Clinical trial NCT03318315: Co-Administration of AS03 Adjuvanted A/H7N9 IIV With IIV4
Official title: A Phase II Study in Healthy Adults (19-64 Years of Age) to Assess the Safety, Reactogenicity and Immunogenicity of Sequential or Simultaneous Intramuscular Administration of an AS03-adjuvanted A/H7N9 Inactivated Influenza Vaccine With Seasonal Influenza Vaccine
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Avian Influenza
Influenza
Influenza Immunisation
Keywords: AS03-adjuvanted Inactivated Influenza Vaccine
Co-Administered
Healthy Adults
Immunogenicity
Inactivated Seasonal Influenza Vaccine
Phase II
Safety
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2017-10-23
Enrollment: 149
Sex: ALL
Minimum age (years): 19
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This is a randomized, un-blinded, Phase II study in males and non-pregnant females, who are in good health, 19 to 64 years of age. This study is designed to assess the safety, reactogenicity, and immunogenicity of a pre-pandemic AS03 (GSK) adjuvanted 2017 monovalent inactivated influenza A/H7N9 vaccine, when two doses are administered 21 days apart either sequentially or simultaneously (within 15 minutes) with licensed seasonal influenza vaccine. Subjects will be randomized into one of three treatment groups. The study will enroll approximately 150 individuals who have no history of influenza A/H7N9 infection or prior receipt of an influenza virus H7 subtype vaccine. Study duration is approximately 16 months with subject participation duration of approximately 13 months. The primary objectives of this study are: 1) to assess the safety and reactogenicity following sequential or simultaneous IM administration of 2 doses of AS03-adjuvanted 2017 H7N9 IIV and one dose of seasonal influenza vaccine (IIV4); 2) to assess the serum HAI and Neut antibody responses against A/H7N9 at approximately 21 days following receipt of two doses of AS03-adjuvanted 2017 H7N9 IIV administered IM approximately 21 days apart; 3) to assess the serum HAI and Neut antibody responses against the seasonal influenza strains at approximately 21 days following receipt of IIV4.

Detailed description: This is a randomized, un-blinded, Phase II study in males and non-pregnant females, who are in good health, 19 to 64 years of age. This clinical trial is designed to assess the safety, reactogenicity, and immunogenicity of a pre-pandemic AS03 (GSK) adjuvanted 2017 monovalent inactivated influenza A/H7N9 vaccine (2017 H7N9 IIV) manufactured by Sanofi Pasteur (3.75 mcg of HA per dose with Phosphate Buffered Saline (PBS) diluent), when two doses are administered 21 days apart either sequentially or simultaneously (within 15 minutes) with licensed seasonal influenza vaccine. Subjects will be randomized into one of three treatment groups. Group 1 will receive two doses of AS03-adjuvanted 2017 H7N9 IIV, each dose administered IM approximately 21 days apart, and one dose of licensed seasonal IIV4 will be administered IM simultaneously (within 15 minutes) with the first dose of AS03 adjuvanted 2017 H7N9 IIV. Group 2 will receive one dose of IIV4 approximately 21 days prior to the IM administration of two doses of AS03-adjuvanted 2017 H7N9 IIV; each dose of AS03-adjuvanted 2017 H7N9 IIV will be given approximately 21 days apart. Group 3 will receive one dose IM of IIV4 as an un-blinded comparator. The study will enroll approximately 150 individuals who have no history of influenza A/H7N9 infection or prior receipt of an influenza virus H7 subtype vaccine. Study duration is approximately 16 months with subject participation duration of approximately 13 months. The primary objectives of this study are: 1) to assess the safety and reactogenicity following sequential or simultaneous IM administration of 2 doses of AS03-adjuvanted 2017 H7N9 IIV and one dose of seasonal influenza vaccine (IIV4); 2) to assess the serum HAI and Neut antibody responses against A/H7N9 at approximately 21 days following receipt of two doses of AS03-adjuvanted 2017 H7N9 IIV administered IM approximately 21 days apart; 3) to assess the serum HAI and Neut antibody responses against the seasonal influenza strains at approximately 21 days following receipt of IIV4. The secondary objectives are: 1) to assess unsolicited non-SAEs following sequential or simultaneous IM administration of AS03-adjuvanted 2017 H7N9 IIV and seasonal influenza vaccine (IIV4); 2) to assess MAAEs, including NOCMCs and PIMMCs, following sequential or simultaneous IM administration of AS03-adjuvanted 2017 H7N9 IIV and IIV4; 3) to assess the HAI and Neut antibody responses at 21 days following receipt of 1 dose of AS03-adjuvanted 2017 H7N9 IIV.

Eligibility criteria: 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. Are males or non-pregnant females, 19 -64 years of age, inclusive.
4. 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 (ER), 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 principal investigator 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 principal investigator 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 (with the exception of inhaled corticosteroids as outlined in the Subject Exclusion Criteria), herbals, vitamins, and supplements are permitted.
5. Oral temperature is less than 100.0°F.
6. Pulse is 47 to 100 beats per minute (bpm), inclusive.
7. Systolic blood pressure is 85 to 150 mmHg, inclusive (subjects \<65 years of age), 85 to 160 mmHg, inclusive (subjects = / \> 65 years of age).
8. Diastolic blood pressure is 55 to 95 mmHg, inclusive.
9. ESR is less than 30 mm per hour.
10. Women of childbearing potential must use an acceptable contraception method from 30 days before first study vaccination until 60 days after last study vaccination.

    - Not sterilized via tubal ligation, bilateral oophorectomy, salpingectomy, hysterectomy, or successful Essure® 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 of 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 first study vaccination, barrier methods such as condoms or diaphragms with spermicide or foam, effective intrauterine devices, NuvaRing®, and licensed hormonal methods such as implants, injectables, or oral contraceptives ("the pill").
11. Women of childbearing potential must have a negative urine or serum pregnancy test within 24 hours prior to study vaccination.

Exclusion Criteria:

1. Have an acute illness, as determined by the site principal investigator 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 principal investigator 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 principal investigator 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 anticancer chemotherapy or radiation therapy (cytotoxic) 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 Guillian-Barre 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.
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 each study vaccination.

    - High-dose defined per age as using inhaled high dose per reference chart https://www.nhlbi.nih.gov/health-pro/guidelines/current/asthma-guidelines/quick-reference-html#estimated-comparative-daily-doses
18. Received a licensed live vaccine within 30 days prior to the first study vaccination, or plan to receive a licensed live vaccine within 30 days before or after each study vaccination.
19. Received or plan to receive a licensed, inactivated, vaccine (excluding all flu vaccines) within 14 days before or after each study vaccination.
20. Received or plan to receive the 2017-2018 inactivated seasonal flu vaccine prior to or during the clinical trial and for the remainder of the 2017-2018 season.
21. Received Ig or other blood products (with exception of Rho D Ig) within 90 days prior to each study vaccination.
22. Received an experimental agent within 30 days prior to the first study vaccination, or expect to receive an experimental agent during the 13-month trial-reporting period.

    - Including vaccine, drug, biologic, device, blood product, or medication.

    -- Other than from participation in this trial.
23. Are participating or plan to participate in another clinical trial with an interventional agent that will be received during the 13-month trial-reporting period.

    - Including licensed or unlicensed vaccine, drug, biologic, device, blood product, or medication.
24. Received or plan to receive an influenza A/H7 vaccine or have a history of influenza A/H7 subtype infection.

    - And assigned to a group receiving influenza A/H7 vaccine.
25. Have traveled to mainland China and had substantial direct contact with live or freshly slaughtered poultry or pigeons within the past five years.

    - Substantial 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 the 21 days after the last 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 or plan to breastfeed at any given time from the first study vaccination until 30 days after the last study vaccination.
28. Plan to travel outside the US (continental US, Hawaii, and Alaska) from enrollment through 21 days after the last study vaccination.

Primary outcomes:
measure: Geometric Mean Titers (GMTs) of Serum Hemagglutination Inhibition (HAI) Antibodies Against the 2017 H7N9 Inactivated Influenza Vaccine (IIV) Strain After Second H7N9 Vaccination
timeFrame: 21 days after second dose of H7N9
measure: GMTs of Serum HAI Antibodies Against Each of the 2017 IIV4 Strains
timeFrame: Day 22
measure: GMTs of Serum Neutralizing Antibodies Against Each of the 2017 IIV4 Strains
timeFrame: Day 22
measure: GMTs of Serum Neutralizing Antibodies Against the 2017 H7N9 IIV Strain After the Second H7N9 Vaccination
timeFrame: 21 days after second dose of H7N9
measure: Number of Participants Reporting Serious Adverse Events (SAEs)
timeFrame: Day 1 up to Day 408
measure: Number of Participants Assessed With Clinical Safety Laboratory AEs After First Vaccination
timeFrame: Day 8
measure: Number of Participants Assessed With Clinical Safety Laboratory AEs After Second Vaccination
timeFrame: Day 29
measure: Number of Participants Assessed With Clinical Safety Laboratory AEs After Third Vaccination
timeFrame: Day 50
measure: Number of Participants Reporting Solicited Injection Site AEs After First Vaccination
timeFrame: Day 1 up to day 8
measure: Number of Participants Reporting Solicited Injection Site AEs After Second Vaccination
timeFrame: Day 22 up to day 29
measure: Number of Participants Reporting Solicited Injection Site AEs After Third Vaccination
timeFrame: Day 43 up to day 50
measure: Occurrence of Study Vaccine-related SAEs
timeFrame: Day 1 up to day 408
measure: Number of Participants Reporting Solicited Systemic AEs After First Vaccination
timeFrame: Day 1 up to day 8
measure: Number of Participating Reporting Solicited Systemic AEs After Second Vaccination
timeFrame: Day 22 up to day 29
measure: Number of Participants Reporting Solicited Systemic AEs After Third Vaccination
timeFrame: Day 43 up to day 50
measure: Percentage of Participants Achieving HAI Seroconversion Against 2017 H7N9 Study Vaccine After Second H7N9 Vaccination
timeFrame: 21 days after second dose of H7N9
measure: Percentage of Participants Achieving Neutralizing Antibody Seroconversion Against 2017 H7N9 Study Vaccine After Second H7N9 Vaccination
timeFrame: 21 days after second dose of H7N9
measure: Percentage of Participants Achieving HAI Seroconversion Against Each of the Study IIV4 Strains
timeFrame: Day 22
measure: Percentage of Participants With HAI Antibody Titer of 1:40 or Greater Against Each of the Study IIV4 Strains
timeFrame: Day 22
measure: Percentage of Participants With HAI Antibody Titer of 1:40 or Greater Against the Influenza 2017 H7N9 Study Vaccine Strain After Second H7N9 Vaccination
timeFrame: 21 days after second dose of H7N9
measure: Percentage of Participants With Neutralizing Antibody Titer of 1:40 or Greater Against Each of the Study IIV4 Strains
timeFrame: Day 22
measure: Percentage of Participants With Neutralizing Antibody Titer of 1:40 or Greater Against the Influenza 2017 H7N9 Study Vaccine Strain After Second H7N9 Vaccination
timeFrame: 21 days after second dose of H7N9
Secondary outcomes:
measure: GMTs of Serum HAI Antibodies Against the Influenza 2017 H7N9 Vaccine Virus at Baseline
timeFrame: Day 1
measure: GMTs of Serum HAI Antibodies Against the Influenza 2017 H7N9 Vaccine Virus After First H7N9 Vaccination
timeFrame: 21 days after first dose of H7N9
measure: GMTs of Serum Neutralizing Antibodies Against the Influenza 2017 H7N9 Vaccine Virus at Baseline
timeFrame: Day 1
measure: GMTs of Serum Neutralizing Antibodies Against the Influenza 2017 H7N9 Vaccine Virus After First H7N9 Vaccination
timeFrame: 21 days after first dose of H7N9
measure: Number of Participants Reporting Unsolicited Non-serious AEs After First Vaccination
timeFrame: Approximately 21 days after first vaccination
measure: Number of Participants Reporting Unsolicited Non-serious AEs After Second Vaccination
timeFrame: Approximately 21 days after second vaccination
measure: Number of Participants Reporting Unsolicited Non-serious AEs After Third Vaccination
timeFrame: Approximately 21 days after third vaccination
measure: Number of Participants Reporting of Medically-Attended Adverse Events (MAAEs), Including New-Onset Chronic Medical Conditions (NOCMCs) and Potentially Immune-Mediated Medical Conditions (PIMMCs)
timeFrame: Day 1 up to day 408
measure: Number of Participants Reporting Study Vaccine-related Unsolicited Non-serious AEs After First Vaccination
timeFrame: Approximately 21 days after first vaccination
measure: Number of Participants Reporting Study Vaccine-related Unsolicited Non-serious AEs After Second Vaccination
timeFrame: Approximately 21 days after second vaccination
measure: Number of Participants Reporting Study Vaccine-related Unsolicited Non-serious AEs After Third Vaccination
timeFrame: Approximately 21 days after third vaccination
measure: Percentage of Participants Achieving HAI Antibody Seroconversion Against the 2017 H7N9 Vaccine Strain After First H7N9 Vaccination
timeFrame: 21 days after first dose of H7N9
measure: Percentage of Participants Achieving Neutralizing Antibody Seroconversion Against the 2017 H7N9 Vaccine Strain After First H7N9 Vaccination
timeFrame: 21 days after first dose of H7N9
measure: Percentage of Participants Achieving Serum HAI Antibody Titers of 1:40 or Greater Against the Influenza 2017 H7N9 Vaccine Strain at Baseline
timeFrame: Day 1
measure: Percentage of Participants Achieving Serum HAI Antibody Titers of 1:40 or Greater Against the Influenza 2017 H7N9 Vaccine Strain After First H7N9 Vaccination
timeFrame: 21 days after first dose of H7N9
measure: Percentage of Participants Achieving Serum Neutralizing Antibody Titers of 1:40 or Greater Against the Influenza 2017 H7N9 Vaccine Strain at Baseline
timeFrame: Day 1
measure: Percentage of Participants Achieving Serum Neutralizing Antibody Titers of 1:40 or Greater Against the Influenza 2017 H7N9 Vaccine Strain After First H7N9 Vaccination
timeFrame: 21 days after first dose of H7N9
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham School of Medicine - Alabama Vaccine Research Clinic
state: Alabama
city: Baltimore
country: United States
facility: University of Maryland School of Medicine - Center for Vaccine Development - Baltimore
state: Maryland
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
Study officials:
References:
citation: Ortiz JR, Spearman PW, Goepfert PA, Cross K, Buddy Creech C, Chen WH, Parker S, Overton ET, Dickey M, Logan HL, Wegel A, Neuzil KM. Safety and immunogenicity of monovalent H7N9 influenza vaccine with AS03 adjuvant given sequentially or simultaneously with a seasonal influenza vaccine: A randomized clinical trial. Vaccine. 2022 May 20;40(23):3253-3262. doi: 10.1016/j.vaccine.2022.03.055. Epub 2022 Apr 22.