Search Results (2,586)

Nucleosides are extensively employed for the development of pharmaceuticals, chemotherapeutic agents, and bioregulators. Background/Objectives: The introduction of an additional chiral functionality into a carbohydrate or heterocyclic base fragment may increase the selectivity of interactions with nucleos(t)ide-metabolizing enzymes and receptors and, in some cases, lead to more specific physiological activities. Methods: An improvement of the selectivity of nucleoside-based drugs can be achieved either by the chemical modification of a carbohydrate or a base constituent or by a combination of these two approaches. Additionally, stereospecific enzymatic cleavage of nucleos(t)ide prodrugs containing biodegradable substituents can reduce cytotoxicity and enhance bioavailability. Results: A series of enantiomerically pure nucleosides modified at the ribose or heterocyclic base were obtained by chemical and enzymatic methods. Novel antiviral or anticancer active compounds, inhibiting viral or cellular enzymes or activating cellular nucleoside kinases have been found among chemically synthesized derivatives. Some exhibit strengthened “ligand–receptor” interaction, acting on receptors of the purinergic signaling system. During recent extensive structure–activity studies, several drugs and their prototypes have been proposed for the treatment of viral infections: the 2′C-fluoromethyl derivative of sofosbuvir (anti-SARS-CoV, preclinical), VV-261 (SFTSV, phase I clinical), balapiravir (dengue, phase I clinical), mericitabine (approved drug for HCV), and lumicitabine (approved drug for RSV and HMPV). Conclusions: Modern literature data within the scope of the present review suggest that direct modification of nucleosides with various chiral functionalities can be considered as an approach to increase their efficacy, specificity and selectivity. Full article

The COVID-19 pandemic underscored the need to better characterize immune and molecular responses following SARS-CoV-2 infection and vaccination. Beyond antibody and cellular immunity, COVID-19 involves oxidative stress and DNA damage, affecting repair mechanisms and metabolic adaptation linked to immune resilience. Here, we present a multidimensional analysis of 20 individuals who recovered from mild COVID-19, integrating clinical features with humoral and cellular immune responses, T cell and myeloid phenotypes, oxidative stress, DNA damage, and metabolomic and lipidomic profiles. Although most individual parameters fell within physiological ranges, network modeling revealed structured associations spanning multiple biological domains. A central finding was a coherent cluster organized around vaccine dose number, linking anti-Spike antibody titers, oxidative stress, bioenergetic signatures, and granulocyte activation. Higher vaccination was associated with stronger humoral responses, lower oxidative stress, and a more balanced myeloid–metabolic profile, suggesting a potential protective role extending beyond antibody induction. Additional associations linked symptom patterns to T cell differentiation states, anti-nucleocapsid responses to systemic inflammation, and anaerobic signatures to DNA damage markers, revealing interconnections between immunometabolism, clinical expression, and genomic stress. Despite the small sample size, these findings offer a preliminary systems-level perspective on mild COVID-19 recovery and illustrate the value of integrative exploratory frameworks in infectious disease research, laying the groundwork for validation in larger longitudinal cohorts. Full article

RNA-dependent RNA-polymerase (RdRp), one of the key enzymes in the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) life cycle, is a recognized druggable target for Coronavirus disease 19 (COVID-19) treatment. Its inhibition has been associated with reduced viral loads in infected individuals. A library of 1562 Philippine Natural Compounds was screened in silico for potential SARS-CoV-2 anti-RdRp activity using a high-throughput virtual screening (VS) approach. Molecular docking experiments and in silico absorption, distribution, metabolism, and excretion (ADME) predictions were used to determine compounds with potential inhibitory capabilities against RdRp. The top three compounds, Vitelignin A (VIT), Vitexoside (VIX), and Cannabifolin C (CAN), were subjected to molecular dynamics (MD) simulations in complex with RdRp, confirming the formation of stable protein-ligand complexes. Overall, these results suggest promising inhibitory capabilities of these three compounds against SARS-CoV-2 RdRp. Their shared presence in extracts of Vitex negundo, a Philippine medicinal plant, warrants further in vitro and in vivo investigation regarding the anti-SARS-CoV-2 activity of its extracts and active components. Full article

Patients with multiple myeloma (MM) exhibit profound immune dysregulation, predisposing them to severe outcomes following SARS-CoV-2 infection. Current evidence highlights shared immunopathological mechanisms linking MM and COVID-19, with particular emphasis on the interleukin-6 (IL-6) axis as a shared amplifier of inflammation rather than the sole driver of disease. MM is characterized by a baseline pro-inflammatory milieu, in part mediated by IL-6, which is further amplified during SARS-CoV-2 infection, resulting in cytokine escalation, complement activation, coagulopathy, and multi-organ injury. This amplification operates within a broader, redundant network that also includes T-cell exhaustion, NK-cell dysfunction, checkpoint signaling, complement and endothelial injury, and treatment-induced immune defects. This overlap provides a mechanistic basis for the disproportionately high morbidity and mortality observed in this population. Even with advancements in vaccination, antiviral therapy, and clinical practice, patients with MM who exhibit impaired vaccine responses, active disease, or treatment-related immune dysfunction continue to experience considerable vulnerability to COVID-19. In addition, MM patients demonstrate suboptimal vaccine-induced immune responses, contributing to persistent vulnerability to severe and breakthrough infections. Modern MM therapies, including anti-CD38 antibodies, BCMA-directed agents, and bispecific T-cell redirecting antibodies, further reshape antiviral immunity by reducing NK cells, inducing plasma cell aplasia, causing hypogammaglobulinemia, and impairing T-cell function. Emerging treatment approaches targeting this shared pathway have been explored, with a focus on mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs). EVs exhibit multimodal properties, including suppression of pro-inflammatory cytokines, restoration of immune homeostasis, inhibition of viral entry, and promotion of tissue repair and regeneration. Early clinical experience in severe COVID-19 populations suggests a favorable short-term safety profile; reported efficacy, however, derives from small, largely uncontrolled or early-phase studies, and the single randomized trial reporting a mortality benefit did so only in an exploratory post hoc subgroup, with its pre-specified primary endpoint not met. Overall, EVs constitute a biologically plausible but as yet unproven adjunctive strategy that warrants further investigation. Critically, no MM patient has ever been enrolled in an EV trial; current rationale for EV use in MM is therefore extrapolated entirely from non-MM populations, and no MM-specific data exist. Difficulties such as EV heterogeneity, manufacturing variability, uncertain pharmacokinetics, limited targeting efficiency, and potential prothrombotic effects must be resolved before their application in MM-specific clinical settings. Full article

Background/Objectives: There is wide variability in the available estimates on the burden of Long-COVID (LC), both among adults and children. Preliminary evidence suggests that this inconsistency may be due, at least in part, to the adoption of uneven diagnostic criteria, proposed by several international entities during the course of the pandemic, but no comprehensive evaluation has been performed so far to quantify the extent of variation among children. This systematic review and meta-analysis aims to update the available epidemiological estimates of LC among pediatric subjects, and to systematically appraise the degree of variability that can be attributed to the diagnostic criteria adopted. Methods: A systematic literature search identified cohort studies providing data on LC among children and adolescents with a previous SARS-CoV-2 infection. We computed (a) proportion and (b) head-to-head meta-analyses (a) to quantify the pooled rates of LC and LC-related symptoms, and (b) to assess the likelihood of developing LC based upon selected demographic and/or clinical characteristics, respectively. Results: In total, 52 cohort studies and 960,089 subjects were included. The pooled rate of LC was 18.1% (95% CI: 13.1–23.6), ranging from 16.2% to 21.6%, according to NIH or WHO diagnostic criteria, respectively. Fatigue, respiratory and neurological symptoms were most commonly reported by LC patients. Stratified analyses showed that females, adolescents (vs. children), subjects with comorbidities, and those with a previous severe COVID-19 (as compared to asymptomatic primary infections) were more likely to develop LC (all p < 0.05). In contrast, the likelihood of LC onset did not significantly vary between individuals with ≥1 anti-SARS-CoV-2 vaccine dose, versus the unvaccinated (pooled OR: 0.92; 95% CI: 0.61–1.41). Conclusions: Although the available estimates may largely vary depending on the adopted definition, LC affects a meaningful proportion of the pediatric population; as such, common clinical criteria and diagnostic approaches are urgently needed. Moreover, given the relevant methodological heterogeneity and the generally poor-to-fair quality of a large part of the available literature, high-quality studies adopting standardized methodologies are warranted to identify at-risk populations and guide the implementation of targeted follow-up strategies. Full article

Persistent infection with high-risk human papillomavirus (HPV), particularly HPV16, is a major driver of HPV-associated cancers; however, strategies for treating established HPV-induced tumors remain scarce. Here, we developed a DNA-based vaccine linking the SARS-CoV-2 spike (S) protein with an HPV16 E7 epitope (aa 49-57) to simultaneously induce antiviral humoral immunity and antitumor cellular responses. We generated 2 constructs, S-E7 and S-RE7, with the latter incorporating a furin cleavage site (R) to enhance antigen processing. In vitro, S-RE7 significantly enhanced E7-specific CD8⁺ T cell activation compared to S-E7, highlighting the importance of the furin sequence. In vivo, both S-linked vaccines elicited robust E7-specific CD8⁺ T cell responses and provided complete protection against TC-1 tumor challenge in a prophylactic murine model, with long-lasting immunity upon tumor rechallenge. In therapeutic settings, vaccination with S-E7 or S-RE7 significantly suppressed tumor growth, extended survival, and reduced circulating myeloid-derived suppressor cells (MDSCs), indicating alleviation of systemic immunosuppression. Notably, S-RE7 demonstrated faster antitumor effects overall in early tumor progression. In addition to cellular immunity, both constructs induced high levels of anti-spike antibodies, with S-RE7 eliciting approximately fourfold higher responses than S-E7. Furthermore, S-RE7 effectively boosted pre-existing anti-spike immunity in mice that were previously vaccinated. This “two-in-one” strategy represents a promising and versatile platform for the prevention and treatment of HPV-associated cancers while maintaining preparedness against potential SARS-CoV-2. Full article

Background and Objectives: Thyroid dysfunction has been increasingly reported during and after SARS-CoV-2 infection, yet prospective longitudinal studies integrating biochemical and imaging assessments remain limited. The aim of this study was to evaluate the evolution of thyroid function and structural changes during a 12-month follow-up after COVID-19 hospitalization. Materials and Methods: This prospective single-center cohort study included adult patients hospitalized with laboratory-confirmed COVID-19 between December 2022 and December 2024. Thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), anti-thyroid peroxidase (anti-TPO), and anti-thyroglobulin antibodies (anti-TG) were assessed during hospitalization and at 1, 3, 6, and 12 months. Color Doppler thyroid ultrasound was performed at baseline and 6 and 12 months. Acute disease severity, vaccination status, and corticosteroid exposure were recorded. Results: Of the 71 enrolled patients, 67 completed the 12-month follow-up. Subacute thyroiditis occurred in 4/67 patients (6.0%; 95% CI: 1.7–12.6%). After excluding individuals with pre-existing disease, newly detected autoimmune thyroiditis was identified in 8/61 patients (13.1%; 95% CI: 5.8–24.2%). Most cases were mild and self-limited. Ultrasound patterns suggestive of autoimmune thyroiditis increased over time, even in patients with minimal biochemical abnormalities. Thyroid hormone trajectories showed interindividual variability, with most values remaining within reference ranges. Associations with inflammatory markers, disease severity, and vaccination status were weak. Conclusions: A subset of patients developed biochemical and structural thyroid changes during the 12 months following COVID-19 hospitalization. These findings highlight the value of targeted thyroid follow-up after COVID-19, particularly in patients with persistent symptoms, borderline TSH values, or ultrasound changes suggestive of autoimmune thyroiditis. Full article

Background: Ischemic stroke has been reported rarely after coronavirus disease 2019 (COVID-19) vaccination, most clearly in association with vaccine-induced immune thrombotic thrombocytopenia (VITT). Nevertheless, temporal proximity alone cannot establish causality, particularly when conventional vascular risk factors are present. We report a case of posterior circulation ischemic stroke occurring 36–48 h after first-dose ChAdOx1 nCoV-19/AZD1222 vaccination without VITT and provide a focused narrative review of the clinical, epidemiological, and mechanistic evidence regarding post-vaccination stroke. Methods: Clinical, laboratory, and neuroimaging data were reviewed retrospectively. A focused narrative literature review was performed to contextualize VITT-related and non-VITT ischemic stroke after COVID-19 vaccination, pharmacovigilance signals, population-based evidence, and proposed biological mechanisms. Results: A 63-year-old man with well-controlled hypertension and a remote history of smoking developed systemic symptoms within 24 h of first-dose ChAdOx1 nCoV-19/AZD1222 vaccination, followed by severe hypertension and acute posterior circulation neurological symptoms 36–48 h after vaccination. Neuroimaging showed an acute left cerebellar infarct extending into the middle cerebellar peduncle, with approximately 50% stenosis of the intradural left vertebral artery. Platelet counts remained normal, D-dimer and anti-PF4 antibody testing were normal, SARS-CoV-2 polymerase chain reaction (PCR) testing was negative, and routine cardiac evaluation did not identify a definite cardioembolic source. Conclusions: This case highlights an early posterior circulation ischemic stroke temporally associated with ChAdOx1 nCoV-19/AZD1222 vaccination in the absence of VITT. Although individual causality cannot be established from a single case, careful reporting of such presentations may improve clinical recognition, etiological evaluation, and pharmacovigilance. Full article

Messenger RNA (mRNA) vaccines represent a transformative platform in vaccinology, with applications extending beyond SARS-CoV-2 to other infectious diseases and cancer immunotherapy. However, patients with solid tumors receiving active anticancer treatment were largely underrepresented in pivotal vaccination trials, limiting understanding of vaccine-induced immunity in this population. In this prospective exploratory study, we assessed humoral and cellular immune responses after two doses of SARS-CoV-2 mRNA vaccines in 39 patients with solid tumors undergoing active treatment. Blood samples were collected before vaccination and approximately two months after the second vaccine dose, prior to the next treatment cycle. Anti-spike IgG, neutralizing antibodies, receptor-binding domain (RBD) levels, interleukin-6 (IL-6), hematological parameters, immune cell subsets, T-cell differentiation, and early apoptosis in αβ and γδ T-cell subsets were analyzed. Vaccination induced a robust humoral response, with high post-vaccination anti-spike IgG levels (median 988.69 BAU/mL), 97.44% seropositivity, 96.88% true seroconversion among baseline IgG−/NAb− patients, and strong neutralizing antibody activity (median 85.73%). Hematological parameters and IL-6 levels remained broadly stable, suggesting no detectable increase in systemic inflammation during the study period. Cellular analyses identified a reduction in peripheral CD19+ B-cell frequencies and decreased early apoptosis, particularly in CD8+ T cells and CD3+CD56+ NKT-like cells. Although changes in T-cell frequencies and differentiation profiles were also observed, these findings were attenuated after exclusion of participants with possible prior SARS-CoV-2 exposure and should be interpreted as exploratory. Overall, these results show that patients with solid tumors receiving active treatment can mount robust humoral responses to SARS-CoV-2 mRNA vaccination and suggest measurable post-vaccination changes in lymphocyte dynamics, including reduced early T-cell apoptosis. Full article

Background/Objectives: Pediatric acute-onset neuropsychiatric syndrome (PANS) describes the rapid onset of obsessive–compulsive symptoms or severe food restriction, accompanied by neuropsychiatric or somatic features that are not better explained by another disorder. PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections) is a related, more narrowly defined construct in which symptoms are temporally associated with group A Streptococcus infection. This review examines clinical symptoms, infectious associations, proposed immune mechanisms, biomarker limitations, and treatment strategies for infection-associated PANS/PANDAS. Methods: A structured narrative search of PubMed/MEDLINE, Embase, the Cochrane Library, Google Scholar/publisher-indexed literature, ClinicalTrials.gov, and reference lists was performed up to 16 June 2026. Original cohorts, case series, systematic reviews, narrative reviews, consensus guidance, mechanistic studies, and registered prospective studies were prioritized. The review was not designed as a PRISMA-ScR scoping review; however, the methods were expanded to improve transparency and align with SANRA principles. Results: Group A Streptococcus remains the best characterized infectious association, although prospective studies have not uniformly demonstrated a consistent temporal relationship between streptococcal infection and neuropsychiatric exacerbations. Parent-reported surveys and case-based literature also describe temporal associations with Mycoplasma pneumoniae, influenza-like illnesses, upper respiratory infections, Borrelia burgdorferi, Epstein–Barr virus, and SARS-CoV-2. Proposed mechanisms include molecular mimicry, anti-D1R and anti-D2R antibodies, other antineuronal antibodies, calcium/calmodulin-dependent protein kinase II signaling, blood–brain barrier vulnerability, cytokine and Th17 effects, neuroinflammatory amplification, basal ganglia/CSTC circuit dysfunction, and gut–oral–brain immune interactions. None currently provides a definitive diagnostic biomarker. Conclusions: Infection-associated PANS is best approached as a clinically defined, heterogeneous neuroimmune presentation that requires rigorous differential diagnosis, multidisciplinary care, cautious treatment escalation, prospective biomarker validation, and large, multicenter treatment trials. Full article

Convergent evolution in protein antigens is common across pathogens, including SARS-CoV-2; the most likely reason is the need to evade the selective pressure exerted by previous infection- or vaccine-elicited immunity. There is a pressing need for automated analysis of convergent mutations. We developed ConvMut, a tool to identify patterns of recurrent mutations in SARS-CoV-2 evolution; we exploited the granular phylogeny-based lineage hierarchy developed by PANGO, allowing us to observe deltas, i.e., groups of mutations that are acquired with respect to the immediately upstream tree nodes. Deltas comprise amino acid substitutions, insertions, and deletions. ConvMut can perform individual protein analysis to identify the most common single mutations acquired independently in a given subtree. Lineages are then gathered into clusters according to user-selected sets of shared mutations. An interactive graph orders the evolutionary steps of clusters, details the acquired amino acid change for each sublineage, and allows us to trace the evolutionary path until a selected lineage. ConvMut also supports frequency analysis for a given nucleotide or amino acid changes at a given residue across a selected phylogenetic subtree. ConvMut facilitates the exploration of convergent evolutionary trends in SARS-CoV-2, providing insights that could support the development of broadly effective anti-Spike monoclonal antibodies and Spike-based vaccines. Full article

This review describes a novel method for increasing the effectiveness of inactivated enveloped whole-virus vaccines by targeting them for extensive uptake by antigen-presenting cells (APCs). Several inactivated whole-virus vaccines with dense glycan shields display suboptimal effectiveness because the multiple carbohydrate chains (glycans) on the virus mask immunogenic peptides and surround the virus with a negative electrostatic charge that decreases uptake by APCs. It is postulated that engineering such vaccinating viruses to present the carbohydrate antigen “α-gal epitope” on the glycan shields will immunocomplex them with the anti-Gal antibody; thus, it will target them for robust uptake by APCs. Anti-Gal is an abundant natural antibody in humans, constituting ~1% of human circulating immunoglobulins. The ligand of anti-Gal is the α-gal epitope, which is naturally synthesized in non-primate mammals and New World monkeys by the glycosylation enzyme α1,3galactosyltransferase. This enzyme is encoded by the GGTA1-gene. Viral vaccines presenting multiple α-gal epitopes on their glycan shield bind anti-Gal and activate the complement system to produce complement chemotactic cleavage peptides C5a and C3a that induce extensive recruitment of APCs to vaccine injection sites. The virion-bound anti-Gal further targets the viral vaccine for robust uptake by APCs, following binding of its Fc “tail” to Fcγ-receptors on APCs. The efficacy of this method was studied in anti-Gal-producing mice with α-gal presenting inactivated influenza virus vaccine and with gp120 of HIV presenting this epitope. These studies indicated that virus vaccines engineered to present α-gal epitopes increase anti-virus antibody production and virus-specific T-cell activation by 15- to 100-fold in comparison to the same vaccines lacking α-gal epitopes. It is suggested that α-gal presenting inactivated SARS-CoV-2 virus vaccines can induce a similar protective long-term immune memory against S- M-, E-, and N-viral proteins. Furthermore, immune-escaping variants of the mutated S-protein may be destroyed by antibodies to M and E proteins, and cells infected with such variants may be killed by cytotoxic T cells specific to peptides of the N-protein. Such an anti-M-, E-, and N-protein immune protection may prevent expansion of these variants and thus may avoid the need for immunization with COVID-19 vaccines every 6 months or following the appearance of new variants. A similar potent immunization may be achieved with an inactivated Ebolavirus vaccine engineered to present α-gal epitopes on the glycan shield. The resulting immune response to the various Ebolavirus proteins also may contribute to cross-reactive protection against other Ebolavirus species containing proteins with evolutionarily conserved structures. An effective method for the preparation of a whole-virus vaccine presenting α-gal epitopes is by arming it with the GGTA1-gene inserted into the viral genome. Such virions will present multiple α-gal epitopes on their glycan shield, which will amplify their immunogenicity instead of reducing it in the wild-type virus. Full article

The immune response is essential in the protection of our body against pathogens; however, the inflammatory response caused by the immune system can become a disease itself. In fact, anti-inflammatory and immune-suppressive drugs are applied to limit the immune response to treat inflammatory diseases. Flavonoids are plant-derived polyphenols extensively investigated for their anti-inflammatory and antioxidant properties in inflammatory diseases. Studies applying isolated compounds as well as using supplements as nutraceuticals based on flavonoids have been conducted. Our review systematically analyzed the top five studied flavonoids between 2020 and 2025: quercetin (1742 articles), kaempferol (642), luteolin (589), apigenin (419), and epicatechin (354), highlighting their major therapeutic applications in diseases affecting the liver (12%), nervous system (11%), and lungs (10%). Mechanistically, these compounds act as multi-target agents mainly by inhibiting NF-κB and inducing Nrf2-dependent antioxidant programs. Application of advanced delivery systems, which increase oral bioavailability by up to 20-fold, overcomes pharmacokinetic bottlenecks. Clinical highlights demonstrated promising therapeutic effects, including reduced intrahepatic lipid accumulation in non-alcoholic fatty liver disease patients following quercetin supplementation (11.5% to 9.6%) and accelerated SARS-CoV-2 clearance after quercetin phytosome administration. The translation of flavonoids into standardized clinical therapies remains limited by the lack of large-scale, well-controlled clinical trials. Full article

The composition of low-polarity extracts obtained by sequential extraction of the aerial parts of Rhododendron adamsii Rehd. with hexane and methyl tert-butyl ether (MTBE) was investigated using GC-MS. The hexane extract was dominated by non-polar components: squalene, n-alkanes (nonacosane, hentriacontane), sesquiterpenes (trans-nerolidol, spathulenol, β-farnesene), and β-sitosterol. The subsequent MTBE extract was enriched in more polar lipids, primarily free triterpenic acids (ursolic and oleanolic acids). A critical finding was the complete absence of diterpene grayanotoxins in all tested extracts, confirming the safety of the non-polar extraction approach. In bioactivity assays, the total hexane extract demonstrated potent inhibitory activity against the SARS-CoV-2 main protease (3CLpro) with IC₅₀ values of 0.0125–0.025 mg/mL, only one order of magnitude higher than the reference inhibitor disulfiram. Fractionation revealed that the activity was distributed among free acids, bound acids, and the unsaponifiable residue, indicating a multicomponent mechanism. Importantly, none of the samples inhibited HIV-1 protease (IC₅₀ > 0.1 mg/mL), demonstrating selectivity for the cysteine protease 3CLpro over the aspartyl protease of HIV-1. These results highlight that sequential non-polar extraction of R. adamsii provides a grayanotoxin-free lipophilic complex with selective anti-SARS-CoV-2 protease activity, paving the way for bioactivity-guided identification of individual inhibitors. 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