Using Process Flow Disruption Analysis to Guide Quality Improvement.

BACKGROUND: Process flow describes the efficiency and consistency with which a process functions. Disruptions in surgical flow have been shown to be associated with an increase in error. Despite this, little experience exists in using surgical flow analysis to guide quality improvement (QI). STUDY DESIGN: In a 900-bed teaching hospital with an annual surgical volume of 24,000 cases, a 4-month observational study of process flow was done by experts in complex system evaluation. Identified flow disruptions were used to guide QI. Statistical analysis included descriptive and bivariate techniques. RESULTS: More than 200 unique process data points were evaluated. There was a high degree of variability in completion of 79 individual intraoperative data elements. Lack of completion of all elements of the time out was associated with number of times the operating room door opened during case (19, 11-27; p = 0.01). Flow disruptions were used to direct surgical QI. One example was a disruption affecting the use of Sugammadex. Resolving this flow disruption resulted in a 59% reduction in the incidence of postoperative respiratory failure (p < 0.01) and a direct and variable cost savings of $447,200 and $313,160, respectively, in the first 12 months. CONCLUSIONS: The use of process flow analysis to direct surgical quality initiatives is a novel approach that emphasizes system-level strategy. Resolving flow disruptions can lead to effective QI that embraces reliability by focusing attention on common processes rather than adverse events that may be unique and therefore difficult to apply broadly.

Features predicting colchicine efficacy in treatment of children with undefined systemic autoinflammatory disease: A retrospective cohort study.

OBJECTIVE: Patients with undefined systemic autoinflammatory diseases (uSAIDs) are challenging to manage, as there are no guidelines or recommendations for targeted therapy. We aimed to evaluate the efficacy of empiric treatment with colchicine in our single-center uSAID population in the United States, as well as the patient characteristics associated with the most robust colchicine response. METHODS: Children with uSAID 18 years old at initial evaluation during 2000-2019 were included if they received 3 months of colchicine therapy. Data on demographics, clinical features, laboratory/ genetic studies, and treatment responses were collected. Most statistics were based on chi-square analyses for categorical data. Complete response to colchicine was defined as resolution of episodes or the presence of minor residual symptoms that did not require any further therapy. A partial response was defined as a decrease in the frequency, severity, or length of episodes but still necessitating additional therapy. Patients were considered nonresponders if they did not experience any improvement with colchicine at target therapeutic dosing. RESULTS: We identified 133 children diagnosed with uSAID who met our inclusion criteria. The median time to starting empiric colchicine was 5 months from the diagnosis of autoinflammatory disease. 92.5% (n = 123) of patients had a beneficial response to colchicine, including 46.6% (n = 62) partial responders and 45.9% (n = 61) complete responders. The presence of a nonurticarial rash was associated with an incomplete colchicine response (29.2% (n = 21) vs 13.1% (n = 8), P = .025). The presence of a heterozygous MEFV mutation in patients who did not fit Familial Mediterranean Fever diagnostic criteria (n = 25) appeared to be associated with a greater likelihood of complete colchicine response, although this was not statistically significant (62.5% (n = 14) vs 42.6% (n =11), P = .08). In MEFV mutation-negative patients, a nonurticarial rash was even more strongly associated with incomplete colchicine response, with an OR of 27.53 (CI [1.59-477], P = .023). The presence of oral ulcers also corresponded to incomplete colchicine response, although this did not reach clinical significance (38.9% (n = 28) vs 24.6% (n = 15), P = .08). There was no significant association between episode duration or frequency and colchicine response. CONCLUSION: Colchicine leads to clinical benefits in most children with uSAID. We, thus, recommend an early trial of colchicine in newly diagnosed patients with uSAID.

Microbiome is not linked to clinical disease severity of familial Mediterranean fever in an international cohort of children.

OBJECTIVES: The severity of familial Mediterranean fever (FMF) may vary in different areas, suggesting a role for environmental factors. We analysed the composition of gut microbiota among children with FMF and healthy controls from Turkey and the USA and determined its effect on disease severity. METHODS: Children with FMF with pathogenic MEFV mutations and healthy controls from Turkey and the USA were enrolled. FMF disease activity was evaluated with the Autoinflammatory Disease Activity Index (AIDAI). Gut bacterial diversity was assessed by sequencing 16S rRNA gene libraries. RESULTS: We included 36 children from Turkey (28 patients with FMF, 8 healthy controls), and 21 patients and 6 controls from the USA. In the Turkish group, 28.6% of patients had severe disease, while 13.3% of US group patients had severe disease. As expected, we observed substantial differences between the gut microbiota of children from the two geographic regions, with Turkish patients and controls exhibiting higher relative abundances of Bacteriodia, while US patients and controls exhibited higher relative abundances of Clostridia. Alpha- and betadiversity did not differ significantly between FMF patients and controls, and neither was predictive of disease severity within each geographic region. We observed differences between FMF patients and controls in the relative abundance of some bacterial taxa at the amplicon sequence variant (ASV) level, but these differences received mixed statistical support. CONCLUSIONS: Among an international cohort of children with FMF, we did not find a strong effect of gut microbiota composition on disease severity. Other environmental or epigenetic factors may be operative.

Applying international organization for standards 9001 to create an effective surgical quality committee.

BACKGROUND: Efforts to improve surgical safety are limited by several factors and no consensus exists regarding the most effective way to improve surgical quality. The use of ISO 9001 quality standards within healthcare is recognized but has not been widely applied for improving surgical outcomes. METHODS: A surgical quality committee was created using ISO 9001:2015 standards. Quality objectives were assessed to understand how any suggested changes will be impacted due to risks and opportunities inherent in the system. RESULTS: The initial quality focus was on surgical site infections in 5 services. Change in surgical infection ratio from 2018 to 2019 showed significant improvement: coronary bypass 1.288 vs. 0.901; Colon 1.359 vs. 0.589; Hysterectomy 2.119 vs. 1.022; Knee 1.391 vs. 0.306; Hip 0 vs. 0.302. CONCLUSIONS: This is one of the first studies using ISO 9001 to improve surgical quality. The results indicate both acceptance and success of applying continual improvement strategies.

Developing Public-Private Partnerships in Plant Pathology Extension: Case Studies and Opportunities in the United States.

Public-private partnerships (PPPs) can be an effective and advantageous way to accomplish extension and outreach objectives in plant pathology. The greatest opportunities for extension-focused PPPs may be in response to large-scale or emerging disease management concerns or in addressing complex issues that impact agriculture, such as climate change, digital technology, and public perception of science. The most fertile ground for forming PPPs is where the needs and strengths of the public and private sectors are complementary. Developing PPPs depends as much on professional relationships as on technical skills or contracts. Defining and making room for the success of all partners, identifying and addressing barriers to success, and earning and maintaining trust are components that contribute to the effectiveness of PPPs. Case studies in plant pathology demonstrate the positive impact PPPs can have on partners and stakeholders and provide guidance on the formation of PPPs in the future.

Safety and immunogenicity of unadjuvanted subvirion monovalent inactivated influenza H3N2 variant (H3N2v) vaccine in children and adolescents.

OBJECTIVE: In response to the emergence of influenza viruses with pandemic potential, we evaluated a swine-origin influenza A/H3N2 variant (H3N2v) vaccine in children. STUDY DESIGN: This multicenter phase II open-label study assessed the safety and immunogenicity of two doses, 21 days apart, of investigational unadjuvanted subvirion monovalent inactivated H3N2v vaccine administered via intramuscular injection. Children 6-35 months of age received 7.5mcg or 15mcg of hemagglutinin (HA)/dose; children 3-17 years of age received 15mcg HA/dose. Safety and reactogenicity were assessed by measuring the occurrence of solicited injection site and systemic reactions in the 7 days after each vaccination; adverse events were assessed for 42 days and serious adverse events for 7 months after the first vaccination. Immunogenicity was evaluated by measuring hemagglutination inhibition (HAI) and neutralizing (Neut) antibodies to H3N2v prior to and 21 days after each vaccination. Cross-reactivity against seasonal H3N2 strains was evaluated. RESULTS: The H3N2v vaccine was well tolerated. Transient mild to moderate injection site tenderness, pain and erythema was observed, with the most commonly reported systemic reactogenicity being irritability in children 6-35 months, and headache and fatigue in children 9-17 years old. Children 6-35 months old, whether they received 7.5mcg or 15mcg/dose, had low HAI and Neut antibody responses after two doses compared to older children. Children under 9 years of age required two doses of vaccine to demonstrate a response, while 9-17 year olds responded well after one dose. Previous influenza vaccination and older age were associated with higher immune responses to H3N2v vaccine. Children 9-17 years of age also developed cross-reactive antibodies against recent seasonal H3N2 influenza viruses. CONCLUSION: The H3N2v vaccine was safe and immunogenic in children and adolescents. Age-related increases in immunogenicity against H3N2v and seasonal H3N2 viruses were observed, suggesting prior priming via infection and/or immunization. Clinical trial registry: The trial is registered with clinicaltrial.gov: NCT02100436.

Safety, Tolerability and Immunogenicity of an MF59-adjuvanted, Cell Culture-derived, A/H5N1, Subunit Influenza Virus Vaccine: Results From a Dose-finding Clinical Trial in Healthy Pediatric Subjects.

BACKGROUND: A/H5N1 influenza virus has significant pandemic potential, and vaccination is the main prophylactic measure. This phase 2, randomized, observer-blind, multicenter study evaluated the safety and immunogenicity of two MF59-adjuvanted, cell culture-derived H5N1 (aH5N1c) vaccine formulations in healthy pediatric subjects 6 months to 17 years old. METHODS: Subjects (N = 662) received 2 aH5N1c doses 3 weeks apart, containing either 7.5 µg (full dose) or 3.75 µg (half dose) hemagglutinin antigen per dose. Local reactions and adverse events (AEs) were assessed by age. Antibody responses were measured by hemagglutination inhibition assay and assessed as geometric mean titers, geometric mean ratios (GMRs) and percentages of subjects achieving titers ≥1:40 and seroconversion (NCT01776554). RESULTS: No vaccine-related serious AEs occurred. Incidence of solicited local reactions and systemic AEs were similar across vaccine groups. Tenderness and irritability in <6-year olds, and injection site pain, myalgia and fatigue in 6-17-year olds were the most commonly reported reactions in both full- and half-dose recipients. Frequencies of AEs were lower after the second dose than the first dose in all vaccine and age groups. Three weeks after the administration of a second dose, both full- and half-dose formulations met the Center for Biologics Evaluation Research and Review (United States) and Committee for Medicinal Products for Human Use (EU) licensure criteria for titers ≥1:40 (full dose 96% subjects; half dose 86%), seroconversion (full dose 96% subjects; half dose 86%), and GMR (full dose GMR 262; half dose 84). Antibody responses were highest in 6-35-month olds. CONCLUSIONS: In pediatric subjects, both aH5N1c vaccine formulations were well tolerated and highly immunogenic, meeting both US and EU licensure criteria for pandemic influenza vaccines.

DNA vaccine priming for seasonal influenza vaccine in children and adolescents 6 to 17 years of age: A phase 1 randomized clinical trial.

BACKGROUND: Children are susceptible to severe influenza infections and facilitate community transmission. One potential strategy to improve vaccine immunogenicity in children against seasonal influenza involves a trivalent hemagglutinin DNA prime-trivalent inactivated influenza vaccine (IIV3) boost regimen. METHODS: Sites enrolled adolescents, followed by younger children, to receive DNA prime (1 mg or 4 mg) intramuscularly by needle-free jet injector (Biojector), followed by split virus 2012/13 seasonal IIV3 boost by needle and syringe approximately 18 weeks later. A comparator group received IIV3 prime and boost at similar intervals. Primary study objectives included evaluation of the safety and tolerability of the vaccine regimens, with secondary objectives of measuring antibody responses at four weeks post boost by hemagglutination inhibition (HAI) and neutralization assays. RESULTS: Seventy-five children ≥6 to ≤17 years old enrolled. Local reactogenicity was higher after DNA prime compared to IIV3 prime (p<0.001 for pain/tenderness, redness, or swelling), but symptoms were mild to moderate in severity. Systemic reactogenicity was similar between vaccines. Overall, antibody responses were similar among groups, although HAI antibodies revealed a trend towards higher responses following 4 mg DNA-IIV3 compared to IIV3-IIV3. The fold increase of HAI antibodies to A/California/07/2009 [A(H1N1)pdm09] was significantly greater following 4 mg DNA-IIV3 (10.12 fold, 5.60-18.27 95%CI) compared to IIV3-IIV3 (3.86 fold, 2.32-6.44 95%CI). Similar neutralizing titers were observed between regimens, with a trend towards increased response frequencies in 4 mg DNA-IIV3. However, significant differences in fold increase, reported as geometric mean fold ratios, were detected against the H1N1 viruses within the neutralization panel: A/New Caledonia/20/1999 (1.41 fold, 1.10-1.81 95%CI) and A/South Carolina/1/1918 (1.55 fold, 1.27-1.89 95%CI). CONCLUSIONS: In this first pediatric DNA vaccine study conducted in the U.S., the DNA prime-IIV3 boost regimen was safe and well tolerated. In children, the 4 mg DNA-IIV3 regimen resulted in antibody responses comparable to the IIV3-IIV3 regimen.

Impact of biologics on disease course in systemic onset juvenile idiopathic arthritis.

To analyze our cohort of patients with systemic onset juvenile idiopathic arthritis (SoJIA) and investigate the impact of biologic disease-modifying antirheumatic drugs (BDMARDs) on disease course. Children who were diagnosed with SoJIA according to International League of Associations for Rheumatology (ILAR) criteria in Boston Children's Hospital between January 1996 and December 2015 were included. Data were collected from patients' charts retrospectively. Demographic features, disease course, and medication usage were identified. There were 76 patients who met ILAR criteria. Most common presenting features were fever (100%), arthralgia (92%), rash (87%), and arthritis (83%). Median follow-up was 69 months. At last visit, 18% still had active disease. Disease course was monophasic in 18 patients (24%), persistent in 24 patients (32%), and polycyclic in 34 patients (45%). Thirty-three percent (n, 6) of children with monophasic disease was diagnosed before 2004 and 67% (n, 12) was diagnosed after 2004 (p = 0.08). Sixty-six percent was treated with a BDMARD. Anakinra (37%) was the most common prescribed BDMARD. Monophasic disease was less common in patients treated with a BDMARD (n, 6, 12%) compared to children not treated with a BDMARD (n, 12, 46%) (p = 0.01). BDMARDs are started earlier (rs, - 0.67; p < 0.001) and diagnosis of SoJIA is made sooner after symptom onset in recent years (rs, - 0.37; p = 0.001). Most patients in our cohort were able to achieve remission. Proportion of monophasic disease tends to increase after 2004 although not statistically significant. In recent years, physicians tend to diagnose SoJIA earlier and treat more aggressively early in the course of the disease with BMARDs. Future prospective research in larger cohorts investigating the effects of BDMARDs on disease course and predictive factors for outcome is needed.

A phase I safety and immunogenicity dose escalation trial of plague vaccine, Flagellin/F1/V, in healthy adult volunteers (DMID 08-0066).

INTRODUCTION: Intentional aerosolization of Yersinia pestis may result in pneumonic plague which is highly fatal if not treated early. METHODS: We conducted a phase 1 randomized, double blind (within each group), placebo controlled, dose escalation trial to evaluate a plague vaccine, Flagellin/F1/V, in healthy adults aged 8 through 45years. Vaccine was administered intramuscularly on Days 0 and 28 at a dose of 1, 3, 6 or 10mcg. Subjects were observed for 4h after vaccination for cytokine release syndrome. Reactogenicity and adverse events (AE) were collected for 14 and 28days, respectively, after each vaccination. Serious AE were collected for the entire study. ELISA antibody and cytokines were measured at multiple time points. Subject's participation lasted 13months. RESULTS: Sixty healthy subjects were enrolled; 52% males, 100% non-Hispanic, 91.7% white and mean age 30.8years. No severe reactogenicity events occurred; most AE were mild. No serious AE related to vaccine occurred. A dose response effect was observed to F1, V and flagellin. The peak ELISA IgG antibody titers (95% CI) after two 10mcg doses of vaccine were 260.0 (102.6-659.0) and 983.6 (317.3-3048.8), respectively, against F1 and V antigens. The 6mcg dose group provided similar titers. Titers were low for the placebo, 1mcg and 3mcg recipients. A positive antibody dose response was observed to F1, V and flagellin. Vaccine antigen specific serum IgE was not detected. There were no significant rises in serum or cellular cytokine responses and no significant IgG increase to flagellin after the second dose. CONCLUSION: The Flagellin/F1/V vaccine exhibited a dose dependent increase in immunogenicity and was well tolerated at all doses. Antibody specific responses to F1, V and flagellin increased as dose increased. Given the results from this trial, testing higher doses of the vaccine may be merited.

Tularemia vaccine: Safety, reactogenicity, "Take" skin reactions, and antibody responses following vaccination with a new lot of the Francisella tularensis live vaccine strain - A phase 2 randomized clinical Trial.

BACKGROUND: Tularemia is caused by Francisella tularensis, a gram-negative bacterium that has been weaponized as an aerosol. For protection of personnel conducting biodefense research, the United States Army required clinical evaluation of a new lot of tularemia live vaccine strain manufactured in accordance with Current Good Manufacturing Practices. METHODS: A phase 2 randomized clinical trial compared the new lot (DVC-LVS) to the existing vaccine that has been in use for decades (USAMRIID-LVS). The vaccines were delivered by scarification to 228 participants. Safety, reactogenicity, take and/or antibody levels were assessed on days 0, 1, 2, 8, 14, 28, 56, and 180. PRINCIPAL RESULTS: Both vaccines were safe and had acceptable reactogenicity profiles during six months of follow-up. There were no serious or grade 3 and 4 laboratory adverse events. Moderate systemic reactogenicity (mostly headache or feeling tired) was reported by ∼23% of participants receiving either vaccine. Injection site reactogenicity was mostly mild itchiness and pain. The frequencies of vaccine take skin reactions were 73% (95% CI, 64, 81) for DVC-LVS and 80% (95% CI, 71, 87) for USAMRIID-LVS. The 90% CI for the difference in proportions was -6.9% (-16.4, 2.6). The rates of seroconversion measured by microagglutination assay on days 28 or 56 were 94% (95% CI, 88, 98; n=98/104) for DVC-LVS and 94% (95% CI, 87, 97; n=103/110) for USAMRIID-LVS (p=1.00). Day 14 sera revealed more rapid seroconversion for DVC-LVS relative to USAMRIID-LVS: 82% (95% CI, 73, 89) versus 55% (95% CI, 45, 65), respectively (p<0.0001). MAJOR CONCLUSIONS: The DVC-LVS vaccine had similar safety, reactogenicity, take and antibody responses compared to the older USAMRIID vaccine, and was superior for early (day 14) antibody production. Vaccination take was not a sensitive surrogate for seroconversion in a multi-center study where personnel at five research clinics performed assessments. ClinicalTrials.gov identifier NCT01150695.

Safety and immunogenicity of a modified vaccinia Ankara vaccine using three immunization schedules and two modes of delivery: A randomized clinical non-inferiority trial.

INTRODUCTION: To guide the use of modified vaccinia Ankara (MVA) vaccine in response to a release of smallpox virus, the immunogenicity and safety of shorter vaccination intervals, and administration by jet injector (JI), were compared to the standard schedule of administration on Days 1 and 29 by syringe and needle (S&N). METHODS: Healthy adults 18-40years of age were randomly assigned to receive MVA vaccine subcutaneously by S&N on Days 1 and 29 (standard), Days 1 and 15, or Days 1 and 22, or to receive the vaccine subcutaneously by JI on Days 1 and 29. Blood was collected at four time points after the second vaccination for plaque reduction neutralization test (PRNT) (primary endpoint) and ELISA (secondary endpoint) antibody assays. For each subject, the peak PRNT (or ELISA) titer was defined by the highest PRNT (or ELISA) titer among all available measurements post second vaccination. Non-inferiority of a non-standard arm compared to the standard arm was met if the upper limit of the 98.33% confidence interval of the difference in the mean log2 peak titers between the standard and non-standard arm was less than 1. RESULTS: Non-inferiority of the PRNT antibody response was not established for any of the three non-standard study arms. Non-inferiority of the ELISA antibody response was established for the Day 1 and 22 compressed schedule and for administration by JI. Solicited local reactions, such as redness and swelling, tended to be more commonly reported with JI administration. Four post-vaccination hypersensitivity reactions were observed. CONCLUSIONS: Evaluations of the primary endpoint of PRNT antibody responses do not support alternative strategies of administering MVA vaccine by S&N on compressed schedules or administration by JI on the standard schedule. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01827371.

Safety and Immunogenicity of Full-Dose Trivalent Inactivated Influenza Vaccine (TIV) Compared With Half-Dose TIV Administered to Children 6 Through 35 Months of Age.

BACKGROUND: Children 6 through 35 months of age are recommended to receive half the dose of influenza vaccine compared with older children and adults. METHODS: This was a 6-site, randomized 2:1, double-blind study comparing full-dose (0.5 mL) trivalent inactivated influenza vaccine (TIV) with half-dose (0.25 mL) TIV in children 6 through 35 months of age. Children previously immunized with influenza vaccine (primed cohort) received 1 dose, and those with no previous influenza immunizations (naive cohort) received 2 doses of TIV. Local and systemic adverse events were recorded. Sera were collected before immunization and 1 month after last dose of TIV. Hemagglutination inhibition antibody testing was performed. RESULTS: Of the 243 subjects enrolled (32 primed, 211 naive), data for 232 were available for complete analysis. No significant differences in local or systemic reactions were observed. Few significant differences in immunogenicity to the 3 vaccine antigens were noted. The immune response to H1N1 was significantly higher in the full-dose group among primed subjects. In the naive cohort, the geometric mean titer for all 3 antigens after 2 doses of TIV were significantly higher in the 12 through 35 months compared with the 6 through 11 months age group. CONCLUSIONS: Our study confirms the safety of full-dose TIV given to children 6 through 35 months of age. An increase in antibody responses after full- versus half-dose TIV was not observed, except for H1N1 in the primed group. Larger studies are needed to clarify the potential for improved immunogenicity with higher vaccine doses. Recommending the same dose could simplify the production, storage, and administration of influenza vaccines.

Comparison of lyophilized versus liquid modified vaccinia Ankara (MVA) formulations and subcutaneous versus intradermal routes of administration in healthy vaccinia-naïve subjects.

BACKGROUND: Modified vaccinia Ankara (MVA) is being developed as a safer smallpox vaccine and is being placed in the US Strategic National Stockpile (SNS) as a liquid formulation for subcutaneous (SC) administration at a dose of 1×10(8) TCID50 in a volume of 0.5mL. This study compared the safety and immunogenicity of the standard formulation, dose and route with both a more stable, lyophilized formulation and with an antigen-sparing intradermal (ID) route of administration. METHODS: 524 subjects were randomized to receive either a full dose of Lyophilized-SC, a full dose of Liquid-SC or 20% (2×10(7) TCID50 in 0.1mL) of a full dose Liquid-ID MVA on Days 0 and 28. Safety and immunogenicity were followed through 180 days post second vaccination. RESULTS: Among the 3 groups, the proportion of subjects with moderate/severe functional local reactions was significantly different (P=0.0013) between the Lyophilized-SC group (30.3%), the Liquid-SC group (13.8%) and Liquid-ID group (22.0%) only after first vaccination; and for moderate/severe measured erythema and/or induration after any vaccination (P=0.0001) between the Lyophilized-SC group (58.2%), the Liquid-SC group (58.1%) and the Liquid-ID group (94.8%) and the reactions lasted longer in the Liquid-ID group. In the ID Group, 36.1% of subjects had mild injection site skin discoloration lasting ≥6 months. After second vaccination Day (42-208), geometric mean of peak neutralization titers were 87.8, 49.5 and 59.5 for the Lyophilized-SC, Liquid-SC and Liquid-ID groups, respectively, and the maximum number of responders based on peak titer in each group was 142/145 (97.9%), 142/149 (95.3%) and 138/146 (94.5%), respectively. At 180 days after the second vaccination, geometric mean neutralization titers declined to 11.7, 10.2 and 10.4 with only 54.3%, 39.2% and 35.2% of subjects remaining seropositive for the Lyophilized-SC, Liquid-SC and Liquid-ID groups, respectively. Both the Lyophilized-SC and Liquid-ID groups were considered non-inferior (primary objective) to the Liquid-SC group. CONCLUSIONS: Transitioning to a lyophilized formulation, which has a longer shelf life, will not negatively impact immunogenicity. In a situation where insufficient vaccine is available, ID vaccination could be used, increasing the number of available doses of vaccine in the SNS 5-fold (i.e., from 20 million to 100 million doses).

Effect of Varying Doses of a Monovalent H7N9 Influenza Vaccine With and Without AS03 and MF59 Adjuvants on Immune Response: A Randomized Clinical Trial.

IMPORTANCE: Human infections with the avian influenza A(H7N9) virus were first reported in China in 2013 and continue to occur. Hemagglutinin H7 administered alone is a poor immunogen necessitating evaluation of adjuvanted H7N9 vaccines. OBJECTIVE: To evaluate the immunogenicity and safety of an inactivated H7N9 vaccine with and without AS03 adjuvant, as well as mixed vaccine schedules that included sequential administration of AS03- and MF59-containing formulations and of adjuvanted and unadjuvanted formulations. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, phase 2 trial at 5 US sites enrolled 980 adults aged 19 through 64 years from September 2013 through November 2013; safety follow-up was completed in January 2015. INTERVENTIONS: The H7N9 vaccine was given on days 0 and 21 at nominal doses of 3.75 µg, 7.5 µg, 15 µg, and 45 µg of hemagglutinin with or without AS03 or MF59 adjuvant mixed on site. MAIN OUTCOMES AND MEASURES: Proportions achieving a hemagglutination inhibition antibody (HIA) titer of 40 or higher at 21 days after the second vaccination; vaccine-related serious adverse events through 12 months after the first vaccination; and solicited signs and symptoms after vaccination through day 7. RESULTS: Two doses of vaccine were required to induce detectable antibody titers in most participants. After 2 doses of an H7N9 formulation containing 15 µg of hemagglutinin given without adjuvant, with AS03 adjuvant, or with MF59 adjuvant, the proportion achieving an HIA titer of 40 or higher was 2% (95% CI, 0%-7%) without adjuvant (n = 94), 84% (95% CI, 76%-91%) with AS03 adjuvant (n = 96), and 57% (95% CI, 47%-68%) with MF59 adjuvant (n = 92) (P < .001 for comparison of the AS03 and MF59 schedules). The 2 schedules alternating AS03-and MF59-adjuvanted formulations led to lower geometric mean titers (GMTs) of (41.5 [95% CI, 31.7-54.4]; n = 92) and (58.6 [95% CI, 44.3-77.6]; n = 96) than the group induced by 2 AS03-adjuvanted formulations (n = 96) (103.4 [95% CI, 78.7-135.9]; P < .001) but higher GMTs than 2 doses of MF59-adjuvanted formulation (n = 94) (29.0 [95% CI, 22.4-37.6]; P < .001). CONCLUSIONS AND RELEVANCE: The AS03 and MF59 adjuvants augmented the immune responses to 2 doses of an inactivated H7N9 influenza vaccine, with AS03-adjuvanted formulations inducing the highest titers. This study of 2 adjuvants used in influenza vaccine formulations with adjuvant mixed on site provides immunogenicity information that may be informative to influenza pandemic preparedness programs. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01942265.

Phase II trial in adults of concurrent or sequential 2009 pandemic H1N1 and 2009-2010 seasonal trivalent influenza vaccinations.

BACKGROUND: During the 2009 influenza pandemic both seasonal and 2009 pandemic vaccines were recommended. We conducted a randomized trial of monovalent 2009-H1N1 vaccine and seasonal trivalent inactivated influenza vaccine (IIV3) given sequentially or concurrently to adults. METHODS: Adults randomized to 4 study groups and stratified by age (18-64 and ≥65 years) received 1 dose of seasonal IIV3 or placebo and 2 doses of 2009-H1N1 vaccine or placebo in one of 4 combinations, i.e., H1N1+Placebo/H1N1+Placebo/IIV3 (HP/HP/V3), H1N1+IIV3/H1N1+Placebo/Placebo (HV3/HP/P), H1N1+Placebo/H1N1+IIV3/Placebo (HP/HV3/P), and IIV3+Placebo/H1N1+Placebo/H1N1 (V3P/HP/H). Intramuscular injections were given three times at 21 day intervals. Sera for antibody assays were obtained prior to and 21 days after each vaccination. Reactogenicity and adverse events were monitored. RESULTS: Eight hundred-five (805) adults were enrolled. All combinations of vaccines were safe and well tolerated. In general, one dose of 2009-H1N1 and one dose of IIV3, regardless of sequence or concurrency of administration, were immunogenic in adults. There were no significant differences in geometric mean titers (GMT) or the proportions of subjects with ≥4-fold rise in antibody responses and titers ≥40 for any vaccine group or between age strata for 2009-H1N1 after the first or second dose, although the vaccine sequence affected the titers to the IIV3 antigens. Hemagglutination inhibition antibody (HAI) GMTs against 2009-H1N1 for the combined age strata 21 days after the first 2009-H1N1 dose were 190.4, 182.1, 232.9 and 157.5 for HP/HP/V3, HV3/HP/P, HP/HV3/P and V3P/HP/H, respectively. While IIV3 GMTs were adequate they were generally lower than the 2009-H1N1 GMTs. In a subset of subjects, there was good correlation between HAI and microneutralization (MN) titers (Spearman's correlation coefficient 0.92). CONCLUSIONS: All vaccine combinations were generally well tolerated. Immune responses to one dose of 2009-H1N1 were adequate regardless of the sequence of vaccination in all age groups, but the sequence affected titers to IIV3 antigens.

Immunogenicity of avian influenza A/Anhui/01/2005(H5N1) vaccine with MF59 adjuvant: a randomized clinical trial.

IMPORTANCE: The need to respond quickly to potential influenza pandemics is important. Immunologic priming (initial presentation of an antigen to allow antibody responses on revaccination) with vaccine directed toward an older avian influenza H5 strain might lead to secondary antibody responses to a single dose of more current H5 avian influenza vaccine. OBJECTIVES: To assess priming with the older avian influenza A/Vietnam/1203/2004(H5N1) (Vietnam) vaccine and to conduct dose-response studies with vaccine directed against the more contemporary H5N1 avian influenza virus, influenza A/Anhui/01/2005 (Anhui). DESIGN, SETTING, AND PARTICIPANTS: Multicenter US randomized clinical trial beginning in June 2010 with follow-up continuing through October 2011 enrolling 72 healthy adults who were vaccinated 1 year previously with the Vietnam vaccine and 565 vaccine-naive adults. INTERVENTIONS: Participants who were previously vaccinated with 90 µg of unadjuvanted Vietnam vaccine were randomly assigned to receive 3.75 µg of avian influenza Anhui vaccine with or without MF59 adjuvant, stratified by 1 vs 2 previous doses (1 dose: n = 18 with MF59 and n = 17 without; 2 doses: n = 19 with MF59 and n = 18 without). Vaccine-naive individuals were randomly assigned to receive Ahnui vaccine with or without MF59 adjuvant in 1 of 5 doses (3.75 µg [n = 55 with MF59 and n = 59 without], 7.5 µg [n = 51 with MF59 and n = 57 without], 15 µg [n = 48 with MF59 and n = 44 without], 45 µg [n = 47 with MF59 and n = 47 without], or 90 µg [n = 57 without adjuvant]) or placebo (n = 100) given at days 0 and 28. MAIN OUTCOMES AND MEASURES: The primary immunogenicity outcome was hemagglutination inhibition assay (HAI) titer against each vaccine antigen 1 month (day 28) and 6 months (day 180) after last vaccination. The primary safety outcomes were local and systemic adverse events on days 0 to 7 after each vaccination and serious adverse events. RESULTS: Previously vaccinated participants manifested secondary antibody responses after receipt of low-dose Anhui vaccine ("boosting"); by day 28, 21% to 50% developed HAI responses of 1:40 or greater. Use of adjuvant was not associated with increased HAI responses. Among vaccine-naive participants (n = 565), the optimum dose was 7.5 µg of antigen with adjuvant (geometric mean titer [GMT], 63.3; 95% CI, 43.0-93.1). The greatest response to unadjuvanted antigen was seen at the highest dose, 90 µg (GMT, 28.5; 95% CI, 19.7-41.2). Local or systemic reactions occurred, respectively, in 40 (78%) and 25 (49%) of 51 participants who received 7.5 µg plus adjuvant vs 50 (88%) and 29 (51%) of 57 who received 90 µg of unadjuvanted vaccine. In general, antibodies were short-lived, and by day 180, HAI titers had decreased to less than 1:20 in all treatment groups. CONCLUSIONS AND RELEVANCE: Previous receipt of a single dose of influenza A(H5N1) Vietnam vaccine was associated with sufficient immunologic priming to facilitate antibody response to a different H5N1 antigen using low-dose Anhui (booster) vaccine. In participants who had not previously received H5 vaccine, low-dose Anhui vaccine plus adjuvant was more immunogenic compared with higher doses of unadjuvanted vaccine. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00680069.

Recommended solutions to the barriers to immunization in children and adults.

Vaccines prevent disease and mortality. They are the foremost achievement of public health programs in the United States and internationally. In the early 90s the National Vaccine Advisory Committee concluded that there were significant barriers to young children being fully immunized including inconvenient and limited clinic hours for immunization, inadequate access to health care, and vaccine administration fees. Barriers to adult immunization also have been identified. This article will discuss research addressing barriers to immunization and possible solutions.

Point-of-Use Mixing of Influenza H5N1 Vaccine and MF59 Adjuvant for Pandemic Vaccination Preparedness: Antibody Responses and Safety. A Phase 1 Clinical Trial.

BACKGROUND: Avian influenza A/H5N1 has threatened human health for nearly 2 decades. Avian influenza A vaccine without adjuvant is poorly immunogenic. A flexible rapid tactic for mass vaccination will be needed if a pandemic occurs. METHODS: A multicenter, randomized, blinded phase 1 clinical trial evaluated safety and antibody responses after point-of-use mixing of influenza A/Indonesia/05/2005 (H5N1) vaccine with MF59 adjuvant. Field-site pharmacies mixed 3.75, 7.5, or 15 mcg of antigen with or without MF59 adjuvant just prior to intramuscular administration on days 0 and 21 of healthy adults aged 18-49 years. RESULTS: Two hundred and seventy subjects were enrolled. After vaccination, titers of hemagglutination inhibition antibody ≥1:40 were achieved in 80% of subjects receiving 3.75 mcg + MF59 vs only 14% receiving 15 mcg without adjuvant (P < .0001). Peak hemagglutination inhibition antibody geometric mean titers for vaccine + MF59 were ∼65 regardless of antigen dose, and neutralizing titers were 2- to 3-fold higher. Vaccine + MF59 produced cross-reactive antibody responses against 4 heterologous H5N1 viruses. Excellent safety and tolerability were demonstrated. CONCLUSIONS: Point-of-use mixing of H5N1 antigen and MF59 adjuvant achieved target antibody titers in a high percentage of subjects and was safe. The feasibility of the point-of-use mixing should be studied further.