A Randomised, Double-blind, Placebo-controlled Phase IIb Trial to Test FLU-v Vaccine
Condition: Influenza
MeSH terms: Influenza, Human
Study type: Interventional
Phase: Phase 2

Summary: 
      FLU-v is a vaccine that aims to protect against a wide range of flu viruses. The purpose of
      this study is to measure the immune responses induced by FLU-v vaccine. This study will look
      at how safe FLU-v is when administered and how successful it is in preventing flu or reducing
      the severity of the flu symptoms.

      The study requires 222 healthy volunteers 18-60 years old. Participation in the study will
      take a maximum of 7 months and consists of 5 visits. During visit 1, subjects will be
      examined by a doctor to make sure they are eligible to enter the study. A 15ml blood sample
      (a tablespoon) will be taken to check general health followed by a general physical exam.
      Medical history and some personal information will be collected. Subjects that have received
      the traditional flu vaccine in the past 6 months, and those females who are pregnant or
      breastfeeding will not be allowed in the study. Subjects of childbearing age must agree to
      use effective contraceptive methods.

      At visit 2, subjects will be randomly allocated to one of the four treatment groups
      summarised below:

        -  Treatment 1: FLU-v (test vaccine) at the start of the study (Day 0) and then again 21
           days later

        -  Treatment 2: FLU-v (test vaccine) with an additional substance added [known as Montanide
           ISA 51] which improves the effect of the test vaccine. Injection will be given on Day 0
           and then Placebo (no test vaccine) alone 21 days later

        -  Treatment 3: Placebo (no test vaccine) injection on Day 0 and then 21 days later

        -  Treatment 4: Placebo (no test vaccine) with an additional substance added [known as
           Montanide ISA 51] on Day 0 and then Placebo (no test vaccine) alone 21 days later
           Treatment will be injected under the skin in the upper arm on day 0 (visit 2) and 21
           days later (visit 3). Blood samples will be taken before treatment (day 0), and on days
           42 (visit 4) and 180 (visit 5) to the immune responses induced by the vaccine.

      Subjects will be asked to complete a diary card to write down any side effects that they may
      experience after vaccination. Subjects will also be asked to complete another diary card to
      document any flu-like symptoms experienced between December 2016 and March 2017, this time is
      officially considered as the flu season. During this period, if the subject experiences
      flu-like symptoms, a collection of a nose and tonsil swab will be arranged by the study site
      to confirm whether they have the flu or not.
    

Detailed description: 
      Rationale: Current seasonal influenza vaccines mainly induce immune responses against viral
      membrane glycoproteins. These proteins, however, undergo continuous mutations by a process
      called antigenic drift. To prevent immune escape, annual vaccination with the latest
      predicted viral strains is adopted. Such vaccination strategy not only poses inconvenience
      and cost-inefficiency, but also results in poor protective effectiveness when the vaccinated
      strains are mismatched with the actual circulating strains. The latter point is especially of
      concern during a pandemic outbreak, when a large geographical area is affected and the
      general population is naïve to the newly re-assorted viral strain due to antigenic shift.

      Objective: To evaluate the safety and immunogenicity of the influenza vaccine (FLU-v, as a
      suspension or adjuvanted as emulsion) targeting conserved immunogenic regions of influenza A
      and B viruses in healthy adults, in particular to show that the TH1 cytokine response at 42
      and 180 days after the first injection is greater in the adjuvanted FLU-v and unadjuvanted
      FLU-v than in the placebo.

      Study design: A total of 222 study participants will be recruited. The study follows a
      factorial design where the two factors are treatment (FLU-v / placebo) and formulation
      (unadjuvanted / suspension, adjuvanted / emulsion). Subjects will be randomised in two strata
      (age 18 to 40, age 41 to 60) to one of the following treatment regimens:

        -  Group 1 (n=74): FLU-v (unadjuvanted) as a suspension in pH neutral HCl/NaOH (0.5mL) on
           Day 0 and Day 21

        -  Group 2 (n=74): (0.5mL) ISA-51-adjuvanted FLU-v emulsified in water for injection (WFI)
           on Day 0, saline (0.5mL) on Day 21

        -  Group 3 (n=37): saline solution (0.5mL ) on Day 0 and Day 21

        -  Group 4 (n=37): WFI and ISA-51 emulsion (0.5mL) on Day 0, saline (0.5mL) on Day 21

      Each administration will be given subcutaneously. Solicited and unsolicited adverse events
      (AEs) will be collected by AE questionnaire/diary card until day 42. Adverse events (AEs) and
      serious adverse events (SAEs) will be collected for the entire study period. The treatments
      will be administered starting in third quarter of 2016 in order to provide protection for the
      subsequent influenza season starting in December 2016. Blood samples will be taken from all
      subjects on day 0 (before FLU-v vaccination), 42 (21 days after the second dosing) and 180
      (159 days after the second dosing) for the evaluation of FLU-v-specific cellular and humoral
      immune responses. Clinical symptom scores to ascertain severity and the incidence of
      RT-PCR-confirmed influenza A and/or B infection will be recorded during the subsequent
      influenza season (December 2016 to March 2017) to decide clinical efficacy of the tested
      vaccines.

      Study population: Healthy volunteers aged 18-60 years. Intervention: FLU-v investigational
      influenza vaccine lyophilised product containing 500 micrograms of total peptides
      reconstituted in either 0.01M HCl (0.25ml) and 0.01M NaOH (0.25ml) to achieve a volume of
      0.5ml, or emulsified in WFI (water for injection, 0.25ml) and ISA-51 (0.25ml) to achieve a
      volume of 0.5ml.

      Primary study parameters/endpoints: For immunogenicity: To compare the change from baseline
      (Day 0) between treatments in cellular immune responses, specifically TH1 cytokines, in all
      groups 42 and 180 days following FLU-v vaccination. For safety: (1) To evaluate the solicited
      AEs in all subjects until 21 days after the last dosing of the study vaccine (FLU-v); (2) To
      evaluate the unsolicited AEs and SAEs in all subjects for the entire study period after the
      first dosing of FLU-v.

      Secondary study parameters/endpoints: To evaluate the humoral immune responses specific to
      FLU-v and TH2 cytokines from baseline in all groups 42 and 180 days following FLU-v
      vaccination.

      Exploratory study parameters/endpoints: For immunogenicity: To evaluate the change from
      baseline in cellular immune responses based on additional CMI assays such as ELISPOT
      (Enzyme-Linked ImmunoSpot) in all groups at 42 and 180 days following FLU-v vaccination, in a
      subset of subjects chosen at random.

      Clinical efficacy: (1) To evaluate the efficacy of FLU-v vaccine in reducing the incidence of
      RT-PCR confirmed influenza A and/or B infections in all subjects during the influenza season
      2016-2017. (2) To evaluate the efficacy of FLU-v vaccine in the reduction of symptom score
      among RT-PCR confirmed influenza A and/or B infection cases during the influenza season
      2016-2017. The relationship between efficacy and cellular and humoral response will be
      explored if possible.

      The effect of previous influenza vaccination on the immunogenicity of FLU-v will be assessed
      in a post-hoc exploratory analysis after stratification of the data based on exposure to the
      influenza vaccine in the previous 24 months or over.

      Nature and extent of the burden and risks associated with participation, benefit and group
      relatedness:

      The intended application of the IMP is as a prophylactic vaccine to prevent influenza virus
      infection by inducing an enhanced influenza-specific immune response. The FLU-v vaccine is
      designed to be delivered either as a naturally particulate suspension (i.e. no adjuvant) or
      emulsified in adjuvant. Particulate and emulsified protein preparations are preferentially
      taken up by phagocytic cells (e.g. dendritic cells) responsible for inducing primary immune
      responses.

      Treatment with FLU-v of up to four doses of 263 μg/occasion or up to two doses of 553
      μg/occasion, with or without adjuvant, was well tolerated in animals with no signs of
      systemic toxicity. In pre-clinical studies, subcutaneous administration of ISA 51 resulted in
      no systemic toxicity. At the injection sites and occasionally in adjacent tissue the injected
      material remained surrounded by a mild chronic inflammatory response. As the IMP is provided
      in one presentation (500 μg of the combined peptide) in lyophilized form for suspension in a
      sealed single-use vial, overdose is highly unlikely.

      In a single centre, randomised, double blind phase I study of the safety, tolerability and
      immunogenicity of FLU-v no safety or tolerability concerns were identified at the doses
      administered (250 μg and 500 μg FLU-v) to the subjects in this clinical study and no safety
      or tolerability concerns were identified following administration of the adjuvant to the
      subjects (1). FLU-v vaccine candidate was demonstrated to be immunogenic in humans, as
      measured by ex vivo γ-interferon production (1).

      Clinical experience with Montanide ISA 51 dates back to the 1990s and most trials were
      related to cancer and Acquired Immune Deficiency Syndrome (AIDS). Currently, cancer trials in
      melanoma, colorectal, prostate, cervical, brain cancer and leukemia are ongoing. Frequency of
      vaccination is often between 2 and 4 weeks, and the number of injections can reach up to 40.
      Route of immunization is most often subcutaneous and volume of injection can reach up to 3mL.
      Most common local reactions are local pain, tenderness, erythema and granuloma at the
      injection site. Less frequently, mild to moderate transient indurations and swelling are
      described. General reactions are mainly 'flu-like symptoms such as chills, fever and
      headaches. Lethargy and nausea are also observed. The intensity is usually mild or moderate.
      No biological changes are generally observed. As the Placebo vaccine is provided in a sealed
      single-use vial, overdose is highly unlikely (Influenza virus (FLU-v) vaccine Investigator's
      Brochure, Edition 2.0, 07 September 2015).
    

Intervention name(s): FLU-v; adjuvanted FLU-v; Saline; Adjuvanted placebo
Intervention type(s): Biological; Biological; Biological; Biological
Intervention description(s): Subcutaneous injection in the upper arm with 500 ug of FLU-v as 0.5ml suspension in 0.01M HCl and 0.01M NaOH; Subcutaneous injection in the upper arm with 500ug of FLU-v emulsified in 0.25ml of Montanide ISA-51 adjuvant (Seppic, France) and 0.25ml of water for injection; Subcutaneous injection in the upper arm with 0.5ml of saline; Subcutaneous injection in the upper arm with an emulsion made with 0.25ml of Montanide ISA-51 adjuvant (Seppic, France) and 0.25ml of water for injection
Other intervention name(s): NaCl
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: broad; universal; vaccine; influenza; peptide; Tcell; UNISEC