Search Results (808)

Public health policy foundationally impacts how pathogens spread, yet despite multiple pathogens of broader societal concern emerging, little research has examined how policy affects pathogen evolution. To evaluate this connection, we examine how varying public health approaches impact how viral immune susceptibility, including resistance to vaccines, evolves. Integrating evolutionary epidemiological modeling and critical geography, we compare how distinct public health responses early in the COVID-19 pandemic affected the potential evolution of immune evasion in SARS-CoV-2 across four territories: Costa Rica, Panama, Texas, and Uruguay. We use parameter estimates inferred from confirmed case and vaccination time series via stochastic ensemble Kalman filtering in each territory. Our analyses suggest viral immune resistance was most likely to emerge in Texas, which relied almost exclusively on vaccines for disease control. In contrast, regions with comparatively fewer health disparities that also rigorously applied interventions, such as shelter-in-place orders and household support, may have better prevented vaccine resistance from evolving. These comparative analyses highlight the key role policy choices play, potentially representing different governance goals for population health and wellbeing. We argue that such choices impact not only disease spread but also pathogen evolution along epidemiologically critical dimensions like viral immune susceptibility. Our study thus demonstrates how public health priorities drive social–evolutionary feedbacks. Full article

The 2019 coronavirus disease pandemic (COVID-19) showed how genetic mutations can alter coronavirus characteristics. However, the evolution of livestock coronaviruses remains understudied. We analyzed 15 bovine coronavirus (BCoV), three porcine hemagglutinating encephalomyelitis virus (PHEV) and 18 porcine respiratory coronavirus (PRCV) isolates, mainly from Belgian livestock collected between 2020 and 2023. Spike gene phylogenetic analysis showed nucleotide substitution rates comparable between BCoV and PRCV, while PHEV appeared slower. Unlike severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), synonymous substitutions were preferred, limiting amino acid variation across decades in the animal coronaviruses. Virus neutralization assays with swine antisera indicated minimal antigenic change in PHEV and PRCV. Recent BCoV isolates showed antigenic divergence from the classical Mebus vaccine strain. The impact of this divergence on vaccine efficacy may warrant further research. Our findings underscore the need for periodic surveillance, as changes in surface proteins may affect pathogenicity, tissue tropism, host range and vaccine efficacy. Full article

The continuous evolution of the SARS-CoV-2 virus, marked by the emergence of new variants, poses a significant threat to the efficacy of existing vaccines. However, a promising approach to addressing vaccine failure caused by viral mutations (particularly in the spike protein) is the development of a variant-proof (conserved), non-spike, multiepitope universal nanostructure vaccine with multifunctionality, biocompatibility, self-adjuvanticity, and structural similarity to pathogens in terms of size and shape. This study aimed to design a self-assembled nanostructure vaccine (SANV) featuring pentameric and trimeric coiled-coil peptide motifs, as well as other functional motifs, including epitopes, TAT, PADRE, and adjuvant. The cytotoxic T lymphocyte (CTL), helper T lymphocyte (HTL), and B lymphocyte (BL) epitopes of SANV were screened from the IEDB with more than 50% individual predicted population coverage (PPC) and fused using linkers to enable self-assembly. The multimerization of the 24 SANV monomers was modeled using the GalaxyHomomer and AlphaFold web servers. Subsequently, the leading SANV constructs with (SANVa9) and without (SANVb6) adjuvant were analyzed for their physicochemical profiles and assessed for antigenicity, allergenicity, solubility, and antioxidant potential. Furthermore, the molecular interactions, specificity, and stability of SANVa9 and SANVb6 with the broadly neutralizing sarbecovirus antibody 5817 and toll-like receptors (TLR2, TLR3, and TLR7) were analyzed using molecular docking and simulation over a 100-nanosecond time scale. Finally, the comparative immune simulation profiles of SANVa9 and SANVb6 with controls indicated stronger, broad-spectrum immune responses that could be translated into in vitro and in vivo studies and warrant further evaluation before clinical use. Full article

Background: The continued evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) created ongoing challenges for molecular diagnostics and variant surveillance. Assays capable of maintaining diagnostic sensitivity across emerging variants while providing variant-related information remain essential for clinical and public health applications. This study evaluated the performance of the GXT96 X3 extraction kit in combination with the FluoroType^® SARS-CoV-2 varID Q version 1.0 assay (Hain LifeScience SA (Pty) Ltd., South Africa) for the detection, semi-quantitative assessment, and variant characterization of SARS-CoV-2 under laboratory conditions. Methods: A total of 220 samples were evaluated, including residual nasopharyngeal clinical specimens (n = 183), reference materials, and cultured SARS-CoV-2 virus dilutions. Residual specimens collected during multiple COVID-19 waves in South Africa (wild-type, Beta, Delta, and Omicron) were compared against standard-of-care (SOC) molecular assays used for routine diagnosis. RNA extraction was performed using the automated GXT96 X3 platform, followed by amplification on the FluoroCycler^® XT using the FluoroType^® SARS-CoV-2 varID Q assay targeting RdRp and N genes, with additional spike gene mutation detection for variant detection. Diagnostic accuracy, agreement (Cohen’s kappa), precision, linearity, and limit of detection (LoD) were assessed. Results: The assay demonstrated a sensitivity of 98.4% (95% CI: 94.2–99.8) and specificity of 100% (95% CI: 95.9–100.0) compared with SOC assays, with an overall agreement of κ = 0.981. Precision analysis showed acceptable reproducibility with a standard deviation of ≤1.49 and a coefficient of variation of ≤3.83%. Regression analysis demonstrated linearity across the dilution series (R² = 0.9882 for RdRp and 0.994 for N genes). The LoD was ≤100 copies/mL for the RdRp gene and 250 copies/mL for the N gene. Variant-associated spike mutations corresponded broadly with epidemiological wave patterns observed in South Africa. Conclusions: Under the evaluated laboratory conditions, the GXT96 X3 extraction platform combined with the FluoroType^® SARS-CoV-2 varID Q assay demonstrated high diagnostic accuracy and reproducibility for SARS-CoV-2 detection across a range of viral loads with additional spike gene mutation detection as an adjunct feature. Full article

Background: Monoclonal antibodies (mAbs) initially played a major role in outpatient COVID-19 management by providing rapid passive immunity and reducing progression to severe disease. However, continuous SARS-CoV-2 evolution progressively compromised the effectiveness of several anti-spike products. This narrative review summarizes the trajectory of COVID-19 mAbs across three phases: early clinical efficacy, loss of efficacy due to immune escape, and future directions. Methods: We conducted a narrative review focusing on mechanisms of action, pivotal clinical trials, and real-world effectiveness of neutralizing anti-spike mAbs and host-directed immunomodulatory mAbs. Emphasis was placed on the impact of variants—especially Omicron—on susceptibility and clinical use, as well as on emerging next-generation platforms. Results: First-generation neutralizing mAbs substantially reduced the hospitalization rates during the Alpha and Delta waves, while immunomodulatory mAbs became standard options for the hyperinflammatory phase in hospitalized patients. With the emergence of Omicron and its sub-lineages, extensive immune escape led to marked reductions in neutralization for many earlier anti-spike agents and consequent restrictions in use. Later-generation approaches targeting more conserved epitopes provided temporary solutions but were also challenged by ongoing antigenic drift. Host-directed immunomodulators retained clinical relevance because their mechanism is independent of viral spike mutations. Conclusions: The clinical role of monoclonal antibodies in COVID-19 has been dynamic and increasingly constrained by viral evolution. Future strategies should prioritize broadly neutralizing antibodies targeting conserved epitopes, innovative delivery platforms, and integration with real-time surveillance to preserve clinical utility in the endemic phase and improve preparedness for future outbreaks. Full article

The SARS-CoV-2 non-structural proteome remains the most clinically validated and strategically important landscape for direct-acting small-molecule antiviral drug discovery. The success of inhibitors targeting the main protease (M^pro, Nsp5) and RNA-dependent RNA polymerase (RdRp, Nsp12) has firmly established viral replication enzymes as tractable, druggable, and therapeutically relevant targets, while setting clear benchmarks for translational antiviral development. Building on this foundation, a second wave of non-structural protein (Nsp) targets has emerged with increasing translational promise, including the papain-like protease (PL^pro), the bifunctional Nsp14 proofreading and capping machinery, Nsp16 2′-O-methyltransferase, Nsp13 helicase, and Nsp15 endoribonuclease. In parallel, additional components such as Nsp1 and the Mac1 domain of Nsp3 continue to expand the antiviral design space, although they remain at earlier stages of chemical validation. In this review, we comprehensively assess SARS-CoV-2 non-structural proteins through a medicinal chemistry and translational lens, with an emphasis on structural tractability, mechanism of action, quality of chemical matter, cellular and in vivo antiviral evidence, evolutionary conservation, resistance liabilities, and developability. Particular attention is given to the features that distinguish tool compounds from genuinely actionable leads and to the opportunities for rational combination regimens that extend beyond first-generation protease- and polymerase-centred therapy. Collectively, the non-structural proteome offers the strongest foundation for next-generation and potentially broader-spectrum coronavirus antivirals with improved resilience to viral evolution. Full article

Background/Objectives: The unprecedented structural and binding data for antibodies to the SARS-CoV-2 virus taken together with the mutations for the spike protein allows for a broad simulation study of antibody–spike protein binding. This provides an understanding of the co-evolution of human immunity and viral immunity escape. Methods: We utilized the YASARA molecular dynamics program to generate initial structures and simulate to equilibration for six SARS-CoV-2 variants and ten different antibodies sampling two different binding regions to the receptor binding domain of the spike (especially for the Class I antibodies in the same part of the spike that attaches to the ACE2 receptor protein) and one to the N-terminal domain of the spike. Starting structures for antibody binding to variant spike protein domains are perturbatively achieved through point mutations and insertions/deletions in the YASARA program. We employed YASARA to measure interfacial hydrogen bound counts between antibodies and variant spike proteins and the HawkDock MMGBSA program to characterize trends in binding energies with mutation for four of the antibodies. We utilized the VMD program to analyze the time course of hydrogen bond populations. Results: As seen in previous studies, interfacial hydrogen bond counts serve as an excellent proxy for binding energies without the large systematic error inherent in the latter. We find that there is generally a decline in antibody binding strength, as measured by interfacial hydrogen bond counts, with viral evolution, but that a modest re-entrance of binding strength is present for most antibodies studied. Generically, the antibody heavy chain binds more strongly to the spike protein, though for approximately half the antibodies the light chain binding strength converges to the heavy chain strength with viral evolution. Conclusions: The key conclusion is that the identified re-entrant immunity, speculatively arising from a balancing of maintenance of ACE2-spike binding while escaping antibodies through mutation, allows for some maintenance and even strengthening of immunity for later viral strains from early infection or vaccination. Full article

Antiviral pulse dosing is shaped by discrete dosing events, two-compartment pharmacokinetics, nonlinear pharmacodynamics, and resistance evolution. To characterize sustained suppression, resistance accumulation, and risk-cost tradeoffs within a unified framework, this study formulates a two-compartment pharmacokinetic-viral dynamic pulse-dosing model with competition between drug-sensitive and drug-resistant strains. Nonlinear metabolic terms, safety constraints, and a mutant selection window (MSW) residence metric are incorporated. Rather than merely superimposing standard logistic growth, Emax pharmacodynamics, and Dirac-delta impulses, the proposed framework couples cross-compartment exposure, MSW residence, resistance ratio feedback, and finite-time stability diagnostics in a discrete-control setting. Pontryagin’s minimum principle is used to derive marginal optimality conditions for impulsive dosing, whereas the numerical implementation adopts a safety-constrained grid search over a finite set of candidate dose intensities. Scenario simulations for SARS-CoV-2 and HIV suggest that, under the assumed mechanisms and parameter ranges examined, high-intensity or high-frequency dosing may improve short-term viral suppression but may also increase MSW crossings and tail residence, thereby amplifying resistance accumulation and finite-time sensitivity risk. The stratified results should therefore be interpreted as a theoretical sensitivity analysis rather than as direct clinical prescribing guidance. The framework may provide a basis for subsequent individualized PK/PD calibration and resistance monitoring. Full article

Reversion of amino acid mutations in structural proteins is common in viral evolution. SARS-CoV-2 provides an unprecedented opportunity for ecological studies, thanks to the abundance of available whole genome sequences. YoyoMut allows regular scanning of open SARS-CoV-2 data, reporting on all cyclic and reverting mutations within all proteins (including Spike), with fine-grained trend visualization distinguishing non-mutated from mutated positions (either fixated or cyclically reversed). In the whole CoVSpectrum database, order of 100 reverting and 50 fixated mutations were identified on Spike. Classification is determined using alternative algorithms (based on threshold or slope inversion); finally, a 3D-protein structure allows us to identify spatial clustering of adjacent mutated positions. Systematic, automated monitoring of these behaviors aids immunologists and structuralists in their manual curation. By generating informative reports, our tool supports daily activities that have practical implications for vaccine and therapeutic anti-Spike monoclonal antibody design: prioritizing analysis of cyclic mutation and reversion models could help avoid the recent failures in their development and inform future strategies. Full article

Understanding how clinical symptoms relate to immune responses during major variant transitions remains important for informing post-pandemic surveillance and vaccination strategies. This study compared symptom patterns and SARS-CoV-2-specific anti-RBD IgM and anti-S1 IgG antibody responses among vaccinated individuals infected during the pre-Omicron and Omicron-dominant periods, representing a key phase in the evolution of SARS-CoV-2 population immunity. A retrospective analysis of 216 confirmed COVID-19 cases was performed by evaluating 11 predefined symptoms together with anti-RBD IgM and anti-S1 IgG levels measured at Day-14 after symptom onset, corresponding to the period when humoral antibody responses are detectable following SARS-CoV-2 infection. Participants with breakthrough infection during the Omicron-dominant period reported fewer symptoms overall compared to the pre-Omicron period, with a median of three versus four symptoms, respectively. Cough was the most common symptom during the Omicron period (82.1%), followed by sore throat (81.4%) and fever (78.6%). In contrast, loss of taste or smell was significantly more frequent in the pre-Omicron period (64.8% versus 22.9%, p < 0.05). IgG levels were significantly higher during the Omicron period than during the pre-Omicron period, increasing by 42.3%, reflecting enhanced antibody responses likely driven by repeated exposure. A consistent association between cough and elevated IgG levels was observed in both periods (p < 0.05), suggesting an association between symptom presentation and the magnitude of the early humoral response. These findings suggest that while clinical symptom profiles evolved across a major SARS-CoV-2 variant transition, certain symptom–antibody relationships remained consistent. Such associations may provide insight into how clinical manifestations relate to immune responses in populations with pre-existing immunity and may support interpretation of symptomatic infection during ongoing SARS-CoV-2 circulation. Full article

SARS-CoV-2, the causative agent of COVID-19, emerged in late 2019 and rapidly developed into a global health crisis. In this study, we analysed 173,194 SARS-CoV-2 genomes from the GISAID database to explore the intra-continental dynamics and distribution of variants across Africa between 2020 and 2024. We have identified 1377 distinct lineages, which were classified by clade to assess associations with infection and mortality rate. So, we conducted a Shannon entropy analysis to confirm the diversity and we applied a Correspondence Analysis (CA). Our findings revealed that one of the deadliest in Africa during the Delta wave, lineage AY.45 predominated in the South Africa cluster, whereas AY.34.1 drove transmission in the Atlantic West Africa cluster, underscoring regional heterogeneity. Furthermore, early in the pandemic, men exhibited a 39% higher risk of infection compared to women (aOR: 1.39, 95% CI [1.34–1.45]), particularly in association with clade G. By contrast, later stages were dominated by clade GRA, which disproportionately affected the elderly (≥70 years; aOR: 1.39, 95% CI [1.33–1.45]) and children (0–9 years; aOR: 1.26, 95% CI [1.20–1.33]). Our analysis highlighted that the pandemic on the African continent unfolded as a mosaic of epidemics shaped by diverse variants and regional epidemiological contexts. These findings emphasize the importance of genomic surveillance to capture local epidemic signatures and inform region-specific public health strategies. Full article

The continued evolution of SARS-CoV-2 has enabled an escape from most monoclonal antibodies, yet a subset of broadly neutralizing antibodies targeting three newly identified super-conserved RBD epitopes—SCORE-A, SCORE-B, and SCORE-C—retains remarkable activity against even the most recent JN.1-derived sublineages. Here, we employed an integrated computational framework combining conformational dynamics, mutational scanning, MM-GBSA binding energetics, and frustration profiling to dissect the molecular mechanisms by which XGI antibodies achieve broad neutralization and resistance to immune escape. Structural analysis revealed that all three SCORE epitopes share a common architecture: a highly conserved, minimally frustrated core that provides stable anchoring, flanked by peripheral regions that accommodate antibody-specific variations. Conformational dynamics showed that SCORE-A antibodies (XGI-183) rigidify the lateral epitope while leaving the RBM partially mobile; SCORE-B antibodies (XGI-198, XGI-203) clamp the RBM apex, directly blocking ACE2; and SCORE-C antibodies (XGI-171) allosterically loosen the RBM loop, impairing receptor engagement indirectly. Mutational scanning identified a hierarchical hotspot organization where primary hotspots (e.g., K356, T500, Y380, T385) are evolutionarily constrained and minimally frustrated, while secondary hotspots (e.g., V503, Y508, S383) are neutrally frustrated and represent the principal sites of immune-driven mutations. MM-GBSA decomposition revealed that van der Waals-driven hydrophobic packing dominates binding, with electrostatic interactions providing auxiliary stabilization. Critically, frustration analysis demonstrated that immune escape hotspots reside precisely in zones of neutral frustration—“energetic playgrounds” that permit mutational exploration without destabilizing the RBD—while minimally frustrated cores are evolutionarily locked. The comparative analysis of conformational versus mutational frustration distributions revealed a unifying principle: aligned neutral frustration yields permissive, escape-prone interfaces; decoupling enables the targeting of constrained cores; and the convergence of minimal frustration in both distributions creates invulnerable interfaces. These findings establish that broad neutralization arises not from ultra-high-affinity anchors but from strategic energy distribution across rigid, evolutionarily informed interfaces, providing a roadmap for designing next-generation therapeutics that target the invulnerable cores of viral surface proteins. Full article

The evolution and spatial dissemination of SARS-CoV-2 Omicron subvariants have been characterized by rapid lineage replacement and complex transmission dynamics influenced by regional connectivity. This study presents a comprehensive discrete phylogeographic analysis of 90,136 SARS-CoV-2 sequences collected in Poland from 2022 to 2024 to reconstruct the dispersal dynamics of major Omicron lineages, including BA.1, BA.2, BA.5, CH.1, XBB.1, and JN.1. Utilizing Bayesian statistical frameworks, we identified significant viral transitions between the 16 Polish voivodeships and established variant-specific dominance windows ranging from 2 to 4 months. Our findings reveal a highly dynamic epidemic landscape with shifting regional epicenters. The initial BA.1 wave was primarily driven by the Mazovian voivodeship, accounting for 36.1% of outward migration events. This pattern shifted dramatically with the rise in BA.2, which was centered in the industrial Silesian region in the south-west, a densely populated area with strong economic ties to neighboring countries, potentially reflecting a different introduction or transmission dynamic. Furthermore, the epidemic landscape continued to reconfigure during the BA.5 wave, marked by the emergence of new transmission hubs in eastern border regions such as Lublin. Subsequent lineages exhibited distinct geographic signatures: BA.5 spread broadly along the Baltic-central corridor, CH.1 was centered in the north-east, XBB.1 re-emerged in the west-central region of Greater Poland, and JN.1 was driven overwhelmingly by Lesser Poland. These transitions highlight that regional transmission hubs are transient and influenced by local factors such as population density, cross-border mobility, and socio-economic connectivity. This study underscores the critical value of dense genomic surveillance in identifying evolving dispersal routes to inform adaptive, region-specific public health interventions. Full article

Given the rapid mutation and high transmissibility of coronaviruses, especially SARS-CoV-2, comparative genomic studies are crucial for understanding viral evolution, transmission dynamics, and therapeutic development. In prior work, we analyzed and compared the spectral distribution patterns of various k-mer subsets across 920 genome sequences, spanning from primates to prokaryotes. This revealed an evolutionary mechanism in genome sequences, indicating the presence of both CG and TA-specific selection modes. In the present study, we further investigate the specific selection modes in coronavirus genomic sequences by examining the intrinsic distribution rules of 32 XYi 6-mer subset spectra. Our results show that coronavirus genomes exhibit only the CG-specific selection mode, with no evidence of TA-specific selection. Using the CG-specific selection mode, we identified CG1 6-mers as the fundamental subset underlying coronavirus genome evolution. To validate the CG1 subset, we constructed phylogenetic relationships for a set of coronaviruses and SARS-CoV-2 variant genomes. Comparative analysis confirmed that the resulting phylogenetic relationships align more closely with established knowledge. This study thus provides a theoretical framework for inferring phylogenetic relationships at the whole-genome level. Full article

Background: Neuropsychiatric manifestations are a recognized complication of COVID-19, yet their temporal evolution across pandemic waves remains poorly characterized in hospitalized cohorts. This study examined whether their prevalence and composition changed across five successive waves. Methods: We conducted a retrospective observational study of 1471 hospitalized adults with confirmed Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection at Sibiu County Emergency Clinical Hospital, Romania (March 2020–January 2025), spanning ancestral through Omicron variants. A custom natural language processing pipeline extracted symptoms, medications, and International Classification of Diseases, 10th Revision (ICD-10) codes from electronic medical records. Nine hierarchical clinical clusters were defined; temporal trends were assessed using multivariable logistic regression with age-stratified replication. Results: Severe neurological presentations (stroke, seizures, hemiparesis) increased six-fold from 3.5% in Wave 1 to 20.1% in Wave 5, while psychiatric symptoms (anxiety, insomnia) declined from 13.3% to 4.3%. Overall, neuropsychiatric burden remained stable (~40–45%), revealing a compositional shift. This neurological trend persisted after multivariable adjustment (adjusted odds ratio 4.34, for Wave 5 vs. Wave 1) and within age-stratified subgroups, was inversely associated with respiratory severity and could not be attributed to vaccination status. The composite neurological severity index independently predicted mortality and intensive care unit admission. Conclusions: Neuropsychiatric manifestations in hospitalized Coronavirus disease of 2019 (COVID-19) patients underwent a compositional shift from psychiatric dominance in early waves to severe neurological dominance in later waves, consistent with a transition from reactive psychiatric presentations toward progressive neurological injury. This pattern, largely independent of measured confounders, underscores the need for sustained neurological surveillance beyond the acute respiratory phase. Full article