Safety and immunogenicity of the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in infants: a phase 2, randomised, double-blind, active-controlled trial in Guinea and Sierra Leone.

BACKGROUND: This study assessed the safety and immunogenicity of the Ad26.ZEBOV and MVA-BN-Filo Ebola virus (EBOV) vaccine regimen in infants aged 4-11 months in Guinea and Sierra Leone. METHODS: In this phase 2, randomised, double-blind, active-controlled trial, we randomly assigned healthy infants (1:1 in a sentinel cohort, 5:2 for the remaining infants via an interactive web response system) to receive Ad26.ZEBOV followed by MVA-BN-Filo (Ebola vaccine group) or two doses of meningococcal quadrivalent conjugate vaccine (control group) administered 56 days apart. Infants were recruited at two sites in west Africa: Conakry, Guinea, and Kambia, Sierra Leone. All infants received the meningococcal vaccine 8 months after being randomly assigned. The primary objective was safety. The secondary objective was immunogenicity, measured as EBOV glycoprotein-binding antibody concentration 21 days post-dose 2, using the Filovirus Animal Non-Clinical Group ELISA. This study is registered with ClinicalTrials.gov (NCT03929757) and the Pan African Clinical Trials Registry (PACTR201905827924069). FINDINGS: From Aug 20 to Nov 29, 2019, 142 infants were screened and 108 were randomly assigned (Ebola vaccine n=75; control n=33). The most common solicited local adverse event was injection-site pain (Ebola vaccine 15 [20%] of 75; control four [12%] of 33). The most common solicited systemic adverse events with the Ebola vaccine were irritability (26 [35%] of 75), decreased appetite (18 [24%] of 75), pyrexia (16 [21%] of 75), and decreased activity (15 [20%] of 75). In the control group, ten (30%) of 33 had irritability, seven (21%) of 33 had decreased appetite, three (9%) of 33 had pyrexia, and five (15%) of 33 had decreased activity. The frequency of unsolicited adverse events was 83% (62 of 75 infants) in the Ebola vaccine group and 85% (28 of 33 infants) in the control group. No serious adverse events were vaccine-related. In the Ebola vaccine group, EBOV glycoprotein-binding antibody geometric mean concentrations (GMCs) at 21 days post-dose 2 were 27 700 ELISA units (EU)/mL (95% CI 20 477-37 470) in infants aged 4-8 months and 20 481 EU/mL (15 325-27 372) in infants aged 9-11 months. The responder rate was 100% (74 of 74 responded). In the control group, GMCs for both age groups were less than the lower limit of quantification and the responder rate was 3% (one of 33 responded). INTERPRETATION: Ad26.ZEBOV and MVA-BN-Filo was well tolerated and induced strong humoral responses in infants younger than 1 year. There were no safety concerns related to vaccination. FUNDING: Janssen Vaccines & Prevention and Innovative Medicines Initiative 2 Joint Undertaking. TRANSLATION: For the French translation of the abstract see Supplementary Materials section

Les encéphalites grave en réanimation pédiatrique : étude descriptive sur 37 cas au centre hospitalier de Rouen

L'encéphalite aiguë est une pathologie neurologique rare et potentiellement grave causée par à une inflammation du parenchyme cérébral. En 2013, des critères diagnostiques précis ont été publiés par des experts. Deux formes cliniques existent, l'encéphalite primitive et l'encéphalite immuno-médiée. L'épidémiologie des encéphalites sévères nécessitant une hospitalisation en réanimation pédiatrique a été peu étudiée.L'objectif principal de l'étude était de classer les encéphalites sévères de l'enfant selon le mécanisme physiopathologique et d'étudier les différentes formes cliniques d'encéphalite en réanimation pédiatrique.Nous avons réalisé une étude rétrospective, épidémiologique, descriptive, mono-centrique, des cas d'encéphalites aiguës hospitalisés en réanimation pédiatrique au Centre Hospitalo-Universitaire de Rouen entre janvier 2000 et novembre 2018.Au total, 37 enfants atteints d'une encéphalite aiguë selon les critères de la conférence de consensus ont été hospitalisés. Une étiologie a été posée pour 20 enfants, dont 4 encéphalites primitives et 16 immuno-médiées. Il s'agissait de 10 cas d'encéphalomyélites aiguës disséminées, 7 cas d'encéphalites infectieuses et 3 cas d'encéphalites auto-immunes. Un agent pathogène a été identifié pour 10 enfants, dont 9 germes et 1 anticorps.Une corticothérapie a été mise en place chez 60 % des enfants au cours de leur hospitalisation.Il y a eu deux décès (5 ')/0) au cours de notre étude. Dix-neuf enfants ont présenté des séquelles neurologiques dans les suites de leur hospitalisation, dont 3 cas de séquelles majeures, 7 cas de séquelles importantes et 9 cas de séquelles modérées.La classification des encéphalites aiguës semble essentielle pour mieux comprendre cette maladie et pour mieux orienter son traitement. Notre étude contribue à une meilleure connaissance épidémiologique des encéphalites en réanimation pédiatrique et du devenir des enfants atteints sur le moyen terme

Ifosfamide-induced encephalopathy due to a novel formulation of ifosfamide

International audienc

Partnership for Research on Ebola VACcination (PREVAC): protocol of a randomized, double-blind, placebo-controlled phase 2 clinical trial evaluating three vaccine strategies against Ebola in healthy volunteers in four West African countries

International audienceAbstract Introduction The Ebola virus disease (EVD) outbreak in 2014–2016 in West Africa was the largest on record and provided an opportunity for large clinical trials and accelerated efforts to develop an effective and safe preventative vaccine. Multiple questions regarding the safety, immunogenicity, and efficacy of EVD vaccines remain unanswered. To address these gaps in the evidence base, the Partnership for Research on Ebola Vaccines (PREVAC) trial was designed. This paper describes the design, methods, and baseline results of the PREVAC trial and discusses challenges that led to different protocol amendments. Methods This is a randomized, double-blind, placebo-controlled phase 2 clinical trial of three vaccine strategies against the Ebola virus in healthy volunteers 1 year of age and above. The three vaccine strategies being studied are the rVSVΔG-ZEBOV-GP vaccine, with and without a booster dose at 56 days, and the Ad26.ZEBOV,MVA-FN-Filo vaccine regimen with Ad26.ZEBOV given as the first dose and the MVA-FN-Filo vaccination given 56 days later. There have been 4 versions of the protocol with those enrolled in Version 4.0 comprising the primary analysis cohort. The primary endpoint is based on the antibody titer against the Ebola virus surface glycoprotein measured 12 months following the final injection. Results From April 2017 to December 2018, a total of 5002 volunteers were screened and 4789 enrolled. Participants were enrolled at 6 sites in four countries (Guinea, Liberia, Sierra Leone, and Mali). Of the 4789 participants, 2560 (53%) were adults and 2229 (47%) were children. Those < 18 years of age included 549 (12%) aged 1 to 4 years, 750 (16%) 5 to 11 years, and 930 (19%) aged 12–17 years. At baseline, the median (25th, 75th percentile) antibody titer to Ebola virus glycoprotein for 1090 participants was 72 (50, 116) EU/mL. Discussion The PREVAC trial is evaluating—placebo-controlled—two promising Ebola candidate vaccines in advanced stages of development. The results will address unanswered questions related to short- and long-term safety and immunogenicity for three vaccine strategies in adults and children. Trial registration ClinicalTrials.gov NCT02876328 . Registered on 23 August 2016