Immunogenicity and Safety of an MF59-adjuvanted Quadrivalent Seasonal Influenza Vaccine in Young Children at High Risk of Influenza-associated Complications: A Phase III, Randomized, Observer-blind, Multicenter Clinical Trial.

BACKGROUND: Vaccination against seasonal influenza is recommended for all children with a history of medical conditions placing them at increased risk of influenza-associated complications. The immunogenicity and efficacy of conventional influenza vaccines among young children are suboptimal; one strategy to enhance these is adjuvantation. We present immunogenicity and safety data for an MF59-adjuvanted quadrivalent influenza vaccine (aIIV4) in healthy children and those at a high risk of influenza-associated complications, based on the results of a recently completed phase III study. METHODS: Children 6 months to 5 years of age (N = 10,644) were enrolled. The study was conducted across northern hemisphere seasons 2013-2014 and 2014-2015. Subjects received either aIIV4 or a nonadjuvanted comparator influenza vaccine. Antibody responses were assessed by hemagglutination inhibition assay against vaccine and heterologous strains. Long-term antibody persistence was assessed (ClinicalTrials.gov: NCT01964989). RESULTS: aIIV4 induced significantly higher antibody titers than nonadjuvanted vaccine in high-risk subjects. aIIV4 antibody responses were of similar magnitude in high-risk and healthy subjects. Incidence of solicited local and systemic adverse events (AEs) was slightly higher in aIIV4 than nonadjuvanted vaccinees, in both the healthy and high-risk groups. Incidence of unsolicited AEs, serious AEs and AEs of special interest were similar for adjuvanted and nonadjuvanted vaccinees in the healthy and high-risk groups. CONCLUSION: aIIV4 was more immunogenic than nonadjuvanted vaccine in both the healthy and high-risk study groups. The reactogenicity and safety profiles of aIIV4 and the nonadjuvanted vaccine were acceptable and similar in 6-month- to 5-year-old high-risk and healthy children.

Efficacy, immunogenicity, and safety evaluation of an MF59-adjuvanted quadrivalent influenza virus vaccine compared with non-adjuvanted influenza vaccine in children: a multicentre, randomised controlled, observer-blinded, phase 3 trial.

BACKGROUND: Young children have immature immune systems and respond poorly to standard influenza vaccines. The oil-in-water emulsion adjuvant MF59 can increase antigen uptake, macrophage recruitment, lymph node migration, and avidity to influenza virus. Therefore, we aimed to assess the relative efficacy, immunogenicity, and safety of an MF59-adjuvanted, quadrivalent, inactivated (subunit) influenza vaccine (aIIV4) compared with a US-licensed non-adjuvanted influenza vaccine in children. METHODS: We did a multicentre, randomised controlled, observer-blinded, phase 3 trial of 146 sites including hospitals, clinics, and clinician offices in nine countries over two influenza seasons. We included children of either sex aged 6 months through 5 years. We stratified eligible participants and randomly assigned them (1:1), using a block size of four, to receive either aIIV4 or non-adjuvanted inactivated influenza vaccine (ie, trivalent inactivated influenza vaccine [IIV3] or quadrivalent inactivated influenza vaccine [IIV4]). We masked participants, parents or guardians, and outcome assessors to the administered vaccine. Designated personnel who were not masked administered aIIV4 in both seasons, or IIV3 in season one and IIV4 in season two. All vaccinations were administered intramuscularly. Children aged 6 through 35 months received one or two 0·25 mL doses, whereas those aged 3 through 5 years received one or two doses of 0·5 mL. The number of doses was dependent on previous vaccination status: vaccine-naive participants received a total of two doses of study vaccine, the first on day 1 and the second on day 29, whereas non-naive participants received only one dose on day 1. The primary outcome was relative vaccine efficacy assessed by RT-PCR-confirmed influenza due to any influenza strain in the overall study population and in prespecified age and dose subgroups. Immunogenicity against homologous and heterologous strains of influenza and safety were also measured. This study is registered with ClinicalTrials.gov, number NCT01964989. FINDINGS: Between Nov 3, 2013, and March 5, 2014 (season one), and between Sept 30, 2014, and March 29, 2015 (season two), 10 644 participants were enrolled in this study. Of these participants, 10 612 were vaccinated (n=5338 with aIIV4 and n=5274 with comparator). Relative vaccine efficacy was not different between aIIV4 and the comparator vaccines in the overall study population (relative vaccine efficacy -0·67, 95% CI -19·81 to 15·41). The relative vaccine efficacy in the 6 through 23-month subgroup was significantly greater for aIIV4 than for the comparator vaccine (relative vaccine efficacy 31·37, 95% CI 3·14-51·38). aIIV4 elicited superior immunogenic response compared with the comparator for all four vaccine strains (geometric mean titre ratios 1·91 [95% CI 1·8-2·0] for A/H1N1, 1·71 [1·6-1·8] for A/H3N2, 2·19 [2·0-2·4] for B/Yamagata, and 2·27 [2·0-2·6] for B/Victoria) and three heterologous strains (1·94 [1·6-2·3] for A/H3N2, 2·17 [1·8-2·6] for B/Yamagata, and 2·12 [1·6-2·7] for B/Victoria) in participants aged 6 months through 5 years. The highest geometric mean titre ratios were observed in participants aged 6 through 23 months. Safety profiles were similar but more frequent solicited adverse events were reported with aIIV4 than with the comparator (3748 [73%] of 5138 vs 3242 [64%] of 5056). INTERPRETATION: Although there was no additional benefit of aIIV4 compared with the US-licensed non-adjuvanted influenza vaccines in the overall study population, in the youngest and most vulnerable population of children in this trial, aIIV4 provided greater protection against influenza than a non-adjuvanted vaccine when assessed in this prespecified age group of 6 through 23 months. Additional clinical benefit was also apparent early after first vaccination in vaccine-naive participants aged 6 months through 5 years. Finally, aIIV4 and comparator had similar efficacy and vaccine safety profiles in children aged 6 months through 5 years. FUNDING: Seqirus UK Ltd.

Kinetics and dynamics of the peripheral neurokinin-1 receptor antagonist SLV317 in healthy individuals.

AIMS: To investigate the pharmacokinetics and the pharmacodynamic effects in dorsal hand veins of the neurokinin-1 receptor antagonist SLV317. METHODS: In a randomized, double-blind, placebo-controlled cross-over study 19 healthy men received a single oral dose of SLV317 or placebo. Blood samples were collected for analysis of SLV317 plasma concentrations and the inhibition of the venodilator response to substance P was evaluated using the hand vein compliance method. RESULTS: Administration of 250 mg SLV317 as an oral solution was well tolerated and resulted in mean peak plasma concentrations (+/- SEM) of 77 +/- 9 ng ml(-1) within 47 +/- 3 min; the mean half-life was 9.9 +/- 1.6 h. In hand veins preconstricted with phenylephrine, local infusion of substance P resulted in a mean venodilation of 56 +/- 8% and 49 +/- 6% (P = 0.91) before administration of SLV317 or placebo, respectively. SLV317 caused a substantial inhibition of substance P-induced venodilation, whereas placebo had no effect (P < 0.001). The maximum antagonizing effect of SLV317 averaged 95 +/- 8% and was observed after 1.47 +/- 00.24 h. Correspondingly, the mean area under the effect curve after administration of SLV317 [278 +/- 67% h(-1); 95% confidence interval (CI) 198, 358] was significantly higher compared with placebo (49 +/- 12% h(-1); 95% CI -24, 122; P < 0.001). CONCLUSIONS: This study demonstrates that the neurokinin-1 receptor antagonist SLV317 is an orally active and highly effective antagonist of substance P-induced effects in humans.