Safety and immunogenicity of a serum-free purified Vero rabies vaccine in comparison with the rabies human diploid cell vaccine (HDCV; Imovax® Rabies) administered in a simulated rabies post-exposure regimen in healthy adults.

A new generation, serum-free, antibiotic-free, purified Vero rabies vaccine (PVRV-NG; Sanofi) has been developed based on the same Pitman-Moore viral strain used for the currently licensed purified Vero cell rabies vaccine (PVRV; Verorab®, Sanofi) and human diploid cell vaccine (HDCV; Imovax® Rabies, Sanofi). PVRV-NG has demonstrated a satisfactory safety profile and induces robust immune responses, with non-inferiority demonstrated versus PVRV when given as a three-dose pre-exposure prophylaxis (PrEP) regimen in healthy children and adults. Here, we evaluated the safety and immunogenic non-inferiority of PVRV-NG compared to HDCV when administered as simulated post-exposure prophylaxis (PEP), with concomitant administration of human rabies immunoglobulin (HRIG), in healthy adults in the USA. Participants were vaccinated according to the 5-dose Essen intramuscular regimen (4-week, 1-injection site regimen, with a single dose given on days 0, 3, 7, 14 and 28) for PEP, with concomitant HRIG administered on day 0. Rabies virus neutralising antibodies (RVNA) were evaluated on days 0, 14, 28 and 42. Non-inferiority of PVRV-NG compared with HDCV was shown if the lower limit of the 95 % confidence interval (CI) for the difference in seroconversion rates (RVNA titers ≥ 0.5 IU/mL on day 14) between PVRV-NG and HDCV was above the non-inferiority margin of -5 %. Safety was evaluated after each vaccination and monitored throughout the study. The difference in seroconversion rate between the PVRV-NG and HDCV groups was -2.8 % (95 % CI, -8.08 to 4.20), indicating that non-inferiority was not demonstrated. The seroconversion rate was < 99 % in both study groups on day 14. There were no major safety concerns identified, and PVRV-NG demonstrated a similar safety profile to HDCV.

Evaluation of mRNA-1273 Covid-19 Vaccine in Children 6 to 11 Years of Age.

BACKGROUND: Vaccination of children to prevent coronavirus disease 2019 (Covid-19) is an urgent public health need. The safety, immunogenicity, and efficacy of the mRNA-1273 vaccine in children 6 to 11 years of age are unknown. METHODS: Part 1 of this ongoing phase 2-3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled expansion evaluation of the selected dose. In part 2, we randomly assigned children (6 to 11 years of age) in a 3:1 ratio to receive two injections of mRNA-1273 (50 µg each) or placebo, administered 28 days apart. The primary objectives were evaluation of the safety of the vaccine in children and the noninferiority of the immune response in these children to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives included determination of the incidences of confirmed Covid-19 and severe acute respiratory syndrome coronavirus 2 infection, regardless of symptoms. Interim analysis results are reported. RESULTS: In part 1 of the trial, 751 children received 50-µg or 100-µg injections of the mRNA-1273 vaccine, and on the basis of safety and immunogenicity results, the 50-µg dose level was selected for part 2. In part 2 of the trial, 4016 children were randomly assigned to receive two injections of mRNA-1273 (50 µg each) or placebo and were followed for a median of 82 days (interquartile range, 14 to 94) after the first injection. This dose level was associated with mainly low-grade, transient adverse events, most commonly injection-site pain, headache, and fatigue. No vaccine-related serious adverse events, multisystem inflammatory syndrome in children, myocarditis, or pericarditis were reported as of the data-cutoff date. One month after the second injection (day 57), the neutralizing antibody titer in children who received mRNA-1273 at a 50-µg level was 1610 (95% confidence interval [CI], 1457 to 1780), as compared with 1300 (95% CI, 1171 to 1443) at the 100-µg level in young adults, with serologic responses in at least 99.0% of the participants in both age groups, findings that met the prespecified noninferiority success criterion. Estimated vaccine efficacy was 88.0% (95% CI, 70.0 to 95.8) against Covid-19 occurring 14 days or more after the first injection, at a time when B.1.617.2 (delta) was the dominant circulating variant. CONCLUSIONS: Two 50-µg doses of the mRNA-1273 vaccine were found to be safe and effective in inducing immune responses and preventing Covid-19 in children 6 to 11 years of age; these responses were noninferior to those in young adults. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; KidCOVE ClinicalTrials.gov number, NCT04796896.).

Performance Evaluation of the Quantitative Point-of-Care LumiraDx D-Dimer Test.

INTRODUCTION: Fibrin degradation product D-dimer can be a valuable indicator for venous thromboembolism (VTE). The use of D-dimer testing in primary care settings can be limited by restricted access to laboratory services. This performance evaluation compares a quantitative, point-of-care (POC) D-dimer assay (LumiraDx D-Dimer Test) with a reference laboratory-based D-dimer assay. METHODS: Plasma samples from patients presenting to secondary care in the UK, USA, and Germany were analyzed centrally using the LumiraDx D-Dimer Test and the reference test (bioMérieux VIDAS D-Dimer Exclusion II immunoassay). Method comparison used Passing-Bablok regression analysis with pre-specified equivalence criteria of r ≥ 0.9 and slope of 0.9-1.1. The NOVEL-3 study (NCT04375982) compared equivalency of fingerstick, venous blood (VB), and plasma samples from the same patient, tested at US primary care clinics next to the patient using the POC LumiraDx D-Dimer device. Measurements obtained from fingerstick and VB samples were compared with results from plasma samples, using Deming regression. The healthy reference range was determined using plasma samples of healthy volunteers, collected by commercial suppliers in Germany and the USA, which were analyzed centrally using the LumiraDx D-Dimer Test and the reference test. RESULTS: The LumiraDx D-Dimer Test demonstrated agreement with the bioMérieux VIDAS D-Dimer Exclusion II immunoassay for plasma samples (r = 0.923, slope of 1.016, n = 1767). There was good agreement between fingerstick/VB samples and plasma samples (r = 0.980-0.986, n = 93) measured using the LumiraDx D-Dimer Test. Overall error rates were 1.8%. The healthy reference range 90% percentile for D-dimer was calculated as 533 µg/l fibrinogen equivalent units (FEU). CONCLUSIONS: The quantitative LumiraDx D-Dimer Test is easy to use and can accurately measure D-dimer levels in a range of blood sample types, including fingerstick samples, which could improve assessment of VTE cases in community and hospital near-patient settings.

Immunogenicity and safety of a quadrivalent meningococcal tetanus toxoid-conjugate vaccine (MenACYW-TT) in adults 56 years of age and older: a Phase II randomized study.

MenACYW-TT is an investigational quadrivalent meningococcal conjugate vaccine intended for the prevention of invasive meningococcal disease (IMD) caused by serogroups A, C, W, and Y in individuals aged 6 weeks and above. This Phase II, randomized, open-label, multicenter, exploratory study assessed the safety and immunogenicity of MenACYW-TT compared with a quadrivalent meningococcal polysaccharide vaccine (MPSV4) in 301 healthy adults aged ≥56 y in the US (NCT01732627). Participants were randomized 2:1 to receive MenACYW-TT or MPSV4. Serum bactericidal assays using human (hSBA) or baby rabbit (rSBA) complement were used to measure functional antibodies against meningococcal serogroups A, C, W, and Y at baseline and 30 d post-vaccination. Safety data were collected up to 30 d post-vaccination. Proportions of study participants with hSBA titers ≥1:8 against serogroups A, C, W, and Y were increased at Day 30 compared with baseline in both vaccine groups. The proportions of participants with hSBA titers ≥1:8 after MenACYW-TT vaccination were comparable to those after MPSV4 vaccination for serogroups A and C (A: 93.8% vs. 85.1%; C: 74.9% vs. 62.8%) and distinctly higher than after MPSV4 for serogroups W and Y (W: 79.5% vs. 60.6%; Y: 80.5% vs. 59.6%). Proportions of participants with rSBA titers ≥1:8 were comparable between vaccine groups for all four serogroups. The reactogenicity profiles of both vaccines were similar. Most unsolicited adverse events (AEs) were of Grade 1 or Grade 2 intensity, and no serious AEs were reported. The MenACYW-TT conjugate vaccine was well tolerated and immunogenic in adults aged ≥56 y.

Immunogenicity of the CYD tetravalent dengue vaccine using an accelerated schedule: randomised phase II study in US adults.

BACKGROUND: The live attenuated tetravalent dengue vaccine (CYD-TDV) is licensed using a 0-, 6- and 12-month schedule in dengue-endemic areas. An effective shorter schedule may provide more rapid, optimal protection of targeted populations during vaccine campaigns in dengue-endemic countries. We compared immune responses to two schedules of CYD-TDV in a non-endemic population. We also evaluated the impact of yellow fever (YF) co-administration. METHODS: This phase II, open-label, multicentre study enrolled 390 healthy 18-45-year-olds in the USA with no prior exposure to dengue. Participants were randomised (4:4:4:1) to four treatment groups stratified by prior YF vaccine status: Group 1, CYD-TDV standard 0-6-12 months schedule; Group 2, CYD-TDV accelerated 0-2-6 months schedule; Group 3, CYD-TDV accelerated schedule with YF co-administered (dose 1); Group 4, YF vaccination only. Neutralising antibody geometric mean titres (GMTs) and percentages of seropositive participants (antibody titres ≥10 [1/dil]) were measured against each dengue serotype using a 50% plaque reduction neutralisation test. RESULTS: On D28 post-CYD-TDV dose 3, there were no marked differences in seropositivity rates and GMTs between Groups 1 and 2. In Groups 1 and 2 respectively, 73.4 and 82.4% were dengue seropositive for ≥3 serotypes, with 50.0 and 42.6% seropositive against all four serotypes. Flavivirus status (FV+ or FV-) at baseline did not markedly affect GMTs and seropositivity rates with either schedule. In Groups 1 and 2, GMTs measured 6 months after the third dose decreased against all serotypes, except for a small increase in GMT for serotype 4 in Group 1. In addition, dengue seropositivity remained above 70% for serotypes 2, 3 and 4 in Groups 1 and 2. Co-administration with YF did not affect antibody responses against dengue and YF or impact vaccine safety following completion of the compressed schedule, compared to dengue or YF vaccination alone. CONCLUSIONS: The live attenuated CYD-TDV vaccine given in a compressed schedule in a non-endemic setting can elicit similar antibody responses to the licensed CYD-TDV schedule. TRIAL REGISTRATION: This trial was registered on cinicaltrials.gov, NCT01488890 (December 8, 2011).

Efficacy, immunogenicity, and safety evaluation of an MF59-adjuvanted quadrivalent influenza virus vaccine compared with non-adjuvanted influenza vaccine in children: a multicentre, randomised controlled, observer-blinded, phase 3 trial.

BACKGROUND: Young children have immature immune systems and respond poorly to standard influenza vaccines. The oil-in-water emulsion adjuvant MF59 can increase antigen uptake, macrophage recruitment, lymph node migration, and avidity to influenza virus. Therefore, we aimed to assess the relative efficacy, immunogenicity, and safety of an MF59-adjuvanted, quadrivalent, inactivated (subunit) influenza vaccine (aIIV4) compared with a US-licensed non-adjuvanted influenza vaccine in children. METHODS: We did a multicentre, randomised controlled, observer-blinded, phase 3 trial of 146 sites including hospitals, clinics, and clinician offices in nine countries over two influenza seasons. We included children of either sex aged 6 months through 5 years. We stratified eligible participants and randomly assigned them (1:1), using a block size of four, to receive either aIIV4 or non-adjuvanted inactivated influenza vaccine (ie, trivalent inactivated influenza vaccine [IIV3] or quadrivalent inactivated influenza vaccine [IIV4]). We masked participants, parents or guardians, and outcome assessors to the administered vaccine. Designated personnel who were not masked administered aIIV4 in both seasons, or IIV3 in season one and IIV4 in season two. All vaccinations were administered intramuscularly. Children aged 6 through 35 months received one or two 0·25 mL doses, whereas those aged 3 through 5 years received one or two doses of 0·5 mL. The number of doses was dependent on previous vaccination status: vaccine-naive participants received a total of two doses of study vaccine, the first on day 1 and the second on day 29, whereas non-naive participants received only one dose on day 1. The primary outcome was relative vaccine efficacy assessed by RT-PCR-confirmed influenza due to any influenza strain in the overall study population and in prespecified age and dose subgroups. Immunogenicity against homologous and heterologous strains of influenza and safety were also measured. This study is registered with ClinicalTrials.gov, number NCT01964989. FINDINGS: Between Nov 3, 2013, and March 5, 2014 (season one), and between Sept 30, 2014, and March 29, 2015 (season two), 10 644 participants were enrolled in this study. Of these participants, 10 612 were vaccinated (n=5338 with aIIV4 and n=5274 with comparator). Relative vaccine efficacy was not different between aIIV4 and the comparator vaccines in the overall study population (relative vaccine efficacy -0·67, 95% CI -19·81 to 15·41). The relative vaccine efficacy in the 6 through 23-month subgroup was significantly greater for aIIV4 than for the comparator vaccine (relative vaccine efficacy 31·37, 95% CI 3·14-51·38). aIIV4 elicited superior immunogenic response compared with the comparator for all four vaccine strains (geometric mean titre ratios 1·91 [95% CI 1·8-2·0] for A/H1N1, 1·71 [1·6-1·8] for A/H3N2, 2·19 [2·0-2·4] for B/Yamagata, and 2·27 [2·0-2·6] for B/Victoria) and three heterologous strains (1·94 [1·6-2·3] for A/H3N2, 2·17 [1·8-2·6] for B/Yamagata, and 2·12 [1·6-2·7] for B/Victoria) in participants aged 6 months through 5 years. The highest geometric mean titre ratios were observed in participants aged 6 through 23 months. Safety profiles were similar but more frequent solicited adverse events were reported with aIIV4 than with the comparator (3748 [73%] of 5138 vs 3242 [64%] of 5056). INTERPRETATION: Although there was no additional benefit of aIIV4 compared with the US-licensed non-adjuvanted influenza vaccines in the overall study population, in the youngest and most vulnerable population of children in this trial, aIIV4 provided greater protection against influenza than a non-adjuvanted vaccine when assessed in this prespecified age group of 6 through 23 months. Additional clinical benefit was also apparent early after first vaccination in vaccine-naive participants aged 6 months through 5 years. Finally, aIIV4 and comparator had similar efficacy and vaccine safety profiles in children aged 6 months through 5 years. FUNDING: Seqirus UK Ltd.

Comparative Assessment of a Single Dose and a 2-dose Vaccination Series of a Quadrivalent Meningococcal CRM-conjugate Vaccine (MenACWY-CRM) in Children 2-10 Years of Age.

BACKGROUND: We compared the immunogenicity, safety and 1-year antibody persistence of a single-dose and a 2-dose series of a licensed meningococcal ACWY-CRM conjugate vaccine (MenACWY-CRM) in 2- to 10-year-old children. METHODS: In this phase III, multicenter, observer-blind study, children aged 2-5 years (n = 359) and 6-10 years (n = 356) were randomized 1:1 to receive 2 doses of MenACWY-CRM (ACWY2) or 1 dose of placebo followed by 1 dose of MenACWY-CRM (ACWY1), 2 months apart. Immunogenicity was measured using serum bactericidal activity with human complement (hSBA). Primary outcomes were to assess the immunologic noninferiority and superiority of ACWY2 versus ACWY1. RESULTS: One-month after the second dose, the hSBA seroresponse in ACWY2 was noninferior to ACWY1 for all 4 serogroups, in both age cohorts, and was superior for serogroups C and Y in the 2- to 5-year-old age cohort and for serogroup Y in the 6- to 10-year-old age cohort. Overall, 90%-99% of subjects in ACWY2 and 65%-96% in ACWY1 had hSBA titers ≥ 8; geometric mean titers were 1.8- to 6.4-fold higher in ACWY2 than ACWY1 across serogroups. At 1 year postvaccination, geometric mean titers declined, and the differences between ACWY2 and ACWY1 remained significant for serogroups A and C in the 2- to 5-year-old age cohort and for serogroups C and Y in the 6- to 10-year-old age cohort. The safety profile of MenACWY-CRM was similar in both groups. CONCLUSIONS: The single dose and 2-dose MenACWY-CRM series were immunogenic and well tolerated. Although antibody responses were greater after 2 doses, especially in the 2- to 5-year-old age cohort, this difference was less pronounced at 1 year postvaccination.

Safety and immunogenicity of different doses and schedules of a live attenuated tetravalent dengue vaccine (TDV) in healthy adults: A Phase 1b randomized study.

INTRODUCTION: A safe, effective dengue vaccine that can simultaneously induce immunity to all four dengue virus serotypes (DENV-1-4) is a public health priority. A chimeric tetravalent dengue vaccine (TDV) based on an attenuated DENV-2 serotype backbone was evaluated in healthy, flavivirus-seronegative adults. METHODS: In this randomized, multicenter, Phase 1b study conducted in the United States, the safety and immunogenicity of TDV were evaluated in 140 participants aged 18-45 years in six dosing regimen study groups. Participants were injected subcutaneously on Days 0 and 90; placebo (saline) was injected where appropriate to maintain double blinding. Three different TDV dosages (TDV, a vaccine in which TDV-4 had been increased three-fold, and a one-tenth TDV dose), and single or double dosing were evaluated in one and/or both arms. Primary endpoints were solicited and unsolicited adverse events (AEs) and seroconversion rates to DENV-1-4 at Day 120. RESULTS: The severity of all AEs was generally mild. The most common unsolicited AEs were headache (52%), fatigue (43%) and myalgia (29%). The incidence of injection site pain ranged from 29 to 64% and 5 to 52% among study groups after the first and second doses, respectively. At Day 120, the ranges of seroconversion rates among the groups were DEN-1: 84-100%; DEN-2: 96-100%; DEN-3: 83-100%; and DEN-4: 33-77%. More than 80% of participants in each group seroconverted to at least three dengue serotypes. Substantial GMT increases from baseline were observed for DEN-1-3 at all time points from Day 30 onward; DEN-4 GMT increases were lower. Increasing TDV-4 slightly increased DEN-4 GMT, did not impact DEN-2 and DEN-3 GMT, but reduced DEN-1 GMT. Neither multiple dosing in both arms, nor one-tenth TDV dosing meaningfully impacted GMT increases relative to TDV. CONCLUSIONS: All TDV doses and dosing schedules were well tolerated and immunogenic in healthy flavivirus-naive adults (ClinicalTrials.gov NCT01511250).

Single-dose fluoroquinolone therapy of acute uncomplicated urinary tract infection in women: results from a randomized, double-blind, multicenter trial comparing single-dose to 3-day fluoroquinolone regimens.

OBJECTIVES: To compare the efficacy and safety of single-dose and 3-day fluoroquinolone treatment of uncomplicated urinary tract infection (UTI). METHODS: Adult women with acute uncomplicated UTI were randomized to receive either a single dose of gatifloxacin (400 mg), 3 days of gatifloxacin (200 mg daily), or 3 days of ciprofloxacin (100 mg twice daily). Patients were assessed at four points during the study: before treatment (within 48 hours before the initiation of the study medication), at the end of treatment (by telephone contact on day 3), and twice after treatment completion (5 to 9 days after treatment [test-of-cure visit] and 29 to 42 days after treatment [only patients with a bacteriologic response of eradication at the test-of-cure visit]). RESULTS: The bacterial eradication rate for the single-dose gatifloxacin, 3-day gatifloxacin, and 3-day ciprofloxacin groups was 90%, 95%, and 89%, respectively; the clinical efficacy rate was 93%, 95%, and 93%, respectively, for microbiologically assessable patients at the test-of-cure visit. Eradication of the most common uropathogens, including Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, was achieved with gatifloxacin and ciprofloxacin. Single-dose gatifloxacin was equivalent to 3-day ciprofloxacin in both microbiologic and clinical efficacy. CONCLUSIONS: Single-dose and 3-day gatifloxacin were microbiologically and clinically equivalent to 3-day ciprofloxacin for the treatment of acute UTI among women. Single-dose gatifloxacin may offer advantages over 3-day fluoroquinolone therapy for uncomplicated UTI by decreasing secondary use of medical resources and improving patient compliance.

Rebuilding Family Relationship Competencies as a Primary Health Intervention.

The authors present Relationship Competence Training (RCT), which is an organized conceptual framework developed by them for assessing a family's ability to mobilize their relational support in times of distress. RTC is a process of studying family relationship patterns and how these patterns influence family health. The RTC model is described as a method of promoting mental health as a part of everyday family health, which is suitable for health care providers working in a wide variety of environments who have in common the desire to offer continuity and value in promoting the health of the families under their care. RCT provides an empathic way of dealing with the "compassion fatigue" that health care providers often experience when managing complex family health issues in constantly changing and quality-strained primary health care environments.