Comparative Assessment of a Single Dose and a 2-dose Vaccination Series of a Quadrivalent Meningococcal CRM-conjugate Vaccine (MenACWY-CRM) in Children 2-10 Years of Age.

BACKGROUND: We compared the immunogenicity, safety and 1-year antibody persistence of a single-dose and a 2-dose series of a licensed meningococcal ACWY-CRM conjugate vaccine (MenACWY-CRM) in 2- to 10-year-old children. METHODS: In this phase III, multicenter, observer-blind study, children aged 2-5 years (n = 359) and 6-10 years (n = 356) were randomized 1:1 to receive 2 doses of MenACWY-CRM (ACWY2) or 1 dose of placebo followed by 1 dose of MenACWY-CRM (ACWY1), 2 months apart. Immunogenicity was measured using serum bactericidal activity with human complement (hSBA). Primary outcomes were to assess the immunologic noninferiority and superiority of ACWY2 versus ACWY1. RESULTS: One-month after the second dose, the hSBA seroresponse in ACWY2 was noninferior to ACWY1 for all 4 serogroups, in both age cohorts, and was superior for serogroups C and Y in the 2- to 5-year-old age cohort and for serogroup Y in the 6- to 10-year-old age cohort. Overall, 90%-99% of subjects in ACWY2 and 65%-96% in ACWY1 had hSBA titers ≥ 8; geometric mean titers were 1.8- to 6.4-fold higher in ACWY2 than ACWY1 across serogroups. At 1 year postvaccination, geometric mean titers declined, and the differences between ACWY2 and ACWY1 remained significant for serogroups A and C in the 2- to 5-year-old age cohort and for serogroups C and Y in the 6- to 10-year-old age cohort. The safety profile of MenACWY-CRM was similar in both groups. CONCLUSIONS: The single dose and 2-dose MenACWY-CRM series were immunogenic and well tolerated. Although antibody responses were greater after 2 doses, especially in the 2- to 5-year-old age cohort, this difference was less pronounced at 1 year postvaccination.

Immune responses to a recombinant, four-component, meningococcal serogroup B vaccine (4CMenB) in adolescents: a phase III, randomized, multicentre, lot-to-lot consistency study.

BACKGROUND: For decades, a broadly effective vaccine against serogroup B Neisseria meningitidis (MenB) has remained elusive. Recently, a four-component recombinant vaccine (4CMenB) has been developed and is now approved in Europe, Canada, Australia and some Latin American countries. This phase III, randomized study evaluated the lot consistency, early immune responses and the safety profile of 4CMenB in 11 to 17-year-old adolescents in Australia and Canada (NCT01423084). METHODS: In total, 344 adolescents received two doses of one of 2 lots of 4CMenB, 1-month apart. Immunogenicity was assessed before, 2-weeks and 1-month following the second vaccination. Serum bactericidal activity using human complement (hSBA) was measured against three reference strains 44/76-SL, 5/99 and NZ98/254, selected to express one of the vaccine antigens; Neisseria adhesin A (NadA), factor H binding protein (fHbp) and porin A (PorA) containing outer membrane vesicle (OMV), respectively. Responses to the Neisseria heparin binding antigen (NHBA) were assessed with enzyme linked immunosorbent assay (ELISA). Local and systemic reactions were recorded for 7 days following each vaccination; unsolicited adverse events were monitored throughout the study. RESULTS: Immunological equivalence of the two lots of 4CMenB was established at 1-month. At baseline, ≤7% of participants had hSBA titers ≥5 to all three reference strains. Two weeks following the second dose of 4CMenB, all participants had hSBA titers ≥5 against fHbp and NadA compared with 84-96% against the PorA reference strains. At 1-month, corresponding proportions were 99%, 100% and 70-79%, respectively. Both lots were generally well tolerated and had similar adverse event profiles. CONCLUSIONS: Two doses of 4CMenB had an acceptable safety profile and induced a robust immune response in adolescents. Peak antibody responses were observed at 14 days following vaccination. While a substantial non-uniform antigen-dependent early decline in antibody titers was seen thereafter, a significant percentage of participants continued to maintain protective hSBA titers at 1-month.

Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial.

CONTEXT: The expression and release of tissue factor is a major trigger for the activation of coagulation in patients with sepsis. Tissue factor pathway inhibitor (TFPI) forms a complex with tissue factor and blood protease factors leading to inhibition of thrombin generation and fibrin formation. OBJECTIVES: To determine if administration of tifacogin (recombinant TFPI) provides mortality benefit in patients with severe sepsis and elevated international normalized ratio (INR) and to assess tifacogin safety in severe sepsis, including patients with low INR. DESIGN AND SETTING: A randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trial conducted from March 21, 2000, through September 27, 2001, in 245 hospitals in 17 countries in North America, Europe, and Israel. PATIENTS: The primary efficacy population consisted of 1754 patients (> or =18 years) with severe sepsis and a high INR (> or =1.2) randomly assigned to intravenous infusion of either tifacogin (0.025 mg/kg per hour for 96 hours, n = 880) or placebo (arginine citrate buffer, n = 874), and 201 patients with a low INR (<1.2) randomly assigned to receive the same dose of either tifacogin or placebo. MAIN OUTCOME MEASURE: All-cause 28-day mortality. RESULTS: Overall mortality at 28 days in the tifacogin-treated group (n = 880) vs the placebo group (n = 874) for high INR was 34.2% vs 33.9%, respectively (P =.88, Pearson chi2 test; P =.75, logistic regression model). None of the protocol-specified secondary end points differed between the tifacogin vs placebo groups. An analysis on the first 722 patients demonstrated a mortality rate of 38.9% for placebo vs 29.1% for tifacogin (P =.006, Pearson chi2 test). Tifacogin significantly attenuated prothrombin fragment 1.2 and thrombin:antithrombin complex levels (P<.001, 2-sample t test) in patients with high and low INR. Overall mortality was lower in the tifacogin response in patients with low INR (12%; n = 83) vs placebo (22.9%; n = 118) (P =.051, Pearson chi2 test; P =.03, logistic regression model). There was an increase in serious adverse events with bleeding in the tifacogin group in both cohorts (6.5% tifacogin and 4.8% placebo for high INR; 6.0% tifacogin and 3.3% placebo for low INR). CONCLUSIONS: Treatment with tifacogin had no effect on all-cause mortality in patients with severe sepsis and high INR. Tifacogin administration was associated with an increase in risk of bleeding, irrespective of baseline INR.

Antibody persistence after primary and booster doses of a quadrivalent meningococcal conjugate vaccine in adolescents.

BACKGROUND: The aim of this study was to evaluate antibody persistence 5 years after primary vaccination with the quadrivalent meningococcal conjugate vaccines MenACWY-CRM or MenACWY-D and 2 years after a booster dose of MenACWY-CRM, in the context of a phase 3 study. METHODS: Subjects (aged 19.2 ± 2.3 years) were assigned to 5 groups according to whether they had previously received primary vaccination (at 14.2 ± 2.2 years) with MenACWY-CRM (N = 131) or MenACWY-D (N = 76), a booster dose of MenACWY-CRM 3 years after primary vaccination with MenACWY-CRM (N = 44) or MenACWY-D (N = 31) or no vaccination (N = 107). The immunogenicity measures were percentages of subjects with serum bactericidal activity (hSBA) ≥ 1:8 for serogroups A, C, W and Y and hSBA geometric mean titers. Comparisons with age-matched, vaccine-naive subjects were performed. RESULTS: A majority of subjects vaccinated 5 years previously maintained hSBA ≥ 1:8 against serogroups C, W and Y in the MenACWY-CRM (59%-82%) and MenACWY-D groups (54%-73%); this was lower for serogroup A in both groups. There was a decline in antibody titers after primary vaccination, especially in the first 2 years postprimary vaccination, with steady concentrations during the next 3 years. Two years after MenACWY-CRM booster vaccination the percentages of subjects with hSBA ≥ 1:8 ranged from 77% to 100% across serogroups and geometric mean titers were 2.5- to 8-fold higher than prebooster values across serogroups. CONCLUSIONS: Booster vaccination with MenACWY-CRM elicited a robust immune response during the 2-year follow-up period, irrespective of previous vaccination.

Comparison of the safety, tolerability, and immunogenicity of a MF59-adjuvanted influenza vaccine and a non-adjuvanted influenza vaccine in non-elderly adults.

The adjuvanted influenza vaccine FLUAD is composed of subunit influenza antigens combined with the MF59-adjuvant emulsion. The vaccine was developed primarily for use in elderly populations, but non-elderly individuals might also benefit. To evaluate this hypothesis, 301 healthy adults were assigned randomly to receive two intramuscular injections of either FLUAD (150 subjects) or a non-adjuvanted vaccine, Fluzone (151 subjects), in two trials conducted at a 1-year interval. Injections consisted of 15 micrograms per 0.5 ml dose. Vaccine composition was A/Texas/36/91 (H1N1), A/Johannesburg/33/94 (H3N2), and B/Harbin/7/94 for the first injection and A/Texas/36/91 (H1N1), A/Nanchang/933/95 (H3N2), and B/Harbin/7/94 for the second injection. Immunogenicity was evaluated at 28 and 180 days post-immunization. FLUAD was generally well tolerated in healthy adults when compared with Fluzone. FLUAD was associated with increased pain at the injection site after immunization. A statistically significant increase in the incidence of injection-site warmth, chills, myalgia, and analgesic/antipyretic use occurred in the FLUAD group after the first injection but not after the second injection. In both groups, most of these local and systemic reactions were classified as mild. FLUAD was more immunogenic than Fluzone following both injections. After the first injection, statistically significant differences were found in the percentage of subjects with four-fold rises in hemagglutinin inhibition (HI) titers at 28 days post-immunization for the B antigen. After the second injection, the FLUAD group had significantly higher HI titers, a significantly higher percentage with a four-fold increase in titer, and a significantly greater percentage of subjects with titers >/=160 for the H3N2 antigen at 28 days. Only minor immunogenicity differences between the two groups were seen at 180 days. Compared with Fluzone, FLUAD was associated with increased immunogenicity and mild post-immunization reactions in healthy adults. The magnitude of increased immunogenicity in healthy adults was less than that seen in elderly populations.