Caractérisation d'un nouveau gène suppresseur de tumeur hSNF5/INI1 impliqué dans les tumeurs rhabdoïdes malignes

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

A Phase I, Open-Label Trial, Evaluating the Safety and Immunogenicity of Candidate Tuberculosis Vaccines AERAS-402 and MVA85A, Administered by Prime-Boost Regime in BCG-Vaccinated Healthy Adults

<div><p>Background</p><p>MVA85A and AERAS-402 are two clinically advanced viral vectored TB vaccine candidates expressing <i>Mycobacterium tuberculosis</i> antigens designed to boost BCG-induced immunity. Clinical trials with candidate malaria vaccines have demonstrated that adenoviral vector based priming immunisation, followed by MVA vector boost, induced high levels of immunity. We present the safety and immunogenicity results of the first clinical trial to evaluate this immunisation strategy in TB.</p><p>Methods</p><p>In this phase 1, open-label trial, 40 healthy previously BCG-vaccinated participants were enrolled into three treatment groups and vaccinated with 1 or 2 doses of AERAS-402 followed by MVA85A; or 3 doses of AERAS-402.</p><p>Results</p><p>Most related adverse events (AEs) were mild and there were no vaccine related serious AEs. Boosting AERAS-402 with MVA85A significantly increased Ag85A-specific T-cell responses from day of vaccination. Two priming doses of AERAS-402 followed by MVA85A boost, resulted in a significantly higher AUC post-peak Ag85A response compared to three doses of AERAS-402 and historical data with MVA85A vaccination alone. The frequency of CD8+ T-cells producing IFN-γ, TNF-α and IL-2 was highest in the group receiving two priming doses of AERAS-402 followed by MVA85A.</p><p>Conclusions</p><p>Vaccination with AERAS-402 followed by MVA85A was safe and increased the durability of antigen specific T-cell responses and the frequency and polyfunctionality of CD8+ T-cells, which may be important in protection against TB. Further clinical trials with adenoviral prime-MVA85A boost regimens are merited to optimise vaccination intervals, dose and route of immunisation and to evaluate this strategy in the target population in TB high burden countries.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01683773" target="_blank">NCT01683773</a>.</p></div

Ad35.CS.01-RTS,S/AS01 Heterologous Prime Boost Vaccine Efficacy against Sporozoite Challenge in Healthy Malaria-Naïve Adults.

In an observer blind, phase 2 trial, 55 adults were randomized to receive one dose of Ad35.CS.01 vaccine followed by two doses of RTS,S/AS01 (ARR-group) or three doses of RTS,S/AS01 (RRR-group) at months 0, 1, 2 followed by controlled human malaria infection.ARR and RRR vaccine regimens were well tolerated. Efficacy of ARR and RRR groups after controlled human malaria infection was 44% (95% confidence interval 21%-60%) and 52% (25%-70%), respectively. The RRR-group had greater anti-CS specific IgG titers than did the ARR-group. There were higher numbers of CS-specific CD4 T-cells expressing > 2 cytokine/activation markers and more ex vivo IFN-γ enzyme-linked immunospots in the ARR-group than the RRR-group. Protected subjects had higher CS-specific IgG titers than non-protected subjects (geometric mean titer, 120.8 vs 51.8 EU/ml, respectively; P = .001).An increase in vaccine efficacy of ARR-group over RRR-group was not achieved. Future strategies to improve upon RTS,S-induced protection may need to utilize alternative highly immunogenic prime-boost regimens and/or additional target antigens.ClinicalTrials.gov NCT01366534

Ex-<i>vivo</i> IFN-γ ELISpot vector responses.

<p>Responses to MVA peptides for CD4+ (A), and CD8+ T-cell epitopes (B) and summed responses to 3 pools of adenovirus peptides (C) in BCG-vaccinated, healthy adults for Group A (AERAS-402, AERAS-402, MVA85A), Group B (AERAS-402, MVA85A) and Group C (AERAS-402, AERAS-402, AERAS-402). Box and whisker plots show median, inter-quartile range, minimum and maximum values. Stars denote significant changes in responses after vaccination (Wilcoxon matched pairs) * p = < 0.05, ** p = < 0.01, *** p = < 0.001, ns = not significant.</p

A Phase 1b Randomized, Controlled, Double-Blinded Dosage-Escalation Trial to Evaluate the Safety, Reactogenicity and Immunogenicity of an Adenovirus Type 35 Based Circumsporozoite Malaria Vaccine in Burkinabe Healthy Adults 18 to 45 Years of Age

<div><p>Background</p><p>Ad35.CS.01 is a pre-erythrocytic malaria candidate vaccine. It is a codon optimized nucleotide sequence representing the <i>P. falciparum</i> circumsporozoite (CS) surface antigen inserted in a replication deficient Adenovirus 35 backbone. A Phase 1a trial has been conducted in the USA in naïve adults and showed that the vaccine was safe. The aim of this study is to assess the safety and immunogenicity of ascending dosages in sub Saharan Africa.</p> <p>Methods</p><p>A double blind, randomized, controlled, dose escalation, phase Ib trial was conducted in a rural area of Balonghin, the Saponé health district (Burkina Faso). Forty-eight healthy adults aged 18-45 years were randomized into 4 cohorts of 12 to receive three vaccine doses (day 0, 28 and 84) of 10⁹, 10¹⁰, 5X10¹⁰, 10¹¹ vp of Ad35.CS.01 or normal saline by intra muscular injection. Subjects were monitored carefully during the 14 days following each vaccination for non serious adverse events. Severe and serious adverse events were collected throughout the participant study duration (12 months from the first vaccination). Humoral and cellular immune responses were measured on study days 0, 28, 56, 84, 112 and 140.</p> <p>Results</p><p>Of the forty-eight subjects enrolled, forty-four (91.7%) received all three scheduled vaccine doses. Local reactions, all of mild severity, occurred in thirteen (27.1%) subjects. Severe (grade 3) laboratory abnormalities occurred in five (10.4%) subjects. One serious adverse event was reported and attributed to infection judged unrelated to vaccine. The vaccine induced both antibody titers and CD8 T cells producing IFNγ and TNFα with specificity to CS while eliciting modest neutralizing antibody responses against Ad35.</p> <p>Conclusion</p><p>Study vaccine Ad35.CS.01 at four different dose levels was well-tolerated and modestly immunogenic in this population. These results suggest that Ad35.CS.01 should be further investigated for preliminary efficacy in human challenge models and as part of heterologous prime-boost vaccination strategies.</p> <p>Trial Registration</p><p><a href="http://clinicaltrials.gov" target="_blank">ClinicalTrials.gov</a> NCT01018459 <a href="http://clinicaltrials.gov/ct2/show/nct01018459" target="_blank"><u>http://clinicaltrials.gov/ct2/show/NCT01018459</u></a></p> </div

Demographics of enrolled subjects.

<p>Abbreviations: BCG, Bacillus Calmette–Guérin; BMI, Body mass index.</p><p>Demographics of enrolled subjects.</p

Total intracellular cytokine responses.

<p>Total intracellular cytokine responses are presented as percentages of CD4+ T-cells or CD8+ T-cells producing mycobacteria-specific IFN-γ, TNF-α and IL-2 cytokines. Percentage of CD4+ (A, C and E) and CD8+ (B, D and F) responses in peripheral blood mononuclear cells to stimulation with Ag85A (A and B), Ag85B (C and D) and TB10.4 (E and F) peptides in healthy, BCG-vaccinated adults from Group A (AAM, green line), Group B (AM, blue line), Group C (AAA, red line) and TB022 (M, black line). Lines show median responses in each group, whiskers show inter-quartile range.</p

<i>Ex-vivo</i> IFN-γ ELISpot insert responses.

<p>Responses to Ag85A (A), Ag85B (B) and TB10.4 (C) in BCG-vaccinated, healthy adults for Group A (AERAS-402, AERAS-402, MVA85A), Group B (AERAS-402, MVA85A) and Group C (AERAS-402, AERAS-402, AERAS-402). Responses to Ag85A are also shown from TB022 (MVA85A). Box and whisker plots show median, inter-quartile range, minimum and maximum values. Stars denote significant changes in responses after vaccination (Wilcoxon matched pairs) * p = < 0.05, ** p = < 0.01, *** p = < 0.001, ns = not significant.</p

The numbers of subjects within each group reporting each related adverse event.

<p>Local adverse events that were reported twice by individual subjects (8 adverse events) in the seven day diary card period are included in the summary adverse event <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0141687#pone.0141687.t002" target="_blank">Table 2</a>.</p><p>All related adverse events were reported during the seven day diary card period apart from one volunteer who reported axillary tenderness at day 20 post second AERAS-402 vaccination which was deemed possibly related to vaccination. Abbreviations: AEs, adverse events; ALT, alanine transaminase; AST, aspartate aminotransferase.</p><p>The numbers of subjects within each group reporting each related adverse event.</p

Serum antibody responses.

<p>Serum antibody responses to Ag85A (A), Ag85B (B) and TB10.4 (C) in the three study groups; Group A (AERAS-402, AERAS-402, MVA85A), Group B (AERAS-402, MVA85A) and Group C (AERAS-402, AERAS-402, AERAS-402). Antibody responses were measured in optical density (OD), data is presented as fold change responses calculated by dividing each time point’s antibody response by its corresponding day 0 response. Box and whisker plots show median, inter-quartile range, minimum and maximum values. Stars denote significant changes in responses after vaccination (Wilcoxon matched pairs) * p = < 0.05, ** p = < 0.01, *** p = < 0.001, ns = not significant.</p