Immunogenicity and Vaccine Shedding After 1 or 2 Doses of rVSVΔG-ZEBOV-GP Ebola Vaccine (ERVEBO®): Results From a Phase 2, Randomized, Placebo-controlled Trial in Children and Adults.

BACKGROUND: The rVSVΔG-ZEBOV-GP vaccine (ERVEBO®) is a single-dose, live-attenuated, recombinant vesicular stomatitis virus vaccine indicated for the prevention of Ebola virus disease (EVD) caused by Zaire ebolavirus in individuals 12 months of age and older. METHODS: The Partnership for Research on Ebola VACcination (PREVAC) is a multicenter, phase 2, randomized, double-blind, placebo-controlled trial of 3 vaccine strategies in healthy children (ages 1-17) and adults, with projected 5 years of follow-up (NCT02876328). Using validated assays (GP-ELISA and PRNT), we measured antibody responses after 1-dose rVSVΔG-ZEBOV-GP, 2-dose rVSVΔG-ZEBOV-GP (given on Day 0 and Day 56), or placebo. Furthermore, we quantified vaccine virus shedding in a subset of children's saliva using RT-PCR. RESULTS: In total, 819 children and 783 adults were randomized to receive rVSVΔG-ZEBOV-GP (1 or 2 doses) or placebo. A single dose of rVSVΔG-ZEBOV-GP increased antibody responses by Day 28 that were sustained through Month 12. A second dose of rVSVΔG-ZEBOV-GP given on Day 56 transiently boosted antibody concentrations. In vaccinated children, GP-ELISA titers were superior to placebo and non-inferior to vaccinated adults. Vaccine virus shedding was observed in 31.7% of children, peaking by Day 7, with no shedding observed after Day 28 post-dose 1 or any time post-dose 2. CONCLUSIONS: A single dose of rVSVΔG-ZEBOV-GP induced robust antibody responses in children that was non-inferior to the responses induced in vaccinated adults. Vaccine virus shedding in children was time-limited and only observed after the first dose. Overall, these data support the use of rVSVΔG-ZEBOV-GP for the prevention of EVD in at-risk children. Clinical Trials Registration. The study is registered at ClinicalTrials.gov (NCT02876328), the Pan African Clinical Trials Registry (PACTR201712002760250), and the European Clinical Trials Register (EudraCT number: 2017-001798-18).

PTH regulates osteogenesis and suppresses adipogenesis through Zfp467 in a feed-forward, PTH1R-cyclic AMP-dependent manner.

Conditional deletion of the PTH1R in mesenchymal progenitors reduces osteoblast differentiation, enhances marrow adipogenesis, and increases zinc finger protein 467 (Zfp467) expression. In contrast, genetic loss of Zfp467 increased Pth1r expression and shifts mesenchymal progenitor cell fate toward osteogenesis and higher bone mass. PTH1R and ZFP467 could constitute a feedback loop that facilitates PTH-induced osteogenesis and that conditional deletion of Zfp467 in osteogenic precursors would lead to high bone mass in mice. Prrx1Cre; Zfp467fl/fl but not AdipoqCre; Zfp467fl/fl mice exhibit high bone mass and greater osteogenic differentiation similar to the Zfp467-/- mice. qPCR results revealed that PTH suppressed Zfp467 expression primarily via the cyclic AMP/PKA pathway. Not surprisingly, PKA activation inhibited the expression of Zfp467 and gene silencing of Pth1r caused an increase in Zfp467 mRNA transcription. Dual fluorescence reporter assays and confocal immunofluorescence demonstrated that genetic deletion of Zfp467 resulted in higher nuclear translocation of NFκB1 that binds to the P2 promoter of the Pth1r and increased its transcription. As expected, Zfp467-/- cells had enhanced production of cyclic AMP and increased glycolysis in response to exogenous PTH. Additionally, the osteogenic response to PTH was also enhanced in Zfp467-/- COBs, and the pro-osteogenic effect of Zfp467 deletion was blocked by gene silencing of Pth1r or a PKA inhibitor. In conclusion, our findings suggest that loss or PTH1R-mediated repression of Zfp467 results in a pathway that increases Pth1r transcription via NFκB1 and thus cellular responsiveness to PTH/PTHrP, ultimately leading to enhanced bone formation.

Real-Time Monitoring of Infectious Disease Outbreaks with a Combination of Google Trends Search Results and the Moving Epidemic Method: A Respiratory Syncytial Virus Case Study.

The COVID-19 pandemic has disrupted the seasonal patterns of several infectious diseases. Understanding when and where an outbreak may occur is vital for public health planning and response. We usually rely on well-functioning surveillance systems to monitor epidemic outbreaks. However, not all countries have a well-functioning surveillance system in place, or at least not for the pathogen in question. We utilized Google Trends search results for RSV-related keywords to identify outbreaks. We evaluated the strength of the Pearson correlation coefficient between clinical surveillance data and online search data and applied the Moving Epidemic Method (MEM) to identify country-specific epidemic thresholds. Additionally, we established pseudo-RSV surveillance systems, enabling internal stakeholders to obtain insights on the speed and risk of any emerging RSV outbreaks in countries with imprecise disease surveillance systems but with Google Trends data. Strong correlations between RSV clinical surveillance data and Google Trends search results from several countries were observed. In monitoring an upcoming RSV outbreak with MEM, data collected from both systems yielded similar estimates of country-specific epidemic thresholds, starting time, and duration. We demonstrate in this study the potential of monitoring disease outbreaks in real time and complement classical disease surveillance systems by leveraging online search data.

A phase I randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and immunogenicity of a live-attenuated quadrivalent dengue vaccine in flavivirus-naïve and flavivirus-experienced healthy adults.

Dengue (DENV) is a mosquito-borne virus with four serotypes causing substantial morbidity in tropical and subtropical areas worldwide. V181 is an investigational, live, attenuated, quadrivalent dengue vaccine. In this phase 1 double-blind, placebo-controlled study, the safety, tolerability, and immunogenicity of V181 in baseline flavivirus-naïve (BFN) and flavivirus-experienced (BFE) healthy adults were evaluated in two formulations: TV003 and TV005. TV005 contains a 10-fold higher DENV2 level than TV003. Two-hundred adults were randomized 2:2:1 to receive TV003, TV005, or placebo on Days 1 and 180. Immunogenicity against the 4 DENV serotypes was measured using a Virus Reduction Neutralization Test (VRNT60) after each vaccination and out to 1 year after the second dose. There were no discontinuations due to adverse events (AE) or serious vaccine-related AEs in the study. Most common AEs after TV003 or TV005 were headache, rash, fatigue, and myalgia. Tri- or tetravalent vaccine-viremia was detected in 63.9% and 25.6% of BFN TV003 and TV005 participants, respectively, post-dose 1 (PD1). Tri- or tetravalent dengue VRNT60 seropositivity was demonstrated in 92.6% of BFN TV003, 74.2% of BFN TV005, and 100% of BFE TV003 and TV005 participants PD1. Increases in VRNT60 GMTs were observed after the first vaccination with TV003 and TV005 in both flavivirus subgroups for all dengue serotypes, and minimal increases were measured PD2. GMTs in the TV003 and TV005 BFE and BFN groups remained above the respective baselines and placebo through 1-year PD2. These data support further development of V181 as a single-dose vaccine for the prevention of dengue disease.

Assessment of Costs and Care Quality Associated With Major Surgical Procedures After Implementation of Maryland's Capitated Budget Model.

Importance: In 2014, Maryland implemented the all-payer model, a distinct hospital funding policy that applied caps on annual hospital expenditures and mandated reductions in avoidable complications. Expansion of this model to other states is currently being considered; therefore, it is important to evaluate whether Maryland's all-payer model is achieving the desired goals among surgical patients, who are an at-risk population for most potentially preventable complications. Objective: To examine the association between the implementation of Maryland's all-payer model and the incidence of avoidable complications and resource use among adult surgical patients. Design, Setting, and Participants: This comparative effectiveness study used hospital discharge records from the Healthcare Cost and Utilization Project state inpatient databases to conduct a difference-in-differences analysis comparing the incidence of avoidable complications and the intensity of health resource use before and after implementation of the all-payer model in Maryland. The analytical sample included 2 983 411 adult patients who received coronary artery bypass grafting (CABG), carotid endarterectomy (CEA), spinal fusion, hip or knee arthroplasty, hysterectomy, or cesarean delivery between January 1, 2008, and December 31, 2016, at acute care hospitals in Maryland (intervention state) and New York, New Jersey, and Rhode Island (control states). Data analysis was conducted from July 2019 to July 2021. Exposures: All-payer model. Main Outcomes and Measures: Complications (infectious, cardiovascular, respiratory, kidney, coagulation, and wound) and health resource use (ie, hospital charges). Results: Of 2 983 411 total patients in the analytical sample, 525 262 patients were from Maryland and 2 458 149 were from control states. Across Maryland and the control states, there were statistically significant but not clinically relevant differences in the preintervention period with regard to patient age (mean [SD], 49.7 [19.0] years vs 48.9 [19.3] years, respectively; P < .001), sex (22.7% male vs 21.4% male; P < .001), and race (0.3% vs 0.4% American Indian, 2.8% vs 4.5% Asian or Pacific Islander, 25.9% vs 12.7% Black, 4.7% vs 11.9% Hispanic, and 63.5% vs 63.4% White; P < .001). After implementation of the all-payer model in Maryland, significantly lower rates of avoidable complications were found among patients who underwent CABG (-11.3%; 95% CI, -13.8% to -8.7%; P < .001), CEA (-1.6%; 95% CI, -2.9% to -0.3%; P = .02), hip arthroplasty (-0.8%; 95% CI, -1.0% to -0.5%; P < .001), knee arthroplasty (-0.4%; 95% CI, -0.7% to -0.1%; P = .01), and cesarean delivery (-1.0%; 95% CI, -1.3% to -0.7%; P < .001). In addition, there were significantly lower increases in index hospital costs in Maryland among patients who underwent CABG (-$6236; 95% CI, -$7320 to -$5151; P < .001), CEA (-$730; 95% CI, -$1367 to -$94; P = .03), spinal fusion (-$3253; 95% CI, -$3879 to -$2627; P < .001), hip arthroplasty (-$328; 95% CI, -$634 to -$21; P = .04), knee arthroplasty (-$415; 95% CI, -$643 to -$187; P < .001), cesarean delivery (-$300; 95% CI, -$380 to -$220; P < .001), and hysterectomy (-$745; 95% CI, -$974 to -$517; P < .001). Significant changes in patient mix consistent with a younger population (eg, a shift toward private/commercial insurance for orthopedic procedures, such as spinal fusion [4.3%; 95% CI, 3.4%-5.2%; P < .001] and knee arthroplasty [1.6%; 95% CI, 1.0%-2.3%; P < .001]) and a lower comorbidity burden across surgical procedures (eg, CABG: -0.7% [95% CI, -0.1% to -0.5%; P < .001]; hip arthroplasty: -3.0% [95% CI, -3.6% to -2.3%; P < .001]) were also observed. Conclusions and Relevance: In this study, patients who underwent common surgical procedures had significantly fewer avoidable complications and lower hospital costs, as measured against the rate of increase throughout the study, after implementation of the all-payer model in Maryland. These findings may be associated with changes in the patient mix.

Protective immune responses against Haemophilus influenza type b elicited by a fully-liquid DTaP-IPV-Hib-HepB vaccine (VAXELIS™).

BACKGROUND: DTaP-IPV-Hib-HepB is a fully-liquid, hexavalent combination vaccine (Vaxelis™) approved for vaccination against diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B, and invasive disease due to Haemophilus influenzae type b (Hib). Hib capsular polysaccharide, polyribosylribitol phosphate (PRP), is conjugated to Neisseria meningitidis outer membrane protein complex (OMPC). Safety and immunogenicity of DTaP-IPV-Hib-HepB were evaluated in 6 Phase III clinical studies including > 5,200 children. Studies included vaccination schedules in the United States (2, 4, 6 months of age) and Europe (2, 3, 4, 12 months of age and 2,4,11-12 months of age). METHODS: Data pertaining to anti-PRP responses of DTaP-IPV-Hib-Hep B compared to control vaccines from 5 Phase III studies are summarized. RESULTS: Post-infant series, the percentage of participants that achieved protective antibody thresholds for PRP (anti-PRP titer ≥ 0.15 µg/mL and ≥ 1.0 µg/mL, respectively) were higher in DTaP-IPV-Hib-HepB recipients compared to recipients who received control vaccines. A high level of protective responses (96.6% at ≥ 0.15 µg/mL [95% CI:94.8, 97.9%]; 72.9% at ≥ 1.0 µg/mL [95% CI:69.2,76.4%]) were seen post-dose 2 of the 2 + 1 vaccination schedule and met superiority criteria over comparator, p-value < 0.001. In the same schedule, prior to administration of the toddler dose (in the second year of life), anti-PRP titers were higher in DTaP-IPV-Hib-HepB recipients (91.4% at ≥ 0.15 µg/mL; 46.8% at ≥ 1.0 µg/mL) as compared to recipients who received control vaccines (63.4% at ≥ 0.15 µg/mL; 17.1% at ≥ 1.0 µg/mL). One-month post-toddler dose, high levels of anti-PRP titers were achieved in both DTaP-IPV-Hib-HepB recipients (99.8% at ≥ 0.15 µg/mL; 96.6% at ≥ 1.0 µg/mL) and recipients who received control vaccines (99.5% at ≥ 0.15 µg/mL; 94.9% at ≥ 1.0 µg/mL). CONCLUSIONS: These results support that DTaP-IPV-Hib-HepB induces a robust and sustained early Hib response. During the high-risk period for Hib disease after the infant vaccine and prior to the toddler dose; >90% of recipients maintained superior protective anti-PRP levels compared to control.

A Phase 1 Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Safety, Tolerability, and Pharmacokinetics of a Respiratory Syncytial Virus Neutralizing Monoclonal Antibody MK-1654 in Healthy Adults.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infection and related morbidity and mortality in infants. Passive immunization with an RSV-neutralizing antibody can provide rapid protection to this vulnerable population. Proof-of-concept for this approach has been demonstrated by palivizumab; however, the use of this antibody is generally restricted to the highest-risk infants due to monthly dosing requirements and its cost. To address the large unmet medical need for most infants, we are evaluating MK-1654, a fully human RSV-neutralizing antibody with half-life extending mutations targeting site IV of the fusion protein. In this 2-part, placebo-controlled, double-blind, first-in-human study, 152 healthy adults were randomized 3:1 to receive a single dose of MK-1654 or placebo in 5 cohorts (100 or 300 mg as an intramuscular dose or 300, 1000, or 3000 mg as an intravenous dose). Safety, pharmacokinetics, antidrug antibodies, and RSV serum-neutralizing antibody titers were evaluated through 1 year. MK-1654 serum concentrations increased proportionally with dose and resulted in corresponding elevations in RSV serum-neutralizing antibody titers. The antibody displayed a half-life of 73 to 88 days and an estimated bioavailability of 69% at the 300-mg dose. The overall safety profile of MK-1654 was similar to placebo, and treatment-emergent antidrug antibodies were low (2.6%) with no associated adverse events. These data support the continued development of MK-1654 for the prevention of RSV disease in infants.

Safety and immunogenicity of a fully-liquid DTaP-IPV-Hib-HepB vaccine (Vaxelis™) in premature infants.

Background: Immune immaturity may put premature infants at increased risk for infections. DTaP-IPV-Hib-HepB vaccine (Vaxelis™), a hexavalent vaccine studied in >6,800 children, has acceptable safety and immunogenicity profiles generally similar to control vaccines. Here we evaluate safety and immunogenicity of DTaP-IPV-Hib-HepB vaccine in premature infants. Methods: Premature infants were identified using prior medical conditions terms "premature baby/delivery" and/or "low birth weight baby". Immunogenicity and safety data were summarized across one Phase II and four Phase III randomized, active-comparator-controlled clinical trials (Protocol 004 in Canada [Control: PENTACEL™]; Protocols 005 and 006 in the US [Control: PENTACEL™]; and Protocols 007 and 008 in the EU [Control: INFANRIX™ hexa]) and one Phase III clinical trial in the UK (PRI01C); no formal statistical comparisons were performed. Results: Overall, 160 infants were considered premature (DTaP-IPV-Hib-HepB = 111 Control = 49). The incidence of adverse events (AEs) for DTaP-IPV-Hib-HepB was comparable between overall and premature populations for all AEs days 1-15 postvaccination (Overall = 96.3%; Premature = 97.3%;), solicited injection-site AEs days 1-5 postvaccination (Overall = 84.1%; Premature = 75.5%), and solicited systemic AEs days 1-5 postvaccination (Overall = 93.7%; Premature = 94.5%). A high percentage of premature infants mounted protective immune responses to antigens contained in DTaP-IPV-Hib-HepB vaccine. Response rates in preterm infants for all antigens (80-99%) were in a similar range to all infants (80-99%) for both DTaP-IPV-Hib-HepB and control vaccines. Conclusions: DTaP-IPV-Hib-HepB vaccine has a low incidence of AEs, an acceptable safety profile, and elicited satisfactory immune responses in premature infants comparable to the overall study population. These findings support vaccination with DTaP-IPV-Hib-HepB vaccine in healthy premature infants.

Intravenous Fibrinolysis for Central Retinal Artery Occlusion: A Cohort Study and Updated Patient-Level Meta-Analysis.

BACKGROUND AND PURPOSE: Central retinal artery occlusion results in sudden, painless, usually permanent loss of vision in the affected eye. There is no proven, effective treatment to salvage visual acuity and a clear, unmet need for an effective therapy. In this work, we evaluated the efficacy of intravenous tissue-type plasminogen activator (IV alteplase) in a prospective cohort study and an updated systematic review and meta-analysis. METHODS: We enrolled consecutive patients with acute central retinal artery occlusion within 48 hours of symptoms onset and with a visual acuity of <20/200 from January 2009 until May 2019. The primary outcomes were safety and functional visual acuity recovery. We compared rates of visual recovery between those treated with alteplase within 4.5 hours of symptom onset to those who did not receive alteplase (including an analysis restricted to untreated patients presenting within the window for treatment). We incorporated these results into an updated systematic review and patient-level meta-analysis. RESULTS: We enrolled 112 patients, of whom 25 (22.3% of the cohort) were treated with IV alteplase. One patient had an asymptomatic intracerebral hemorrhage after IV alteplase treatment. Forty-four percent of alteplase-treated patients had recovery of visual acuity when treated within 4.5 hours versus 13.1% of those not treated with alteplase (P=0.003) and 11.6% of those presenting within 4 hours who did not receive alteplase (P=0.03). Our updated patient-level meta-analysis of 238 patients included 67 patients treated with alteplase within 4.5 hours since time last known well with a recovery rate of 37.3%. This favorably compares with a 17.7% recovery rate in those without treatment. In linear regression, earlier treatment correlated with a higher rate of visual recovery (P=0.01). CONCLUSIONS: This study showed that the administration of intravenous alteplase within 4.5 hours of symptom onset is associated with a higher likelihood of a favorable visual outcome for acute central retinal artery occlusion. Our results strongly support proceeding to a randomized, placebo-controlled clinical trial.

A double-blind, randomized, multicenter, controlled study to evaluate the immunogenicity, safety, and tolerability of varicella vaccine (VARIVAX™) passage extension 34 (PE34) process administered concomitantly with measles, mumps, and rubella vaccine (M-M-R™ II).

The varicella vaccine passage extension (VAR-PE) process was undertaken to extend the availability of varicella zoster virus (VZV)-containing vaccines. This study (V210-A03; NCT03239873) assessed the immunogenicity, safety, and tolerability of VAR-PE process in comparison with varicella vaccine commercial product 2016 (VAR) randomized 1:1 in 600 healthy children 12 to 23 months of age administered concomitantly with measles-mumps-rubella (MMR) vaccine. The VZV seroconversion rate at 6 weeks Postdose 1 in the PP population was 100% for both groups. VZV antibody response rates and GMTs of VZV antibodies to VAR-PE induced and were non-inferior to those induced by VAR 6 weeks Postdose 1. From Day 1 through Day 42, adverse events (AEs) were reported by 81.3% of participants Postdose 1 and 67.9% Postdose 2. From Day 1 through Day 42 Postdose 1, injection-site AEs related to varicella vaccine were reported by 31.1% and 29.7% of participants in VAR-PE and VAR, respectively, and Postdose 2, by 25.7% and 25.5% of participants in the VAR-PE and VAR groups, respectively. Systemic AEs were generally comparable for the 2 vaccination groups, with the exception of pyrexia and otitis media higher in VAR-PE, and diarrhea and teething higher in VAR. The incidence of systemic AEs was generally lower Postdose 2 compared with Postdose 1.

Integrated Safety Profile of a New Approved, Fully Liquid DTaP5-HB-IPV-Hib Vaccine.

BACKGROUND: DTaP5-HB-IPV-Hib is a fully liquid, hexavalent vaccine containing a 5-antigen pertussis component, approved since 2016 in Europe [Vaxelis; DTaP5-HB-IPV-Hib vaccine: Diphtheria, tetanus, pertussis (5 acellular components: pertussis toxoid [PT], filamentous haemagglutinin [FHA], pertactin (PRN), and fimbriae Types 2 and 3 [FIM]), hepatitis B (recombinant DNA: rDNA), poliomyelitis (inactivated) and Haemophilus influenzae type b conjugate vaccine (adsorbed); MCM Vaccine B.V., The Netherlands] for primary and booster vaccination in infants and toddlers against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and invasive diseases caused by Haemophilus influenzae type b. The comparator vaccine (control) was INFANRIX hexa (GlaxoSmithKline Biologics S.A., Rixensart, Belgium) (DTaP3-IPV-HepB/Hib) in European studies and PENTACEL (DTaP5-IPV/Hib) (Sanofi Pasteur, Swiftwater, PA) in US studies. METHODS: Data from 6 studies were integrated and analyzed to provide a comprehensive safety profile. Numbers and proportions of subjects with adverse events (AEs) were summarized by treatment group. Group differences in proportion of AEs were calculated. RESULTS: Among the DTaP5-HB-IPV-Hib (N = 5223) and 2295 control (N = 2295) groups, solicited injection-site and systemic AEs were very common. Serious AEs were reported by 3.9% of DTaP5-HB-IPV-Hib and 3.7% of control subjects. Vaccine-related serious AEs occurred infrequently, 0.2% for both groups. Most AEs were mild-to-moderate and did not lead to subject withdrawal. Group differences for solicited systemic AEs were small (<3%) and not statistically significant, except for pyrexia (estimated difference 9.4% [95% CI: 6.7%-12%]). The difference was driven by the 2 US studies where the PENTACEL control group had a lower fever rate. Among European studies, there was no significant difference in rates of pyrexia between DTaP5-HB-IPV-Hib and INFANRIX hexa. CONCLUSIONS: The safety of DTaP5-HB-IPV-Hib is consistent with the safety profile of its components and similar to comparator vaccines, including INFANRIX hexa. The vaccine provides a new, fully liquid and convenient hexavalent vaccination option for use with various vaccination schedules in Europe.

Safety and immunogenicity of VAQTA® in children 12-to-23 months of age with and without administration of other US pediatric vaccines.

Safety and immunogenicity data from 5 clinical trials conducted in the US in children 12-to-23 months old where HAVi was administered alone or concomitantly with other pediatric vaccines (M-M-R®II, Varivax®, TRIPEDIA®, Prevnar®, ProQuad®, PedvaxHIB®, and INFANRIX®) were combined. Among 4,374 participants receiving ≥ 1 dose of HAVi, 4,222 (97%) had safety follow-up and the proportions reporting adverse events (AE) were comparable when administered alone (69.4%) or concomitantly with other pediatric vaccines (71.1%). The most common solicited injection-site AEs were pain/tenderness (Postdose 1: 25.8%; Postdose 2: 26.1%) and redness (Postdose 1: 13.6%; Postdose 2: 15.1%). The most common vaccine-related systemic AEs were fever (≥ 100.4ºF, 12.2%) and irritability (8.1%). Serious AEs (SAEs) were observed at a rate of 0.4%; 0.1% were considered vaccine-related. No deaths were reported within 14 days following a dose of HAVi. These integrated analyses also showed that protective antibody concentrations were elicited in 100% of toddlers after two doses and 92% after a single dose, regardless of whether HAVi was given concomitantly with other vaccines or alone. These results demonstrate that HAVi was well-tolerated whether given alone or concomitantly with other vaccines, with a low incidence of vaccine-related SAEs. HAVi was immunogenic in this age group regardless of whether administered with or without other pediatric vaccines and whether 1 or 2 doses were administered. HAVi did not impact the immune response to other vaccines. These data continue to support the routine use of HAVi with other pediatric vaccines in children ≥ 12 months of age.

By Default: The Effect of Prepopulated Prescription Quantities on Opioid Prescribing in the Emergency Department.

INTRODUCTION: Opioid prescribing patterns have come under increasing scrutiny with the recent rise in opioid prescriptions, opioid misuse and abuse, and opioid-related adverse events. To date, there have been limited studies on the effect of default tablet quantities as part of emergency department (ED) electronic order entry. Our goal was to evaluate opioid prescribing patterns before and after the removal of a default quantity of 20 tablets from ED electronic order entry. METHODS: We performed a retrospective observational study at a single academic, urban ED with 58,000 annual visits. We identified all adult patients (18 years or older) seen in the ED and discharged home with prescriptions for tablet forms of hydrocodone and oxycodone (including mixed formulations with acetaminophen). We compared the quantity of tablets prescribed per opioid prescription 12 months before and 10 months after the electronic order-entry prescription default quantity of 20 tablets was removed and replaced with no default quantity. No specific messaging was given to providers, to avoid influencing prescribing patterns. We used two-sample Wilcoxon rank-sum test, two-sample test of proportions, and Pearson's chi-squared tests where appropriate for statistical analysis. RESULTS: A total of 4,104 adult patients received discharge prescriptions for opioids in the pre-intervention period (151.6 prescriptions per 1,000 discharged adult patients), and 2,464 post-intervention (106.69 prescriptions per 1,000 discharged adult patients). The median quantity of opioid tablets prescribed decreased from 20 (interquartile ration [IQR] 10-20) to 15 (IQR 10-20) (p<0.0001) after removal of the default quantity. While the most frequent quantity of tablets received in both groups was 20 tablets, the proportion of patients who received prescriptions on discharge that contained 20 tablets decreased from 0.5 (95% confidence interval [CI] [0.48-0.52]) to 0.23 (95% CI [0.21-0.24]) (p<0.001) after default quantity removal. CONCLUSION: Although the median number of tablets differed significantly before and after the intervention, the clinical significance of this is unclear. An observed wider distribution of the quantity of tablets prescribed after removal of the default quantity of 20 may reflect more appropriate prescribing patterns (i.e., less severe indications receiving fewer tabs and more severe indications receiving more). A default value of 20 tablets for opioid prescriptions may be an example of the electronic medical record's ability to reduce practice variability in medication orders actually counteracting optimal patient care.

The Impact of an Emergency Department Front-End Redesign on Patient-Reported Satisfaction Survey Results.

INTRODUCTION: For emergency department (ED) patients, delays in care are associated with decreased satisfaction. Our department focused on implementing a front-end vertical patient flow model aimed to decrease delays in care, especially care initiation. The physical space for this new model was termed the Flexible Care Area (FCA). The purpose of this study was to quantify the impact of this intervention on patient satisfaction. METHODS: We conducted a retrospective study of patients discharged from our academic ED over a one-year period (7/1/2013-6/30/2014). Of the 34,083 patients discharged during that period, 14,075 were sent a Press-Ganey survey and 2,358 (16.8%) returned the survey. We subsequently compared these survey responses with clinical information available through our electronic health record (EHR). Responses from the Press-Ganey surveys were dichotomized as being "Very Good" (VG, the highest rating) or "Other" (for all other ratings). Data abstracted from the EHR included demographic information (age, gender) and operational information (e.g. - emergency severity index, length of stay, whether care was delivered entirely in the FCA, utilization of labs or radiology testing, or administration of opioid pain medications). We used Fisher's exact test to calculate statistical differences in proportions, while the Mantel-Haenszel method was used to report odds ratios. RESULTS: Of the returned surveys, 62% rated overall care for the visit as VG. However, fewer patients reported their care as VG if they were seen in FCA (53.4% versus 63.2%, p=0.027). Patients seen in FCA were less likely to have advanced imaging performed (12% versus 23.8%, p=0.001) or labs drawn (24.8% vs. 59.1%, p=0.001). Length of stay (FCA mean 159 ±103.5 minutes versus non-FCA 223 ±117 minutes) and acuity were lower for FCA patients than non-FCA patients (p=0.001). There was no statistically significant difference between patient-reported ratings of physicians or nurses when comparing patients seen in FCA vs. those not seen in FCA. CONCLUSION: Patients seen through the FCA reported a lower overall rating of care compared to patients not seen in the FCA. This occurred despite a shorter overall length of stay for these patients, suggesting that other factors have a meaningful impact on patient satisfaction.

DTaP5-IPV-Hib-HepB, a hexavalent vaccine for infants and toddlers.

INTRODUCTION: Combination vaccines reduce the 'shot burden' and simplify the childhood immunization schedule. Only 5-valent DTaP-based vaccines are licensed in the U.S. Areas covered: A new combination vaccine - DTaP5-IPV-Hib-HepB - is described, which induces antibody responses in infants (given in different schedules, including a 2, 4, and 6-month schedule) that are similar to the respective component vaccines. The vaccine appears to be safe and would be expected to protect against six diseases: diphtheria, tetanus, pertussis, hepatitis B, H influenzae type b, and polio. Administration is associated with higher rates of mild fever, but without significant safety signals. Expert commentary: Incorporation of this hexavalent vaccine into the U.S. schedule could improve coverage rates and timeliness, and addition to the E.U. market would add depth to the available repertoire of combination vaccines.

A Phase III Randomized, Double-blind, Clinical Trial of an Investigational Hexavalent Vaccine Given at Two, Three, Four and Twelve Months.

BACKGROUND: Combination vaccines simplify vaccination visits and improve coverage and timeliness. Diphtheria-tetanus toxoids-acellular pertussis 5, hepatitis B, inactivated poliovirus vaccine and Haemophilus influenzae type b (DTaP5-HB-IPV-Hib) is a new investigational, fully liquid, combination vaccine containing a 5-antigen pertussis component and is designed to protect against 6 infectious diseases. METHODS: In this multicenter, double-blind, comparator-controlled, phase III study (NCT01341639) conducted in Finland, Germany and Belgium, healthy infants were randomized 1:1 to receive 1 of 2 immunization regimens. The DTaP5-HB-IPV-Hib group received the investigational hexavalent vaccine (DTaP-HB-IPV-Hib) and the Control group received Infanrix-hexa (DTPa3-HBV-IPV/Hib) at 2, 3, 4 and 12 months of age. Both groups received concomitantly Prevnar 13 (PCV13) and Rotateq (RV5) at 2, 3 and 4 months of age and ProqQad (MMRV) at 12 months of age. MMRV was also administered to all study subjects at 13 months of age. RESULTS: A total of 628 subjects in the DTaP5-HB-IPV-Hib group and 622 subjects in the Control group were randomized. In a per-protocol analysis, immune responses to vaccine antigens 1 month after dose 3 and after the toddler dose were noninferior in the DTaP5-HB-IPV-Hib group as compared with the Control group. The DTaP5-HB-IPV-Hib group responses to MMRV given concomitantly at 12 months were all noninferior compared with the Control group. Solicited adverse event rates after any dose, including fever, were similar in both groups. Most adverse events were mild-to-moderate and did not lead to subject withdrawal. Vaccine-related serious adverse events occurred infrequently in the DTaP5-HB-IPV-Hib group (0.3%) and the Control group (0.2%). CONCLUSIONS: The safety and immunogenicity of DTaP5-HB-IPV-Hib is comparable to Control when administered in the 2-month, 3-month, 4-month and 12-month schedule. DTaP5-HB-IPV-Hib has the potential to provide a new hexavalent option for pediatric combination vaccines, aligned with recommended immunizations in Europe.

Lot-to-lot Consistency, Safety, Tolerability and Immunogenicity of an Investigational Hexavalent Vaccine in US Infants.

BACKGROUND: This multicenter phase III study (NCT01340937) evaluated the consistency of immune responses to 3 separate lots of diphtheria-tetanus toxoids-acellular pertussis 5, inactivated poliovirus vaccine, Haemophilus influenzae type b, and hepatitis B (DTaP5-IPV-Hib-HepB), an investigational hexavalent vaccine (HV). METHODS: Healthy infants were randomized (2:2:2:1) to receive HV or Pentacel (Control). Groups 1, 2 and 3 received HV at 2, 4 and 6 months, and Control at 15 months. Group 4 received Control at 2, 4, 6 and 15 months, plus Recombivax HB (HepB) at 2 and 6 months. Concomitant Prevnar 13 was given to all groups at 2, 4, 6 and 15 months; pentavalent rotavirus vaccine (RV5) was given to all groups at 2, 4 and 6 months. Blood specimens (3-5 mL) were collected immediately before administration of dose 1, postdose 3, immediately before toddler dose, and after toddler dose. Adverse events were recorded after each vaccination. RESULTS: The 3 manufacturing lots of HV induced consistent antibody responses to all antigens. Immunogenicity of HV was noninferior to Control for all antibodies, except for pertussis filamentous hemagglutinin geometric mean concentration postdose 3, and pertussis pertactin (PRN) geometric mean concentration after toddler dose. Postdose 3 immunogenicity of concomitantly administered Prevnar 13 was generally similar (except for serotype 6B) when given with HV or Control. Adverse events of HV were similar to Control, except for a higher rate of fever ≥38.0°C [49.2% vs. 35.4%, estimated difference 13.7% (8.4, 18.8)]. CONCLUSIONS: HV demonstrated lot-to-lot manufacturing consistency; safety and immunogenicity were comparable with the licensed vaccines. HV provides a new combination vaccine option within the US 2-month, 4-month and 6-month vaccine series.

Extensive Postradiation Ocular and Diffuse Cranial Neuromyotonia Mimicking Myasthenia Gravis.

BACKGROUND: Ocular neuromyotonia is a rare, but well-recognized, complication of cranial irradiation. CASE REPORT: Using figures and videos, we report a 52-year-old man with extensive ocular, brainstem, and lower cranial nerve neuromyotonia postradiation therapy for a fourth ventricle glioma who, in the context of an apparently positive edrophonium test, was initially misdiagnosed with myasthenia gravis. CONCLUSIONS: This is the first case of postirradiation neuromyotonia to be reported with such extensive cranial nerve and brainstem involvement.

A Phase III randomized, double-blind, clinical trial of an investigational hexavalent vaccine given at 2, 4, and 11-12 months.

BACKGROUND: Combination vaccines simplify vaccination visits and improve coverage and timeliness. DTaP5-HB-IPV-Hib is a new investigational, fully-liquid, combination vaccine designed to protect against 6 infectious diseases, including 5 pertussis antigens and OMPC instead of PT as conjugated protein for Hib component. METHODS: In this multicenter, double-blind, comparator-controlled, Phase III study (NCT01480258) conducted in Sweden, Italy, and Finland, healthy infants were randomized 1:1 to receive one two immunization regimens. The DTaP5-HB-IPV-Hib Group received the investigational hexavalent vaccine (DTaP5-HB-IPV-Hib) and the Control Group received Infanrix-hexa (DTPa3-HBV-IPV/Hib) at 2, 4 and 11-12months of age. Both groups received concomitantly Prevnar 13 (PCV13) and Rotateq (RV5) or Rotarix (RV1) at 2, 4months of age and PCV13 at 11-12months. Subjects administered RV5 received a 3rd dose at 5months of age. RESULTS: A total of 656 subjects were randomized to the DTaP5-HB-IPV-Hib Group and 659 subjects to Control Group. Immune responses to all vaccine antigens post-toddler dose were non-inferior in the DTaP5-HB-IPV-Hib Group as compared to the Control Group. Additionally, the post-dose 2 and pre-toddler DTaP5-HB-IPV-Hib anti-PRP responses were superior. The DTaP5-HB-IPV-Hib Group responses to concomitant RV1 were non-inferior compared to the Control Group. Solicited adverse event rates after any dose were similar in both groups, except for higher rates of pyrexia (6.4% difference; 95% CI: 1.5,11.3) and somnolence (5.8% difference; 95% CI: 1.7,9.8) in the DTaP5-HB-IPV-Hib Group. Vaccine-related serious adverse events occurred infrequently in the DTaP5-HB-IPV-Hib Group (0.3%) and the Control Group (0.5%). CONCLUSIONS: The safety and immunogenicity of DTaP5-HB-IPV-Hib is generally comparable to Control when administered in the 2, 4, 11-12month schedule. Early Hib responses were superior versus Control. DTaP5-HB-IPV-Hib could provide a new hexavalent option for pediatric combination vaccines, aligned with recommended immunizations in Europe. STUDY IDENTIFICATION: V419-008 CLINICALTRIALS.GOV identifier: NCT01480258.