Performance of the Cepheid Methicillin-Resistant Staphylococcus aureus/S. aureus Skin and Soft Tissue Infection PCR Assay on Respiratory Samples from Mechanically Ventilated Patients for S. aureus Screening during the Phase 2 Double-Blind SAATELLITE Study.

We investigated the performance of the Xpert methicillin-resistant Staphylococcus aureus (MRSA)/S. aureus skin and soft tissue (SSTI) quantitative PCR (qPCR) assay in SAATELLITE, a multicenter, double-blind, phase 2 study of suvratoxumab, a monoclonal antibody (MAb) targeting S. aureus alpha-toxin, for reducing the incidence of S. aureus pneumonia. The assay was used to detect methicillin-susceptible S. aureus (MSSA) and MRSA in lower respiratory tract (LRT) samples from mechanically ventilated patients. LRT culture results were compared with S. aureus protein A (spa) gene cycle threshold (CT) values. Receiver operating characteristic (ROC) and Youden index were used to determine the CT cutoff for best separation of culture-S. aureus-negative and S. aureus-positive patients. Of 720 screened subjects, 299 (41.5%) were S. aureus positive by qPCR, of whom 209 had culture data: 162 (77.5%) were S. aureus positive and 47 (22.5%) were S. aureus negative. Culture results were negatively affected by antibiotic use and cross-laboratory variability. An inverse linear correlation was observed between CT values and quantitative S. aureus culture results. A spa CT value of 29 (≈2 × 103 CFU/mL) served as the best cutoff for separation between culture-negative and culture-positive samples. The associated area under the ROC curve was 83.8% (95% confidence interval [CI], 78 to 90%). Suvratoxumab provided greater reduction in S. aureus pneumonia or death than placebo in subjects with low S. aureus load (CT ≥ 29; relative risk reduction [RRR], 50.0%; 90% CI, 2.7 to 74.4%) versus the total study population (RRR, 25.2%; 90% CI, -4.3 to 46.4%). The qPCR assay was easy to perform, sensitive, and standardized and provided better sensitivity than conventional culture for S. aureus detection. Quantitative PCR CT output correlated with suvratoxumab efficacy in reducing S. aureus pneumonia incidence or death in S. aureus-colonized, mechanically ventilated patients.

Evaluation of MEDI8852, an Anti-Influenza A Monoclonal Antibody, in Treating Acute Uncomplicated Influenza.

We evaluated MEDI8852, a human IgG1 monoclonal antibody that binds a highly conserved influenza A hemagglutinin stalk epitope, in outpatients with uncomplicated influenza A infection. A total of 126 subjects aged 18 to 65 years were enrolled during the 2015 to 2016 Northern and 2016 Southern Hemisphere seasons. Subjects with symptom onset ≤5 days before dosing were randomized to four cohorts: 750 mg (cohort 1) or 3,000 mg (cohort 2) MEDI8852 (single intravenous infusion) plus 75 mg oseltamivir, placebo plus 75 mg oseltamivir (cohort 3), and 3,000 mg MEDI8852 alone (cohort 4). Subjects were monitored through day 10 for solicited influenza symptoms, day 28 for adverse events (AEs), and day 101 for serious AEs and AEs of special interest. Nasopharyngeal samples were collected through day 7 for confirmation of influenza A infection, viral shedding, and oseltamivir and MEDI8852 susceptibility. Slightly more AEs were reported in subjects receiving MEDI8852 (cohorts 1, 2, and 4 combined: 39/93, 41.9%) than oseltamivir only (cohort 3: 10/32, 31.3%). Most AEs were mild or moderate. The most common AE was bronchitis (11/93, 11.8%; 1/32, 3.1%). The median (range) decrease in viral shedding (log10 virus genome copies/ml) was similar between the two groups (-3.58 [-6.2. 0.5]; -3.43 [-5.9, 0.9]). Genotypic analyses found a limited number of hemagglutinin and neuraminidase amino acid changes between viruses isolated before and after therapy; however, none appeared within a known oseltamivir-resistant site or MEDI8852-binding region. The safety profile of MEDI8852 supports its continued development for treatment of patients hospitalized with influenza A infection. (This study has been registered at ClinicalTrials.gov under identifier NCT02603952.).

A phase 1 study to evaluate the safety and pharmacokinetics of MEDI8852, an anti-influenza A monoclonal antibody, in healthy adult volunteers.

MEDI8852 is an IgG1 kappa monoclonal antibody that is being developed to treat patients hospitalized with influenza A. We evaluated the safety and tolerability, pharmacokinetics, and anti-drug antibodies (ADA) of a single intravenous dose of MEDI8852 in healthy adult volunteers (NCT02350751). Forty subjects were randomized to receive either MEDI8852 (250, 750, 1,500, or 3000 mg) (n = 32) or placebo (n = 8) on day 1. Dose escalation was based on cumulative safety data through day 8. Subjects were followed through day 101 for safety, pharmacokinetics, and ADA. Treatment-emergent adverse events (TEAEs) were comparable (37.5%; 37.5%); all TEAEs were mild (grade 1) or moderate (grade 2) in severity. The most frequently reported TEAEs were headache (9.4%, 12.5%) and hypoglycemia (12.5%, 12.5%); all subjects with hypoglycemia were asymptomatic and did not require treatment. No subjects discontinued the study due to a TEAE. Mean area under the curve from time 0 to last sampling time point, area under the curve from time 0 to infinity, and observed maximum concentration for MEDI8852 were dose proportional. The terminal half-life ranged from 19.4 to 22.6 days. No ADAs were detected. A population pharmacokinetic model demonstrated good concentration separation between the 750- and 3000-mg dose groups.

Co-administration of the adjuvanted recombinant zoster vaccine with other adult vaccines: An overview.

BACKGROUND: The adjuvanted recombinant zoster vaccine (RZV; Shingrix®, GSK) is a subunit vaccine that has been approved for the prevention of herpes zoster in adults. Co-administration of two vaccines in a single visit is a strategy to improve overall vaccine coverage. OBJECTIVES: This review aims to consolidate available clinical data on RZV co-administration, providing an overview of safety, reactogenicity and immunogenicity. METHODS: RZV co-administration data were obtained from five randomised, open-label, phase III clinical trials with similar study designs. The co-administered vaccines included: quadrivalent seasonal inactivated influenza vaccine (IIV4; NCT01954251), 23-valent pneumococcal polysaccharide vaccine (PPSV23; NCT02045836), reduced-antigen-content diphtheria-tetanus-acellular pertussis vaccine (Tdap; NCT02052596), 13-valent pneumococcal conjugate vaccine (PCV13; NCT03439657) and COVID-19 mRNA-1273 booster (NCT05047770). Eligible participants were healthy adults aged ≥50 years. RESULTS: A total of 3,974 participants were vaccinated (co-administration: 1,973; sequential: 2,001) across the five trials. Vaccine response rates to RZV were similar for co-administration (range: 95.8-99.1 %) and sequential groups (range: 95.1-99.1 %). Immune responses to RZV and the other vaccines (with the exception of pertactin) were non-inferior when the vaccines were co-administered compared with sequentially administered. Overall incidences of solicited local and general adverse events (AEs), unsolicited AEs, serious AEs or potential immune-mediated diseases were similar after co-administration or sequential administration. Myalgia was the most common solicited systemic AE (co-administration: 38-64 %; sequential: 30-59 %). Shivering and fever were more common after co-administration (16 % and 21 %, respectively) than after sequential administration (both 7 %) of RZV and PPSV23. CONCLUSIONS: Co-administration of RZV with routine vaccines does not significantly alter the reactogenicity, immunogenicity or safety of RZV or the co-administered vaccine. Healthcare practitioners should consider routine co-administration of RZV with other adult vaccines to improve vaccination coverage.

Efficacy, reactogenicity, and safety of the adjuvanted recombinant zoster vaccine for the prevention of herpes zoster in Chinese adults ≥ 50 years: A randomized, placebo-controlled trial.

Phase III multi-country studies (ZOE-50/70) demonstrated that the adjuvanted recombinant zoster vaccine (RZV) was well tolerated and prevented herpes zoster (HZ) in healthy ≥ 50-year-olds, with a vaccine efficacy (VE) > 90% across age groups. These pivotal trials did not enroll participants from mainland China where RZV is licensed, therefore similar clinical data are missing for this population. In this phase IV observer-blind study (NCT04869982) conducted between 2021 and 2023 in China, immunocompetent and medically stable ≥ 50-year-olds were randomized 1:1 to receive two RZV or placebo doses, 2 months apart. This study assessed the VE (overall, as confirmatory objective, and descriptively by age category [50-69-year-olds/≥ 70-year-olds]), reactogenicity, and safety of RZV in this Chinese population. Of the 6138 enrolled participants, 99.2% completed the study. During a mean follow-up period of 15.2 (±1.1) months, 31 HZ episodes were confirmed (RZV = 0; placebo = 31) for an incidence rate of 0.0 vs 8.2 per 1000 person-years and an overall VE of 100% (89.82-100). The descriptive VE was 100% (85.29-100) for 50-69-year-olds and 100% (60.90-100) for ≥ 70-year-olds. Solicited adverse events (AEs) were more frequent in the RZV vs the placebo group (median duration: 1-3 days for both groups). Pain and fatigue were the most frequent local and general AEs (RZV: 72.1% and 43.4%; placebo: 9.2% and 5.3%). The frequencies of unsolicited AEs, serious AEs, potential immune-mediated diseases, and deaths were similar between both groups. RZV is well tolerated and efficacious in preventing HZ in Chinese ≥ 50-year-olds, consistent with efficacy studies including worldwide populations with similar age and medical characteristics.

What is the context? Herpes zoster, commonly known as shingles, is a painful rash resulting from the reactivation of the dormant virus causing chickenpox.Vaccines preventing shingles, such as Shingrix, were shown to be well tolerated and efficacious in healthy adults over 50 years of age from Europe, North and Latin America, Australia, and Asia (Taiwan, Hong Kong, Korea, Japan).However, data on real-world protective effect of Shingrix are limited in some regions where the vaccine is licensed for use, such as mainland China.What is new? We analyzed data from Chinese adults aged 50 years or older to determine the efficacy and safety of Shingrix.Around 6000 participants were divided in two equal groups to receive two doses of Shingrix or two doses of a placebo, given 2 months apart.We found that, during the study period, the vaccine was 100% efficacious in preventing shingles.We showed that the vaccine had an acceptable safety profile in this Chinese population.What is the impact? Shingrix is efficacious and well tolerated in Chinese adults over 50 years of age, as it is in similarly aged populations from other evaluated regions.

Association of healthcare worker behaviors with coronavirus disease 2019 (COVID-19) risk during four pandemic periods and characteristics associated with high-risk behaviors.

In a large healthcare worker cohort, we quantified the association between behaviors and risk of coronavirus disease 2019 (COVID-19) during different pandemic phases, adjusting for prior infection and vaccination. Individual characteristics, including personal concerns, were associated with these behaviors. Public health messaging should target high-risk populations and behaviors as the pandemic evolves.

Alterations in CNS activity induced by botulinum toxin treatment in spasmodic dysphonia: an H215O PET study.

Speech-related changes in regional cerebral blood flow (rCBF) were measured using H(2)(15)O positron-emission tomography in 9 adults with adductor spasmodic dysphonia (ADSD) before and after botulinum toxin (BTX) injection and 10 age- and gender-matched volunteers without neurological disorders. Scans were acquired at rest and during production of continuous narrative speech and whispered speech. Speech was recorded during scan acquisition for offline quantification of voice breaks, pitch breaks, and percentage aperiodicity to assess correlations between treatment-related changes in rCBF and clinical improvement. Results demonstrated that speech-related responses in heteromodal sensory areas were significantly reduced in persons with ADSD, compared with volunteers, before the administration of BTX. Three to 4 weeks after BTX injection, speech-related responses were significantly augmented in these regions and in left hemisphere motor areas commonly associated with oral-laryngeal motor control. This pattern of responses was most strongly correlated with the objective measures of clinical improvement (decreases in the frequency of voice breaks, pitch breaks, and percentage aperiodicity). These data suggest a pathophysiological model for ADSD in which BTX treatment results in more efficient cortical processing of sensory information, making this information available to motor areas that use it to more effectively regulate laryngeal movements.

Utility of the daily prospective National Institute of Mental Health Life-Chart Method (NIMH-LCM-p) ratings in clinical trials of bipolar disorder.

This study investigated the assets of the daily prospective National Institute of Mental Health Life-Chart Method (NIMH-LCM-p or LCM-p) for use in clinical trials in bipolar disorder. Fifty-two outpatients, who met DSM-III-R criteria for bipolar disorder, were randomly assigned in a double-blind design to an intended 1 year of treatment with lithium or carbamazepine, a crossover to the opposite drug in the second year, and then to a combination of both agents in the third year. For each patient, the LCM-p was initiated upon admission and was continued on a daily basis. Overall therapeutic effect for each phase (intended year) was assessed by using the Clinical Global Impressions-Bipolar Version (CGI-BP) scale. Kruskal-Wallis analysis of variance was used to examine the detailed course-of-illness variables derived from the LCM-p (e.g., percentage of time ill, average severity of illness, episodes per year, and mood switches per year) in relation to the global assessments of treatment response (CGI-BP). Most of the individual LCM-p-derived illness variables varied significantly (P <.05) as a function of global treatment response. Since global ratings of the degree of improvement can represent very different proportions of improvement in percentage of time ill, average severity of mania or depression, or frequency of manic and depressive episodes, the LCM-p provides the basis for a comprehensive description of both the illness course and the response to treatment. The LCM-p appears to have considerable utility in clinical trials of pharmacological and other interventions of bipolar disorder. It provides a detailed characterization of the severity, frequency, and duration of manic and depressive episodes, which facilitates the assessment of global improvement and allows for the quantification of separate components of the illness, which are or are not responsive to a given treatment.