Evaluation of the immunogenicity and safety of different doses and formulations of a broad spectrum influenza vaccine (FLU-v) developed by SEEK: study protocol for a single-center, randomized, double-blind and placebo-controlled clinical phase IIb trial.

BACKGROUND: Current influenza vaccines, based on antibodies against surface antigens, are unable to provide protection against newly emerging virus strains which differ from the vaccine strains. Therefore the population has to be re-vaccinated annually. It is thus important to develop vaccines which induce protective immunity to a broad spectrum of influenza viruses. This trial is designed to evaluate the immunogenicity and safety of FLU-v, a vaccine composed of four synthetic peptides with conserved epitopes from influenza A and B strains expected to elicit both cell mediated immunity (CMI) and humoral immunity providing protection against a broad spectrum of influenza viruses. METHODS: In a single-center, randomized, double-blind and placebo-controlled phase IIb trial, 222 healthy volunteers aged 18-60 years will be randomized (2:2:1:1) to receive two injections of a suspension of 500 µg FLU-v in saline (arm 1), one dose of emulsified 500 µg FLU-v in Montanide ISA-51 and water for injection (WFI) followed by one saline dose (arm 2), two saline doses (arm 3), or one dose of Montanide ISA-51 and WFI emulsion followed by one saline dose (arm 4). All injections will be given subcutaneously. Primary endpoints are safety and FLU-v induced CMI, evaluated by cytokine production by antigen specific T cell populations (flow-cytometry and ELISA). Secondary outcomes are measurements of antibody responses (ELISA and multiplex), whereas exploratory outcomes include clinical efficacy and additional CMI assays (ELISpot) to show cross-reactivity. DISCUSSION: Broadly protective influenza vaccines able to provide protection against multiple strains of influenza are urgently needed. FLU-v is a promising vaccine which has shown to trigger the cell-mediated immune response. The dosages and formulations tested in this current trial are also estimated to induce antibody response. Therefore, both cellular and humoral immune responses will be evaluated. TRIAL REGISTRATION: EudraCT number 2015-001932-38 ; retrospectively registered clinicaltrials.gov NCT02962908 (November 7th 2016).

Influenza vaccine effectiveness estimates in the Dutch population from 2003 to 2014: The test-negative design case-control study with different control groups.

Information about influenza vaccine effectiveness (IVE) is important for vaccine strain selection and immunization policy decisions. The test-negative design (TND) case-control study is commonly used to obtain IVE estimates. However, the definition of the control patients may influence IVE estimates. We have conducted a TND study using the Dutch Sentinel Practices of NIVEL Primary Care Database which includes data from patients who consulted the General Practitioner (GP) for an episode of acute influenza-like illness (ILI) or acute respiratory infection (ARI) with known influenza vaccination status. Cases were patients tested positive for influenza virus. Controls were grouped into those who tested (1) negative for influenza virus (all influenza negative), (2) negative for influenza virus, but positive for respiratory syncytial virus, rhinovirus or enterovirus (non-influenza virus positive), and (3) negative for these four viruses (pan-negative). We estimated the IVE over all epidemic seasons from 2003/2004 through 2013/2014, pooled IVE for influenza vaccine partial/full matched and mismatched seasons and the individual seasons using generalized linear mixed-effect and multiple logistic regression models. The overall IVE adjusted for age, GP ILI/ARI diagnosis, chronic disease and respiratory allergy was 35% (95% CI: 15-48), 64% (95% CI: 49-75) and 21% (95% CI: -1 to 39) for all influenza negative, non-influenza virus positive and pan-negative controls, respectively. In both the main and subgroup analyses IVE estimates were the highest using non-influenza virus positive controls, likely due to limiting inclusion of controls without laboratory-confirmation of a virus causing the respiratory disease.

Influenza Vaccine Effectiveness in the Netherlands from 2003/2004 through 2013/2014: The Importance of Circulating Influenza Virus Types and Subtypes.

Influenza vaccine effectiveness (IVE) varies over different influenza seasons and virus (sub)types/lineages. To assess the association between IVE and circulating influenza virus (sub)types/lineages, we estimated the overall and (sub)type specific IVE in the Netherlands. We conducted a test-negative case control study among subjects with influenza-like illness or acute respiratory tract infection consulting the Sentinel Practices over 11 influenza seasons (2003/2004 through 2013/2014) in the Netherlands. The adjusted IVE was estimated using generalized linear mixed modelling and multiple logistic regression. In seven seasons vaccine strains did not match the circulating viruses. Overall adjusted IVE was 40% (95% CI 18 to 56%) and 20% (95% CI -5 to 38%) when vaccine (partially)matched and mismatched the circulating viruses, respectively. When A(H3N2) was the predominant virus, IVE was 38% (95% CI 14 to 55%). IVE against infection with former seasonal A(H1N1) virus was 83% (95% CI 52 to 94%), and with B virus 67% (95% CI 55 to 76%). In conclusion IVE estimates were particularly low when vaccine mismatched the circulating viruses and A(H3N2) was the predominant influenza virus subtype. Tremendous effort is required to improve vaccine production procedure and to explore the factors that influence the IVE against A(H3N2) virus.

Evaluating the immunogenicity and safety of a BiondVax-developed universal influenza vaccine (Multimeric-001) either as a standalone vaccine or as a primer to H5N1 influenza vaccine: Phase IIb study protocol.

INTRODUCTION: Influenza is a major respiratory viral infection of humans with high mortality and morbidity rates and profound economic impact. Although influenza vaccines are generally updated yearly to match the viruses expected in the coming season, genetic mutation and reassortment can result in unexpected novel strains. Therefore, it is important to develop universal vaccines inducing protective immunity to such strains before they appear. This clinical trial is designed to evaluate the safety and immunogenicity of Multimeric-001 (M-001), which contains conserved epitopes of influenza A and B. M-001 is able to induce both humoral and cellular immunity and provides broad strain coverage. METHODS: In a multicenter, randomized, double-blind, and controlled phase IIb trial, 222 healthy volunteers aged 18 to 60 years will be randomized into 3 groups (1:1:1) to receive either 2 intramuscular injections of 0.5 mg M-001 (arm 1), 1.0 mg M-001 (arm 2), or saline (arm 3-placebo), before receiving an investigational (whole virus, inactivated, aluminum phosphate gel [AlPO4]-adjuvanted) prepandemic influenza vaccine (H5N1). Primary outcomes are safety and cellular immune responses (cell-mediated immunity [CMI]) induced by M-001, evaluated by multiparametric flow cytometry of intracellular cytokines. The secondary outcome is the serum hemagglutination inhibition (HAI) titer toward the H5N1 vaccine strain. Additionally, exploratory outcomes include evaluation of CMI by quantitative reverse transcription polymerase chain reaction of cytokine mRNA, HAI titers toward H5-drifted strains, serum single radial hemolysis titers toward the H5N1 study vaccine, and the association between CMI markers and antibody response. DISCUSSION: There is a need for influenza vaccines that give the population a broader protection against multiple strains of influenza virus. M-001 might be such vaccine which will be tested in this current trial as a standalone vaccine and as a pandemic primer. Both cellular and humoral immune responses will be evaluated. TRIAL REGISTRATION: EudraCT number: 2015-001979-46.

Safety and tolerability evaluation of the use of Montanide ISA™51 as vaccine adjuvant: A systematic review.

Montanide ISA™51 (ISA 51) is a vaccine adjuvant which has been tested in therapeutic and prophylactic vaccine trials. The aim of this review is to present a comprehensive examination of the safety and tolerability of ISA 51 containing vaccines. A systematic literature search was conducted in PubMed, EMBASE and clinicaltrials.gov . Eligible studies were categorized into: (A) uncontrolled studies with non-healthy subjects, (B) controlled studies with non-healthy subjects, and (C) controlled studies with healthy subjects. Reported adverse events (AEs) were assessed. 91 studies were included in our review. Generally observed AEs included injection site reaction; injection site pain; myalgia; headache; gastro-intestinal disorders; fatigue and fever - regardless of the administration route and subject characteristic. Specific AEs, e.g. injection site reactions and rash, were more frequently reported from subjects receiving ISA 51-adjuvanted vaccines than from subjects receiving antigen or ISA 51 only. The reported AEs were mainly mild to moderate in intensity. Serious AEs (SAEs) were reported in 27% of the uncontrolled trials and 2 trials conducted with healthy subjects. Notably, 2 other trials conducted with healthy subjects were stopped due to unacceptable AEs. Some studies indicate that the mixing procedure of antigen and adjuvant might influence the occurrence of AEs. Reports on SAEs and premature termination of 2 trials advise caution when using ISA 51. Yet, AEs might be preventable by proper mixing of vaccine and adjuvant to a stable emulsion. Trials including an active control group are needed for a fair evaluation of adjuvant safety.

Influenza Vaccine Research funded by the European Commission FP7-Health-2013-Innovation-1 project.

Due to influenza viruses continuously displaying antigenic variation, current seasonal influenza vaccines must be updated annually to include the latest predicted strains. Despite all the efforts put into vaccine strain selection, vaccine production, testing, and administration, the protective efficacy of seasonal influenza vaccines is greatly reduced when predicted vaccine strains antigenically mismatch with the actual circulating strains. Moreover, preparing for a pandemic outbreak is a challenge, because it is unpredictable which strain will cause the next pandemic. The European Commission has funded five consortia on influenza vaccine development under the Seventh Framework Programme for Research and Technological Development (FP7) in 2013. The call of the EU aimed at developing broadly protective influenza vaccines. Here we review the scientific strategies used by the different consortia with respect to antigen selection, vaccine delivery system, and formulation. The issues related to the development of novel influenza vaccines are discussed.

National Differences in Requirements for Ethical and Competent Authority Approval for a Multinational Vaccine Trial under the EU Directive 2001/20/EC.

Obtaining approval for a multinational vaccine trial from an ethics committee and the national competent authority of different Member States of the European Union (EU) is challenging under clinical trial Directive 2001/20/EC because of the differences in the implementation of the directive in national laws of Member States. In this review the national differences in requirements for ethical and competent authority approval are illustrated. The national ethical and competent authority review procedures in Finland, Hungary, The Netherlands, Norway and Slovenia are described under the EU trial directive after discussing the provisions of the trial directive related to both review procedures. The review illustrates the differences between the countries in the documents that have to be submitted for the review procedures, the submission procedures and the language requirements of the documents, the organization of the ethics committees and the role of the competent authority in the approval procedure.