Immunogenicity and Safety of a Quadrivalent Meningococcal Conjugate Vaccine Versus Nimenrix in Healthy Adolescents: A Randomized Phase IIIb Multicenter Study.

INTRODUCTION: Many immunization programs in Europe recommend quadrivalent meningococcal vaccinations, which are often administered concomitantly with other vaccines. We compared the immune response of a tetanus toxoid conjugated quadrivalent meningococcal vaccine (MenACYW-TT, MenQuadfi®) with another quadrivalent meningococcal conjugate vaccine (MCV4-TT; Nimenrix®) when administered alone or concomitantly with Tdap-IPV and 9vHPV vaccines in adolescents. METHODS: In this phase IIIb trial, healthy adolescents (MenC-naïve or MenC-primed before 2 years of age) from Spain, Italy, Hungary, and Singapore were randomized in a 3:3:2 ratio to receive either MenACYW-TT or MCV4-TT alone, or MenACYW-TT concomitantly with 9vHPV and Tdap-IPV. The primary objective was to demonstrate the non-inferiority of the seroprotection rate (human serum bactericidal assay [hSBA] titer ≥ 1:8) to serogroups A, C, W, and Y 30 days post-vaccination with a single dose of MenACYW-TT or MCV4-TT. Secondary objectives included describing hSBA titers for the four serogroups before and 1 month following vaccination and according to MenC priming status. RESULTS: A total of 463 participants were enrolled (MenACYW-TT, n = 173; MCV4-TT, n = 173; MenACYW-TT/9vHPV/Tdap-IPV n = 117). Non-inferiority based on seroprotection was demonstrated for MenACYW-TT versus MCV4-TT for all serogroups. Immune responses were comparable whether MenACYW-TT was administered alone or concomitantly with Tdap-IPV and 9vHPV. Post-vaccination hSBA GMTs were higher in MenACYW-TT vs. MCV4-TT for serogroups C, Y, and W and comparable for serogroup A. The percentages of participants with an hSBA vaccine seroresponse were higher in MenACYW-TT vs. MCV4-TT for all serogroups. For serogroup C, higher GMTs were observed in both MenC-naïve or -primed participants vaccinated with MenACYW-TT vs. MCV4-TT. Seroprotection and seroresponse were higher in MenC-naïve participants vaccinated with MenACYW-TT vs. MCV4-TT and comparable in MenC-primed. The safety profiles were comparable between groups and no new safety concerns were identified. CONCLUSIONS: These data support the concomitant administration of MenACYW-TT with 9vHPV and Tdap-IPV vaccines in adolescents. TRIAL REGISTRATIONS: Clinicaltrials.gov, NCT04490018; EudraCT: 2020-001665-37; WHO: U1111-1249-2973.

MenACYW conjugate vaccine has been made to protect against meningococcal disease caused by four common types of bacteria (germs) called Neisseria meningitidis (or meningococcus), A, C, W, and Y. Many people, particularly adolescents, have the germs of this disease in their nose or throat, and therefore may develop the disease or transmit the bacteria to other people. Hence, adolescent meningococcal vaccination against serogroups ACWY is increasingly recommended in several countries. This study assessed the immune response to these serogroups in healthy adolescents after one dose of MenACYW conjugate vaccine or Nimenrix^®, a meningococcal licensed vaccine. Moreover, the immune response and safety were assessed when the vaccines were given alone or when given concomitantly with other adolescent vaccines, including the human papillomavirus (9vHPV) and tetanus, diphtheria, pertussis, and poliomyelitis (Tdap-IPV) vaccines. A total of 463 adolescents (aged 10­17 years) participated in this study and received either MenACYW or Nimenrix^® alone, or MenACYW concomitantly with 9vHPV and Tdap-IPV vaccine. The immune response induced by MenACYW was as good as the immune response induced by Nimenrix^®, and when given alone or concomitantly with 9vHPV and Tdap IPV vaccines. None of the participants experienced any serious side effects of any vaccine. The most common non-serious side effects were injection site pain, muscle pain, and headache. These data support the use of MenACYW in adolescents, with or without concomitant administration with 9vHPV and Tdap-IPV, which may help to increase the number of adolescents vaccinated.

Antibody persistence and booster responses 24-36 months after different 4CMenB vaccination schedules in infants and children: A randomised trial.

OBJECTIVES: This phase IIIb, open-label, multicentre, extension study (NCT01894919) evaluated long-term antibody persistence and booster responses in participants who received a reduced 2 + 1 or licensed 3 + 1 meningococcal serogroup B vaccine (4CMenB)-schedule (infants), or 2-dose catch-up schedule (2-10-year-olds) in parent study NCT01339923. MATERIALS AND METHODS: Children aged 35 months to 12 years (N = 851) were enrolled. Follow-on participants (N = 646) were randomised 2:1 to vaccination and non-vaccination subsets; vaccination subsets received an additional 4CMenB dose. Newly enrolled vaccine-naïve participants (N = 205) received 2 catch-up doses, 1 month apart (accelerated schedule). Antibody levels were determined using human serum bactericidal assay (hSBA) against MenB indicator strains for fHbp, NadA, PorA and NHBA. Safety was also evaluated. RESULTS: Antibody levels declined across follow-on groups at 24-36 months versus 1 month post-vaccination. Antibody persistence and booster responses were similar between infants receiving the reduced or licensed 4CMenB-schedule. An additional dose in follow-on participants induced higher hSBA titres than a first dose in vaccine-naïve children. Two catch-up doses in vaccine-naïve participants induced robust antibody responses. No safety concerns were identified. CONCLUSION: Antibody persistence, booster responses, and safety profiles were similar with either 2 + 1 or 3 + 1 vaccination schedules. The accelerated schedule in vaccine-naïve children induced robust antibody responses.

Varicella vaccine without human serum albumin versus licensed varicella vaccine in children during the second year of life: a randomized, double-blind, non-inferiority trial.

BACKGROUND: GSK's varicella vaccine contains human serum albumin (HSA) which is used to stabilize the virus and prevent immunogens from adhering to the injection vial walls. However, because HSA is derived from human blood, there is a theoretical risk that it might contain infectious agents which could be unsafe for humans. Given this concern, a study was undertaken to compare the immunogenicity and safety of a new formulation without HSA with the currently licensed varicella vaccine in the Czech Republic and Hungary. METHODS: Healthy children aged 11-21 months received two doses of the varicella vaccine either with or without HSA. Antibody titres against varicella-zoster virus (anti-VZV) were measured 42 days after each dose, using an immunofluorescence assay (IFA, cut-off = 4dilution(-1)) and enzyme linked immunosorbent assay (ELISA, cut-off = 25 mIU/ml). Solicited local symptoms were recorded during a 4-day post-vaccination follow-up period; solicited general and unsolicited symptoms were recorded during a 43-day post-vaccination follow-up period and serious adverse event (SAEs) were recorded throughout the study. RESULTS: Of 244 children (mean age = 15.2 months [SD = 3.2]) vaccinated in the study, 233 (vaccine without HSA N = 117; vaccine containing HSA N = 116) formed the according-to-protocol immunogenicity cohort. Observed seroconversion/seroresponse rates were >98 and 100 %, 42 days after doses 1 and 2, respectively. The rates were within the same range in both groups, irrespective of the testing assay. The varicella vaccine without HSA was non-inferior to the licensed vaccine in terms of anti-VZV antibody Geometric Mean Titre/Concentration ratio (1.12 [95 % CI:0.86-1.46] by IFA; 1.12 [95 % CI:0.93-1.33] by ELISA) approximately six weeks after the first dose of the 2-dose vaccination course. The incidence of solicited and unsolicited symptoms was similar after both vaccines; low-grade fever was numerically higher after the first dose of the varicella vaccine without HSA. Seven SAEs were reported, none of which were fatal or considered to be vaccine-related. CONCLUSIONS: The first dose of a new varicella vaccine without HSA was immunologically non-inferior to the licensed varicella vaccine. After two doses, both vaccines had acceptable safety profiles in children aged 11-21 months in the Czech Republic and Hungary. TRIAL REGISTRATION: NCT00568334 , registered on 5 December 2007 ( www.clinicaltrials.gov ).

The impact of serum lipids on risk for microangiopathy in patients with type 2 diabetes mellitus.

BACKGROUND: Few large-scale, real-world studies have assessed the relative associations of lipid fractions with diabetic microvascular events. The main objective of this study was to evaluate the association of the lipid profile components, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG), and non-high density lipoprotein cholesterol (non-HDL-C) with microvascular complications (MVCs) in type 2 diabetes mellitus (T2DM) patients. METHODS: This observational cohort study queried the HealthCore Integrated Research Database (HIRDSM) for newly-diagnosed (Index Date) 18-64-year-old patients with diabetes mellitus between 01/01/2005-06/30/2010. Inclusion required ≥ 12 months pre-index continuous health plan eligibility and ≥ 1 pre-index lipid profile result. Patients with polycystic ovary syndrome and prior MVCs were excluded. Incident complications were defined as the earliest occurrence of diabetic retinopathy, peripheral neuropathy, and/or nephropathy post-index. Cox proportional models and Kaplan-Meier (KM) curves were used to evaluate associations among variables. RESULTS: Of the patients (N=72,267), 50.05% achieved HDL-C, 64.28% LDL-C, 59.82% TG, and 56.79% non-HDL-C American Diabetes Association goals at baseline. During follow-up (mean, 21.74 months), there were 5.21 microvascular events per 1,000 patient-months. A 1-mg/dL increase in HDL-C was associated with 1% decrease in any MVC risk (P< .0001), but for LDL-C, TG, and non-HDL-C, 1-mg/dL increase resulted in increases of 0.2% (P< .0001), 0.1% (P<0.001) and 0.3% (P<0.001) in MVC risk. Patients achieving HDL-C goals had a 11% lower risk of MVC versus non-achievers (RR 0.895, [95% CI, 0.852-0.941], P< .0001). Similarly, TG goal attainment was associated with a lowered risk for any MVC (RR 0.849, [95% CI, 0.808-0.892], P< .0001). Evaluation of KM survival curves demonstrated no significant difference in the risk of MVCs between patients achieving vs. not achieving LDL-C goals, but did demonstrate a difference in MVC risk between patients achieving vs. not achieving non-HDL-C goals. CONCLUSION: This study demonstrates significant independent associations among lipid fractions and risk for microangiopathy. These findings suggest that attaining established ADA goals for HDL-C, TG, and non-HDL-C may reduce risk for microvascular events among patients with diabetes.

Development of an interactive model of the burden of future coronary heart disease from an employer perspective.

OBJECTIVE: To create a computer-based model for employers to better understand the burden of coronary heart disease (CHD) to their organizations. METHODS: A user-friendly model was developed to allow employers to evaluate the burden of CHD. Inputs include the demographic distribution by age and sex, prevalence of CHD and CHD risk factors, direct and indirect medical costs of CHD events, and discount and inflation rates. The model contains prediction equations derived from National Health and Nutrition Examination Survey data and Framingham Heart Study equations, used with employer inputs to predict future CHD events and expenditures. RESULTS: Interactive graphs are presented for the employer's covered population alongside regional benchmarks. The time horizon and population may be adjusted. CONCLUSIONS: This interactive model illustrates how pragmatic outcomes research can be converted into a transparent model addressing health care budget issues that is readily understood by corporate managers.

Impact of fixed-dose and multi-pill combination dyslipidemia therapies on medication adherence and the economic burden of sub-optimal adherence.

OBJECTIVE: To compare medication adherence between patients initiating fixed-dose combination versus multi-pill combination dyslipidemia therapies and assess the association between optimal adherence (MPR > or = 80%) and cardiovascular disease (CVD)-associated total healthcare resource utilization (THR) and costs (THC). RESEARCH DESIGN AND METHODS: The HealthCore Integrated Research Database was used to identify patients > or =18 years newly initiating fixed-dose combination [niacin extended-release (NER) and lovastatin (NERL)] or multi-pill combination therapies [NER and simvastatin (NER/S) or lovastatin (NER/L)] between 1/1/2000 and 6/30/2006 (index date), with minimum 18 months of follow-up. Adherence was measured using medication possession ratio (MPR). Three multivariate models were developed controlling for demographic and clinical characteristics. A logistic model evaluated the association between study cohorts and optimal adherence, while negative binomial and gamma models estimated the association between optimal adherence and CVD-associated THR and THC, respectively. RESULTS: In all, 6638 NERL, 1687 NER/S, and 663 NER/L patients were identified. Fixed-dose combination patients were younger [mean (SD) ages of 51.9 (10.5) vs. 56.0 (9.4) [NER/S] and 56.1 (10.6) [NER/L]; p < 0.01], had lower comorbidity (Deyo-Charlson Index 0.50 +/- 0.9 vs. 0.7 +/- 1.1 and 0.6 +/- 1.1, p < 0.01 and p < 0.05) and comprised fewer males (73.1 vs. 83.0% and 77.7%; p < 0.01 and p = 0.1). Fixed-dose combination patients had higher average 1-year MPR versus NER/S and NER/L patients (0.54 +/- 0.35 vs. 0.50 +/- 0.35 and 0.47 +/- 0.34, p < 0.01). NER/S and NER/L patients were 31.3% (95% CI: 22.9-39.5%) and 39.1% (95% CI: 26.7-49.4%) less likely to be optimally adherent than fixed-dose combination patients (p < 0.01). Additionally, optimally adherent patients had 8% and 40% decreases in annual CVD-attributable THR [0.920 (95% CI: 0.857-0.989); p = 0.023] and THC [0.601 (95% CI: 0.427-0.845); p = 0.003] versus sub-optimally adherent patients. Key limitations of the study include the limited ability of MPR to analyze the continuity of medication usage, inability to capture data on other key variables including race, income, and clinical characteristics such as smoking history, absence of laboratory values on all study patients, inability to capture over-the-counter fills of niacin, and inability to show causality of results obtained. CONCLUSIONS: Adherence was significantly higher among patients initiating fixed-dose combination versus multi-pill combination dyslipidemia therapies in this managed-care population. Additionally, patients with optimal adherence had a significantly lower CVD-associated THR and THC versus patients with sub-optimal adherence.

Model-based simulation to explore the cost-effectiveness of following practice guidelines for triglyceride and low-density lipoprotein cholesterol control among patients with diabetes mellitus and mixed dyslipidemia.

BACKGROUND: The National Cholesterol Education Program Adult Treatment Panel III guidelines recommend maintaining lipid levels within particular targets to reduce the risk of coronary heart disease (CHD) events. OBJECTIVE: The objective of this simulation study was to evaluate the cost-effectiveness of following guideline-recommended care compared with current practice or usual care for patients with diabetes mellitus (DM) and mixed dyslipidemia (ie, high low-density lipoprotein cholesterol [LDL-C] and triglyceride [TG] levels). METHODS: A simulation model using a US health care payer perspective was designed to predict changes in lipid levels (LDL-C, TG, high-density lipoprotein cholesterol, and total cholesterol) and long-term CHD risk. Data about patients with DM and uncontrolled TG and/or LDL-C were taken from an electronic medical records database to develop the description of current care (eg, statin, fibrate, or no medication) and cholesterol levels. Patients with uncontrolled lipid levels who were not following guideline recommendations were assumed to be receiving combination treatment (ie, coadministration of statin and fibrate) or monotherapy for the uncontrolled lipids under guideline care. Results from a previous study were used to project incremental benefits of combination treatment compared with monotherapy. CHD events were predicted based on risk equations. A 20-year model of direct costs and quality-adjusted life-years (QALYs) was created. RESULTS: Among patients switched to guideline therapy, the model predicted 72% achieved 2 lipid targets and 44% achieved 3 lipid targets in 1 year. Over 20 years, in a modeled sample of 1000 patients, 176 myocardial infarction and angina events would be avoided by following guideline care. Total present value of costs for drug treatment and medical care for CHD events would be $33,626 per patient for guideline treatment versus $25,264 per patient for current care. The discounted QALY gain would be 0.18 per patient for an incremental cost per QALY of $50,315. CONCLUSIONS: The results of this model simulation suggest that for patients with DM and mixed dyslipidemia, following treatment guidelines rather than current practice (including combination therapy rather than monotherapy) would result in more patients achieving lipid targets, fewer CHD events, and more QALYs gained at a reasonable cost (less than $109,000) per QALY.

Attainment of combined optimal lipid values and the impact of lipid medication on cardiovascular outcomes and costs in a commercially insured population in the US.

OBJECTIVE: To determine factors associated with the achievement of optimal lipid values (OLVs) and subsequent impact on clinical and economic outcomes. METHODS: An observational managed care database analysis was conducted among treatment-naïve adults with elevated cardiovascular (CV) risk, >or=12 months follow-up and full lipid panel from the 1st January 2002 to the 28th February 2005. Achievement of guideline-based levels for low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides was evaluated via laboratory data. Annual CV-attributable resource utilisation was assessed via medical and pharmacy claims data. Clinical and economic outcomes associated with the achievement of OLVs were assessed using multivariate regression. RESULTS: A total of 52,778 patients were followed for a mean (standard deviation) of 27 (10) months with 13% achieving combined OLVs at baseline and 23% after 4 years. Of patients, 69% did not initiate lipid-modifying medication. The achievement of combined OLVs reduced the risk of CV event (odds ratio=0.86; 95% confidence interval 0.78-0.95), resource utilisation (inpatient visits: 3.36 vs. 4.41 per 100 patient years, p<0.0001; emergency department visits: 1.1 vs. 2.4 per 100 patient years, p<0.05) and costs: $703 vs. $903 per patient year, p<0.0001. CONCLUSIONS: Simultaneous achievement of OLVs was rare in this patient population. Physicians should be encouraged to manage multiple risk factors aggressively to improve clinical and economic outcomes associated with CV disease.