Tracking the immune response profiles elicited by the BNT162b2 vaccine in COVID-19 unexperienced and experienced individuals.

Multiple vaccines have been approved to control COVID-19 pandemic, with Pfizer/BioNTech (BNT162b2) being widely used. We conducted a longitudinal analysis of the immune response elicited after three doses of the BNT162b2 vaccine in individuals who have previously experienced SARS-CoV-2 infection and in unexperienced ones. We conducted immunological analyses and single-cell transcriptomics of circulating T and B lymphocytes, combined to CITE-seq or LIBRA-seq, and VDJ-seq. We found that antibody levels against SARS-CoV-2 Spike, NTD and RBD from wild-type, delta and omicron VoCs show comparable dynamics in both vaccination groups, with a peak after the second dose, a decline after six months and a restoration after the booster dose. The antibody neutralization activity was maintained, with lower titers against the omicron variant. Spike-specific memory B cell response was sustained over the vaccination schedule. Clonal analysis revealed that Spike-specific B cells were polyclonal, with a partial clone conservation from natural infection to vaccination. Spike-specific T cell responses were oriented towards effector and effector memory phenotypes, with similar trends in unexperienced and experienced individuals. The CD8 T cell compartment showed a higher clonal expansion and persistence than CD4 T cells. The first two vaccinations doses tended to induce new clones rather than promoting expansion of pre-existing clones. However, we identified a fraction of Spike-specific CD8 T cell clones persisting from natural infection that were boosted by vaccination and clones specifically induced by vaccination. Collectively, our observations revealed a moderate effect of the second dose in enhancing the immune responses elicited after the first vaccination. Differently, we found that a third dose was necessary to restore comparable levels of neutralizing antibodies and Spike-specific T and B cell responses in individuals who experienced a natural SARS-CoV-2 infection.

Long-term dynamics of natural killer cells in response to SARS-CoV-2 vaccination: Persistently enhanced activity postvaccination.

Natural Killer (NK) cells play a significant role in the early defense against virus infections and cancer. Recent studies have demonstrated the involvement of NK cells in both the induction and effector phases of vaccine-induced immunity in various contexts. However, their role in shaping immune responses following SARS-CoV-2 vaccination remains poorly understood. To address this matter, we conducted a comprehensive analysis of NK cell phenotype and function in SARS-CoV-2 unexposed individuals who received the BNT162b2 vaccine. We employed a longitudinal study design and utilized a panel of 53 15-mer overlapping peptides covering the receptor binding domain (RBD) of the SARS-CoV-2 Spike protein to assess NK cell function at 0 and 20 days following the first vaccine, and 30 and 240 days following booster. Additionally, we evaluated the levels of total IgG anti-Spike antibodies and their potential neutralizing ability. Our findings revealed an increased NK cell activity upon re-exposure to RBD when combined with IL12 and IL18 several months after booster. Concurrently, we observed that the frequencies of NKG2A + NK cells declined over the course of the follow-up period, while NKG2C increased only in CMV positive subjects. The finding that NK cell functions are inducible 9 months after vaccination upon re-exposure to RBD and cytokines, sheds light on the role of NK cells in contributing to SARS-CoV-2 vaccine-induced immune protection and pave the way to further studies in the field.

Revisiting Numerical Solutions of Weakly Bound Noble Gases' Vibrational Energy Levels Modeled by the Improved Lennard- Jones Potential.

We revisit the numerical solutions of vibrational eigenstates of weakly bound homonuclear and heteronuclear noble gas pairs by applying a Fortran program based on the Numerov method. The harmonic, Lennard-Jones (LJ), and Improved Lennard- Jones (ILJ) potential models have been implemented to represent the potential energy curves (PECs). The obtained vibrational energies spectrum was tested on the experimental data and accurate ab initio calculations at CCSD(T)/CBS level. The vibrational eigenvalues and eigenfunctions can be reproduced accurately within the ILJ potential model. Moreover, considering from the calculated lifetime of van der Waals (vdW) complexes, the implementation of ILJ rather than standard LJ potential model has a significant impact on the systems dynamics by providing more representative atomic trajectories when the function is incorporated in force fields for molecular dynamics (MD) simulations. Overall, the ILJ function is the best suited potential model for the representation of vibrational motions and the determination of vibrational energy levels of weakly bound systems, both at equilibrium and non-equilibrium conditions.

Carbapenem or new ß-lactam-ß-lactamase inhibitors? An Italian survey supported by SITA, SIMIT and SIAARTI to identify the factors affecting empiric antimicrobial therapy choice in real-life clinical practice.

While a tailored antibiotic treatment plan is often straightforward, what we often observe in daily clinical practice is a highly variable approach when defining empirical therapy. Specifically, a debate exists on preference to spare the new ß-lactams and ß-lactamase inhibitors (BL-BLIs) or to apply a carbapenem-sparing strategy first. To investigate, we designed a web survey aimed at investigating the variables considered relevant to empirically choosing one antibiotic over the other. Submitted to Italian infectious diseases and intensive care physicians through the support of Società Italiana di Malattie Infettive e Tropicali (SIMIT), Società Italiana di Terapia Antinfettiva (SITA) and Società Italiana Anestesia, Analgesia, Rianimazione e Terapia Intensiva (SIAARTI). We found that demographic characteristics were irrelevant when deciding for empirical therapy. Clinical and anamnestic data were most meaningful. Significantly considered were underlying comorbidities and previous exposure to antimicrobial treatments. History of third-generation cephalosporin-resistant, carbapenem-resistant and/or metallo-ß-lactamase-producing Enterobacterales rectal colonisation and/or infection were considered the most relevant by most physicians. Unexpectedly, clinicians considered less the source of infection. These results prompt the need of straightforward methods to retrieve medical histories and the magnitude of rectal colonisation data, often not routinely obtained.

New Antibiotics Against Multidrug-Resistant Gram-Negative Bacteria in Liver Transplantation: Clinical Perspectives, Toxicity, and PK/PD Properties.

Antimicrobial resistance is a growing global health problem, and it is especially relevant among liver transplant recipients where infections, particularly when caused by microorganisms with a difficult-to-treat profile, are a significant cause of morbidity and mortality. We provide here a complete dissection of the antibiotics active against multidrug-resistant Gram-negative bacteria approved over the last years, focusing on their activity spectrum, toxicity profile and PK/PD properties, including therapeutic drug monitoring, in the setting of liver transplantation. Specifically, the following drugs are presented: ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, imipenem/relebactam, cefiderocol, and eravacycline. Overall, studies on the safety and optimal employment of these drugs in liver transplant recipients are limited and especially needed. Nevertheless, these pharmaceuticals have undeniably enhanced therapeutic options for infected liver transplant recipients.

COVID-19 Vaccine in Lung and Liver Transplant Recipients Exceeds Expectations: An Italian Real-Life Experience on Immunogenicity and Clinical Efficacy of BNT162b2 Vaccine.

This study assessed humoral and T cell-mediated immune responses to the BNT162b2 vaccine in orthotopic liver transplant (OLT) and lung transplant (LUT) recipients who received three doses of the vaccine from March 2021 at our institution. Serum samples were collected 60 days post-second and third dose to quantify antibodies against the spike region of SARS-CoV-2 while whole blood samples were collected to analyze the SARS-CoV-2-specific T-cell response using an IFN-γ ELISpot assay. We enrolled 244 OLT and 120 LUT recipients. The third dose increased antibody titres in OLT recipients (from a median value of 131 after the second dose to 5523 IU/mL, p < 0.001) and LUT recipients (from 14.8 to 1729 IU/mL, p < 0.001). T-cell response also increased in OLT recipients (from 8.5 to 23 IFN-γ SFU per 250,000 PBMC, p < 0.001) and LUT recipients (from 8 to 15 IFN-γ SFU per 250,000 PBMC, p < 0.001). A total of 128 breakthrough infections were observed: two (0.8%) OLT recipients were hospitalized due to COVID-19 and one died (0.4%); among LUT recipients, seven were hospitalized (5.8%) and two patients died (1.7%). In conclusion, the three-dose schedule of the BNT162b2 vaccine elicited both humoral and T cell-mediated responses in solid organ transplant recipients. The risk of severe COVID-19 post-vaccination was low in this population.

MET Oncogene Targeting for Cancer Immunotherapy.

The MET receptor is one of the main drivers of 'invasive growth', a multifaceted biological response essential during embryonic development and tissue repair that is usurped by cancer cells to induce and sustain the malignant phenotype. MET stands out as one of the most important oncogenes activated in cancer and its inhibition has been explored since the initial era of cancer-targeted therapy. Different approaches have been developed to hamper MET signaling and/or reduce MET (over)expression as a hallmark of transformation. Considering the great interest gained by cancer immunotherapy, this review evaluates the opportunity of targeting MET within therapeutic approaches based on the exploitation of immune functions, either in those cases where MET impairment is crucial to induce an effective response (i.e., when MET is the driver of the malignancy), or when blocking MET represents a way for potentiating the treatment (i.e., when MET is an adjuvant of tumor fitness).

Treatable traits and challenges in the clinical management of non-tuberculous mycobacteria lung disease in people with cystic fibrosis.

INTRODUCTION: Over the last ten years an increasing prevalence and incidence of non-tuberculous mycobacteria (NTM) has been reported among patients with cystic fibrosis (CF) Viviani (J Cyst Fibros, 15(5):619-623, 2016). NTM pulmonary disease has been associated with negative clinical outcomes and often requires pharmacological treatment. Although specific guidelines help clinicians in the process of diagnosis and clinical management, the focus on the multidimensional assessment of concomitant problems is still scarce. MAIN BODY: This review aims to identify the treatable traits of NTM pulmonary disease in people with CF and discuss the importance of a multidisciplinary approach in order to detect and manage all the clinical and behavioral aspects of the disease. The multidisciplinary complexity of NTM pulmonary disease in CF requires careful management of respiratory and extra-respiratory, including control of comorbidities, drug interactions and behavioral factors as adherence to therapies. CONCLUSIONS: The treatable trait strategy can help to optimize clinical management through systematic assessment of all the aspects of the disease, providing a holistic treatment for such a multi-systemic and complex condition.

Polyphenol-Rich Extracts from Agroindustrial Waste and Byproducts: Results and Perspectives According to the Green Chemistry and Circular Economy.

Polyphenols are natural secondary metabolites found in plants endowed with multiple biological activities (antioxidant, anti-inflammatory, antimicrobial, cardioprotective, and anticancer). In view of these properties, they find many applications and are used as active ingredients in nutraceutical, food, pharmaceutical, and cosmetic formulations. In accordance with green chemistry and circular economy strategies, they can also be recovered from agroindustrial waste and reused in various sectors, promoting sustainable processes. This review described structural characteristics, methods for extraction, biological properties, and applications of polyphenolic extracts obtained from two selected plant materials of the Mediterranean area as olive (Olea europaea L.) and pomegranate (Punica granatum L.) based on recent literature, highlighting future research perspectives.

Epidemiology, Clinical Manifestations, and Outcome of Mucormycosis in Solid Organ Transplant Recipients: A Systematic Review of Reported Cases.

Mucormycosis is an emerging disease primarily affecting the immunocompromised host, but scarce evidence is available for solid organ transplant recipients (SOTRs). We systematically reviewed 183 cases occurring in SOTRs, exploring epidemiology, clinical characteristics, causative pathogens, therapeutic approaches, and outcomes. Kidney transplants accounted for half of the cases, followed by heart (18.6%), liver (16.9%), and lung (10.4%). Diagnosis showed a dichotomous distribution, with 63.7% of cases reported within 100 days of transplantation and 20.6% occurring at least 1 year after transplant. The 90-day and 1-year mortality rates were 36.3% and 63.4%, respectively. Disseminated disease had the highest mortality at both time points (75% and 93%). Treatment with >3 immunosuppressive drugs showed a significant impact on 90-day mortality (odds ratio [OR], 2.33; 95% CI, 1.02-5.66; P = .0493), as did a disseminated disease manifestation (OR, 8.23; 95% CI, 2.20-36.71; P = .0027) and the presence of diabetes (OR, 2.35; 95% CI, 1.01-5.65; P = .0497). Notably, prophylaxis was administered to 12 cases with amphotericin B. Further investigations are needed to validate these findings and to evaluate the potential implementation of prophylactic regimens in SOTRs at high risk.

Clinical characteristics and outcomes of vaccinated patients hospitalised with SARS-CoV-2 breakthrough infection: Multi-IPV, a multicentre study in Northern Italy.

BACKGROUND: Despite the well-known efficacy of anti-COVID-19 vaccines in preventing morbidity and mortality, several vaccinated individuals are diagnosed with SARS-CoV-2 breakthrough infection, which might require hospitalisation. This multicentre, observational, and retrospective study aimed to investigate the clinical characteristics and outcomes of vaccinated vs. non-vaccinated patients, both hospitalised with SARS-CoV-2 infection in 3 major hospitals in Northern Italy. METHODS: Data collection was retrospective, and paper and electronic medical records of adult patients with a diagnosed SARS-CoV-2 infection were pseudo-anonymised and analysed. Vaccinated and non-vaccinated individuals were manually paired, using a predetermined matching criterion (similar age, gender, and date of hospitalisation). Demographic, clinical, treatment, and outcome data were compared between groups differing by vaccination status using Pearson's Chi-square and Mann-Whitney tests. Moreover, multiple logistic regression analyses were performed to assess the impact of vaccination status on ICU admission or intra-hospital mortality. RESULTS: Data from 360 patients were collected. Vaccinated patients presented with a higher prevalence of relevant comorbidities, like kidney replacement therapy or haematological malignancy, despite a milder clinical presentation at the first evaluation. Non-vaccinated patients required intensive care more often than their vaccinated counterparts (8.8% vs. 1.7%, p = 0.002). Contrariwise, no difference in intra-hospital mortality was observed between the two groups (19% vs. 20%, p = 0.853). These results were confirmed by multivariable logistic regressions, which showed that vaccination was significantly associated with decreased risk of ICU admission (aOR=0.172, 95%CI: 0.039-0.542, p = 0.007), but not of intra-hospital mortality (aOR=0.996, 95%CI: 0.582-1.703, p = 0.987). CONCLUSIONS: This study provides real-world data on vaccinated patients hospitalised with COVID-19 in Northern Italy. Our results suggest that COVID-19 vaccination has a protective role in individuals with higher risk profiles, especially regarding the need for ICU admission. These findings contribute to our understanding of SARS-CoV-2 infection outcomes among vaccinated individuals and emphasise the importance of vaccination in preventing severe disease, particularly in those countries with lower first-booster uptake rates.

Use of Cefiderocol in Adult Patients: Descriptive Analysis from a Prospective, Multicenter, Cohort Study.

INTRODUCTION: Cefiderocol is a siderophore cephalosporin showing activity against various carbapenem-resistant Gram-negative bacteria (CR-GNB). No data currently exist about real-world use of cefiderocol in terms of types of therapy (e.g., empirical or targeted, monotherapy or combined regimens), indications, and patient characteristics. METHODS: In this multicenter, prospective study, we aimed at describing the use of cefiderocol in terms of types of therapy, indications, and patient characteristics. RESULTS: Cefiderocol was administered as empirical and targeted therapy in 27.5% (55/200) and 72.5% (145/200) of cases, respectively. Overall, it was administered as monotherapy in 101/200 cases (50.5%) and as part of a combined regimen for CR-GNB infections in the remaining 99/200 cases (49.5%). In multivariable analysis, previous isolation of carbapenem-resistant Acinetobacter baumannii odds ratio (OR) 2.56, with 95% confidence interval (95% CI) 1.01-6.46, p = 0.047] and previous hematopoietic stem cell transplantation (OR 8.73, 95% CI 1.05-72.54, p = 0.045) were associated with administration of cefiderocol as part of a combined regimen, whereas chronic kidney disease was associated with cefiderocol monotherapy (OR 0.38 for combined regimen, 95% CI 0.16-0.91, p = 0.029). Cumulative 30-day mortality was 19.8%, 45.0%, 20.7%, and 22.7% in patients receiving targeted cefiderocol for infections by Enterobacterales, A. baumannii, Pseudomonas aeruginosa, and any metallo-ß-lactamase producers, respectively. CONCLUSIONS: Cefiderocol is mainly used for targeted treatment, although empirical therapies account for more than 25% of prescriptions, thus requiring dedicated standardization and guidance. The almost equal distribution of cefiderocol monotherapy and cefiderocol-based combination therapies underlines the need for further study to ascertain possible differences in efficacy between the two approaches.

Increase in invasive group A streptococcal infections in Milan, Italy: a genomic and clinical characterization.

Background: Group A Streptococcus (GAS) causes multiple clinical manifestations, including invasive (iGAS) or even life-threatening (severe-iGAS) infections. After the drop in cases during COVID-19 pandemic, in 2022 a sharp increase of GAS was reported globally. Methods: GAS strains collected in 09/2022-03/2023 in two university hospitals in Milan, Italy were retrospectively analyzed. Clinical/epidemiological data were combined with whole-genome sequencing to: (i) define resistome/virulome, (ii) identify putative transmission chains, (iii) explore associations between emm-types and clinical severity. Results: Twenty-eight isolates were available, 19/28 (67.9%) from adults and 9/28 (32.1%) from pediatric population. The criteria for iGAS were met by 19/28 cases (67.9%), of which 11/19 (39.3%) met the further criteria for severe-iGAS. Pediatric cases were mainly non-invasive infections (8/9, 88.9%), adult cases were iGAS and severe-iGAS in 18/19 (94.7%) and 10/19 (52.6%), respectively. Thirteen emm-types were detected, the most prevalent being emm1 and emm12 (6/28 strains each, 21.4%). Single nucleotide polymorphism (SNP) analysis of emm1.0 and emm12.0 strains revealed pairwise SNP distance always >10, inconsistent with unique transmission chains. Emm12.0-type, found to almost exclusively carry virulence factors speH and speI, was mainly detected in children and in no-iGAS infections (55.6 vs. 5.3%, p = 0.007 and 66.7 vs. 0.0%, p < 0.001, respectively), while emm1.0-type was mainly detected in severe-iGAS (0.0 vs. 45.5%, p = 0.045). Conclusions: This study showed that multiple emm-types contributed to a 2022/2023 GAS infection increase in two hospitals in Milan, with no evidence of direct transmission chains. Specific emm-types could be associated with disease severity or invasiveness. Overall, these results support the integration of classical epidemiological studies with genomic investigation to appropriately manage severe infections and improve surveillance.