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Efficacy of FLU-v in an H1N1 Influenza Human Challenge Model

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ClinicalTrials.gov Identifier: NCT03180801
Recruitment Status : Completed
First Posted : June 8, 2017
Last Update Posted : June 8, 2017
Sponsor:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
PepTcell Limited

Brief Summary:

FLU-v is a broad spectrum influenza vaccine that targets regions in the influenza virus that are conserved among many different influenza strains.This study aims to assess efficacy of FLU-v vaccine in protecting healthy FLU-v vaccinated volunteers against an influenza challenge delivered intranasally under quarantine.

Efficacy of FLU-v will be assessed by measuring the incidence and severity of the disease in the treatment groups compared to the placebo group. In addition, the immune responses of the volunteers to FLU-v will also be explored.


Condition or disease Intervention/treatment Phase
Influenza Biological: adjuvanted FLU-v Biological: adjuvanted placebo Other: Influenza challenge Phase 2

Detailed Description:

Influenza virus is a highly variable virus. Most of its variability comes from the proteins on its surface, NA and HA. Current vaccines use these highly immunogenic proteins to induce production of neutralising antibodies, however because these proteins change from strain to strain, the antibody response is only efficient against the strain present in the vaccine and if the circulating strain is different to that in the deployed vaccine, it will not be protective.

FLU-v, a novel peptide vaccine, aims to provide a broad-spectrum response and for that it uses as antigens viral proteins that are conserved throughout the different strains. These proteins are not located on the surface of the influenza virus like NA and HA are, but internally. These antigens are not capable of producing neutralising antibodies but can induce cytotoxic T cell responses and non-neutralising antibodies. When cells are infected with influenza, these internal viral antigens are presented on the surface of infected cells. Vaccination with FLU-v generates a population of T cells and non-neutralising antibodies that can recognise these antigens on the surface of infected cells. On recognition, T cells are activated and secrete Th1 cytokines such as INF-gamma, TNF-alpha, and release granzyme and perforin. Non-neutralising antibodies will activate complement and/or induce cytotoxic responses led by Natural Killer cells (NK cells). These T cells and antibody actions will result in the destruction of infected cells.

A series of pharmacology, safety and toxicology studies have been carried out in two animal species, the mouse and the rat. Pharmacology studies have demonstrated that FLU-v is able to generate both a cell mediated and humoral response in vaccinated animals and that the cell mediated response is enhanced when FLU-v is injected together with an adjuvant. A safety pharmacology study in rats demonstrated that FLU-v had no biologically relevant effects on cardiovascular or respiratory parameters when administered subcutaneously alone or in combination with the adjuvant.

The current study, a randomized, double-blind, placebo-controlled trial, will assess the efficacy and safety of adjuvanted FLU-v administered as 2 vaccinations or 1 vaccination vs placebo prior to intranasal challenge with the Influenza A 2009 H1N1 human virus.

In this study, the main efficacy comparisons are for each of the FLU-v groups to placebo. The study will also compare the two FLU-v dosing arms but will only have power to detect a significant difference in Mild to Moderate Influenza Disease (MMID) rates between the FLU-v groups and placebo and not against each other.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 123 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Phase IIb Study of the Efficacy of FLU-v, a Broad Spectrum Influenza Vaccine in an H1N1 Influenza Healthy Human Challenge Model
Actual Study Start Date : August 18, 2016
Actual Primary Completion Date : March 31, 2017
Actual Study Completion Date : May 25, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Flu Flu Shot

Arm Intervention/treatment
Placebo Comparator: Group 1 adjuvanted placebo
0.5ml adjuvanted placebo on Day -43 and on Day -22 followed by influenza challenge on day 0
Biological: adjuvanted placebo
Subcutaneous injection in the upper arm with 0.5ml emulsion made of 0.25ml of WFI and 0.25ml of adjuvant Montanide ISA-51

Other: Influenza challenge
On day 0, administration with an intranasal sprayer of 1ml of PBS containing 10(7) TCID50 of Influenza A 2009 H1N1 human virus manufactured under GMP in certified Vero cells.

Experimental: Group 2 adjuvanted FLU-v one dose
0.5ml (500mcg) adjuvanted FLU-v vaccine on Day -43 and adjuvanted placebo on Day -22 followed by influenza challenge on day 0
Biological: adjuvanted FLU-v
Subcutaneous injection in the upper arm with 500mcg of FLU-v as 0.5ml emulsion in 0.25ml of WFI and 0.25ml of adjuvant Montanide ISA-51

Biological: adjuvanted placebo
Subcutaneous injection in the upper arm with 0.5ml emulsion made of 0.25ml of WFI and 0.25ml of adjuvant Montanide ISA-51

Other: Influenza challenge
On day 0, administration with an intranasal sprayer of 1ml of PBS containing 10(7) TCID50 of Influenza A 2009 H1N1 human virus manufactured under GMP in certified Vero cells.

Experimental: Group 3 adjuvanted FLU-v two doses
0.5ml (500mcg) adjuvanted FLU-v vaccine on Day -43 and on Day -22 followed by influenza challenge on day 0
Biological: adjuvanted FLU-v
Subcutaneous injection in the upper arm with 500mcg of FLU-v as 0.5ml emulsion in 0.25ml of WFI and 0.25ml of adjuvant Montanide ISA-51

Other: Influenza challenge
On day 0, administration with an intranasal sprayer of 1ml of PBS containing 10(7) TCID50 of Influenza A 2009 H1N1 human virus manufactured under GMP in certified Vero cells.




Primary Outcome Measures :
  1. Incidence of MMID [ Time Frame: From 24h post-viral inoculation (Day 1) until the end of the quarantine phase on Day 7 or until two negative diagnostic tests for influenza on two separate but consecutive days are obtained and subject is otherwise clinically stable. ]
    To determine the effect of FLU-v on reducing the incidence of Mild to Moderate Influenza Disease (MMID) defined as detectable viral shedding plus at least one symptom of influenza


Secondary Outcome Measures :
  1. Effect of disease severity [ Time Frame: From inoculation day (Day 0) until the end of the quarantine phase on Day 7 or until two negative diagnostic tests for influenza on two separate but consecutive days are obtained and subject is otherwise clinically stable ]
    To determine the overall effect on measurements of influenza disease severity by means of recording duration and quantitation of viral shedding, duration of influenza symptoms, total number of symptoms experienced, and symptom severity score as measured by FLU-PRO Symptom Questionnaire.

  2. Incidence of vaccine related Adverse Events [ Time Frame: for 21 days after each vaccination ]
    To determine the incidence of vaccine related adverse events by means of a diary card

  3. Safety and tolerability of FLU-v [ Time Frame: For the duration of the trial from day -43 to day +63 ]
    To determine the safety and tolerability of FLU-v after vaccination in healthy subjects subsequently challenged with influenza A 2009 H1N1 human challenge virus by means of recording the incidence of treatment emergent AEs (TEAEs), severity, seriousness and causality, the absolute values and changes from baseline in routine clinical and laboratory parameters, vaccine related physical examination findings and concomitant medications.


Other Outcome Measures:
  1. Immunogenicity of FLU-v [ Time Frame: At Screening (Day -90 to Day -43), Post-vaccination (Day -2/Day -1/Day 0) and post-influenza challenge (Day 35/Day 63) ]
    To determine the antibody and cellular responses specific to FLU-v.

  2. Broadness of protection [ Time Frame: At Screening (Day -90 to Day -43), Post-vaccination (Day -2/Day -1/Day 0) and post-influenza challenge (Day 35/Day 63) ]
    To determine whether the cellular responses induced by vaccination with FLU-v are able to recognize antigenically different strains of influenza (ie. H1N1, H3N2, H5N1) and in doing so demonstrating the broadness of the response. For this PBMCs from prevaccination, post-vaccination and post-challenge from subjects will be exposed in vitro to different influenza virus strains. Viral recognition by PBMCs will be assessed by measuring secretion of inflammatory cytokines and other inflammatory mediators using techniques such as multiplex ELISA.



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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Healthy males and females aged ≥18 and ≤55 years of age at the point of enrolment.
  2. Willingness to remain in isolation for the duration of viral shedding and to comply with all study requirements.
  3. The following criteria are applicable to subjects in a heterosexual relationship and female subjects in a same sex relationship (i.e., the criteria do not apply to male subjects in a same sex relationship):

    1. True abstinence- when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g. calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception).

      Or

    2. Two forms of effective contraceptive methods among (between) the couple, which are defined as:

      • For males: condom with spermicidal foam/gel/film/cream, sterilisation (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate. This applies only to males participating in the study).
      • For females:

    Women no longer of child bearing potential (post-menopausal females are defined as having a history of amenorrhea for at least 2 years, otherwise they should have documented status as being surgically sterile or post hysterectomy. The latter applies only to females participating in the study). If of childbearing potential, then acceptable forms of contraception include:

    • Established (a minimum of 2 weeks prior to admission) use of oral, injected or implanted hormonal methods of contraception.
    • Placement of an intrauterine device (IUD) or intrauterine system (IUS).
    • Barrier methods of contraception or occlusive cap (diaphragm or cervical/vault caps), both with one of the following - spermicidal foam/gel/film/cream/suppository.

      • The longevity of contraception is as follows:

    Males:

    • Comply with agreed contraception at entry to quarantine, and continuing until 90 days after the date of viral challenge/last dosing with IMP (whichever occurs last).
    • Must not donate sperm following discharge from quarantine until 90 days after the date of viral challenge/last dosing with IMP (whichever occurs last).

    Females:

    If of childbearing potential must have a negative pregnancy test at screening and just prior to the date of Viral Challenge, and must be using contraception consisting of two forms of birth control (one of which must be a barrier method) starting from at least 2 weeks prior to the first vaccination and continuing until 90 days after the date of Viral Challenge/last dosing with IMP (whichever occurs last).

  4. Willing to have samples stored for future research.
  5. Sero-suitable to the study challenge virus within 90 days of Day 0.
  6. Agrees to abstain from alcohol intake 24 hours before admission on Day -2 or Day -1 and all other outpatient visits.
  7. Agrees to not use prescription or over-the-counter medications (including aspirin, decongestants, antihistamines, and other NSAIDs), and herbal medication (including, but not limited to, Vitamin C, Vitamin D, immune booster products, herbal tea, St. John's Wort), within 14 days prior to study vaccine administration through the final follow-up visit, unless approved by the investigator and sponsor medical monitor.
  8. An informed consent document signed and dated by the subject and the Investigator or delegate.
  9. A history of childhood asthma before the age of 12 years is acceptable provided the subject is asymptomatic without treatment. Subjects with a single episode of wheezing (lasting less than 2 weeks) after the age of 12 years can be included at the Investigator's discretion provided the episode was more than 1 year ago and did not require a hospital admission and/or oral/intravenous steroids.
  10. In good health with no history of major medical conditions that will interfere with subject safety, as defined by medical history, physical examination, and routine laboratory tests and determined by the Investigator at a screening evaluation.

    • A subject with a history of Herpes type 1 or 2 infection may be included if there are no active lesions present and the subject is not taking active medication.
    • A subject with or without any evidence of atopy including any history of allergic rhinitis, dermatitis, and conjunctivitis will be included as long as they do not conflict with exclusion criteria. Mild to moderate arthritis of non-inflammatory origin may be allowed if the subject is not at risk from relative immobility in the Quarantine Unit and does not require regular medication.
  11. A documented medical history for a minimum of the last 2 years prior to inoculation.

Exclusion Criteria:

  1. Any subjects who have smoked 10 pack years at any time. Of those subjects that have smoked less than 10 pack years at any time, a subject will be excluded: If regular smokers (e.g., smoking every day) at the time of enrolment. If current casual smoker or use of smoking / nicotine-related products, they must agree to refrain from smoking during the in-patient stay
  2. Presence of self-reported or medically documented significant medical condition including but not limited to:

    • Chronic pulmonary disease (e.g., asthma (except what is stated in inclusion criteria 9), COPD)
    • Chronic cardiovascular disease (e.g., cardiomyopathy, congestive heart failure, cardiac surgery, ischemic heart disease, known anatomic defects).
    • Chronic medical conditions requiring close medical follow-up or hospitalisation during the past 5 years (e.g., insulin dependent diabetes mellitus, renal dysfunction, haemoglobinopathies).
    • Immunosuppression, or immunodeficiency or ongoing malignancy.
    • Neurological and neurodevelopmental conditions (e.g., cerebral palsy, epilepsy, stroke, seizures).
    • Post infectious or post vaccine neurological sequelae.
    • Hyperlipidemia requiring medical therapy per current American College of Cardiology (ACC) and American Heart Association (AHA) guidelines published in 2013.
  3. Individual with body mass index (BMI) <18 and >35.
  4. Acute illness within 7 days of first vaccine administration day
  5. Clinically significant abnormal electrocardiogram (ECG) and/or parameters, as determined by the Investigator
  6. Subjects with clinically significant abnormal systolic and diastolic blood pressure or clinically significant abnormal pulse rate.
  7. Subject has abnormal pulmonary function as measured by spirometry defined as a forced vital capacity or forced expiratory volume in 1 second (FEV1) < 80% of predicted or peripheral arterial oxygen saturation (SpO2) < 92% on room air.
  8. Known allergy to treatments for influenza (including but not limited to oseltamivir, nonsteroidals).
  9. Known allergy to 2 or more classes of antibiotics (e.g. penicillins, cephalosporins, fluoroquinolones, or glycopeptides). Known allergy to excipients in the challenge virus inoculum
  10. Daily or household contact with vulnerable populations.
  11. Receipt of any investigational drug:

    • within 3 months prior to the planned date of Viral Challenge/first dosing with IMP (whichever occurs first).
    • Receipt of three or more investigational drugs within the previous 12 months prior to the planned date of Viral Challenge/first dosing with IMP (whichever occurs first).
    • Prior inoculation with a virus from the same virus-family as the Challenge Virus.
    • Prior participation in another Human Viral Challenge study with a respiratory virus in the preceding 12 months taken from the date of Viral Challenge/first dosing with IMP (whichever occurs first) in the previous study to the date of expected Viral Challenge in this study.
  12. Receipt of any vaccine within 6 months of enrolment.
  13. Self-reported or known history of alcoholism or drug abuse (including marijuana) within 6 months prior to enrolment, or positive urine/serum test for drugs of abuse during the study
  14. Self-reported or known history of psychiatric or psychological issues that require treatment and are deemed by the PI to be a contraindication to protocol participation.
  15. History of a previous severe allergic reaction with generalized urticaria, angioedema, or anaphylaxis.
  16. History or evidence of autoimmune disease or known immunodeficiency of any cause - with the exception of atopic dermatitis/eczema and atopic rhinitis.
  17. Subjects with any history of physician diagnosed and/or objective test confirmed asthma (except as per inclusion criteria 9), reactive airway disease, COPD, pulmonary hypertension, or chronic lung condition of any aetiology.
  18. Positive human immunodeficiency virus (HIV) within 60 days of first vaccination visit, active hepatitis A (HAV), B (HBV), or C (HCV) test.
  19. Any significant abnormality altering the anatomy of the nose or nasopharynx (including significant nasal polyps).
  20. Venous access deemed inadequate for the phlebotomy and cannulation demands of the study.
  21. Any nasal or sinus surgery within 6 months of Viral Challenge.
  22. Recurrent history of fainting.
  23. Those employed or immediate relatives of those employed at hVIVO or the Sponsor.
  24. Any clinically significant history of epistaxis (nosebleeds) within the last 12 months and/or history of being hospitalized due to epistaxis on any previous occasion.
  25. Females who:

    • Are breastfeeding,
    • or have been pregnant within 6 months prior to the study,
    • or have a positive pregnancy test at any point during screening or prior to first dosing with IMP.
  26. Presence of fever, defined as subject presenting with a temperature reading of > 38.0°C on Day -43
  27. Receipt of blood or blood products, or loss (including blood donations) of 470 mL or more of blood during the 3 months prior to the planned date of first dosing with IMP or planned during the 3 months after the final visit.
  28. Receipt of systemic (intravenous and/or oral) glucocorticoids or systemic antiviral drugs within 6 months prior to the planned date of first dosing with IMP.
  29. Any other finding that, in the opinion of the Investigator, deems the subject unsuitable for the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03180801


Locations
United Kingdom
hVIVO Services Limited
London, United Kingdom, E1 2AX
Sponsors and Collaborators
PepTcell Limited
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
Principal Investigator: Jeremy Dennison, Dr Hammersmith Medicines Research
Principal Investigator: Balpreet Matharu, Dr hVIVO Services Limited
Study Director: Matthew J Memoli, PhD National Institute of Allergy and Infectious Diseases (NIAID)

Publications:

Responsible Party: PepTcell Limited
ClinicalTrials.gov Identifier: NCT03180801     History of Changes
Other Study ID Numbers: FLU-v-004
2016-002134-74 ( EudraCT Number )
First Posted: June 8, 2017    Key Record Dates
Last Update Posted: June 8, 2017
Last Verified: June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by PepTcell Limited:
broad
universal
vaccine
influenza
peptide
T cell
H1N1
human challenge

Additional relevant MeSH terms:
Influenza, Human
Orthomyxoviridae Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Respiratory Tract Diseases
Vaccines
Immunologic Factors
Physiological Effects of Drugs