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Acute respiratory infections (ARIs) are diseases that significantly impact public health, traditional PCR panels often fail to detect acute respiratory infections (ARIs) due to unmonitored viruses, primer mismatches, or geographically isolated variants. To overcome these diagnostic limitations, the primary purpose of this study is to uncover hidden viral etiologies through a stringent mNGS bioinformatic algorithm. By applying untargeted metagenomic sequencing to 300 previously test-negative nasopharyngeal samples across diverse cohorts in Peru, this research aims to characterize undetected pathogens and support national genomic surveillance. Genomic material was amplified via sequence-independent single-primer amplification (SISPA) and sequenced using the Illumina platform. Following quality filtering and human read depletion, taxonomic identification was performed using Kraken2. A stringent custom filtration algorithm based on taxon-specific reads per million ratios (RPMr), SMNR and MAPQ thresholds. Unbiased mNGS of 300 test-negative respiratory samples revealed a viral landscape dominated by Coronaviridae (67.2%; predominantly SARS-CoV-2), followed by Picornaviridae (13.6%), Orthoherpesviridae (12.0%), Paramyxoviridae (5.6%), Anelloviridae (0.8%), and Adenoviridae (0.8%). Agnostic mNGS bypasses targeted assay limitations, revealing that 35.66% of previously negative samples contained hidden pathogens. This approach proves pivotal for respiratory virus surveillance, enhancing pathogen tracking and outbreak detection. Full article

Background/Objectives: Schools are recognised sites of exposure to respiratory viruses for students and staff, representing a recognised public health concern. Environmental air sampling has been developed as a non-invasive surveillance approach that can detect circulating respiratory viruses, including those shed by asymptomatic persons, without the need for individual testing. However, the methodological and operational evidence base for this approach within educational settings remains nascent. This scoping review systematically maps the extant literature, characterising targeted respiratory viruses, sampling and analytical methodologies, assessed environmental covariates, and critical knowledge gaps. Methods: Adhering to the PRISMA-ScR guidelines, a systematic search of PubMed, Web of Science, and ScienceDirect was executed without temporal restrictions. Results: Eleven studies met the inclusion criteria. Viral RNA detection frequencies exhibited substantial heterogeneity (0–98.5%), primarily attributable to the study design parameters, single-target assays yielding lower positivity versus broad-spectrum multiplex panels, compounded by the stringency of concurrent infection-control interventions. In the singular investigation reporting comprehensive viral ranking, rhinovirus predominated, followed by respiratory syncytial virus (RSV-A/B), and influenza A/B. SARS-CoV-2 detection was profoundly influenced by the pandemic phase dynamics. Critically, all positive detections signified nucleic acid presence, with zero studies confirming viable virions via infectivity assays, representing a fundamental interpretive limitation. Conclusions: Airborne respiratory viral RNA from infected school occupants is unequivocally detectable, positioning environmental sampling as a promising adjunct to clinical surveillance for syndromic characterisation. Nevertheless, translating this approach into a robust, real-time operational infection-control instrument necessitates rigorous methodological harmonisation, alongside comprehensive assessments of viral infectivity, economic viability, and pragmatic feasibility to bridge prevailing translational gaps. Beyond mapping the primary studies, this review additionally benchmarks school-based sampling against practice in hospitals, universities, and other congregate settings, evaluates surface sampling as a complementary environmental modality, and analyses the dilution-limited regime that governs airborne viral detection in ventilated classrooms, which defines the performance envelope that next-generation high-flow, low-loss samplers must meet. Full article

The toxicological risk and development of resistance associated with synthetic drugs and supplements can be reduced by focusing efforts on medicinal plants that are of interest in pharmacognostic research to find new drugs or templates for the development of new bioactive compounds. The parasitic plant Cuscuta spp. has significant pharmacological activity at the extract level, but there is limited data on the bioactivity of its chemical compounds. In the present study, we aimed to investigate the antiviral potential of extracts obtained from different parts of two species, C. campestris and C. epithymum. The two species clearly differ in their flavonoid profiles, which could also suggest different antiviral activities of the extracts. We used methanol and aqueous extracts, MDBK, VERO E6 clone 76 and BGM cell lines, HSV-1, HSV-2 strain DD (acyclovir-resistant), HCoV-229E and SARS-CoV-2, maximum tolerable concentration, the MTT test, the plaque-forming method and the HPLS-MS analysis. It was found that the metabolic composition varies depending on the host plant. We hypothesize that differences in the composition of the extracts lead to differences in antiviral activity. Some of the tested methanol extracts showed a pronounced inhibitory effect, both on replication and on extracellular virions, in relation to the ACV-resistant strain of HSV type 2 and SARS-CoV-2 in comparison with the other viral models used by us. The strongest antiviral effect was shown by the methanol extract of C. campestris with host Chenopodium spp. against SARS-CoV-2, as the virus inhibition was about 100%, and the virucidal effect showed a decrease in the viral titer by more than 2.5 lg. Based on the results obtained, we assume possible antagonistic interaction of individual metabolites in the total methanol extracts. Extract C3, applied at the maximum tolerable concentration and one level lower, inhibits SARS-CoV-2 about 100 percent. SARS-CoV-2-infected cells preserved mitochondrial activity and relatively preserved lysosomal activity; this is also the reason why the MTT test, as well as neutral red staining, is not applicable to this viral model propagated in the VERO E6 cell line. Full article

Background/Objectives: Most evidence on SARS-CoV-2 infection in pregnancy comes from hospitalised or symptomatic cohorts sampled early in the pandemic. We described maternal and neonatal outcomes in an unselected cohort of PCR-confirmed infections ending in live birth, identified characteristics associated with neonatal intensive care unit (NICU) admission and with prolonged maternal hospitalisation, and benchmarked event rates against national data. Methods: A retrospective cohort of all pregnant women with a positive nasopharyngeal SARS-CoV-2 RT-PCR result at a Turkish tertiary centre between March 2020 and May 2023. Of 151 women identified, 133 had retrievable records; eight pregnancies did not end in a live birth, leaving 125. Prespecified subgroups (NICU admission; maternal stay >3 days) were compared using Mann–Whitney U and χ²/Fisher exact tests, and cohort proportions with 2024 Turkish national rates by one-sample exact binomial tests. Results: The mean maternal age was 29.9 ± 5.5 years and gestational age at delivery was 38.0 ± 2.0 weeks; 19 women (15.2%) delivered preterm and 76 (60.8%) were diagnosed in the third trimester. Sixteen neonates (12.8%) required NICU care and two mothers (1.6%) intensive care; there were no maternal deaths or stillbirths. NICU admission was associated with preterm birth (56.2% vs. 9.2%, p < 0.001) and lower Apgar scores, and prolonged maternal stay with preterm birth, pregnancy-related comorbidity, and caesarean delivery (all p ≤ 0.001). Neither the trimester of infection nor vaccination status was associated with either outcome. Caesarean (64.0%) and preterm birth (15.2%) rates did not exceed national values (p = 0.58 and p = 0.42). Conclusions: Adverse outcomes clustered with preterm delivery and pre-existing pregnancy complications rather than with the timing of infection. Without a matched control group, and with power limited to large effects, these descriptive findings cannot exclude a clinically important effect of SARS-CoV-2. Full article

Coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), exposed critical gaps in global preparedness for rapidly evolving viral pandemics. Though current antiviral treatments have shown some efficacy in managing COVID-19, substantial limitations, such as inefficient targeted drug delivery, aberrant host immune responses, and inadequate preparedness for future viral pandemics, were also evident. These challenges underscore the urgent need for target-specific, precise and efficient therapeutic strategies to modulate viral entry and immune dysregulation. Extracellular vesicles (EVs), cell-released cargo-carrying nanoscale vesicles, can both facilitate and inhibit viral infection depending on their cargo composition. Thus, endogenous EVs can promote or inhibit COVID-19 pathogenesis by modulating critical pathways, including angiotensin-converting enzyme 2 (ACE2)-mediated viral entry, transmembrane protease serine 2 (TMPRSS2)- dependent spike protein activation, nuclear factor kappa B (NF-κB)-driven inflammatory signaling, and NLRP3 inflammasome activation. In contrast, engineered EVs, such as ACE2-expressing EVs, mesenchymal stem cell-derived EVs and microRNA-enriched EVs, have therapeutic potential as they can facilitate antiviral defense through immune modulation, viral neutralization and suppression of cytokine storm. Moreover, EV-associated nucleic acids, proteins and lipids can act as biomarkers for disease detection and severity stratification. A deeper understanding of EV-virus mechanistic insights can enhance preparedness for similar viral diseases. In this review, we provide a comprehensive analysis of the molecular mechanisms underlying EV-virus interactions highlighting the therapeutic and diagnostic potential of EVs in tackling COVID-19 and future viral pandemics. Full article

Background: Organising pneumonia secondary to COVID-19 (OP-COVID-19) is a recognised inflammatory complication of SARS-CoV-2 infection. We assessed the 2-year clinical, radiological, and functional evolution of patients hospitalised with OP-COVID-19 and identified factors independently associated with long-term fibrotic-like lesions. Methods: This ambispective longitudinal study included adults consecutively hospitalised with OP-COVID-19 from March 2020 to February 2021. Diagnosis was based on clinical assessment and high-resolution computed tomography (HRCT). Patients underwent standardised follow-up at 3, 6, 12, and 24 months after hospital discharge, including clinical assessment, chest HRCT, pulmonary function tests, and the six-minute walk test. Longitudinal radiological changes were assessed using paired comparisons, and exploratory multivariable logistic regression identified factors independently associated with long-term fibrotic-like lesions. Results: OP-COVID-19 was diagnosed in 271 patients (4.9%), and 228 were included in the follow-up cohort. Inflammatory HRCT abnormalities resolved progressively, with paired comparisons showing a significant reduction in consolidations, peribronchovascular opacities, crazy-paving pattern, reversed halo sign, and perilobular opacities at 3–6 months compared with the initial HRCT (p < 0.05 for all). Among the 221 patients with an ascertainable final radiological outcome, persistent pulmonary abnormalities were observed in 14.9%, including fibrotic-like lesions in 10.4%. No statistically detectable late radiological progression was observed among patients undergoing extended imaging follow-up. The need for respiratory support during the acute phase (odds ratio [OR] 5.79, 95% confidence interval [CI] 1.81–18.52), bronchial dilatation (OR 3.50, 95% CI 1.10–11.11), and architectural distortion and/or volume loss on initial HRCT (OR 4.72, 95% CI 1.80–12.35) were independently associated with long-term fibrotic-like abnormalities. Pulmonary function was largely preserved, with mildly reduced diffusing capacity for carbon monoxide (DLCO) in the assessed subsets. Conclusions: OP-COVID-19 has a favourable long-term prognosis, with progressive resolution of inflammatory abnormalities in most patients. Fibrotic-like lesions occur in a minority of patients and are associated with greater initial disease severity and early structural abnormalities on HRCT. These findings support risk-stratified follow-up for patients with OP-COVID-19. Full article

Isolation, quarantine, and contact tracing are some of the most critical and commonly employed non-pharmaceutical interventions used to control the spread of COVID-19. However, the effectiveness of these strategies and their implementation depends on many factors, including a country’s population, the availability of resources to diagnose and effectively isolate infected individuals, culture and societal beliefs, family dynamics, and the feasibility and acceptability of isolation and quarantine policies among the public. This narrative review aims to appraise the evidence on the implementation strategies and shortcomings of isolation and quarantine strategies adopted during the COVID-19 pandemic. Previous evidence has found that early quarantine and isolation of COVID-19 patients were more effective than late adoption (5-fold vs. 2.6-fold). Approximately 90% of outbreaks could have been managed if 80% of contacts were monitored, traced, and isolated within four days of the index case being identified. For each new case of COVID-19, around thirty-six individuals should be traced. When the percentage of asymptomatic individuals is greater than 30%, isolation and contact tracing alone cannot contain the infection. The delay between symptom onset and isolation was the most important factor in determining infection control. Symptom-based isolation strategies should not be considered the sole criterion for isolation, as many asymptomatic individuals escaped isolation and increased the risk of disease transmission. Digital contact tracing, telemedicine, and artificial intelligence (AI)-based surveillance systems are potential adjuncts to support isolation and quarantine measures. Changes in societal behaviors and cultural norms, fear of stigma, psychological issues, economic burden, poverty, poor literacy rates, lack of public trust in government, and language were identified as challenges and barriers associated with the effective implementation of isolation and quarantine measures during the COVID-19 pandemic. Full article

Background/Objectives: Respiratory pathogens such as influenza virus and SARS-CoV-2 pose major threats to global public health. Current vaccines provide limited mucosal protection against respiratory infection, while vaccine-induced immunity can wane over time. Intranasal vaccination has emerged as a promising approach to induce mucosal immunity, however relatively low immunogenicity and limited durability remain major challenges. Various strategies have therefore been explored to improve intranasal vaccine efficacy, including mucosal adjuvants and alternative vaccine platforms. In this study, we evaluated the magnitude and durability of systemic and mucosal immune responses induced by an adenoviral vector vaccine. Methods: Six-week-old female C57BL/6 mice were immunized intranasally or intramuscularly with a single dose of an adenoviral vector vaccine and compared with mice receiving one or two doses of an intranasal CpG-adjuvanted protein vaccine. Humoral immune responses in serum and BALF, as well as cellular immune responses in the mLNs, lungs, and blood, were evaluated. We further assessed Ova-specific CD8 T cells with a lung-resident phenotype by class I MHC-peptide tetramer staining combined with intravascular labeling, allowing their direct ex vivo identification. Results: A single dose of intranasal adenoviral vector vaccination elicited potent serum IgG and BALF IgA responses, together with antigen-specific CD8 T cell responses in the blood, mLNs, and lungs. Notably, these systemic and respiratory mucosal immune responses were sustained for up to 4 months after vaccination, with lung-resident CD8 T cell responses detected at this time point. In contrast, intramuscular adenoviral vector vaccination predominantly induced systemic immunity. Intranasal CpG-adjuvanted protein vaccination induced weaker responses after a single dose, while booster vaccination enhanced systemic antibody and cellular responses but showed limited induction of mucosal immunity. Conclusions: A single intranasal dose of Ad5-Ova induced systemic and respiratory mucosal immune responses comparable to those observed after two-dose Ova+CpG vaccination, while maintaining these responses for up to 4 months. These findings suggest adenoviral vectors as a promising platform for inducing long-lasting respiratory mucosal immunity. Full article

Lower respiratory tract infections (LRTIs) are a leading infectious cause of death in children worldwide. Complete blood count (CBC)-derived inflammatory ratios are low-cost and widely available, yet their reported performance varies. We reviewed 46 PubMed-indexed studies (2016–2026) in children aged 0–18 years with viral, bacterial, or mycobacterial LRTI. The findings were mapped across diagnosis, etiological differentiation, severity, and outcome prediction. The neutrophil-to-lymphocyte ratio (NLR) was the most investigated marker, with the broadest evidence base for severity assessment and for separating bacterial from viral disease, although its performance remained pathogen-, population-, and endpoint-dependent; it was elevated in severe pertussis, tuberculosis, Mycoplasma pneumoniae, Streptococcus pneumoniae, and SARS-CoV-2 infection, whereas findings in respiratory syncytial virus infection were conflicting. The platelet-to-lymphocyte ratio had the next broadest evidence base for severity, and the systemic immune-inflammation index was consistently elevated in Mycoplasma pneumoniae and SARS-CoV-2 infection. No single ratio performed consistently across all etiologies. Ratios governed by one dominant immunopathogenic mechanism behaved predictably; those whose numerator and denominator respond to the same process did not. Cut-offs were neither standardized, age-specific, nor externally validated, and most estimates derived from retrospective cohorts in few countries; reported values therefore represent association and discrimination rather than validated prediction. Standardized, age-specific thresholds are needed before these markers can support routine risk stratification. Full article

In the post-pandemic era, identifying children who are most susceptible to severe illness and COVID-19-related mortality is essential for guiding public health policies. This study examined the risk factors for COVID-19-related severe illness and mortality from 2023 to mid-2025. We conducted a population-based cohort study using nationwide Brazilian data from patients aged <18 years with laboratory-confirmed SARS-CoV-2 infection between January 2023 and June 2025. The primary outcomes were COVID-19-related severity and death. Separate binary multivariable logistic regression models were developed for each of the outcomes. Among 465,689 children, 1.3% (n = 5963) developed severe illness, and 0.18% (n = 847) died. Factors associated with an increased risk of severe illness included age < 2 years, presence of comorbidities, Indigenous ethnicity, and lack of vaccination. Neurological disorders conferred the highest risk among the clinical conditions (adjusted odds ratio [aOR] = 34.1; 95% CI: 27.9–41.8). Regional differences were also observed; the North and Northeast regions showed higher mortality (aOR = 2.3; 95% CI: 1.8–3.0) than the Central-West region. Compared with White ethnicity, non-White ethnicities had higher mortality: Indigenous (aOR = 23.5; 95% CI: 13.5–39.3), Black (aOR = 1.95; 95% CI: 1.29–2.92), and Brown (aOR = 1.43; 95% CI: 1.18–1.73) ethnicities. Lack of any vaccine dose was associated with a significantly increased risk of severe illness (aOR = 1.39; 95% CI: 1.15–1.67. p < 0.001) and death (aOR = 2.1; 95% CI: 1.3–3.5; p < 0.001). In the post-pandemic era, younger age, comorbidities, sociodemographic disparities, and lack of vaccination were associated with an increased risk of severe illness and COVID-19-related death in the pediatric population. Full article

From a health perspective, the 21st century has witnessed the emergence and global impact of several major viral diseases, most notably coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, which has been associated with a substantial burden of secondary fungal infections. Patients suffering from COVID-19 illnesses frequently developed fungal co-infections, which can worsen clinical outcomes and complicate therapeutic efforts. Hospitalized individuals with viral infections are particularly susceptible to invasive fungal pathogens, including Aspergillus, Candida, and Mucorales species. The co-pathogenesis between respiratory virus and fungi is complex, involving dynamic interactions among the pathogens and the host immune system. Opportunistic fungal infections were found to be more prevalent in COVID-19-infected individuals, who require mechanical ventilation, have diabetes, or exhibit neutropenia. This review aims to provide a comprehensive overview of fungal co-infections associated with COVID-19 disease, with a focus on their pathogenesis, biomarkers, diagnostic approaches, and potential treatment strategies. Overall, the available evidence indicates that viral-induced immune dysregulation, epithelial barrier damage, and clinical risk factors contribute to the development and severity of fungal co-infections in COVID-19 patients. Early recognition using reliable biomarkers and standardized diagnostic approaches, together with timely and pathogen-directed antifungal therapy, are essential for improving clinical outcomes. Full article

Many people are affected by difficult-to-understand clinical phenomena associated with acute SARS-CoV-2 infection and by post-acute sequelae of COVID-19 (PASC, or long COVID, LC). The mechanisms responsible for the clinical phenomena have not been well established. The host cell receptor for SARS-CoV-2 is human angiotensin-converting enzyme 2 (ACE2), which binds the SARS-CoV-2 spike protein receptor-binding domain (RBD) to initiate infection. We hypothesized that some people may produce anti-RBD antibodies that sufficiently resemble ACE2 structure to have ACE2-like catalytic activity after infection, and such antibodies are hypothesized to contribute to disease pathogenesis. Our previous studies showed that ACE2-like catalytic activity was associated with immunoglobulin in some acute and convalescent COVID-19 patients. ACE2-like catalytic activity correlated with blood pressure changes following a moderate exercise challenge in people convalescing from COVID-19. To further establish that ACE2-like catalytic activity could be attributed to antibodies, we screened human monoclonal antibodies (mAbs) against SARS-CoV-2 spike protein from three different research centers and others purchased from a commercial source for ACE2-like catalytic activity. We identified four human monoclonal antibodies with ACE2-like catalytic activity. The ACE2-like catalytic activity of these mAbs was not inhibited by MLN-4760, a compound that inhibits native human ACE2 catalytic activity, nor by EDTA, unlike native ACE2, a zinc metalloprotease, but was inhibited by an overlapping pool of spike peptides. Enzyme kinetic studies showed that the mAbs had substantially lower Vmax and K_m values than native ACE2, consistent with the characteristics of other catalytic antibodies. The data therefore suggested that the antibodies cleave ACE2 substrate via a mechanism different from native ACE2. The identification of specific mAbs with ACE2-like catalytic activity supports the hypothesis that antibodies induced by SARS-CoV-2 infection could help mediate the pathogenesis of COVID-19 and LC, and, more generally, the hypothesis that catalytic antibodies induced by infectious agents can contribute to disease pathogenesis. Full article

Long COVID, defined by the National Academies of Sciences as an infection-associated chronic condition persisting at least three months following SARS-CoV-2 infection, presents a growing public health challenge. Despite national prevalence estimates of 11 to 15 percent among U.S. adults who have had COVID-19, the general population estimates of approximately 5 to 7 percent population-level symptom burden in diverse metropolitan areas remain insufficiently characterized. A cross-sectional survey was administered to adults residing in Houston and Harris County. Participants self-reported infection history, persistent symptoms lasting at least 90 days, health status, access to care, and functional impacts. Descriptive statistics summarize infected and affected, symptom frequency, and functional limitations. Of 264 eligible respondents who tested positive for COVID and rated the worst symptoms, 92 (34.85 percent) met the operational definition of Long COVID, representing an estimated sample-based prevalence of 16.91 percent across all 544 survey respondents. Given the use of convenience sampling, this figure should be interpreted as descriptive of this sample rather than as a generalized population-level estimate. Fatigue was the most reported persistent symptom (69.32 percent), followed by brain fog (62.5 percent), shortness of breath (48.84 percent), headache or migraine (43.02 percent), and joint or muscle pain (41.38 percent). Cognitive and functional symptoms predominate over respiratory symptoms. These findings demonstrate a substantial burden of persistent, multisystem symptoms in a sample of community-dwelling urban adults, highlighting the need for longitudinal research and targeted public health strategies to address long-term consequences of SARS-CoV-2 infection in diverse metropolitan settings. Full article

Coronaviruses comprise a diverse group of enveloped, positive-sense single-stranded RNA viruses capable of causing high morbidity in humans and livestock. The repeated emergence of severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2 underscores the critical need for broad-spectrum countermeasures. Mounting evidence demonstrates that successful coronavirus infection depends on the manipulation of host cellular pathways governing translation, metabolism, autophagy, and survival. The mechanistic target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that functions via the mammalian target of rapamycin complex 1 (mTORC1) and complex 2 (mTORC2) to integrate extracellular and intracellular signals. Rather than remaining passive metabolic bystanders, coronaviruses actively exploit and rewrite host PI3K/Akt/mTOR networks to facilitate structural translation, assemble double-membrane replication organelles, suppress autophagic clearance, and reprogram protective innate and adaptive immune landscapes. This review provides a comprehensive synthesis of the molecular mechanisms dictating coronavirus–mTOR interactions across human pathogens and high-impact veterinary models. We detail the clinical consequences of dysregulated mTOR signaling—including immunometabolic perturbations, long-term metabolic memory, and tissue-specific complications—and evaluate the therapeutic potential of allosteric rapalogs, dual ATP-competitive inhibitors, and natural compounds as host-directed platforms designed to complement conventional antiviral regimens and enhance global pandemic preparedness. Full article

Background: COVID-19 vaccines have proven effective in reducing severe disease and mortality from SARS CoV-2 infection. The underlying molecular mechanisms and alterations in the human serum metabolome influencing the effectiveness and development of immunity remain unclear. Methods: Serum samples were collected from 29 healthy individuals at three time points: prior to vaccination (A), post-first dose (B), and post-second dose (C). Untargeted high-resolution (HR) liquid chromatography coupled with mass spectrometry (LC-MS) was performed on these samples. Metabolites showing significant differential abundance at each time point were identified, and both multivariate and univariate statistical analyses were performed to determine changes associated with the pairwise comparisons, priming (A vs. B), booster (B vs. C), and the overall vaccine effect (A vs. C). Vaccination-specific features were determined after excluding metabolites associated with SARS-CoV-2 IgG seropositivity to better isolate vaccine-driven metabolic changes. Bioinformatics, pathway, and network analyses were conducted using Ingenuity Pathway Analysis (IPA) to identify relevant pathways. Results: Our study identified significant metabolic changes across the three time points. A total of 377 metabolites were identified, of which 59 metabolites, including prostaglandins, eicosanoids, and lipids, were shared across all three groups. The majority of these metabolites showed an initial decrease after the first dose, followed by broad upregulation after the second dose. We identified 1 (downregulated), 34 (26 upregulated and 8 downregulated), and 18 (2 upregulated and 16 downregulated) unique metabolites in the priming, booster, and the overall vaccine effect groups, respectively. L-3-hydroxykynurenine was observed to be significantly reduced by the priming dose effect. By contrast, the booster effect showed decreased myo-inositol 1,3,4,5-tetrakisphosphate, while levels of DL-DOPA, 3-methoxytyrosine, and prostaglandin-esterified phospholipids, including PC(P-16:0/PGF1α) and PE(PGF1α/18:0), increased. On the other hand, the overall vaccine effect revealed decreased cyclic AMP and increased 3′-O-methyladenosine levels. These changes were associated with perturbations in arachidonic acid metabolism, glycerophospholipid metabolism, arginine biosynthesis, and steroid hormone biosynthesis. IPA network analysis identified AKT, TP53, EGFR, and cAMP as key dysregulated nodes. Conclusions: Longitudinal metabolomic profiling demonstrated that COVID-19 vaccination induced distinct but interrelated biochemical changes throughout the vaccination course. The priming dose induced a limited set of early metabolic changes, whereas the booster was associated with more significantly changed metabolites that were involved in lipid, bile acid, steroid, amino acid, and nucleotide pathways. Together, these findings indicate that sequential vaccination is associated with dose-dependent systemic metabolic adaptation, with the booster dose having the largest number of dysregulated metabolites. Full article