Optimized flagellin enhances systemic and mucosal immune responses induced by SARS-CoV-2 virus-like particle vaccines.

Intranasal administration of a DNA vaccine complexed with sugar-functionalized chitosan induces protective immunity against SARS-CoV-2 in mice.

Static thresholds for mechanical power (MP) may not prevent ventilator-induced lung injury because risk depends on exposure duration and the underlying respiratory compliance. We aimed to quantify how MP intensity and exposure duration interact with respiratory compliance to predict oxygenation changes consistent with acute respiratory distress syndrome worsening or 14-day mortality. A retrospective analysis of 2 large intensive care datasets. ICUs in the Netherlands and the United States from 2003 to 2016 and 2008 to 2019, respectively. Mechanically ventilated adults with oxygenation levels consistent with moderate to severe acute respiratory distress syndrome. None. Time-dependent Cox proportional hazards models stratified by respiratory compliance estimated the hour-specific associations of immediate exceedance and cumulative time above MP thresholds with the primary outcome. Estimated effects were integrated into a risk-adjusted mechanical-power score. Among 2150 mechanically ventilated acute respiratory distress syndrome patients risk from MP exposure was dictated by respiratory compliance: in higher-compliance lungs, risk followed a dose-response pattern, with immediate hazard beginning at 10 J/min (hazard ratio = 1.04) and cumulative harm amplifying significantly over time. Conversely, for low-compliance patients, risk was confined to a narrow power band (11-20 J/min) without evidence of cumulative harm. With risk-adjusted MP score as a predictor of outcome eXtreme Gradient Boosting yielded an area under the receiver operating characteristic curve of 0.863. A single "safe" MP threshold is insufficient for guiding ventilation; the risk of lung injury is governed by a dynamic interplay of power intensity, duration, and the patient's respiratory compliance. The risk-adjusted MP score unifies these factors into a time-varying, clinically interpretable metric that warrants prospective validation for personalized ventilator management.

Current coronavirus disease 2019 (COVID-19) vaccines effectively prevent severe disease but induce primarily systemic immunity without mucosal protection in the respiratory tract, which is mandatory for protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the prevention of viral transmission. Vaccination strategies capable of inducing local immunity at the site of infection are therefore needed. Here, we evaluated a poly (lactic-co-glycolic acid) (PLGA) microparticle-based vaccine co-encapsulating the receptor binding domain (RBD) of SARS-CoV-2 Spike protein with the TLR3/RIG-1 agonist Riboxxim, employing a subcutaneous prime and intranasal boost immunization schedule. BALB/c mice received subcutaneous prime immunization followed by intranasal boost with PLGA microparticles containing RBD/Riboxxim. Antibody responses were assessed by enzyme-linked immunosorbent assay (ELISA), neutralization by competitive ELISA and T-cell responses by enzyme-linked immune spot assay, intracellular cytokine staining and flow cytometry. Memory responses were evaluated 30 days post boost immunization. Vaccination induced robust RBD-specific IgG and IgA antibody titres in both serum and bronchoalveolar lavage fluid, with neutralizing capacity against the Wuhan-Hu-1 strain. Strong CD4+ and CD8+ T-cell responses were detected systemically and in the respiratory tract. Importantly, the vaccine generated durable immunological memory, including tissue-resident memory T-cells in the respiratory tract and long-lived IgG and IgA memory B-cells in secondary lymphoid organs. PLGA microparticle-based vaccination induces potent systemic and mucosal immune responses against SARS-CoV-2 RBD. This adaptable platform represents a promising approach for mucosal vaccination strategies, with potential for rapid adaptation to emerging variants.

The envelope-anchored trimeric spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mediates the attachment and entry of the virus within human cells by utilizing the angiotensin converting enzyme 2 (ACE2) as a receptor, present in the epithelial cells of the upper respiratory tract and lungs. The ACE2 interaction interface with the SARS-CoV-2 spike protein was utilized to design an ACE2-derived peptide sequence (FD11) that targeted the viral spike protein. It was found to be non-cell penetrating, while invivo studies revealed the non-cytotoxic nature of the peptide molecule. The minimum effective concentration of the peptide was found to be 10 μM with 95% cell viability in Vero E6 cell line. The IC50 of the peptide was found to be around 6.4 μM. Treatment of the peptide in SARS-CoV-2 infected Vero E6 cells was found to decrease the infectivity as compared to control. This presents a simple approach where host-pathogen protein interaction-interface derived peptides can be used for binding with substrate macromolecules to target and modulate pathogen infectivity.

Discovery of 3-phenyl-2H-aziridine derivatives as potent irreversible inhibitors of SARS-CoV-2 main protease via enzyme kinetics and microscale thermophoresis.

Reliable assessment of disease state probabilities for an individual following a specific exposure event, such as an occupational exposure, is critical for managing isolation and quarantine and reducing onward transmission to susceptible individuals. Such assessments are particularly important for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), where infection, testing, and infectiousness vary substantially across individuals and time since exposure. We present a method, accompanying software programs, and a publicly available website for calculating the probability that an individual is in each disease state immediately following an exposure event that may or may not have resulted in transmission of SARS-CoV-2. The framework integrates timing of exposure, test type and timing, and symptom status to estimate probabilities of latent infection, infectiousness, recovery, or no infection. We illustrate the utility of this approach by calculating: (i) the time at which an exposed individual's risk of being infectious falls below an acceptable threshold; (ii) the benefit of a second test for asymptomatic individuals with an initial negative test; (iii) the value of polymerase chain reaction (PCR) and antigen testing for case counting; and (iv) the time at which the risk that an infected individual remains infectious becomes comparable to background population risk. The results demonstrate that test interpretation should not be done naively: a negative test may reflect absence of transmission, a false-negative result, rapid resolution of infection, or an unusually prolonged latent period, each with distinct implications for risk management. Accurate differentiation among possible disease states following exposure is essential for informed public health decision-making. Our software provides a rigorous, transparent means to assess and clearly communicate state probabilities, enabling more nuanced interpretation of test results and better-supported decisions regarding isolation, quarantine, and testing strategies.

Antiviral potential of galactose-binding lectin from Vatairea macrocarpa seeds against SARS-CoV-2.

The continual emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants drives the need to update evidence on coronavirus disease 2019 (COVID-19) severity and disease burden, and better understand the impact on prevention, treatment, and healthcare systems. This systematic review aimed to determine relative disease severity, through comparative measures of hospitalization, intensive care unit admission and mortality, between SARS-CoV-2 variants of concern emerging since Omicron was first identified. A protocol was registered a priori (PROSPERO ID: CRD42024619193). Systematic searches of MEDLINE and EMBASE databases were conducted in November 2024 and supplemented by conference searches from 2022-2024. Population, Exposure, Comparisons, Outcomes (PECO) criteria were used to screen publications for inclusion. Critical appraisal tools published in the Joanna Briggs Institute (JBI) Handbook for Evidence Synthesis were used to assess the risk of bias of the primary studies included. The outcomes associated with Omicron variants, identified by sequencing or predominance periods, included hospitalization, admission to intensive care, death, and various composite endpoints. Thirty-two studies fulfilled the eligibility criteria, most reported on relative disease severity for early Omicron BA.5 (n = 23) and XBB (n = 24) variants. Overall, COVID-19 severity appeared largely comparable across the various Omicron subvariants. Among the subset of studies that directly compared various severity outcomes to earlier SARS-CoV-2 variants (n = 7), some reported modest increases or decreases in severity. However, these differences were generally not statistically significant. Five studies stratifying outcomes by the presence of comorbid conditions noted that comorbidities were predictors of significantly worse COVID-19 disease outcomes (p = 0.000-0.027). Overall, this systematic review found the severity of COVID-19 disease to be comparable among Omicron subvariants. As SARS-CoV-2 subvariants continue to emerge, these results highlight the continuing need for vaccination against SARS-CoV-2 infection alongside early antiviral intervention to support short-term management and long-term reduction of COVID-19-associated morbidity and mortality.

Patients with inborn errors of immunity (IEI) have high risks of severe complications after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although vaccination is effective in preventing severe coronavirus disease 2019 (COVID-19), boosters are required as the protection provided wanes over time. A greater number of boosters may be required in IEI patients compared to healthy individuals because of their immunodeficient state, but no such data are available. We investigated and compared the immunogenicity between 4 doses of COVID-19 vaccination for patients with IEI and 3 doses for healthy individuals. In the current study (NCT04800133), either BNT162b2 or CoronaVac was administered as dose 4. Healthy individuals who received 3 doses were included for comparison. Humoral and cellular immunogenicity against wild-type and JN.1 SARS-CoV-2 was assessed between IEI patients and healthy individuals. IEI patients had lower humoral and cellular immunogenicity than healthy individuals after 3 doses of COVID-19 vaccination. After dose 4, IEI patients obtained immunogenicity similar to that of healthy individuals who received 3 doses. A fourth dose of BNT162b2 significantly enhanced humoral and cellular immunogenicity against wild-type SARS-CoV-2 and humoral responses against JN.1 SARS-CoV-2. In contrast, CoronaVac had minimal effect on humoral responses to wild-type and JN.1 SARS-CoV-2. Six patients experienced breakthrough infections, which did not result in hospitalization or death. A fourth dose of BNT162b2 was immunogenic and safe for most IEI patients. The fourth dose of vaccination is recommended for IEI patients to improve protection against COVID-19, particularly before travel to areas with high endemic transmission.

Respiratory viruses as key drivers of pulmonary fibrosis: integrated pathways from barrier injury to immune-fibrotic crosstalk.

Obeldesivir is an orally administered prodrug of the nucleoside GS-441524. Invitro and preclinical studies have shown that obeldesivir can inhibit severe acute respiratory syndrome coronavirus 2, respiratory syncytial virus, and filoviruses with a high barrier to resistance. Prior population pharmacokinetic modeling has shown that certain factors, such as coronavirus disease 2019 (COVID-19), body weight, and renal function, can impact GS-441524 exposure. This study aimed to evaluate the pharmacokinetics and safety of obeldesivir in Japanese and white participants. In this phase 1 study, healthy Japanese and white participants in the USA who were aged 18-65 years, were nonsmokers, had a body mass index of 18.0-30.0 kg/m2, and had normal renal/hepatic function were administered a single 350 mg oral dose of obeldesivir. Serial blood samples were collected up to 72 h postdose. Safety was assessed via physical examinations, clinical laboratory parameters, and treatment-emergent adverse events. Plasma pharmacokinetic exposures of GS-441524 were higher in Japanese participants compared with white participants but were within the ranges observed in previous phase 1 studies. Differences in body weight between the populations in the study likely contributed to the increases in exposure. Obeldesivir was generally safe and well tolerated in both Japanese and white participants. These findings indicate that obeldesivir is likely to have favorable pharmacokinetic exposures and safety across different racial populations, supporting its potential use in treating multiple viral infections.

We assessed whether 1) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is associated with the risk of type 1 diabetes and 2) SARS-CoV-2 vaccination or infection is associated with disease severity at type 1 diabetes diagnosis. Every Finnish child aged 5-14 years diagnosed with type 1 diabetes (case subjects, n = 433) during a 16-month period (September 2021 to December 2022) were compared with three control subjects matched for age, sex, and municipality. Information on coronavirus disease 2019 (COVID-19) vaccinations was obtained from the National Vaccination Register. SARS-CoV-2 infections were identified based on circulating antibody titer in samples obtained soon after the diagnosis of type 1 diabetes. COVID-19 vaccinations preceding type 1 diabetes diagnosis were not associated with risk of type 1 diabetes (hazard ratio 1.30, 95% CI 0.97-1.72, P = 0.076). Vaccinations were linked to less severe symptoms at the time of diagnosis. Children with protective HLA genotypes were more common among the vaccinated case subjects compared with unvaccinated case subjects. Vaccinations were inversely associated with insulin autoantibody positivity. There was no association between SARS-CoV-2 and type 1 diabetes symptoms or autoantibodies at the time of type 1 diabetes diagnosis. There was no significant association between SARS-CoV-2 vaccination and risk of type 1 diabetes. Neither COVID-19 vaccinations nor SARS-CoV-2 infections explain the more severe symptoms at type 1 diabetes diagnosis observed in Finnish children after the beginning of the COVID-19 pandemic. Parents who vaccinate their children are more likely to seek medical care. This may result in less severe symptoms in their children at diagnosis of diabetes.

Aryl-functionalized mono- and diketone curcumin derivatives inhibit SARS-CoV-2 Spike:ACE2 interactions.

Allosteric Targeting of the ACE2 Dimer Interface by a Medium-sized Compound Inhibits SARS-CoV-2 Entry.

The novel coronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) primarily affects the respiratory system, producing lung findings - notably ground-glass opacities (GGOs) - on high-resolution computed tomography (HRCT) that closely mimic those seen in malignancy-related pulmonary lesions. Cancer patients, owing to their immunocompromised state, are particularly susceptible to COVID-19 infection and carry a worse prognosis. This overlap in radiological findings between COVID-19 pneumonia and malignancy-associated pulmonary changes poses a significant diagnostic challenge, risking misdiagnosis and delayed management. To study the role of HRCT Thorax in the identification and evaluation of typical manifestations of suspected COVID-19 infection in patients with preexisting malignancies. To identify atypical HRCT features of suspected COVID-19 infection in patients with preexisting malignancies. This retrospective cross-sectional study was conducted between August 2020 and February 2021 in the CT section of the Department of Radio-diagnosis at a tertiary care hospital. A total of 100 patients satisfying the inclusion-exclusion criteria, referred for HRCT Thorax with suspected COVID-19 infection and having preexisting malignancies, were enrolled. Categorical variables were presented as number and percentage, and continuous variables as mean ± standard deviation and median. Data were visualized using bar diagrams and pie diagrams. The study included 56 female and 44 male patients; 64% were RT-PCR positive and 36% negative. Mean age was 55 ± 13.3 years (range: 24-70 years). The most common malignancy was breast cancer, followed by lung and cervical cancer; 5 patients had a history of pulmonary metastasis. The predominant HRCT pattern was GGOs (78%), typically asymmetrical, peripheral, bilateral, and subpleural with lower lobe predilection. Consolidation concurrent with GGO was found in 33%, and sole patchy consolidation in 7%. Pleural effusion was present in 34%. Additional atypical findings included bronchiectasis (32%), lymphadenopathy (27%), crazy paving (22%), vascular changes (19%), and reticular opacities (17%). CT severity scoring showed 22% score 0, 30% mild (1-8), 32% moderate (9-15), and 16% severe (>15). The overall 30-day mortality was 22%, predominantly in lung cancer (25%), followed by oral cancer (18%). Disease severity was more pronounced in males. HRCT Thorax is a valuable diagnostic tool in cancer patients suspected of COVID-19 infection, demonstrating both typical findings (bilateral subpleural GGOs, lower lobe predilection) and atypical findings (consolidation, pleural effusion, lymphadenopathy, fibrotic changes) more prevalent in oncological patients. A CT severity score >8 in oncological patients can serve as a severity predictor to guide hospitalization and management decisions.

Multiple sclerosis (MS) is an immune-mediated and demyelinating disease affecting oligodendrocytes, leading to neurodegeneration. Immunocompromised individuals may have a reduced antibody response after vaccination, and this insufficient immune response in COVID-19 individuals might contribute to the pathophysiology of MS. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds the angiotensin-converting enzyme 2 (ACE2) to entry into the host's cell and infect human cells. Evaluation of the effects of drugs for the treatment of MS, such as fingolimod, cladribine, dimethyl fumarate, and teriflunomide, on the expression of ACE2 in human lung carcinoma cell lines. We used Calu-3 human lung adenocarcinoma cells, physiologically expressing the ACE2 gene, and A549-hACE2-TMPRSS2 human lung carcinoma cells, overexpressing the human ACE2 gene, and challenged them with the pro-inflammatory interleukin-1β (IL-1β) in the presence or absence of MS drugs, and assessed ACE2 mRNA and protein levels. MS drugs affected ACE2 mRNA and protein levels differently in Calu-3 and A549-hACE2-TMPRSS2 cells. Fingolimod (50 nM) significantly reduced ACE2 protein levels under inflammatory conditions in Calu-3 cells. Cladribine reduced ACE2 protein levels in A549-hACE2-TMPRSS2 cells. Dimethyl fumarate increased ACE2 protein levels in Calu-3 cells under both basal and pro-inflammatory conditions. Teriflunomide increased ACE2 protein levels in Calu-3 cells and ACE2 mRNA levels in A549-hACE2-TMPRSS2 cells, both in basal and pro-inflammatory conditions. We incubated cells with drug concentrations similar to those found in the plasma of relapsing-remitting MS patients treated with disease-modifying drugs (DMD), although they act via different mechanisms. Fingolimod acts on sphingosine-1-phosphate receptors and inhibiting class 1 histone deacetylase could suppress ACE2 expression, independently of its immunosuppressive action, or might act at post-transcriptional levels. Fingolimod also stimulates the secretion of neurotrophic factors in the CNS and exerts neuroprotective effects. Data suggest that drugs used in the treatment of MS can modify ACE2 expression; specifically, fingolimod reduces ACE2 expression and may have a protective role against SARS-CoV-2 infection.

To investigate whether IgG to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens could reveal undetected SARS-CoV-2 exposure in a cohort of Malawian pregnant women participating in the REVAMP clinical trial. A secondary analysis of serological samples from a randomised controlled trial of iron supplementation in pregnancy, which began recruiting women in November 2018 and had its last visit occurring in September 2021. Resource-limited setting in Zomba and Blantyre, Southern Malawi. Pregnant women with ultrasound-confirmed singleton pregnancies in the second trimester, with haemoglobin <100 g/L and randomised at enrolment to receive either intravenous ferric carboxymaltose or standard oral iron, where no coronavirus disease 2019 (COVID-19) clinical cases or SARS-CoV-2 positive tests were reported during the pandemic (April 2020-September 2021). Primary outcome was the levels of antibodies and seropositivity to SARS-CoV-2 antigens in the cohort of women across the duration of the trial. Secondary outcomes were the impact of IgG levels and seropositivity to SARS-CoV-2 on pregnancy outcomes. At delivery, IgG levels to SARS-CoV-2 antigens increased sharply by 18.5%-29.7% every 30 days during COVID-19 waves 2 and 3. Overall seropositivity reached 39.3% during the pandemic; however, 14.7% pre-pandemic seropositivity demonstrates cross-reactive antibody responses. Pandemic pregnancies showed improved outcomes with longer gestations (mean difference: 0.6 weeks (95% CI 0.2 to 0.9)) and higher birth weights (mean difference: 169.3 g (65.9-272.6)). SARS-CoV-2 IgG levels were not associated with pregnancy outcomes. Serological testing was able to detect exposure to SARS-CoV-2 in a population without clinical indications of the disease, suggesting that serosurveillance is more sensitive than relying on clinical data to monitor pathogen exposure in the community. Additionally, this highlights pregnancy cohorts as valuable sentinel populations for infectious disease surveillance in resource-limited settings. This trial was prospectively registered at ANZCTR: ACTRN12618001268235.

SARS-CoV-2 infection, viral burden, and variant-specific outcomes in hospitalized patients with heart failure.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a major global health challenge, characterised by a heterogeneous clinical spectrum. While metabolomic studies have identified disruptions in amino acid, lipid, nucleotide, and energy metabolism during COVID-19, these investigations often lack fine-grained clinical stratification. In this study, we performed untargeted metabolomic profiling of plasma from 25 participants, including five healthy controls and twenty COVID-19 patients classified into four severity groups (COV1–COV4) based on pulmonary involvement and the need for respiratory support. Using ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS), 541 metabolites were detected and analysed across all samples. Principal component analysis revealed a progressive metabolic divergence corresponding to disease severity. Monocarboxylic acid dysregulation was predominant in early to moderate cases (COV1–COV3), whereas severe disease (COV4) demonstrated a shift toward pyrimidine metabolism enrichment, consistent with heightened nucleotide turnover driven by viral replication and immune cell proliferation. Phenylalanine metabolism emerged as a consistently enriched pathway in COV1–COV3, suggesting aromatic amino acid perturbations as early markers of metabolic stress and immune activation. In contrast, pyrimidine pathway activation in COV4 could reflect profound systemic metabolic reprogramming associated with critical illness. These findings provide novel insights into COVID-19 pathophysiology, highlighting stage-specific metabolic signatures and potential biomarkers for disease monitoring. Our results support the concept of metabolomics-guided precision medicine, offering a rationale for targeted therapeutic interventions based on disease stage and metabolic phenotype.