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Reducing the Burden of Influenza after Solid-Organ Transplantation: the STOP-FLU trial [Swiss Trial in Solid Organ Transplantation on Prevention of influenza]

English title Reducing the Burden of Influenza after Solid-Organ Transplantation: the STOP-FLU trial [Swiss Trial in Solid Organ Transplantation on Prevention of InFLUenza]
Applicant Manuel Oriol
Number 173545
Funding scheme Investigator Initiated Clinical Trials (IICT)
Research institution Service des Maladies Infectieuses Département de Médecine Interne CHUV
Institution of higher education University of Lausanne - LA
Main discipline Internal Medicine
Start/End 01.06.2017 - 30.09.2021
Approved amount 1'651'666.00
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All Disciplines (2)

Discipline
Internal Medicine
Respiratory Diseases

Keywords (6)

Safety; Solid-organ transplantation; Allograft function; Influenza vaccine; Large nested project; STCS

Lay Summary (French)

Lead
En cas de grippe, les patients transplantés d’organes sont à risque accru de complications sévères pouvant aller jusqu’au décès. La vaccination annuelle antigrippale reste la mesure préventive principale et est recommandé par l’OFSP. Malheureusement, les patients transplantés ont une capacité réduite à produire des anticorps en réponse à la vaccination antigrippale. Il est donc important de développer des nouvelles stratégies visant à améliorer l’efficacité du vaccin parmi ces patients.
Lay summary

Contenu et objectifs du travail de recherche 

Nous avons conçu une étude qui évaluera trois stratégies différentes de vaccination antigrippale. L'étude se déroulera dans les six centres de transplantation suisses (Bâle, Berne, Genève, Lausanne, St.-Galle et Zurich) et l’Epatocentro de Lugano. Les patients participants seront repartis en 3 groupes. Le premier groupe (groupe contrôle) recevra une injection intramusculaire du vaccin contre la grippe sans changements par rapport à la pratique habituelle. Les participants attribués aux deux autres groupes recevront soit l’administration d’un vaccin contenant l’adjuvant MF59 par voie intramusculaire, soit l’injection du vaccin par voie intradermique. À la fin de l’étude, le taux d’anticorps produit et la quantité d’effets indésirables survenus seront comparés entre les patients attribués aux différents groupes. 

Contexte scientifique et social du projet de recherche

Cette étude adresse un sujet très important en transplantation et en santé publique: la prévention de la grippe par la vaccination. La comparaison de trois différentes stratégies de vaccination nous permettra de déterminer quelle approche permet d’obtenir une protection optimale contre la grippe. De plus, les résultats de cet essai clinique pourraient également être appliqués à d’autres personnes souffrant d’un affaiblissement du système immunitaire à haut risque de complication en cas de grippe. 

 
Direct link to Lay Summary Last update: 31.05.2017

Responsible applicant and co-applicants

Employees

Project partner

Associated projects

Number Title Start Funding scheme
177522 Swiss Transplant Cohort Study 01.02.2018 Cohort Studies Large
148512 Swiss Transplant Cohort Study 01.02.2014 Cohort Studies Large

Abstract

Background: Respiratory viral infections contribute considerably to the burden of disease among immunocompromised patients. In solid-organ transplant (SOT) recipients, influenza is associated with significant morbidity and may affect allograft function. Influenza vaccination remains the key preventive strategy against influenza, but the immunogenicity of this vaccine is suboptimal in SOT recipients. Several strategies have been evaluated to increase the effect of influenza vaccination in this high-risk population. These include the administration of a booster dose, an intradermal vaccination route, or the use of adjuvanted vaccines, among others. So far, none of these strategies have been assessed in adequately powered trials and thereby it remains unclear which vaccine strategy protects best and is safe in this population. Aims of the study: We will evaluate the efficacy and safety of two novel vaccination strategies with the aim of improving protection against influenza in SOT recipients. Methodology: In this nationwide clinical trial, we will randomize SOT recipients =3 months post transplant (n=780) to receive either 1) the standard inactivated intramuscular influenza vaccine, or 2) the MF59-adjuvanted influenza vaccine or 3) the intradermal influenza vaccine with topical imiquimod gel at the site of vaccination. Imiquimod is an immunomodulatory drug known to increase vaccine responses when used as a topical adjuvant. Patient recruitment will be conducted at all six Swiss transplant centers and in Ticino, in collaboration with the local Clinical Trial Units (CTU). It is estimated that more than 6000 SOT recipients are currently followed at these seven centers. Recruitment will be done over two consecutive influenza seasons (2017/18 and 2018/19). The study will be performed within the frame of the Swiss Transplant Cohort Study (STCS). The existing STCS infrastructure will facilitate the study recrutement and the collection of data.The primary endpoint will be the seroconversion rate to at least one viral strain, defined as a =4-fold increase in hemagglutination-inhibition titers, at day 28 after influenza vaccination. The main secondary endpoint will be the rate of clinical and subclinical influenza (diagnosed by screening and/or clinically-indicated PCR). Safety endpoints will be the development of anti-HLA antibodies, the incidence of acute rejection, and the rates of local and systemic adverse events. For the primary endpoint, the estimated sample size of 260 patients per group will allow us to detect a difference of 11-24% in serocovension rate between groups (0.46 in the standard group, 0.59 in the adjuvanted vaccine group, and 0.70 in the intradermal vaccine with imiquimod group) with a power of 0.80 and an a-level of 0.05 (corrected for multiple testing), assuming a 10% drop-out rate. An increase of 10-20% in seroconversion rate would be considered a clinically significant difference to justify a preferential clinical use of one of these vaccines. Immune responses elicited by influenza vaccine will be assessed in future sub-studies using stored samples, including T-cell and B-cell-mediated immune responses, changes in gene expression profiles, and genetic markers for vaccine response. Significance of research: With this study, we address a highly important topic in modern transplant medicine and public health, i.e. the prevention of influenza through vaccination. The intervention including three different strategies of influenza vaccination will allow us to determine the best vaccine approach for optimal protection against influenza, with a potential immediate application in the clinical practice. In addition, results from this trial could be also applied in other high-risk immunocompromised populations, such as stem-cell transplant recipients or patients receiving biological therapies. The project might further increase our understanding of vaccine-induced immunity by finding novel immune markers for vaccine response.
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