Analyse des déterminants et modélisation de la réponse immunitaire post-vaccination dans les stratégies vaccinales expérimentales

Specific methodological challenges exist in vaccine clinical trials, due principally to specificities of vaccine development, clinical trial design, absence of validate correlate of protection, and complexities of new immunological assays for evaluating immunogenicity of vaccine candidates. These require methodological research to define the most appropriate methods. This thesis focuses on methodological research to optimize methods used in the clinical development of vaccines, especially to propose and develop statistical methods to model immunogenicity, using HIV and Ebola vaccine clinical trials as an example.We first investigated the dynamics of the immune responses post-vaccination and showed that early sampling time points should be considered in future clinical trials to better understand the role of the early CD4 helper T cells and to evaluate their predictive role in the immune response to vaccines. Then, we developed a new bivariate modelling approach for the analysis of the cellular immune response (assessed by intracellular cytokine staining, ICS) that showed good statistical performances and should become the new statistical standard method for ICS analyses invaccine trials. This work will have a direct impact on the assessment on the ICS response in vaccine clinical trials. Regarding the humoral response, we showed that there are still significant uncertainties in the determinants of the antibody response after preventive vaccination against Ebola virus disease. This emphasizes the interest of harmonizing measurement methods and study designs. Furthermore, it indicates the need of randomized multi arm Ebola vaccine trials for accurate comparison of immunogenicity between different vaccine strategies. Finally, we presented the methodology of an international randomized phase 2 trial against Ebola, and in particular a methodological and ethical reflection related to the enrollment of study personnel in Ebola vaccine trial in a nonepidemic context. Methods developed in this thesis will contribute to improve the design and analysis of future vaccine trials, and also could be transposable more widely to other research domains.Les essais cliniques de vaccins posent des défis méthodologiques particuliers, principalement liés à la spécificité du développement des vaccins, les schémas des essais cliniques, de l'absence d'un corrélat de protection validé et de la complexité des techniques immunologiques évaluant l'immunogénicité des candidats vaccins. Celles-ci nécessitent des recherches méthodologiques pour définir les méthodes les plus appropriées. Cette thèse porte sur la recherche méthodologique visant à optimiser les méthodes utilisées dans le développement clinique des vaccins,notamment pour proposer et développer des méthodes statistiques de modélisation de l'immunogénicité, en prenant comme exemple les essais cliniques des vaccins contre le VIH et le virus Ebola. Nous avons d'abord étudié la dynamique des réponses immunitaires après la vaccination et montré qu'il faudrait tenir compte des temps de mesure précoce dans les futurs essais cliniques pour mieux comprendre le rôle des lymphocytes T CD4 auxiliaires et évaluer leur rôle prédictif dans la réponse immunitaire aux vaccins. Ensuite, nous avons développé une nouvelle approche de modélisation bivariée pour l'analyse de la réponse cellulaire mesurée par la technique de cytométrie en flux de marquage des cytokines intracellulaires (ICS). Cette nouvelle méthode amontré de très bonnes performances statistiques et devrait devenir la nouvelle méthode statistique standard pour les analyses ICS dans les essais vaccinaux. Ce travail aura un impact direct sur l'évaluation de la réponse du ICS dans les essais cliniques de vaccins. En ce qui concerne la réponse humorale, nous avons montré qu'il subsiste des incertitudes importantes sur les déterminants de la réponse anticorps après une vaccination préventive contre le virus Ebola. Cela met l'accent sur l'intérêt d'harmoniser les méthodes de mesure et les schémas d'étude. De plus, il indique le besoin de mettre en place des essais cliniques randomisés à bras multiples sur le vaccin contre le virus Ebola pour une comparaisonprécise de l'immunogénicité entre les différentes stratégies vaccinales. Nous avons présenté enfin la méthodologie d’un essai randomisé de phase 2 contre le virus Ebola évaluant trois stratégies vaccinales dans quatre pays d’Afrique de l’Ouest, et plus particulièrement pour finir une réflexion méthodologique et éthique sur la question de l’inclusion des personnels de l’essai dans un essai clinique vaccinale contre le virus Ebola en période non-épidémique. Les méthodes développées dans le cadre de cette thèse contribueront à améliorer la conception et l'analyse desfuturs essais vaccinaux, et pourraient également être transposées plus largement à d'autres domaines de recherche

Efficacy of an online video to promote health insurance literacy among students

This study describes the production and evaluation of an online video explaining health insurance functioning to university students in France. The video was produced by a multidisciplinary team following a design thinking approach. A qualitative evaluation was performed using semi-structured interviews with 30 students. Results showed that, after watching the video, students had remarkably improved their knowledge and obtained clear information on health insurance functioning. This study underscores the importance of using innovative digital communication tools to efficaciously promote health insurance literacy

Enrolling study personnel in Ebola vaccine trials: from guidelines to practice in a non-epidemic context.

BACKGROUND: Enrolling participants in clinical trials can be challenging, especially with respect to prophylactic vaccine trials. The vaccination of study personnel in Ebola vaccine trials during the 2014-2016 epidemic played a crucial role in inspiring trust and facilitating volunteer enrollment. We evaluated the ethical and methodological considerations as they applied to an ongoing phase 2 randomized prophylactic Ebola vaccine trial that enrolled healthy volunteers in Guinea, Liberia, Sierra Leone, and Mali in a non-epidemic context. METHODS: On the assumption that the personnel on site involved in executing the protocol, as well as community mobilizers (not involved in the on-site procedures), might also volunteer to enter the trial, we considered both ethical and methodological considerations to set clear rules that can be shared a priori with these persons. We reviewed the scientific and gray literature to identify relevant references and then conducted an analysis of the ethical and methodological considerations. RESULTS: There are currently no regulations preventing a clinical investigator or site staff from participating in a trial. However, the enrollment of personnel raises the risk of undue influence and challenges the basic ethical principle of voluntary participation. The confidentiality of personal medical information, such as HIV test results, may also be difficult to ensure among personnel. There is a risk of disruption of trial operations due to the potential absence of the personnel for their commitment as trial participants, and there is also a potential for introducing differential behavior of on-site staff as they obtain access to accumulating information during the trial (e.g., the incidence of adverse events). Blinding could be jeopardized, given knowledge of product-specific adverse event profiles and the proximity to unblinded site staff. These aspects were considered more relevant for on-site staff than for community mobilizers, who have limited contact with site staff. CONCLUSION: In a non-epidemic context, ethical and methodological considerations limit the collective benefit of enrolling site staff in a vaccine trial. These considerations do not apply to community mobilizers, whose potential enrollment should be considered as long as they meet the inclusion criteria and they are not exposed to any form of coercion

Trials

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

Trials

OBJECTIVES: To assess the efficacy of several repurposed drugs to prevent hospitalisation or death in patients aged 65 or more with recent symptomatic SARS-CoV-2 infection (COVID-19) and no criteria for hospitalisation. TRIAL DESIGN: Phase III, multi-arm (5) and multi-stage (MAMS), randomized, open-label controlled superiority trial. Participants will be randomly allocated 1:1:1:1:1 to the following strategies: Arm 1: Control arm Arms 2 to 5: Experimental treatment arms Planned interim analyses will be conducted at regular intervals. Their results will be reviewed by an Independent Data and Safety Monitoring Board. Experimental arms may be terminated for futility, efficacy or toxicity before the end of the trial. New experimental arms may be added if new evidence suggests that other treatments should be tested. A feasibility and acceptability substudy as well as an immunological substudy will be conducted alongside the trial. PARTICIPANTS: Inclusion criteria are: 65-year-old or more; Positive test for SARS-CoV-2 on a nasopharyngeal swab; Symptoms onset within 3 days before diagnosis; No hospitalisation criteria; Signed informed consent; Health insurance. Exclusion criteria are: Inability to make an informed decision to participate (e.g.: dementia, guardianship); Rockwood Clinical Frailty Scale ≥7; Long QT syndrome; QTc interval > 500 ms; Heart rate 5.5 mmol/L or <3.5 mmol/L; Ongoing treatment with piperaquine, halofantrine, dasatinib, nilotinib, hydroxyzine, domperidone, citalopram, escitalopram, potent inhibitors or inducers of cytochrome P450 CYP3A4 isoenzyme, repaglinide, azathioprine, 6-mercaptopurine, theophylline, pyrazinamide, warfarin; Known hypersensitivity to any of the trial drugs or to chloroquine and other 4-aminoquinolines, amodiaquine, mefloquine, glafenine, floctafenine, antrafenine, ARB; Hepatic porphyria; Liver failure (Child-Pugh stage ≥B); Stage 4 or 5 chronic kidney disease (GFR <30 mL/min/1.73 m²); Dialysis; Hypersentivity to lactose; Lactase deficiency; Abnormalities in galactose metabolism; Malabsorption syndrome; Glucose-6-phosphate dehydrogenase deficiency; Symptomatic hyperuricemia; Ileus; Colitis; Enterocolitis; Chronic hepatitis B virus disease. The trial is being conducted in France in the Bordeaux, Corse, Dijon, Nancy, Paris and Toulouse areas as well as in the Grand Duchy of Luxembourg. Participants are recruited either at home, nursing homes, general practices, primary care centres or hospital outpatient consultations. INTERVENTION AND COMPARATOR: The four experimental treatments planned in protocol version 1.2 (April 8(th), 2020) are: (1) Hydroxychloroquine 200 mg, 2 tablets BID on day 0, 2 tablets QD from day 1 to 9; (2) Imatinib 400 mg, 1 tablet QD from day 0 to 9; (3) Favipiravir 200 mg, 12 tablets BID on day 0, 6 tablets BID from day 1 to 9; (4) Telmisartan 20 mg, 1 tablet QD from day 0 to 9. The comparator is a complex of vitamins and trace elements (AZINC Forme et Vitalité®), 1 capsule BID for 10 days, for which there is no reason to believe that they are active on the virus. In protocol version 1.2 (April 8th, 2020): People in the control arm will receive a combination of vitamins and trace elements; people in the experimental arms will receive hydroxychloroquine, or favipiravir, or imatinib, or telmisartan. MAIN OUTCOME: The primary outcome is the proportion of participants with an incidence of hospitalisation and/or death between inclusion and day 14 in each arm. RANDOMISATION: Participants are randomized in a 1:1:1:1:1 ratio to each arm using a web-based randomisation tool. Participants not treated with an ARB or ACEI prior to enrolment are randomized to receive the comparator or one of the four experimental drugs. Participants already treated with an ARB or ACEI are randomized to receive the comparator or one of the experimental drugs except telmisartan (i.e.: hydroxychloroquine, imatinib, or favipiravir). Randomisation is stratified on ACEI or ARBs treatment at inclusion and on the type of residence (personal home vs. nursing home). BLINDING (MASKING): This is an open-label trial. Participants, caregivers, investigators and statisticians are not blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 1057 participants will be enrolled if all arms are maintained until the final analysis and no additional arm is added. Three successive futility interim analyses are planned, when the number of participants reaches 30, 60 and 102 in the control arm. Two efficacy analyses (interim n°3 and final) will be performed successively. TRIAL STATUS: This describes the Version 1.2 (April 8(th), 2020) of the COVERAGE protocol that was approved by the French regulatory authority and ethics committee. The trial was opened for enrolment on April 15(th), 2020 in the Nouvelle Aquitaine region (South-West France). Given the current decline of the COVID-19 pandemic in France and its unforeseeable dynamic in the coming months, new trial sites in 5 other French regions and in Luxembourg are currently being opened. A revised version of the protocol was submitted to the regulatory authority and ethics committee on June 15(th), 2020. It contains the following amendments: (i) Inclusion criteria: age ≥65 replaced by age ≥60; time since first symptoms <3 days replaced by time since first symptoms <5 days; (ii) Withdrawal of the hydroxychloroquine arm (due to external data); (iii) increase in the number of trial sites. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on April 22(nd), 2020 (Identifier: NCT04356495): and on EudraCT on April 10(th), 2020 (Identifier: 2020-001435-27). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2)

Correction to: 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.

Following the publication of the original article [1], we were notified of an error in the affiliation of 3 authors of the article: Celine Roy, Laura Richert and Genevieve Chene. Their affiliation was initially mentioned as: “Partnership for Research on Ebola Virus in Liberia (PREVAIL), Monrovia, Liberia” However, their correct affiliation is: Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, CHU Bordeaux, CIC 1401, EUCLID/F-CRIN Clinical Trials Platform, F-33000, Bordeaux, France.tp

Efficacy of an online video to promote health insurance literacy among students

This study describes the production and evaluation of an online video explaining health insurance functioning to university students in France. The video was produced by a multidisciplinary team following a design thinking approach. A qualitative evaluation was performed using semi-structured interviews with 30 students. Results showed that, after watching the video, students had remarkably improved their knowledge and obtained clear information on health insurance functioning. This study underscores the importance of using innovative digital communication tools to efficaciously promote health insurance literacy

Recent developments in clinical trial designs for HIV vaccine research.

International audienceHIV vaccine strategies are expected to be a crucial component for controlling the HIV epidemic. Despite the large spectrum of potential candidate vaccines for both prophylactic and therapeutic use, the overall development process of an efficacious HIV vaccine strategy is lengthy. The design of clinical trials and the progression of a candidate strategy through the different clinical development stages remain methodologically challenging, mainly due to the lack of validated correlates of protection. In this review, we describe recent advances in clinical trial designs to increase the efficiency of the clinical development of candidate HIV vaccine strategies. The methodological aspects of the designs for early- (phase I and II) and later -stage (phase IIB and III) development are discussed, taking into account the specificities of both prophylactic and therapeutic HIV vaccine development