Modifiers of COVID-19 vaccine efficacy: Results from four COVID-19 prevention network efficacy trials.

Questions remain regarding the effect of baseline host and exposure factors on vaccine efficacy (VE) across pathogens and vaccine platforms. We report placebo-controlled data from four Phase 3 COVID-19 trials during the early period of the pandemic. This was a cross-protocol analysis of four randomized, placebo-controlled efficacy trials (Moderna/mRNA1273, AstraZeneca/AZD1222, Janssen/Ad26.COV2.S, and Novavax/NVX-CoV2373) using a harmonized design. Trials were conducted in the United States and international sites in adults ≥ 18 years of age. VE was assessed for symptomatic and severe COVID-19. We analyzed 114,480 participants from both placebo and vaccine arms, enrolled July 2020 to February 2021, with follow up through July 2021. VE against symptomatic COVID-19 showed little heterogeneity across baseline socio-demographic, clinical or exposure characteristics, in either univariate or multivariate analysis, regardless of vaccine platform. Similarly, VE against severe COVID-19 in the single trial (Janssen) with sufficient endpoints for analysis showed little evidence of heterogeneity. COVID-19 VE is not influenced by baseline host or exposure characteristics across efficacy trials of different vaccine platforms and countries when well matched to circulating virus strains. This supports use of these vaccines, regardless of platform type, as effective tools in the near term for reducing symptomatic and severe COVID-19, particularly for older individuals and those with common co-morbidities during major variant shifts. Clinical trial registration numbers: NCT04470427, NCT04516746, NCT04505722, and NCT04611802.

Primary Care Counseling of Parents Regarding Childhood Screen Media Use.

Parental beliefs and motivation are instrumental in improving childhood digital media use (DMU). Parents (n = 611) completed questionnaires about childhood DMU assessing knowledge, interest in counseling, motivation to change, self-efficacy, and beliefs. Less than a third correctly recognized screen time limits. Twenty-seven percent received childhood DMU information from a doctor, while 46% stated they would like such information. Only 2% had a doctor-recommended DMU plan. Interest in DMU topics, motivation to improve, and management self-efficacy were moderate. Top negative beliefs were addiction to DMU (52%), sleep problems (39%), obesity (33%), social skills (33%), and inappropriate content (32%). Differences between age categories existed for social (48%, P = .01) and language (14%, P = .01) concerns (highest for toddlers), attention concerns (27%, P = .02; highest in preschoolers), and depression (13%, P < .001) and low self-esteem (8%, P = .04; highest in teens). Findings support further development of approaches to address DMU, tailored by age-specific common parental views.

Feasibility of Post-hospitalization Telemedicine Video Visits for Children With Medical Complexity.

OBJECTIVES: To evaluate feasibility and acceptability of post-hospitalization telemedicine video visits (TMVV) during hospital-to-home transitions for children with medical complexity (CMC); and explore associations with hospital utilization, caregiver self-efficacy (CSE), and family self-management (FSM). METHOD: This non-randomized pilot study assigned CMC (n=28) to weekly TMVV for four weeks post-hospitalization; control CMC (n=20) received usual care without telemedicine. Feasibility was measured by time to connection and proportion of TMVV completed; acceptability was measured by parent-reported surveys. Pre/post-discharge changes in CSE, FSM, and hospital utilization were assessed. RESULTS: 64 TMVV were completed; 82 % of patients completed 1 TMVV; 54 % completed four TMVV. Median time to TMVV connection was 1 minute (IQR=2.5). Parents reported high acceptability of TMVV (mean 6.42; 1 -7 scale). CSE and FSM pre/post-discharge were similar for both groups; utilization declined in both groups post-discharge. DISCUSSION: Post-hospitalization TMVV for CMC were feasible and acceptable during hospital-to-home transitions.

Capacity Building for a New Multicenter Network Within the ECHO IDeA States Pediatric Clinical Trials Network.

Introduction: Research capacity building is a critical component of professional development for pediatrician scientists, yet this process has been elusive in the literature. The ECHO IDeA States Pediatric Clinical Trials Network (ISPCTN) seeks to implement pediatric trials across medically underserved and rural populations. A key component of achieving this objective is building pediatric research capacity, including enhancement of infrastructure and faculty development. This article presents findings from a site assessment inventory completed during the initial year of the ISPCTN. Methods: An assessment inventory was developed for surveying ISPCTN sites. The inventory captured site-level activities designed to increase clinical trial research capacity for pediatrician scientists and team members. The inventory findings were utilized by the ISPCTN Data Coordinating and Operations Center to construct training modules covering 3 broad domains: Faculty/coordinator development; Infrastructure; Trials/Research concept development. Results: Key lessons learned reveal substantial participation in the training modules, the importance of an inventory to guide the development of trainings, and recognizing local barriers to clinical trials research. Conclusions: Research networks that seek to implement successfully completed trials need to build capacity across and within the sites engaged. Our findings indicate that building research capacity is a multi-faceted endeavor, but likely necessary for sustainability of a unique network addressing high impact pediatric health problems. The ISPCTN emphasis on building and enhancing site capacity, including pediatrician scientists and team members, is critical to successful trial implementation/completion and the production of findings that enhance the lives of children and families.

Glycemic control is associated with dyslipidemia over time in youth with type 2 diabetes: The SEARCH for diabetes in youth study.

BACKGROUND: Dyslipidemia has been documented in youth with type 2 diabetes. There is a paucity of studies examining dyslipidemia over time in youth with type 2 diabetes and associated risk factors. OBJECTIVE: To evaluate lipids at baseline and follow-up and associated risk factors in youth with type 2 diabetes. METHODS: We studied 212 youth with type 2 diabetes at baseline and after an average of 7 years of follow-up in the SEARCH for Diabetes in Youth Study. Abnormal lipids were defined as high-density lipoprotein cholesterol (HDL-C) < 35, low-density lipoprotein cholesterol (LDL-C) > 100, or triglycerides >150 (all mg/dl). We evaluated participants for progression to abnormal lipids (normal lipids at baseline and abnormal at follow-up), regression (abnormal lipids at baseline and normal at follow-up), stable normal, and stable abnormal lipids over time for HDL-C, LDL-C, and triglycerides. Associations between hemoglobin A1c (HbA1c) and adiposity over time (area under the curve [AUC]) with progression and stable abnormal lipids were evaluated. RESULTS: HDL-C progressed, regressed, was stable normal, and stable abnormal in 12.3%, 11.3%, 62.3%, and 14.2% of participants, respectively. Corresponding LDL-C percentages were 15.6%, 12.7%, 42.9%, and 28.8% and triglycerides were 17.5%, 10.8%, 55.7%, and 16.0%. Each 1% increase in HbA1c AUC was associated with a 13% higher risk of progression and stable abnormal triglycerides and a 20% higher risk of progression and stable abnormal LDL-C. Higher adiposity AUC was marginally (p = 0.049) associated with abnormal HDL-C. CONCLUSIONS: Progression and stable abnormal LDL-C and triglycerides occur in youth with type 2 diabetes and are associated with higher HbA1c.

Site-Level Variation in the Characteristics and Care of Infants With Neonatal Opioid Withdrawal.

BACKGROUND AND OBJECTIVES: Variation in pediatric medical care is common and contributes to differences in patient outcomes. Site-to-site variation in the characteristics and care of infants with neonatal opioid withdrawal syndrome (NOWS) has yet to be quantified. Our objective was to describe site-to-site variation in maternal-infant characteristics, infant management, and outcomes for infants with NOWS. METHODS: Cross-sectional study of 1377 infants born between July 1, 2016, and June 30, 2017, who were ≥36 weeks' gestation, with NOWS (evidence of opioid exposure and NOWS scoring within the first 120 hours of life) born at or transferred to 1 of 30 participating hospitals nationwide. Site-to-site variation for each parameter within the 3 domains was measured as the range of individual site-level means, medians, or proportions. RESULTS: Sites varied widely in the proportion of infants whose mothers received adequate prenatal care (31.3%-100%), medication-assisted treatment (5.9%-100%), and prenatal counseling (1.9%-75.5%). Sites varied in the proportion of infants with toxicology screening (50%-100%) and proportion of infants receiving pharmacologic therapy (6.7%-100%), secondary medications (1.1%-69.2%), and nonpharmacologic interventions including fortified feeds (2.9%-90%) and maternal breast milk (22.2%-83.3%). The mean length of stay varied across sites (2-28.8 days), as did the proportion of infants discharged with their parents (33.3%-91.1%). CONCLUSIONS: Considerable site-to-site variation exists in all 3 domains. The magnitude of the observed variation makes it unlikely that all infants are receiving efficient and effective care for NOWS. This variation should be considered in future clinical trial development, practice implementation, and policy development.

The ACT NOW Clinical Practice Survey: Gaps in the Care of Infants With Neonatal Opioid Withdrawal Syndrome.

OBJECTIVES: The incidence of neonatal opioid withdrawal syndrome (NOWS) has increased fivefold over the last 10 years. Standardized NOWS care protocols have revealed many improved patient outcomes. Our objective for this study is to describe results of a clinical practice survey of NOWS management practices designed to inform future clinical studies in the diagnosis and management of NOWS. METHODS: A cross-sectional survey was administered to medical unit directors at 32 Institutional Development Award States Pediatric Clinical Trial Network and 22 Neonatal Research Network sites in the fall of 2017. Results are presented as both the number and percentage of positive responses. Ninety-five percent Wilson confidence intervals (CIs) were generated around estimates, and χ2 and Fisher's exact tests were used to compare the association between unit type and reporting of each protocol. RESULTS: Sixty-two responses representing 54 medical centers were received. Most participating NICU and non-ICU sites reported protocols for NOWS management, including NOWS scoring (98% NICU; 86% non-ICU), pharmacologic treatment (92% NICU; 64% non-ICU), and nonpharmacologic care (79% NICU; 79% non-ICU). Standardized protocols for pharmacologic care and weaning were reported more frequently in the NICU (92% [95% CI: 80%-97%] and 94% [95% CI: 83%-98%], respectively) compared with non-ICU settings (64% [95% CI: 39%-84%] for both) (P < .05 for both comparisons). Most medical centers reported morphine as first-line therapy (82%; 95% CI: 69%-90%) and level 3 and level 4 NICUs as the location of pharmacologic treatment (83%; 95% CI: 71%-91%). CONCLUSIONS: Observed variations in care between NICUs and non-ICUs revealed opportunities for targeted interventions in training and standardized care plans in non-ICU sites.

Health care access and glycemic control in youth and young adults with type 1 and type 2 diabetes in South Carolina.

Affordability and geographic accessibility are key health care access characteristics. We used data from 481 youth and young adults (YYA) with diabetes (389 type 1, 92 type 2) to understand the association between health care access and glycemic control as measured by HbA1c values. In multivariate models, YYA with state or federal health insurance had HbA1c percentage values 0.68 higher (P = 0.0025) than the privately insured, and those without insurance 1.34 higher (P < 0.0001). Not having a routine diabetes care provider was associated with a 0.51 higher HbA1c (P = 0.048) compared to having specialist care, but HbA1c did not differ significantly (P = 0.069) between primary vs specialty care. Distance to utilized provider was not associated with HbA1c among YYA with a provider (P = 0.11). These findings underscore the central role of health insurance and indicate a need to better understand the root causes of poorer glycemic control in YYA with state/federal insurance.

Statewide Longitudinal Progression of the Whole-Patient Measure of Safety in South Carolina.

Meaningful improvement in patient safety encompasses a vast number of quality metrics, but a single measure to represent the overall level of safety is challenging to produce. Recently, Perla et al. established the Whole-Person Measure of Safety (WPMoS) to reflect the concept of global risk assessment at the patient level. We evaluated the WPMoS across an entire state to understand the impact of urban/rural setting, academic status, and hospital size on patient safety outcomes. The population included all South Carolina (SC) inpatient discharges from January 1, 2008, through to December 31, 2013, and was evaluated using established definitions of highly undesirable events (HUEs). Over the study period, the proportion of hospital discharges with at least one HUE significantly decreased from 9.7% to 8.8%, including significant reductions in nine of the 14 HUEs. Academic, large, and urban hospitals had a significantly lower proportion of hospital discharges with at least one HUE in 2008, but only urban hospitals remained significantly lower by 2013. Results indicate that there has been a decrease in harm events captured through administrative coded data over this 6-year period. A composite measure, such as the WPMoS, is necessary for hospitals to evaluate their progress toward reducing preventable harm.

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.

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.

IRB reliance: An informatics approach.

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.

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.

Leveraging a Statewide Clinical Data Warehouse to Expand Boundaries of the Learning Health System.

Learning Health Systems (LHS) require accessible, usable health data and a culture of collaboration-a challenge for any single system, let alone disparate organizations, with macro- and micro-systems. Recently, the National Science Foundation described this important setting as a cyber-social ecosystem. In 2004, in an effort to create a platform for transforming health in South Carolina, Health Sciences South Carolina (HSSC) was established as a research collaboration of the largest health systems, academic medical centers and research intensive universities in South Carolina. With work beginning in 2010, HSSC unveiled an integrated Clinical Data Warehouse (CDW) in 2013 as a crucial anchor to a statewide LHS. This CDW integrates data from independent health systems in near-real time, and harmonizes the data for aggregation and use in research. With records from over 2.7 million unique patients spanning 9 years, this multi-institutional statewide clinical research repository allows integrated individualized patient-level data to be used for multiple population health and biomedical research purposes. In the first 21 months of operation, more than 2,800 de-identified queries occurred through i2b2, with 116 users. HSSC has developed and implemented solutions to complex issues emphasizing anti-competitiveness and participatory governance, and serves as a recognized model to organizations working to improve healthcare quality by extending the traditional borders of learning health systems.

Evolution and Initial Experience of a Statewide Care Transitions Quality Improvement Collaborative: Preventing Avoidable Readmissions Together.

Increasing scrutiny of hospital readmission rates has spurred a wide variety of quality improvement initiatives. The Preventing Avoidable Readmissions Together (PART) initiative is a statewide quality improvement learning collaborative organized by stakeholder organizations in South Carolina. This descriptive report focused on initial interventions with hospitals. Eligible participants included all acute care hospitals plus home health organizations, nursing facilities, hospices, and other health care organizations. Measures were degree of statewide participation, curricular engagement, adoption of evidence-based improvement strategies, and readmission rate changes. Fifty-nine of 64 (92%) acute care hospitals and 9 of 10 (90%) hospital systems participated in collaborative events. Curricular engagement included: webinars and coaching calls (49/59, 83%), statewide in-person meetings (35/59, 59%), regional in-person meetings (44/59, 75%), and individualized consultations (46/59, 78%). Among 34 (58%) participating hospitals completing a survey at the completion of Year 1, respondents indicated complete implementation of multidisciplinary rounding (58%), post-discharge telephone calls (58%), and teach-back (32%), and implementation in process of high-quality transition records (52%), improved discharge summaries (45%), and timely follow-up appointments (39%). A higher proportion of hospitals had significant decreases (≥10% relative change) in all-cause readmission rates for acute myocardial infarction (55.6% vs. 30.4%, P=0.01), heart failure (54.2% vs. 31.7%, P=0.09), and chronic obstructive pulmonary disease (41.7% vs. 33.3%, P=0.83) between 2011-2013 compared to earlier (2009-2011) trends. Focus on reducing readmissions is driving numerous, sometimes competing, quality improvement initiatives. PART successfully engaged the majority of acute care facilities in one state to harmonize and accelerate adoption of evidence-based care transitions strategies.

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.

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 Nordic's (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 BN's 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 BN's 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 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.