Clinical trial NCT03738241: 2017 A/H7N9 IIV Revaccination
Official title: A Phase II Study to Assess the Safety, Reactogenicity and Immunogenicity of a Single Dose of 2017 A/H7N9 Inactivated Influenza Vaccine (IIV) Administered Intramuscularly With or Without AS03 Adjuvant in 2013 A/H7N9 IIV Primed or A/H7 IIV Naïve Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Avian Influenza
Influenza Immunisation
Keywords: A/H7N9 Inactivated Influenza Vaccine
AS03 Adjuvant
Immunogenicity
Influenza
Phase II
Reactogenicity
Safety
Vaccine
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2018-11-13
Enrollment: 304
Sex: ALL
Minimum age (years): 19
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This is a Phase II clinical trial in up to 420 males and non-pregnant females, 19 to 70 years of age, inclusive, who are in good health and meet all eligibility criteria. This clinical trial is designed to assess the safety, reactogenicity and immunogenicity of one dose of a monovalent inactivated split influenza 2017 A/H7N9 virus vaccine (2017 A/H7N9 IIV), administered intramuscularly (IM) at 3.75 mcg hemagglutinin (HA) per dose, given with or without AS03 adjuvant to subjects primed with a monovalent inactivated split influenza 2013 A/H7N9 virus vaccine (2013 A/H7N9 IIV) in DMID Protocols 13-0032 and 13-0033, or to those who are A/H7 IIV-naïve. Phosphate buffered saline (PBS) diluent will be used to achieve the targeted dosage. The study will be conducted at 9 Vaccine and Treatment Evaluation Unit (VTEU) sites (including their subcontractors). Study duration is approximately 17 months with subject participation duration up to 13 months. The primary objectives are: 1) to assess the safety and reactogenicity of 2017 A/H7N9 IIV given with or without AS03 adjuvant following receipt of one dose of study vaccine; 2) to assess the serum hemagglutination inhibition (HAI) and neutralizing (Neut) antibody responses following receipt of the study vaccine.

Detailed description: This is a Phase II clinical trial in up to 420 males and non-pregnant females, 19 to 70 years of age, inclusive, who are in good health and meet all eligibility criteria, which include a screening erythrocyte sedimentation rate (ESR) laboratory evaluation. This clinical trial is designed to assess the safety, reactogenicity and immunogenicity of one dose of a monovalent inactivated split influenza 2017 A/H7N9 virus vaccine (2017 A/H7N9 IIV) manufactured by Sanofi Pasteur (SP), administered intramuscularly (IM) at 3.75 mcg hemagglutinin (HA) per dose, given with or without AS03 adjuvant manufactured by GlaxoSmithKline Biologicals (GSK), to subjects primed with a monovalent inactivated split influenza 2013 A/H7N9 virus vaccine (2013 A/H7N9 IIV) in DMID Protocols 13-0032 and 13-0033, or to those who are A/H7 IIV-naïve. Phosphate buffered saline (PBS) diluent manufactured by Patheon Manufacturing Services LLC will be used to achieve the targeted dosage. Subjects who received the 2013 A/H7N9 IIV in DMID Protocols 13-0032 and 13-0033 or are A/H7 IIV-naïve will be stratified by prior receipt of 2013 A/H7N9 IIV, as well as by site and prior receipt of licensed, seasonal influenza vaccine (defined as receipt of at least one of the 2017-2018 and/or 2018-2019 licensed, seasonal influenza vaccines versus none), then randomly assigned in a 1:1 ratio to 1 of 2 treatment arms to receive 1 dose of 2017 A/H7N9 IIV at 3.75 mcg HA per dose with or without AS03 adjuvant. The study will be conducted at 9 Vaccine and Treatment Evaluation Unit (VTEU) sites (including their subcontractors). Study duration is approximately 17 months with subject participation duration up to 13 months. The primary objectives are: 1) to assess the safety and reactogenicity of 2017 A/H7N9 IIV given with or without AS03 adjuvant following receipt of one dose of study vaccine; 2) to assess the serum hemagglutination inhibition (HAI) and neutralizing (Neut) antibody responses following receipt of the study vaccine. Secondary objectives are: 1) to assess unsolicited non-serious adverse events (AEs) following receipt of the study vaccine; 2) to assess medically-attended adverse events (MAAEs), including new-onset chronic medical conditions (NOCMCs) and potentially immune-mediated medical conditions (PIMMCs), following receipt of the study vaccine; 3) To assess the kinetics and durability of serum HAI and Neut antibody responses following receipt of the study vaccine.

Eligibility criteria: Inclusion Criteria:

Subjects eligible to participate in this trial must meet all of the following inclusion criteria:

1. Provide written informed consent prior to initiation of any study procedures.
2. Are able to understand and comply with planned study procedures and be available for all study visits.
3. Must agree to the collection of venous blood per protocol.
4. Must agree to have residual specimens and samples/specimens collected during this trial specifically for the purpose of future research stored for future research use.
5. Are males or non-pregnant females, 19 to 70 years of age, inclusive.
6. Are in good health\* \*As determined by medical history and physical examination to evaluate acute or currently ongoing chronic medical diagnoses or conditions, defined as those that have been present for at least 90 days, which would affect the assessment of the safety of subjects or the immunogenicity of study vaccinations. Chronic medical diagnoses or conditions should be stable for the last 60 days (no hospitalizations, emergency room or urgent care for condition and no adverse symptoms that need medical intervention such as medication change/supplemental oxygen). This includes no change in chronic prescription medication, dose or frequency as a result of deterioration of the chronic medical diagnosis or condition in the 60 days prior to enrollment. Any prescription change that is due to change of health care provider, insurance company, etc., or that is done for financial reasons, as long as in the same class of medication, will not be considered a deviation of this inclusion criterion. Any change in prescription medication due to improvement of a disease outcome, as determined by the site PI or appropriate sub-investigator, will not be considered a deviation of this inclusion criterion. Subjects may be on chronic or as needed (prn) medications if, in the opinion of the site PI or appropriate sub-investigator, they pose no additional risk to subject safety or assessment of reactogenicity and immunogenicity and do not indicate a worsening of medical diagnosis or condition. Similarly, medication changes subsequent to enrollment and study vaccination are acceptable provided there was no deterioration in the subject's chronic medical condition that necessitated a medication change, and there is no additional risk to the subject or interference with the evaluation of responses to study vaccination. Note: Topical, nasal and inhaled medications (except inhaled corticosteroids as outlined in the Subject Exclusion Criteria as well as herbals, vitamins and supplements are permitted.
7. Oral temperature is less than 100.0 degrees Fahrenheit.
8. Pulse is 47 to 100 beats per minute, inclusive.
9. Systolic blood pressure is 85 to 150 mmHg, inclusive.
10. Diastolic blood pressure is 55 to 95 mmHg, inclusive.
11. Erythrocyte Sedimentation Rate (ESR) is less than 30 mm per hour.
12. Women of childbearing potential\*\* must use an acceptable contraception method\*\*\* from 30 days before study vaccination until 60 days after study vaccination.

    \*\*Not sterilized via tubal ligation, bilateral oophorectomy, salpingectomy, hysterectomy, or successful Essure(R) placement (permanent, non-surgical, non-hormonal sterilization) with documented radiological confirmation test at least 90 days after the procedure, and still menstruating or \<1 year has passed since the last menses if menopausal.

    \*\*\*Includes non-male sexual relationships, abstinence from sexual intercourse with a male partner, monogamous relationship with vasectomized partner who has been vasectomized for 180 days or more prior to the subject receiving the study vaccination, barrier methods such as condoms or diaphragms/cervical cap with spermicide, effective intrauterine devices, NuvaRing(R), and licensed hormonal methods such as implants, injectables or oral contraceptives ("the pill").
13. Women of childbearing potential must have a negative urine or serum pregnancy test within 24 hours prior to study vaccination.
14. Received 1 or 2 doses of 2013 A/H7N9 IIV with or without AS03 or MF59 adjuvant in DMID Protocols 13-0032 or 13-0033, or are A/H7 IIV-naïve.

Exclusion Criteria:

Subjects eligible to participate in this trial must not meet any of the following exclusion criteria:

1. Have an acute illness\*, as determined by the site PI or appropriate sub-investigator, within 72 hours prior to study vaccination.

   \*An acute illness which is nearly resolved with only minor residual symptoms remaining is allowable if, in the opinion of the site PI or appropriate sub-investigator, the residual symptoms will not interfere with the ability to assess safety parameters as required by the protocol.
2. Have any medical disease or condition that, in the opinion of the site PI or appropriate sub-investigator, is a contraindication to study participation\*\*.

   \*\*Including acute or chronic medical disease or condition, defined as persisting for at least 90 days, that would place the subject at an unacceptable risk of injury, render the subject unable to meet the requirements of the protocol, or may interfere with the evaluation of responses or the subject's successful completion of this trial.
3. Have immunosuppression as a result of an underlying illness or treatment, a recent history or current use of immunosuppressive or immunomodulating disease therapy.
4. Use of cytotoxic anticancer chemotherapy or radiation therapy within 3 years prior to study vaccination.
5. Have known active neoplastic disease or a history of any hematologic malignancy. Non-melanoma, treated, skin cancers are permitted.
6. Have known human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection.
7. Have known hypersensitivity or allergy to eggs, egg or chicken protein, squalene-based adjuvants, or other components of the study vaccine.
8. Have a history of severe reactions following previous immunization with licensed or unlicensed influenza vaccines.
9. Have a personal or family history of narcolepsy.
10. Have a history of Guillain-Barré Syndrome (GBS).
11. Have a history of convulsions or encephalomyelitis within 90 days prior to study vaccination.
12. Have a history of Potentially Immune-Mediated Medical Conditions (PIMMCs).
13. Have a history of alcohol or drug abuse within 5 years prior to study vaccination.
14. Have any diagnosis, current or past, of schizophrenia, bipolar disease or other psychiatric diagnosis that may interfere\*\*\* with subject compliance or safety evaluations.

    \*\*\*As determined by the site PI or appropriate sub-investigator.
15. Have been hospitalized for psychiatric illness, history of suicide attempt, or confinement for danger to self or others within 10 years prior to study vaccination.
16. Have taken oral or parenteral (including intra-articular) corticosteroids of any dose within 30 days prior to study vaccination.
17. Have taken high-dose inhaled corticosteroids\*\*\*\* within 30 days prior to study vaccination.

    \*\*\*\*High-dose defined as per age as using inhaled high-dose per reference chart in the National Heart, Lung and Blood Institute Guidelines for the Diagnosis and Management of Asthma (EPR-3) or other lists published in UPTODATE.
18. Received or plan to receive a licensed, live vaccine within 30 days before or after study vaccination.
19. Received or plan to receive a licensed, inactivated vaccine (excluding all licensed, seasonal IIVs) within 14 days before or after study vaccination.
20. Received or plan to receive a licensed, seasonal IIV within 21 days before or after study vaccination.
21. Received immunoglobulin or other blood products (except Rho D immunoglobulin) within 90 days prior to study vaccination.
22. Received an experimental agent\*\*\*\*\* within 30 days prior to study vaccination or expect to receive an experimental agent\*\*\*\*\*\* during the trial-reporting period\*\*\*\*\*\*\*.

    \*\*\*\*\*Including vaccine, drug, biologic, device, blood product, or medication.

    \*\*\*\*\*\*Other than from participation in this trial.

    \*\*\*\*\*\*\*Approximately 12 months after study vaccination.
23. Are participating or plan to participate in another clinical trial with an interventional agent\*\*\*\*\*\*\*\* that will be received during the trial-reporting period\*\*\*\*\*\*\*\*\*.

    \*\*\*\*\*\*\*\*Including licensed or unlicensed vaccine, drug, biologic, device, blood product, or medication.

    \*\*\*\*\*\*\*\*\*Approximately 12 months after study vaccination.
24. Have a history of influenza A/H7 subtype infection.
25. Had substantial direct contact\*\*\*\*\*\*\*\*\*\* with live or freshly slaughtered poultry or pigeons while in mainland China within the past five years.

    \*\*\*\*\*\*\*\*\*\*Substantial direct contact is defined as visited a poultry farm and/or a live poultry market.
26. Occupational exposure to or substantial direct physical contact\*\*\*\*\*\*\*\*\*\*\* with birds in the past year and through 21 days after study vaccination.

    \*\*\*\*\*\*\*\*\*\*\*Exposure to free range chickens in the yard is exclusionary. Casual contact with birds at petting zoos or county or state fairs or having pet birds does not exclude subjects from study participation.
27. Female subjects who are breastfeeding.
28. Plan to travel outside the US (continental US, Hawaii and Alaska) from the time of study vaccination through 21 days after study vaccination.

Primary outcomes:
measure: Geometric Mean Titers (GMT) of Serum Hemagglutination Inhibition (HAI) Antibodies on Day 22 Against the 2017 Influenza A/H7N9 Vaccine Virus
timeFrame: Day 22
measure: Geometric Mean Titers (GMT) of Serum Neutralizing (Neut) Antibodies on Day 22 Against the 2017 Influenza A/H7N9 Vaccine Virus
timeFrame: Day 22
measure: Number of Participants Reporting Serious Adverse Events (SAEs)
timeFrame: Day 1 through Day 366
measure: Number of Participants Reporting Clinical Safety Laboratory Adverse Events (AEs)
timeFrame: Day 1 to Day 8
measure: Number of Participants Reporting Solicited Injection Site Reactogenicity Events
timeFrame: Day 1 through Day 8
measure: Number of Participants Reporting Solicited Systemic Reactogenicity Events
timeFrame: Day 1 through Day 8
measure: Percentage of Participants Achieving Hemagglutination Inhibition (HAI) Antibody Titer of 1:40 or Greater on Day 22 Against the 2017 Influenza A/H7N9 Vaccine Virus
timeFrame: Day 22
measure: Percentage of Participants Achieving Neutralizing (Neut) Antibody Titer of 1:40 or Greater on Day 22 Against the 2017 Influenza A/H7N9 Vaccine Virus
timeFrame: Day 22
measure: Percentage of Participants Achieving Hemagglutination Inhibition (HAI) Antibody Seroconversion on Day 22 Against the 2017 Influenza A/H7N9 Study Vaccine Virus
timeFrame: Day 22
measure: Percentage of Participants Achieving Neutralizing (Neut) Antibody Seroconversion on Day 22 Against the 2017 Influenza A/H7N9 Study Vaccine Virus
timeFrame: Day 22
Secondary outcomes:
measure: Geometric Mean Titers (GMT) of Serum Hemagglutination Inhibition (HAI) Antibodies on Day 8 Against the 2017 Influenza A/ H7N9 Vaccine Virus
timeFrame: Day 8
measure: Geometric Mean Titers (GMT) of Serum Hemagglutination Inhibition (HAI) Antibodies on Day 181 Against the 2017 Influenza A/ H7N9 Vaccine Virus
timeFrame: Day 181
measure: Geometric Mean Titers (GMT) of Serum Neutralizing (Neut) Antibodies on Day 8 Against the 2017 Influenza A/H7N9 Vaccine Virus
timeFrame: Day 8
measure: Geometric Mean Titers (GMT) of Serum Neutralizing (Neut) Antibodies on Day 181 Against the 2017 Influenza A/H7N9 Vaccine Virus
timeFrame: Day 181
measure: Geometric Mean Titers (GMTs) of Serum Hemagglutination Inhibition (HAI) Antibodies on Day 22 Against the 2013 Influenza A/H7N9 Vaccine Virus (Priming Vaccine Virus)
timeFrame: Day 22
measure: Geometric Mean Titers (GMTs) of Serum Neutralizing (Neut) Antibodies on Day 22 Against the 2013 Influenza A/H7N9 Vaccine Virus (Priming Vaccine Virus)
timeFrame: Day 22
measure: Number of Participants Reporting Medically-Attended Adverse Events (MAAEs), New-Onset Chronic Medical Conditions (NOCMCs), and Potentially Immune-Mediated Medical Conditions (PIMMCs)
timeFrame: Day 1 through Day 366
measure: Number of Participants Reporting Unsolicited Non-serious AEs
timeFrame: Day 1 through Day 22
measure: Percentage of Participants Achieving Hemagglutination Inhibition (HAI) Antibody Titer of 1:40 or Greater on Day 8 Against the 2017 Influenza A/H7N9 Vaccine Virus
timeFrame: Day 8
measure: Percentage of Participants Achieving Hemagglutination Inhibition (HAI) Antibody Titer of 1:40 or Greater on Day 181 Against the 2017 Influenza A/H7N9 Vaccine Virus
timeFrame: Day 181
measure: Percentage of Participants Achieving Neutralizing (Neut) Antibody Titer of 1:40 or Greater on Day 8 Against the 2017 Influenza A/H7N9 Vaccine Virus
timeFrame: Day 8
measure: Percentage of Participants Achieving Neutralizing (Neut) Antibody Titer of 1:40 or Greater on Day 181 Against the 2017 Influenza A/H7N9 Vaccine Virus
timeFrame: Day 181
measure: Percentage of Participants Achieving Hemagglutination Inhibition (HAI) Antibody Seroconversion on Day 8 Against the 2017 Influenza A/H7N9 Vaccine Virus
timeFrame: Day 8
measure: Percentage of Participants Achieving Hemagglutination Inhibition (HAI) Antibody Seroconversion on Day 181 Against the 2017 Influenza A/H7N9 Vaccine Virus
timeFrame: Day 181
measure: Percentage of Participants Achieving Neutralizing (Neut) Antibody Seroconversion on Day 8 Against the 2017 Influenza A/H7N9 Vaccine Virus
timeFrame: Day 8
measure: Percentage of Participants Achieving Neutralizing (Neut) Antibody Seroconversion on Day 181 Against the 2017 Influenza A/H7N9 Vaccine Virus
timeFrame: Day 181
measure: Percentage of Participants Achieving Hemagglutination Inhibition (HAI) Antibody Titer of 1:40 or Greater on Day 22 Against the 2013 Influenza A/H7N9 Vaccine Virus (Priming Vaccine Virus)
timeFrame: Day 22
measure: Percentage of Participants Achieving Neutralizing (Neut) Antibody Titer of 1:40 or Greater on Day 22 Against the 2013 Influenza A/H7N9 Vaccine Virus (Priming Vaccine Virus)
timeFrame: Day 22
measure: Percentage of Participants Achieving Hemagglutination Inhibition (HAI) Antibody Seroconversion on Day 22 Against the 2013 Influenza A/H7N9 Vaccine Virus (Priming Vaccine Virus)
timeFrame: Day 22
measure: Percentage of Participants Achieving Neutralizing (Neut) Antibody Seroconversion on Day 22 Against the 2013 Influenza A/H7N9 Vaccine Virus (Priming Vaccine Virus)
timeFrame: Day 22
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory Children's Center - Pediatric Infectious Diseases
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa - Vaccine Research and Education Unit
state: Iowa
city: Baltimore
country: United States
facility: University of Maryland Baltimore - School of Medicine - Medicine
state: Maryland
city: Saint Louis
country: United States
facility: Saint Louis University - Center for Vaccine Development
state: Missouri
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center - Infectious Diseases
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University Medical Center - Infectious Diseases
state: Tennessee
city: Galveston
country: United States
facility: The University of Texas Medical Branch - Sealy Center for Vaccine Development (SCVD)
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine - Molecular Virology and Microbiology
state: Texas
city: Seattle
country: United States
facility: Kaiser Permanente Washington Health Research Institute - Vaccines and Infectious Diseases
state: Washington
Study officials:
References: