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SARS-CoV-2, the virus responsible for coronavirus disease COVID-19, is a highly transmissible pathogen that has caused substantial global morbidity and mortality. The ongoing COVID-19 pandemic caused by this virus has had a significant impact on public health and the global economy. One approach to combating COVID-19 is the development of broadly neutralizing antibodies for prevention and treatment. In this work, we performed an in silico ligand-based screening of the PDB database to search for unique anti-SARS-CoV-2 motifs. The collected data were organized and presented in a classified SARS-CoV-2 Ligands Database, categorized based on the number of ligands and structural components of the spike glycoprotein. The database contains 1797 entries related to the structures of the spike glycoprotein (UniProt ID: P0DTC2), including both full-length molecules and their fragments (individual domains and their combinations) with various ligands, such as angiotensin-converting enzyme II and antibodies. The database’s capabilities allow users to explore various datasets according to the research objectives. To search for motifs in the receptor-binding domain (RBD) most frequently involved in antibody binding sites, antibodies were classified into four classes according to their location on the RBD; for each class, special binding motifs are revealed. In the RBD binding sites, specific tyrosine-containing motifs were found. Data obtained may help speed up the creation of new antibody-based therapies, and guide the rational design of next-generation vaccines. Full article

The COVID-19 outbreak has made it evident that the nature and behavior of SARS-CoV-2 requires constant research and surveillance, owing to the high mutation rates that lead to variants. This work focuses on the statistical analysis of energy measures as biomarkers of SARS-CoV-2. The main purpose of this study is to determine which energy measure can differentiate between SARS-CoV-2 variants, human cell receptors (GRP78 and ACE2), and their combinations. The dataset includes energy measures for different biological structures categorized by variants, receptors, and combinations, representing the sequence of variants and receptors. A multiple analysis of variance (ANOVA) test for equality of means and a Bartlett test for equality of variances are applied to energy measures. Results from multiple ANOVA show (a) the presence of significant differences in energy across variants, receptors, and combinations, (b) that average energy is significant only for receptors and combinations, but not for variants, and (c) the absence of significant differences observed for standard deviation across variants or combinations, but that there are significant differences across receptors. The results from the Bartlett tests show that (a) there is a presence of significant differences in the variances in energy across the variants and combinations, but no significant differences across receptors, (b) there is an absence of significant differences in variances across any group (variants, receptors, combinations), and (c) there is an absence of significant differences in variances for standard deviation of energy across variants, receptors, or combinations. In summary, it is concluded that energy and mean energy are the key biomarkers used to differentiate receptors and combinations. In addition, energy is the primary biomarker where variances differ across variants and combinations. These findings can help to implement tailored interventions, address the SARS-CoV-2 issue, and contribute considerably to the global fight against the pandemic. Full article

Although the SARS-CoV-2 pandemic no longer poses a global emergency, the virus continues to diversify and acquire immunoevasive properties. Understanding the molecular pathways that shape SARS-CoV-2 pathogenesis has become essential. In this paper, we summarize the most recent current evidence on how the spike protein structurally evolves, on changes in key non-structural proteins, such as nsp14, and on host factors, such as TMPRSS2 and neuropilin-1. These changes, together, shape viral entry, replication fidelity and interferon antagonism. Given the emerging Omicron variants of SARS-CoV-2, recent articles in the literature, cryo-EM analyses, and artificial intelligence-assisted mutational modeling were analyzed to infer and contextualize mutation-driven mechanisms. It is through these changes that the virus adapts and evolves, such as optimizing angiotensin-converting enzyme binding, modifying antigenic surfaces, and accumulating mutations that affect CD8⁺ T-cell recognition. Multi-omics data studies further support SARS-CoV-2 pathogenesis through convergent evidence linking viral adaptation to host immune and metabolic reprogramming, as occurs in myocarditis, liver injury, and acute kidney injury. By integrating proteomic, transcriptomic, and structural findings, this work presents how the virus persists and dictates disease severity through interferon antagonism (ORF6, ORF9b, and nsp1), adaptive immune evasion, and metabolic rewiring. All these insights underscore the need for next-generation interventions that provide a multidimensional framework for understanding the evolution of SARS-CoV-2 and guiding future antiviral strategies. Full article

Background/Objectives: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the global COVID-19 pandemic, which led to hundreds of millions of human infections and more than seven million deaths worldwide. Major variants of concern, particularly the Omicron variant and its associated subvariants, can escape the vaccines developed so far to target previous strains/subvariants. Therefore, effective vaccines that broadly neutralize different Omicron subvariants and show good protective efficacy are needed to prevent further spread of Omicron. The spike (S) protein, including its receptor-binding domain (RBD), is a key vaccine target. Methods: Here, we designed a unique mRNA vaccine encoding Omicron-KP.3 RBD based on RBD-truncated S protein backbone of an earlier Omicron subvariant EG.5 (KP3 mRNA), and evaluated its stability, immunogenicity, neutralizing activity, and protective efficacy in a mouse model. Results: Our data showed that the nucleoside-modified, lipid nanoparticle-encapsulated mRNA vaccine was stable at various temperatures during the period of detection. In addition, the vaccine elicited potent antibody responses with broadly neutralizing activity against multiple Omicron subvariants, including KP.2, KP.3, XEC, and NB.1.8.1. This mRNA vaccine protected immunized transgenic mice from challenge with SARS-CoV-2 Omicron-KP.3. Immune serum also protected against subsequent virus challenge, with the level of protection associating positively with the serum neutralizing antibody titer. Conclusions: Taken together, the data presented herein suggest that this newly designed mRNA vaccine has potential against current and future Omicron subvariants. Full article

Respiratory viruses such as SARS-CoV-2, influenzas A and B, respiratory syncytial virus (RSV), human metapneumovirus (hMPV), human parainfluenza virus type 3 (HPIV-3), and rhinoviruses remain major causes of global morbidity. Their rapid evolution, high transmissibility, and limited therapeutic options, together with the absence of approved vaccines for several pathogens, highlight the need for broad-acting and pathogen-independent antiviral strategies. Nitric oxide exhibits antiviral activity through redox-dependent mechanisms, including S-nitrosylation of cysteine-containing viral proteins and disruption of redox-sensitive structural domains. Clinical studies conducted during the SARS-CoV-2 pandemic demonstrated that a nitric oxide nasal spray (NONS) rapidly reduced nasal viral load and transmission. In this study, we evaluated the in vitro virucidal activity of the NONS against a panel of clinically relevant respiratory viruses representing four major virus families. Virus suspensions of approximately 10⁴ CCID₅₀ were exposed to a full-strength NONS for contact times ranging from 5 s to 2 min at room temperature, followed by neutralization and quantification of residual infectivity using endpoint dilution assays. The NONS rapidly reduced viral infectivity across all viruses tested, achieving >3 log₁₀ reductions within 2 min. SARS-CoV-2 variants including Alpha, Beta, Gamma, Delta, Omicron BA.1, and XBB 2.0 were reduced to levels at or below the assay detection limit within 30 s to 2 min. Influenza A and B viruses showed the fastest loss of infectivity, reaching detection limits within 10–15 s. RSV, hMPV, HPIV-3, and human rhinovirus 14 were similarly inactivated within 1–2 min. These findings demonstrate that the NONS exhibits rapid and broad-spectrum virucidal activity against diverse respiratory viruses and supports its potential role in pandemic preparedness but also seasonal use. Full article

Respiratory infections are a major public health threat. Significant global mortality is caused by influenza viruses, the new SARS-CoV-2 virus, and the Respiratory Syncytial Viruses (RSVs). Wastewater-based epidemiology (WBE) has recently emerged as a valuable tool for monitoring these pathogens, providing insights into their evolution, transmission patterns, and co-circulation within populations. This study aimed to track influenza viruses (A and B), the new SARS-CoV-2 virus, and the Respiratory Syncytial Viruses (RSVs) (type A and B) during the pandemic period (from October 2020 to October 2021) in a middle-size Spanish city (Valladolid) and its surrounding areas. Viral concentration was performed using an aluminum-based precipitation method, followed by RNA extraction and RT-qPCR quantification targeting the N1 and N2 regions of the SARS-CoV-2 nucleocapsid gene, the N gene for both RSV-A and RSV-B, and the M and non-structural protein genes for influenza A and B, respectively. The results demonstrated the utility of WBE in predicting increases in clinical cases of SARS-CoV-2, as evidenced by a high correlation (r > 0.5). For RSV-A, the findings aligned with previous studies. Interestingly, particularly considering the length and period of analysis, influenza A, influenza B, and RSV-B viruses were not observed during the study period. In addition, the prevalence of RSV-A decreased during the SARS-CoV-2 pandemic, likely due to the implementation of non-pharmaceutical interventions. In conclusion, this study reaffirms that WBE provides critical epidemiological insights, complements clinical surveillance, and supports public health authorities in making informed and timely decisions. Full article

The COVID-19 pandemic accelerated vaccine innovation but also exposed weaknesses in global access and manufacturing. Yeast-based platforms, particularly Saccharomyces cerevisiae and Pichia pastoris, also known as Komagataella phaffii, offer a practical complement to vector systems. These eukaryotic microorganisms combine safety, scalability, and cost-effectiveness with the ability to express complex antigens and assemble virus-like particles. Building on the success of the recombinant hepatitis B vaccine, recent advances in glycoengineering, CRISPR-based host optimization, and surface display technologies have expanded the utility of yeast-based platforms for the rapid development of vaccines. Yeast-derived SARS-CoV-2 receptor-binding domain (RBD) subunit vaccines, such as Corbevax and Abdala (CIGB-66), demonstrate that affordable, immunogenic, and thermostable products are feasible at scale. Emerging innovations in glycan humanization, thermostable formulations, and oral or mucosal delivery highlight the potential of yeast-based vaccines for decentralized manufacturing and equitable pandemic preparedness. This review summarizes recent technical and clinical progress in yeast-based vaccine research, positioning these platforms as accessible and adaptable tools for future outbreak responses and global immunization strategies. Full article

The coronavirus disease 2019 (COVID-19) pandemic remains a significant public health threat globally with significant socio-economic impacts. People living with human immunodeficiency virus (HIV) (PLWH) have a high risk of severe outcomes of COVID-19 due to immunosuppression. Clinical manifestation of COVID-19 in HIV patients largely remains unclear. We carried out a pilot study to investigate the clinical laboratory data and circulating cytokines in PLWH infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in Tatarstan, Russia. Serum samples were collected from three groups: PLWH with COVID-19 (PLWH/COVID-19), COVID-19-only, and uninfected controls. We found an increased risk of severe COVID-19 in PLWH/COVID-19 patients compared to COVID-19-only. Four fatal cases were in PLWH/COVID-19, while there was no fatality in COVID-19-only. Pro-inflammatory cytokines, such as IL-5, IL-6, IL-9, and IL-15, were elevated in PLWH/COVID-19 compered to COVID-19-only. These preliminary findings highlight the potential for more severe COVID-19 in PLWH/COVID-19 where pro-inflammatory cytokines could play pathogenic role. Full article

Background: Heart failure (HF) remains a major global health challenge, with orthotopic heart transplantation (OHT) serving as the gold-standard therapy for end-stage disease. Chronic immunosuppression required to prevent graft rejection increases the risk of infections and malignancies. The COVID-19 pandemic underscored the particular vulnerability of transplant recipients to severe SARS-CoV-2 infection. Specific immunosuppressive agents used in OHT patients may differentially affect SARS-CoV-2 infection. In particular, mTOR inhibitors may modulate viral replication and immune responses, potentially influencing disease severity. Objectives: This study evaluated the impact of immunosuppressive regimens—particularly mTOR inhibitors—on COVID-19 outcomes in heart transplant recipients, comparing mTOR-based therapy (with or without calcineurin inhibitors, CNIs) to non-mTOR-based regimens. Methods: This single-center retrospective observational study included 556 orthotopic heart transplant recipients (76.3% male; median age, 58 years) followed from March 2020 to March 2024. To compare patients receiving mTOR inhibitors with similar non-mTOR recipients, 3:1 propensity score matching was performed based on age, sex, and body mass index. Among the study population, 88 patients (15.8%) received mTOR inhibitors (everolimus or sirolimus), of whom 66 were concomitantly treated with calcineurin inhibitors and 22 without. Data were obtained from the National Health Fund database and clinical follow-ups. Results: Overall mortality was 13.5%, and COVID-19-related mortality 3.2%. COVID-19 incidence was 33% in the mTOR group versus 36.7% in the non-mTOR group (p = 0.52). Hospitalization rates were 3.4% and 6.4% (p = 0.29), respectively. All-cause mortality was higher among mTOR users (21.6% vs. 11.7%, p = 0.02), especially in the mTOR+CNI subgroup. Notably, no COVID-19-related deaths occurred in the mTOR CNI-free group. Conclusions: mTOR-based immunosuppression was non-inferior to standard therapy for COVID-19 outcomes. The absence of COVID-19-related deaths in patients on mTOR CNI-free regimens suggests potential protective effects that merit further investigation. Full article

Background/Objectives: Notwithstanding the declaration by the World Health Organization in May 2023 regarding the conclusion of the COVID-19 pandemic, new cases of this potentially lethal infection continue to be documented globally, exerting a sustained influence on the worldwide economy and social structures. Contemporary SARS-CoV-2 variants, while associated with a reduced propensity for severe acute pathology, retain the capacity to induce long-term post-COVID syndrome, including in ambulatory patient populations. This clinical phenomenon may be attributable to potential autoimmune reactions hypothetically triggered by antiviral antibodies, thereby underscoring the need for developing novel, universal vaccines against COVID-19. The nucleocapsid protein (N), being one of its most conserved and highly immunogenic components of SARS-CoV-2, presents a promising target for such investigative efforts. However, the protective role of anti-N antibodies, generated during natural infection or through immunization with N-based vaccines, alongside the potential adverse effects associated with their production, remains to be fully elucidated. In the present study, we aim to identify potential sites of homology in structures or sequences between the SARS-CoV-2 N protein and human antigens detected using hyperimmune sera against N protein obtained from mice, rabbits, and hamsters. Methods: We employed Western blot analysis of lysates from human cell lines (MCF7, HEK293T, THP-1, CaCo2, Hep2, T98G, A549) coupled with mass spectrometric identification to assess the cross-reactivity of polyclonal and monoclonal antibodies generated against recombinant SARS-CoV-2 N protein with human self-antigens. Results: We showed that anti-N antibodies developed in mice and rabbits exhibit pronounced immunoreactivity towards specific components of the human proteome. In contrast, anti-N immunoglobulins from hamsters showed no non-specific cross-reactivity with either hamster or human proteomic extracts because of the lack of autoreactivity or immunogenicity differences. Subsequent mass spectrometric analysis of the immunoreactive bands identified principal autoantigenic targets, which were predominantly heat shock proteins (including HSP90-beta, HSP70, mitochondrial HSP60, and HSPA8), histones (H2B, H3.1–3), and key metabolic enzymes (G6PD, GP3, PKM, members of the 1st family of aldo-keto reductases). Conclusions: The results obtained herein highlight the differences in the development of anti-N humoral responses in humans and in the Syrian hamster model. These data provide a foundational basis for formulating clinical recommendations to predict possible autoimmune consequences in COVID-19 convalescents and are of critical importance for the rational design of future N protein-based, cross-protective vaccine candidates against novel coronavirus infections. Full article

The COVID-19 pandemic, unleashed by SARS-CoV-2 in 2019 and amplified by variants such as Omicron, exposed global vulnerabilities, with over 700 million cases and 7 million deaths, fueling persistent fears of future pandemics from zoonotic RNA viruses amid accelerating urbanization and climate-driven spillovers [...] Full article

The ongoing COVID-19 pandemic, caused by SARS-CoV-2, continues to pose major global health challenges despite extensive vaccination efforts. Variant escape, waning immunity, and reduced vaccine efficacy in immunocompromised populations underscore the urgent need for complementary antiviral therapeutics. Here, we report the design, synthesis, and biological evaluation of precision-engineered dermatan sulfate (DS)-mimetic glycopolymers as multi-targeted inhibitors of SARS-CoV-2. Guided by molecular docking and virtual screening, sulfation at the C2 and C4 positions of iduronic acid was identified as critical for binding to the viral spike protein and inhibiting host and viral enzymes, including heparanase (HPSE) and main protease (M^pro). Chemically synthesized DS disaccharides were covalently grafted onto polymer scaffolds via a post-modification strategy, yielding glycopolymers with well-defined assembly that form uniform nanoparticles under physiological conditions. Surface plasmon resonance and pseudovirus assays revealed strong binding to the viral spike protein (K_D ≈ 177 nM), potent viral neutralization, and minimal cytotoxicity. Cellular uptake studies further demonstrated efficient internalization of nanoparticles and intracellular inhibition of HPSE and M^pro. These results establish a modular, non-anticoagulant, and glycosaminoglycan-mimetic platform for the development of broad-spectrum antiviral agents to complement vaccination and enhance preparedness against emerging coronavirus variants. Full article

Post-translational modifications (PTMs) are crucial chemical alterations occurring on proteins post-synthesis, impacting various cellular processes. During viral infections, PTMs are shown to play a multitude of roles in viral replication, host interaction, and immune evasion. Thus, these modifications can influence infectivity, with direct impact on the anti-viral host immune responses and potentially viral adaptation across species. This field is still scarcely explored, whilst understanding PTMs is not only important to advance the knowledge of virus pathology but also potentially to provide insights for vaccine development. In this review, we attempt to summarize the latest findings mainly published over the last 10 years, focusing on the roles of PTMs involved in virus infection and anti-viral immune responses, in the context of relevant human respiratory infections: influenza A virus (IAV), respiratory syncytial virus (RSV), and SARS-CoV-2. We decided to concentrate on these three viruses because they currently represent a global health problem due to recurrent outbreaks and pandemic potential. A deeper characterization of the PTMs may help in understanding virus–host interaction with possible implications on curative strategies. Further, we will report on cutting-edge technologies to study in vitro virus infection in different cellular-based systems. In particular, we describe and discuss the application of 2D and 3D lung organoid cell-culture systems as in vitro models to mimic respiratory environments and to study the PTMs in a controlled setting. Finally, we will discuss the importance of PTMs in the context of next-generation vaccine design, especially for their potential role to offer effective protection against respiratory viruses. Full article

During the COVID-19 pandemic, the global focus on SARS-CoV-2 overshadowed the epidemiology of other respiratory pathogens. This study aimed to characterize the circulation of endemic human coronaviruses (HCoVs) in Brazil. We retrospectively analyzed results from 22,472 PCR tests for HCoVs (from 5183 patients) and 601,278 tests for SARS-CoV-2 (from 475,856 patients) between November 2019 and June 2021. HCoVs were detected in 160 patients (3.09%), with HCoV-NL63 as the most frequent species. HCoV circulation was intermittent, with positivity peaks up to 4% but also periods of up to six months with an absence of detections in 2020, contrasting with the sustained high positivity of SARS-CoV-2 (22.37%). Co-infections were frequent: 26.25% of HCoV-positive patients were co-infected with at least one other respiratory pathogen, most commonly Rhinovirus/Enterovirus, and cases involving up to five pathogens were observed, seven patients had co-infections between HCoVs and SARS-CoV-2. These findings reveal the persistent, often cryptic, circulation of HCoVs during the pandemic and highlight their role as key components in complex multi-pathogen infections. This underscores the critical importance of implementing comprehensive molecular diagnostic panels in routine respiratory surveillance to ensure accurate etiology, guide appropriate clinical management, and fully assess the public health burden of non-SARS-CoV-2 coronaviruses. Full article