Assess the Safety and Immunogenicity of M-001 as A Standalone Influenza Vaccine and as A H5N1 Vaccine Primer in Adults

• For each vaccine group the incidence rate of subjects with solicited AE(s) with 95% confidence interval [ Time Frame: Day 0 to Day 42 (21 days after the last M-001 dosing) ]
  All subjects
• For each vaccine group the percentage of subjects with SAE(s) with 95% confidence interval [ Time Frame: Day 0 to Day 180 (study conclusion) ]
  All subjects
• For each vaccine group the influenza-specific cellular immune responses evaluated by multi-parametric FACS analysis [ Time Frame: Days 0 and 42 (21 days after the last M-001 dosing) ]
  All subjects

• HAI to the vaccine strain [ Time Frame: Days 0, 63 ]
  titers of HAI to H5N1 will be measured at baseline and after H5N1 immunization
• Cell mediated immunity [ Time Frame: Days 0, 21, 42 ]
  FACS analysis after administration of M-001

• Exploratory: For each vaccine group the antibody responses to the non-H5 vaccine strains evaluated by hemaglutination inhibition (HI) assay [ Time Frame: Days 0 and 63 (21 days after the H5N1 immunization) ]
  All subjects
• Exploratory: For each vaccine group the influenza-specific cellular immune responses evaluated by quantitative reserve transcription polymerase chain reaction (qRT-PCR) assay [ Time Frame: Days 0, 42 and 63 ]
  In all groups, in a subset of 60 subjects
• Exploratory: For each vaccine group the antibody responses to the H5 vaccine strain evaluated by single radial hemolysis (SRH) assay [ Time Frame: Days 0 and 63 (21 days after the H5N1 immunization) ]
  All subjects
• Exploratory: The association between cellular immune markers and humoral immune responses will be examined. [ Time Frame: Days 0, 42 and 63 ]

• exploratory: HAI to non vaccine strains [ Time Frame: Days 0, 63 ]
  (1) To evaluate the titers of HAI to H5N1 viruses that are not contained in the H5N1 vaccine.
• qRT-PCR [ Time Frame: Days 0, 63 ]
  (1)To evaluate the cellular immune responses based on qRT-PCR (quantitative reverse transcription polymerase chain reaction) assays in all groups on day 0 and 42 (21 days following the last M-001 dosing), in a subset of 60 subjects; (2) To evaluate the cellular immune responses based on qRT-PCR assays in all groups on day 63 (21 days following the H5N1 vaccination), in a subset of 60 subjects;
• SRH [ Time Frame: Days 0, 63 ]
  To evaluate the serum single radial hemolysis (SRH) titers in all groups on day 0 and 63 (21 days following the H5N1 vaccination) in all subjects towards the H5N1 study vaccine strain;

"Multimeric-001" (M-001) contains conserved, common linear influenza epitopes that activate both cellular and humoral arms of the immune system against a wide variety of influenza A and B strains. Apart from its direct action, M-001 is an attractive candidate for priming immune responses to pandemic influenza vaccine in the adult population. The current clinical study was designed to assess M-001's standalone and priming action in subjects aged 18-60 years old.

This is a Phase IIb study comprising 222 participants. Eligible subjects were randomized to receive two sequential intramuscular injection of 0.5mg or 1.0mg M-001 (treatment), or two placebo (saline) injection, before receiving the sub optimal dose of H5N1 pandemic vaccine.

• Influenza
• Healthy

• Biological: Multimeric 001 (M-001)
  Multimeric 001 is a recombinant protein comprising 9 conserved peptides from influenza A and B
• Biological: H5N1 influenza vaccine
  Alum adjuvanted whole virion inactivated H5N1 vaccine produced by FluArt (Hungary)
• Biological: Saline
  0.9% NaCl in double distilled water

• Experimental: A: M-001 0.5mg & H5N1 influenza vaccine

  Biological/Vaccine: Two Multimeric-001 administrations followed by H5N1 influenza vaccine

  Two administrations of non adjuvanted M-001, 0.5mg followed by 3mcg Alum/H5N1 influenza vaccine at intervals of 19-23 days

  Interventions:

  • Biological: Multimeric 001 (M-001)
  • Biological: H5N1 influenza vaccine
• Experimental: B: M-001 1.0mg & H5N1 influenza vaccine

  Biological/Vaccine: Two Multimeric-001 administrations followed by H5N1 influenza vaccine

  Two administrations of non adjuvanted M-001, 1.0mg followed by 3mcg Alum/H5N1 influenza vaccine at intervals of 19-23 days

  Interventions:

  • Biological: Multimeric 001 (M-001)
  • Biological: H5N1 influenza vaccine
• Placebo Comparator: C: Saline & H5N1 influenza vaccine

  Biological/Vaccine: Two saline administrations followed by H5N1 influenza vaccine

  Two administrations of saline followed by 3mcg Alum/H5N1 influenza vaccinated intervals of 19-23 days

  Interventions:

  • Biological: H5N1 influenza vaccine
  • Biological: Saline

Inclusion Criteria:

• Healthy male or non-pregnant female (as indicated by a negative urine pregnancy test immediately prior to vaccine administration) between the ages of 18 and 60 years, inclusive;
• Women of childbearing potential (not surgically sterile or postmenopausal for greater than or equal to one year) and men must agree to practice adequate contraception (a combination of barrier plus hormone methods or intra uterine device (IUD) for women and a condom for men) throughout the study treatment and for at least up to day 51 (for female) and day 111 (for male) of the trial (i.e. 30 (for female) and 90 (for male) days after the last dose of the IMP);
• Is in good health, as determined by vital signs (heart rate, blood pressure, armpit temperature), blood chemistry test (electrolytes, renal/kidney function, liver function, C-reactive protein, complete blood count), medical history, general physical examination, self-reported illness and clinical judgment of the investigator;
• Able to understand and comply with planned study procedures;
• Provides signed informed consent form after receiving a detailed explanation of the study protocol prior to any study procedures.

Exclusion Criteria

A potential subject who meets any if the following criteria will be excluded from participation in this study:

• Has a known allergy to components of the vaccine (e.g. egg products).
• Has a history of severe reactions following immunization.
• Persons with immune deficiency/disorder, whether due to genetic defect, immunodeficiency disease, or immunosuppressive therapy.
• Has a positive urine pregnancy test prior to vaccination or women who are breastfeeding.

• Has a history of any of the following (reported by subjects):

  • Acute disseminated encephalomyelitis (ADEM);
  • Active neoplastic disease;
  • Asthma or severe allergic disease;
  • Bleeding disorders
  • Chronic Hepatitis B and/or C infection;
  • Chronic liver disease;
  • Diabetes mellitus;
  • Guillain-Barré syndrome;
  • HIV;
  • Rheumatoid arthritis or other autoimmune diseases;
  • Severe renal disease;
  • Transplant recipients;
  • Unstable or progressive neurological disorders.

• Receipt of medicines/treatments that may affect evaluation of immunogenicity such as:

  • Oral or parenteral steroids, high-dose inhaled steroids (greater than 800 micrograms/day of beclomethasone dipropionate or equivalent) or other immunosuppressive or cytotoxic drugs;
  • Immunoglobulin or other blood products (within the 3 months prior to vaccination in this study);
  • Experimental agent (vaccine, drug, biologic, device, blood product, or medication) within 1 month prior to vaccination in this study, or expects to receive an experimental agent (during the study period).
  • Influenza antiviral medication (within the 4 weeks prior to vaccination in this study).
• Has received any influenza vaccine within 6 months prior to vaccination in this study.
• Has influenza-like illness within 6 months prior to vaccination in this study.
• Has an acute illness, including an armpit temperature greater than 38 degrees Celsius (oC), within 1 week of vaccination.
• Has a history of alcohol or drug abuse.
• Any abnormal haematology values and/or serum chemistries judged by the Investigator as clinically significant.
• Ineligible subject based on the judgement of the investigator.
• In case there is uncertainty about the participant's medical status regarding any of the exclusion criteria mentioned, the participant's primary care physician will be consulted. Consultation of the primary care physician will only take place after having received written approval from the participant, and will concern medical information about exclusion criteria only.