between March 2021 and March 2023.
METHODS
A total of 528 clinical samples were analyzed using next-generation sequencing (NGS), Nextclade lineage assignment, and complementary bioinformatics approaches. The structural effects of selected mutations were further evaluated using protein-protein docking, PDBe PISA interface analysis, MM/GBSA binding free energy calculations, and 100-ns molecular dynamics simulations.
RESULTS
Between 2021 and 2023, BA.5.2 accounted for 32.4% of sequenced isolates, whereas XBB.1.9.1 became the predominant lineage during the later phase of the study (14.2%). Structural analysis demonstrated that the interaction interface between the M protein dimer and the Fab fragment remained largely conserved across all investigated variants. However, MM/GBSA calculations revealed mutation-dependent differences in binding energetics, with the BA.5 (Q19E, A38S, A63T) variant exhibiting the least favorable binding free energy despite preservation of the overall interaction interface. Molecular dynamics simulations further showed that the investigated E protein variants maintained compact conformations with reduced conformational fluctuations relative to the wild-type protein throughout the simulation.
CONCLUSIONS
Combined genomic surveillance and structural analyses demonstrated that the investigated Omicron-associated mutations largely preserved the overall architecture of the M protein-Fab interaction interface while modulating residue-level energetic contributions and the conformational dynamics of the E protein. These findings indicate that the investigated mutations primarily affect interaction energetics and protein dynamics rather than inducing major structural rearrangements. The integrated computational framework presented in this study provides a useful approach for evaluating the structural consequences of newly emerging SARS-CoV-2 variants and prioritizing mutations for future experimental validation.
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.
H. Ishigaki, Kenichi Otaki, Naoko Kitagawa et al.· Virology· 0 citations
The continuous emergence of SARS-CoV-2 variants of concern has highlighted important limitations of first-generation COVID-19 vaccines developed against the ancestral Wuhan spike protein. Although these vaccines provided strong protection against severe disease and mortality, the accumulation of mutations in the spike protein, particularly within the receptor-binding domain (RBD), progressively reduced their ability to prevent infection and facilitated immune escape. In contrast, vaccine approaches that combine multiple complementary viral antigens have shown greater potential to maintain broad protective immunity despite ongoing viral evolution and immune escape. In this article, we discuss the scientific basis of a plant-produced recombinant COVID-19 cocktail vaccine that demonstrated sustained immunogenicity and cross-variant effectiveness despite being designed from the ancestral Wuhan SARS-CoV-2 sequence. Based on our experimental studies, we propose that this broad protective potential results from the integration of three key design elements: (i) targeting conserved and functionally constrained epitopes within the RBD, (ii) combining RBD and nucleocapsid (N) proteins in a multi-antigen vaccine formulation, and (iii) applying glycoengineering strategies to optimize antigen structure and immune recognition, thereby broadening the immune response and reducing susceptibility to viral immune escape. We further discuss the advantages of plant molecular farming, particularly transient expression in Nicotiana benthamiana, as a rapid, scalable, and cost-effective platform for recombinant vaccine production. Our studies demonstrated that plant-produced glycosylated and deglycosylated RBD antigens retain functional receptor-binding activity and induce strong neutralizing antibody responses. Moreover, when combined with the N protein, these antigens maintained effectiveness against highly divergent SARS-CoV-2 variants, including Omicron. Importantly, the principles underlying this vaccine design may extend beyond COVID-19. The strategic combination of conserved and immunologically complementary antigens provides a rational framework for the development of broadly protective vaccines against future pandemic threats and other rapidly evolving emerging pathogens. In particular, our findings suggest that integrating conserved and immunologically complementary antigens may represent a universal vaccine design strategy to combat future pandemics caused by rapidly evolving pathogens.
T. Mamedov· Transactions of the Institut...· 0 citations
The recent global expansion of the SARS-CoV-2 variant NB.1.8.1 has driven the emergence of sublineages PQ.16.1.1 and RK.1, which independently acquired the D420N mutation in their receptor-binding domains and and now dominate the Asia-Pacific region. Evaluations utilizing surface plasmon resonance and pseudovirus assays demonstrate that these sublineages exhibit significantly reduced human ACE2 receptor engagement compared to their parental strain. However, this functional cost is offset by a marked ability to evade humoral immunity, specifically demonstrating profound resistance to Class 1 neutralizing monoclonal antibodies and convalescent plasma from Wuhan-Hu-1-primed individuals. This convergent evolution exemplifies a classical viral trade-off, sacrificing receptor binding efficiency to escape population-level immune pressure. Consequently, these findings suggest these variants will soon spread globally and emphasize the critical need for ongoing surveillance to monitor D420N-carrying lineages.