Reducing the Burden of Influenza After Solid-Organ Transplantation

Objectives: The primary objective of this study is to compare the immunogenicity of two novel vaccination strategies, consisting in vaccination with a HD influenza vaccine or an MF59a influenza vaccine, to the standard-dose non-adjuvanted vaccination (standard of care) in a population of SOT recipients.

The main secondary objectives are to evaluate the efficacy of the novel vaccination strategies in reducing the incidence of influenza, to correlate the humoral responses to vaccination with protection from influenza and to assess the influence of immunosuppression on influenza vaccine responses.

Safety objectives include the assessment of the reactogenicity of the different vaccines and to describe the incidence of acute rejection and the development of anti-Human Leucocyte Antigens (HLA) antibodies after vaccination.

Study design: Prospective double-blinded randomized controlled three-arm parallel group superiority multicenter trial.

Inclusion / Exclusion criteria: Study participants will be enrolled among ≥18-year old stable SOT recipients ≥3 months after transplantation, regularly followed at their respective outpatient clinic at the 7 transplant centers and scheduled to receive the annual influenza vaccine. Candidates will be excluded in case of previous severe reaction or allergy to one of the study vaccines or in case of treatment for acute rejection, among others.

Measurements and procedures: At day 0, after giving informed consent, eligible patients will be randomized in a 1:1:1 ratio into 3 arms: standard quadrivalent intramuscular vaccine (control), HD trivalent vaccine and MF59a trivalent vaccine. After vaccination participants will be followed for a period of 6 months. Safety will be assessed immediately after vaccination and 7, 28 and 180 days after vaccination, and blood sampling for immunogenicity analysis will be performed at baseline, 7, 28 and 180 days after vaccination. Additionally to evaluate the vaccine safety, anti-HLA antibodies will be measured at baseline and at days 28 and 180 after vaccination. Hemagglutinin titers will be determined by hemagglutination inhibition assay (HIA) according to standardized methods. During the influenza season, the development of influenza will be systematically assessed by polymerase chain reaction (PCR) by surveillance nasopharyngeal swab.

Study Product / Intervention: The study intervention consists in the intramuscular administration of either a HD vaccine (containing 60 µg of antigen of each of the three viral strains) [Fluzone-HD®] or a MF59a vaccine (containing 15 µg of antigen of each of the three viral strains with a MF59 adjuvant) [Fluad®].

Control Intervention: The control intervention consists in the administration of the standard quadrivalent non-adjuvanted intramuscular influenza vaccine (VaxigripTetra®), containing 15 µg of each of the four viral strains.

Number of Participants with Rationale: The investigators plan to enroll 780 patients (260 patients per study group). Sample size was calculated to find a significant difference between the three groups for the primary endpoint. The lowest seroconversion rate of 46% for standard dose, a mid seroconversion rate of 59% with MF59a vaccine, and the highest seroconversion rate of 70% with HD vaccine has been assumed. A 10% drop out rate is assumed and the number of patients has been rounded up to get balanced groups. In each group 260 patients are required which amounts to 780 patients.

Inclusion criteria

• Provision of written, informed consent
• Age ≥18 years
• Stable outpatients based on clinical judgement
• ≥ 3 months after solid organ transplantation

Exclusion criteria

• Known hypersensitivity to any component (antigen, adjuvant, excipient or preservative) of study vaccines; the composition of the study vaccines is as follows:

• VaxigripTetra®: hemagglutinin, egg protein, formaldehyde, octylphenol ethoxylate/octoxynol 9 (Triton® X-100), neomycin
• Fluad®: hemagglutinin, neuraminidase, egg protein, squalene, polysorbate 80, sorbitan trioleate, sodium citrate, citric acid, kanamycin sulphate, neomycin sulphate, barium sulphate, formaldehyde, cetyl trimethylammonium bromide
• Fluzone-HD®: hemagglutinin, egg protein, formaldehyde, octylphenol ethoxylate/octoxynol 9 (Triton® X-100)
• Previous life-threatening reaction to influenza vaccine (i.e. Guillain Barré Syndrome)
• Ongoing therapy for rejection (including steroid pulse or prednisone > 2mg/kg/day over more than 14 days)
• Ongoing therapy with intravenous immunoglobulin (IVIG) and/or eculizumab
• Current or past (within 6 months) therapy with rituximab
• Abo incompatible transplantation
• Unable to comply with study protocol
• Pregnancy or breastfeeding