Christine B. Turley

Safety and immunogenicity of a recombinant M2e-flagellin influenza vaccine (STF2.4xM2e) in healthy adults.

BACKGROUND The ectodomain of matrix protein 2 (M2e) is a promising candidate for a broadly protective influenza A vaccine because it is highly conserved and antibodies to M2e are protective in animal models. STF2.4xM2e (VAX102) is a recombinant fusion protein that links four tandem copies of the M2e antigen to Salmonella typhimurium flagellin, a TLR5 ligand used as an adjuvant. The objectives of this first-in-human study were to assess the safety and immunogenicity of VAX102 given as a prime-boost regimen to healthy adults. METHODS Sixty subjects 18-49 years old were enrolled in a multicenter, double-blind, randomized, placebo-controlled trial (Study 1). Based on pre-clincial data, initial design included doses starting at 10 μg, with an escalation plan. After reactogenicity was noted at the 10 μg dose, the trial was redesigned to evaluate 0.3, 1.0, and 3 μg doses. Following this study, 16 subjects were enrolled in Study 2, an open label, low dose study, to evaluate doses of 0.03 and 0.1 μg. In both trials, vaccine or placebo was given intramuscularly (i.m.) at 0 and 28 days. Clinical and laboratory safety assessments took place 1 and 7 days after immunization. Immune responses to M2e and flagellin were assessed by ELISA at 7, 14 and 28 days after each dose. Seroconversion was defined as a serum IgG anti-M2e antibody value ≥0.174 μg/ml and a fourfold rise in concentration. RESULTS Doses of 0.03-1 μg were safe and well tolerated in all subjects. Doses of 0.03 and 0.1 μg produced limited immunogenicity (38% and 75% respectively), after the second dose of vaccine. Doses of 0.3 and 1.0 μg were immunogenic in 18 (75%) of 24 vaccinees after the first dose and 23 (96%) after the second dose. In the 1.0 μg group, the geometric mean M2e antibody concentration was 0.4 μg/ml after the first dose and 1.7 μg/ml after the booster dose. M2e antibody concentrations and seroconversion rates were not significantly different at higher doses (p>0.05). Immune response to flagellin was robust but did not appear to interfere with M2e antibody responses after the booster dose. Following the first injection of VAX102 at higher doses (3 and 10 μg), self-limited but severe symptoms were noted in some subjects and were associated with elevated levels of C-reactive protein. Although not directly measured, this reaction was believed to be mediated by cytokine release. CONCLUSIONS VAX102 was safe and induced high antibody levels to M2e at 0.3 and 1.0 μg doses. The TLR5 ligand, S. typhimurium flagellin, is a novel approach to adjuvant-like activity through activation of innate immunity, and when fused to multiple copies of the M2e protein, the vaccine was able to induce a fourfold rise in antibody in humans, to a previously non-immunogenic, highly-conserved portion of the influenza virus. Clinical correlates of protection that may be afforded by M2e antibody in humans are a future focus of investigation.

Safety and efficacy of a cytomegalovirus glycoprotein B (gB) vaccine in adolescent girls: A randomized clinical trial.

BACKGROUND Cytomegalovirus (CMV) is a leading cause of congenital infection and an important target for vaccine development. METHODS CMV seronegative girls between 12 and 17 years of age received CMV glycoprotein B (gB) vaccine with MF59 or saline placebo at 0, 1 and 6 months. Blood and urine were collected throughout the study for evidence of CMV infection based on PCR and/or seroconversion to non-vaccine CMV antigens. RESULTS 402 CMV seronegative subjects were vaccinated (195 vaccine, 207 placebo). The vaccine was generally well tolerated, although local and systemic adverse events were significantly more common in the vaccine group. The vaccine induced gB antibody in all vaccine recipients with a gB geometric mean titer of 13,400 EU; 95%CI 11,436, 15,700, after 3 doses. Overall, 48 CMV infections were detected (21 vaccine, 27 placebo). In the per protocol population (124 vaccine, 125 placebo) vaccine efficacy was 43%; 95%CI: -36; 76, p=0.20. The most significant difference was after 2 doses, administered as per protocol; vaccine efficacy 45%, 95%CI: -9; 72, p=0.08. CONCLUSION The vaccine was safe and immunogenic. Although the efficacy did not reach conventional levels of significance, the results are consistent with a previous study in adult women (Pass et al. N Engl J Med 2009;360:1191) using the same formulation.

Systems survivor: a program for house staff in systems-based practice.

Background: The Systems-Based Practice competency expanded the scope of graduate medical education. Innovative approaches are needed to teach this material. Purpose: We have designed and implemented a rotation in Systems-Based Practice focused on the interrelationships of patient care, clinical revenue, and the physicians role within health care systems. Methods: Experiential learning occurs during a 5-day rotation through 26 areas encompassing the clinical revenue cycle, guided by “expert” staff. Using a reversal of the TV show Survivor, house staff begin conceptually “alone” and discover they are members of a large, dedicated team. Assessment results, including a system knowledge test and course evaluations, are presented. Results: Twenty-five residents from four clinical departments participated in Year 1. An increase in pretest to posttest knowledge scores of 14.8% (p ≤ 0.001) was observed, with high program evaluations. Conclusions: “Systems Survivor” is successful in providing an innovative opportunity to explore complex health care systems and is an effective curriculum.

Safety and immunogenicity of IMVAMUNE® smallpox vaccine using different strategies for a post event scenario

INTRODUCTION Reintroduction of Variola major as an agent of bioterrorism remains a concern. A shortened dosing schedule of Bavarian Nordics (BN) IMVAMUNE(®) (modified vaccinia Ankara vaccine against smallpox) was compared to the currently recommended 0- and 28-day schedule for non-inferiority by evaluating the magnitude and kinetics of the immune responses. METHODS Subjects were assigned to receive IMVAMUNE or placebo administered subcutaneously on Days 0 and 7, Days 0 and 28, or Day 0. Blood was collected for antibody and cell-mediated immune assays. Subjects were followed for safety for 12 months after last vaccination. RESULTS The primary endpoint of this study was the geometric mean antibody titers (GMT) at 14 days post last vaccination. Of 208 subjects enrolled, 191 received vaccine (Group: 0+7, Group: 0+28 and Group: 0) and 17 received placebo. Moderate/severe systemic reactogenicity after any vaccination were reported by 31.1%, 25.4%, and 28.6% of the subjects for Group: 0+7, Group: 0+28, and Group: 0, respectively (Chi-square test, P=0.77). Based on BNs Plaque Reduction Assay GMTs, Group: 0+7 was non-inferior to Group: 0+28 at Day 4, 180, and 365 after the second vaccination. On Day 14, Group: 0+7 and Group: 0+28 GMT were 10.8 (CI: 9.0, 12.9) and 30.2 (CI: 22.1, 41.1), respectively. Based on BNs Enzyme-linked immunosorbent assay, the proportion of subjects with positive titers for Group: 0+28 was significantly greater than that for Group: 0+7 after second vaccination at Days 4 and 180. By Day 14 after the second dose, the IFN-γ enzyme-linked immunosorbent spot (ELISPOT) responses were similar for Group: 0+28 and Group: 0+7. CONCLUSION Overall, a standard dose of IMVAMUNE (0.5 mL of 1 x 10(8) TCID/mL) administered subcutaneously was safe and well tolerated. A second dose of IMVAMUNE at Day 28 compared to Day 7 provided greater antibody responses and the maximal number of responders. By Day 14 after the second dose, IFN-γ ELISPOT responses were similar for Group: 0+28 and Group: 0+7.

Seroprevalence and Risk Factors for Cytomegalovirus Infections in Adolescent Females

BACKGROUND Congenital cytomegalovirus (CMV) is a leading cause of disability, including sensorineural hearing loss, developmental delay, and mental retardation. Understanding risk factors for acquisition of CMV infection in adolescent females will help determine vaccine strategies. METHODS Females (12-17 years) were recruited from primary care settings in Cincinnati, Galveston, Houston, and Nashville from June 2006 to July 2010 for a seroepidemiologic study, from which seronegative participants were recruited for a CMV vaccine trial. Participants (n = 1585) responded to questions regarding potential exposures. For those with young children in the home (n = 859), additional questions were asked about feeding and changing diapers, and for those > 14 years of age (n = 1162), questions regarding sexual activity were asked. Serum was evaluated for CMV antibody using a commercial immunoglobulin G assay. RESULTS Cytomegalovirus antibody was detected in 49% of participants. In the univariate analyses, CMV seroprevalence was significantly higher among African Americans, those with children < 3 years of age in the home, and those with a history of oral, anal, or vaginal intercourse. Among those with young children in the home, feeding children and changing diapers further increased the association with CMV infection. However, in the final multivariate analysis, only African Americans and household contact with young children were associated with CMV infection. CONCLUSIONS By age 12, evidence of CMV infection was common. Multiple factors regarding race and personal behaviors likely contribute to seroconversion earlier in life.

Safety and Immune Responses in Children After Concurrent or Sequential 2009 H1N1 and 2009–2010 Seasonal Trivalent Influenza Vaccinations

BACKGROUND Administering 2 separate vaccines for seasonal and pandemic influenza was necessary in 2009. Therefore, we conducted a randomized trial of monovalent 2009 H1N1 influenza vaccine (2009 H1N1 vaccine) and seasonal trivalent inactivated influenza vaccine (TIV; split virion) given sequentially or concurrently in previously vaccinated children. METHODS Children randomized to 4 study groups and stratified by age received 1 dose of seasonal TIV and 2 doses of 2009 H1N1 vaccine in 1 of 4 combinations. Injections were given at 21-day intervals and serum samples for hemagglutination inhibition antibody responses were obtained prior to and 21 days after each vaccination. Reactogenicity and adverse events were monitored. RESULTS All combinations of vaccines were safe in the 531 children enrolled. Generally, 1 dose of 2009 H1N1 vaccine and 1 dose of TIV, regardless of sequence or concurrency of administration, was immunogenic in children ≥ 10 years of age; children <10 years of age required 2 doses of 2009 H1N1 vaccine. CONCLUSIONS Vaccines were generally well tolerated. The immune responses to 2009 H1N1 vaccine were adequate regardless of the sequence of vaccination in all age groups but the sequence affected titers to TIV antigens. Two doses of 2009 H1N1 vaccine were required to achieve a protective immune response in children <10 years of age. CLINICAL TRIALS REGISTRATION NCT00943202.

Safety and immunogenicity of sequential rotavirus vaccine schedules

BACKGROUND AND OBJECTIVES: Although both licensed rotavirus vaccines are safe and effective, it is often not possible to complete the schedule by using the same vaccine formulation. The goal of this study was to investigate the noninferiority of the immune responses to the 2 licensed rotavirus vaccines when administered as a mixed schedule compared with administering a single vaccine formulation alone. METHODS: Randomized, multicenter, open-label study. Healthy infants (6–14 weeks of age) were randomized to receive rotavirus vaccines in 1 of 5 different schedules (2 using a single vaccine for all doses, and 3 using mixed schedules). The group receiving only the monovalent rotavirus vaccine received 2 doses of vaccine and the other 4 groups received 3 doses of vaccine. Serum for immunogenicity testing was obtained 1 month after the last vaccine dose and the proportion of seropositive children (rotavirus immunoglobulin A ≥20 U/mL) were compared in all the vaccine groups. RESULTS: Between March 2011 and September 2013, 1393 children were enrolled and randomized. Immune responses to all the sequential mixed vaccine schedules were shown to be noninferior when compared with the 2 single vaccine reference groups. The proportion of children seropositive to at least 1 vaccine antigen at 1 month after vaccination ranged from 77% to 96%, and was not significantly different among all the study groups. All schedules were well tolerated. CONCLUSIONS: Mixed schedules are safe and induced comparable immune responses when compared with the licensed rotavirus vaccines given alone.

IRB reliance

Multi-site Institutional Review Board (IRB) review of clinical research projects is an important but complex and time-consuming activity that is hampered by disparate non-interoperable computer systems for management of IRB applications. This paper describes our work toward harmonizing the workflow and data model of IRB applications through the development of a software-as-a-service shared-IRB platform for five institutions in South Carolina. Several commonalities and differences were recognized across institutions and a core data model that included the data elements necessary for IRB applications across all institutions was identified. We extended and modified the system to support collaborative reviews of IRB proposals within routine workflows of participating IRBs. Overall about 80% of IRB application content was harmonized across all institutions, establishing the foundation for a streamlined cooperative review and reliance. Since going live in 2011, 49 applications that underwent cooperative reviews over a three year period were approved, with the majority involving 2 out of 5 institutions. We believe this effort will inform future work on a common IRB data model that will allow interoperability through a federated approach for sharing IRB reviews and decisions with the goal of promoting reliance across institutions in the translational research community at large.

Differences in Hospital Readmission Risk across All Payer Groups in South Carolina

OBJECTIVE To evaluate differences in hospital readmission risk across all payers in South Carolina (SC). DATA SOURCES/STUDY SETTING South Carolina Revenue and Fiscal Affairs Office (SCRFA) statewide all payer claims database including 2,476,431 hospitalizations in SC acute care hospitals between 2008 and 2014. STUDY DESIGN We compared the odds of unplanned all-cause 30-day readmission for private insurance, Medicare, Medicaid, uninsured, and other payers and examined interaction effects between payer and index admission characteristics using generalized estimating equations. DATA COLLECTION SCRFA receives claims and administrative health care data from all SC health care facilities in accordance with SC state law. PRINCIPAL FINDINGS Odds of readmission were lower for females compared to males in private, Medicare, and Medicaid payers. African Americans had higher odds of readmission compared to whites across private insurance, Medicare, and Medicaid, but they had lower odds among the uninsured. Longer length of stay had the strongest association with readmission for private and other payers, whereas an increased number of comorbidities related to the highest readmission odds within Medicaid. CONCLUSIONS Associations between index admission characteristics and readmission likelihood varied significantly with payer. Findings should guide the development of payer-specific quality improvement programs.

Priming professionals for a complex communication environment: Findings from a pilot study

ABSTRACT Factors such as time pressure, distractions, and profession-specific jargon can contribute to poor communication in complex working environments such as healthcare. Technical solutions are often sought to improve patient care when simple improvements in communication would suffice. This article describes an icebreaker activity, an interprofessional game, aimed to prime and engage experienced healthcare professionals on the topic of communication, specifically related to care transitions. By using unexpected content from veterinary care, cycling messages rapidly, and by adding distractors, we were successful in creating openness to considering communication needs in new ways. Participants completed an evaluation following this intervention. It was found that the activity was effective at raising awareness of communication problems and the activity caused participants to view care transitions communications in new ways. In particular, it was reported that this activity illustrated opportunities for communication improvement at multiple levels including peer-to-peer and with patients. This interprofessional activity can illustrate communication barriers, both within and beyond healthcare, in an interactive and engaging manner.