Avian Influenza, Immunisation
Conditions
Keywords
H7N9 pandemic, inactivated influenza vaccine (pIIV), live attenuated influenza vaccine (pLAIV), MF59 adjuvant
Brief summary
A phase I prospective, randomized study in healthy adult subjects at a single center. Adult subjects age 18 to 47 years and meeting all enrollment criteria will choose to participate as subjects who receive inactivated vaccine followed by a live vaccine boost at 4 weeks (Group 1), 12 weeks (Group 2), or 24 weeks (Group 3), or to be in an observational group (Group 4) which will not be scheduled for a booster dose but may serve as a roll-over group for subjects who withdraw prior to the second vaccination but agree to remain in follow-up. A fifth group will receive two intramuscular doses of adjuvanted H7N9 pIIV separated by four weeks. The primary objectives of this study are to (1) assess the safety of H7N9 pLAIV administered to individuals who have previously received MF59-adjuvanted or unadjuvanted H7N9 pIIV, (2) evaluate the ability of a single dose of unadjuvanted H7N9 pIIV to prime for enhanced immunogenicity (booster response) to subsequent administration of antigenically-matched H7N9 pLAIV vaccine, and to (3) evaluate the ability of a single dose of MF59-adjuvanted H7N9 pIIV to prime for enhanced immunogenicity (booster response) to subsequent administration of antigenically-matched H7N9 pLAIV vaccine.
Detailed description
The study will be conducted as a Phase I prospective, randomized study in healthy adult subjects at a single center. Adult subjects age 18 to 47 years and meeting all enrollment criteria will choose to participate as subjects who receive unadjuvanted or adjuvanted H7H9 pIIV vaccine followed by a live vaccine boost at 4 weeks (Group 1, n=24), 12 weeks (Group 2, n=24), or 24 weeks (Group 3, n=24), or to be in an observational group (Group 4, n=16) which will not be scheduled for a booster dose but may serve as a roll-over group for subjects who withdraw prior to the second vaccination but agree to remain in follow-up. Within each group, subjects will be randomized at a 1:1 ratio to receive a single dose of either unadjuvanted H7N9 pIIV at 15 mcg (Subgroup A), or the same vaccine adjuvanted with the oil-in-water emulsion, MF59, (Subgroup B) delivered intramuscularly. Finally, a fifth group (Group 5, n=12) will receive two intramuscular doses of adjuvanted H7N9 pIIV separated by four weeks. The total duration of study participation for all subjects will be approximately 13 months. Recruitment, enrollment and administration of study product will be suspended when one of the following occurs in the clinical or research laboratory at the clinical site: at least two respiratory cultures or PCR assays are determined to be positive for influenza or at least 10% diagnostic tests (rapid tests, respiratory cultures or PCR assays) performed for influenza as positive during two consecutive weeks in the clinical or research laboratory at the clinical site. Recruitment, enrollment and administration of study product may be resumed after 2 weeks without a signal that influenza is still circulating in the community, as defined by the same measures that indicate the start of influenza season (i.e., less than 2 respiratory cultures or PCR assays are determined to positive for influenza or less than 10% of diagnostic tests performed or influenza with positive results). The primary objectives of this study are to (1) assess the safety of H7N9 pLAIV administered to individuals who have previously received MF59-adjuvanted or unadjuvanted H7N9 pIIV, (2) evaluate the ability of a single dose of unadjuvanted H7N9 pIIV to prime for enhanced immunogenicity (booster response) to subsequent administration of antigenically-matched H7N9 pLAIV vaccine, and to (3) evaluate the ability of a single dose of MF59-adjuvanted H7N9 pIIV to prime for enhanced immunogenicity (booster response) to subsequent administration of antigenically-matched H7N9 pLAIV vaccine. The secondary objectives of this study are to (1) assess the safety of priming with MF59-adjuvanted H7N9 pIIV or unadjuvanted H7N9 pIIV, (2) assess the immune response in subjects vaccinated with a single dose of MF59-adjuvanted H7N9 pIIV or a single dose of unadjuvanted H7N9 pIIV, and to (3) compare the booster effect seen after intervals of 4 weeks, 12 weeks, or 24 weeks within each priming group.
Interventions
BIOLOGICALInfluenza Virus Vaccine, Live Attenuated H7N9 Anhui 2013/AA ca
MedImmune supplies pLAIV vaccines as a colorless to pale yellow and clear to slightly cloudy suspension in single, unit-dose, Becton-Dickinson Accuspray™ Nasal Spray Systems sprayer devices. Each filled sprayer device contains a 0.5 mL dose of 10\^7FFU of H7N9 Anhui 2013/AA ca vaccine. Group I receives the IN dose on Day 29, Group 2 on Day 85, and Group 3 on Day 169.
Sanofi supplies the monovalent influenza A/H7N9 virus vaccine as a sterile, clear, and slightly opalescent suspension in single-dose vials containing 15 mcg HA per 0.5 mL. Group 1 through Group5 will receive the IM vaccine on Day 1
DRUGMF59 adjuvant
Novartis supplies the MF59 adjuvant as an oil-in-water milky emulsion in single-use vials containing a fill volume of 0.7 mL. Group 1 through Group 5 will receive MF59 IM on Day 1.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 47 Years
Healthy volunteers
Yes
Inclusion criteria
1. Provide written informed consent prior to initiation of any study procedures, including future use of specimens. 2. Are able to understand and comply with planned study procedures and be available for all study visits. 3. Are males or non-pregnant, non-breastfeeding females, 18 to 47 years old, inclusive. 4. Are in good health, as determined by medical history, and targeted physical examination to ensure any existing medical diagnoses or conditions (except those exclusionary) are stable\* \*\*. \*Stable chronic medical condition - no change in prescription medication, dose, or frequency of medication in the last 3 months (defined as 90 days) and health outcomes of the specific disease are considered to be within acceptable limits in the last 6 months (defined as 180 days). Any 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 violation 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 violation 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. Note: Topical, nasal, and inhaled medications (with the exception of steroids as outlined in the Subject
Exclusion criteria
), vitamins, and contraceptives are permitted. 5. Oral temperature is less than 100.4 degrees Fahrenheit. 6. Pulse is 55 to 100 bpm, inclusive. 7. Systolic blood pressure is 90 to 140 mmHg, inclusive. 8. Diastolic blood pressure is 55 to 90 mmHg, inclusive. 9. Women of childbearing potential\* in sexual relationships with men must use an acceptable method of contraception\*\* from 30 days prior to pIIV administration until 90 days after last study vaccination. \*Not sterilized via tubal ligation, bilateral oophorectomy or hysterectomy and still menstruating or \< 1 year of the last menses if menopausal). \*\*Includes, but is not limited to, abstinence from intercourse with a male partner, monogamous relationship with a vasectomized partner, male condoms with the use of applied spermicide, intrauterine devices, and licensed hormonal methods, with use of a highly effective method of contraception for a minimum of 30 days prior to study product exposure and agree to practice highly effective contraception for the duration of study product exposure, including 3 months (defined as 90 days) after the last study vaccination. A highly effective method of contraception is defined as one which results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly. 10. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 24 hours prior to study vaccination.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of subjects achieving a serum HAI antibody titer of 1:40 or greater against the H7N9 antigen contained in the study vaccines for Group 3 | Day 197 |
| Geometric mean titers determined by neuraminidase inhibiting antibody by enzyme-linked lectin assay (ELLA) | Day 29 |
| Geometric mean titers determined by neuraminidase inhibiting antibody by enzyme-linked lectin assay (ELLA) for Group 2 | Day 113 |
| Geometric mean titers determined by neuraminidase inhibiting antibody by enzyme-linked lectin assay (ELLA) for Group 3 | Day 197 |
| Geometric mean titers determined by neuraminidase inhibiting antibody by enzyme-linked lectin assay (ELLA) for Groups 1, 5 | Day 57 |
| Occurrence of respiratory reactogenicity following pLAIV vaccination for Group 1 | Day 29 through Day 39 |
| Occurrence of respiratory reactogenicity following pLAIV vaccination for Group 2 | Day 85 through Day 95 |
| Occurrence of respiratory reactogenicity following pLAIV vaccination for Group 3 | Day 169 through Day 179 |
| Occurrence of solicited systemic reactogenicity following pLAIV vaccination for Group 1 | Day 29 through Day 39 |
| Occurrence of solicited systemic reactogenicity following pLAIV vaccination for Group 2 | Day 85 through Day 95 |
| Occurrence of solicited systemic reactogenicity following pLAIV vaccination for Group 3 | Day 169 through Day 179 |
| Occurrence of study vaccine-related serious adverse events following pLAIV vaccination for Group 1 | Day 29 through Day 209 |
| Occurrence of study vaccine-related serious adverse events following pLAIV vaccination for Group 2 | Day 85 through Day 265 |
| Occurrence of study vaccine-related serious adverse events following pLAIV vaccination for Group 3 | Day 169 through Day 349 |
| Occurrence of study vaccine-related unsolicited non-serious adverse events following pLAIV vaccination for Group 1 | Day 29 through Day 57 |
| Occurrence of study vaccine-related unsolicited non-serious adverse events following pLAIV vaccination for Group 2 | Day 85 through 113 |
| Occurrence of study vaccine-related unsolicited non-serious adverse events following pLAIV vaccination for Group 3 | Day 169 through 197 |
| Percentage of subjects achieving a serum HAI antibody titer of 1:40 or greater against the H7N9 antigen contained in the study vaccines for Group 2 | Day 113 |
| Percentage of subjects achieving a serum HAI antibody titer of 1:40 or greater against the H7N9 antigen contained in the study vaccines for Groups 1, 5 | Day 57 |
| Percentage of subjects achieving seroconversion (a pre-vaccination HAI titer <1:10 and a post-vaccination HAI titer = / > 1:40 or a pre-vaccination HAI titer = / > 1:10 and a minimum four-fold rise in post-vaccination HAI antibody titer) for Group 2 | Day 113 |
| Percentage of subjects achieving seroconversion (a pre-vaccination HAI titer <1:10 and a post-vaccination HAI titer = / > 1:40 or a pre-vaccination HAI titer = / > 1:10 and a minimum four-fold rise in post-vaccination HAI antibody titer) for Group 3 | Day 197 |
| Percentage of subjects achieving seroconversion (a pre-vaccination HAI titer <1:10 and a post-vaccination HAI titer = / > 1:40 or a pre-vaccination HAI titer = / > 1:10 and a minimum four-fold rise in post-vaccination HAI antibody titer) for Groups 1,5 | Day 57 |
| Percentage of subjects shedding vaccine virus as detected by rRT-PCR following pLAIV vaccination for Group 1 | Day 29 through Day 36 |
| Percentage of subjects shedding vaccine virus as detected by rRT-PCR following pLAIV vaccination for Group 2 | Day 85 through Day 92 |
| Percentage of subjects shedding vaccine virus as detected by rRT-PCR following pLAIV vaccination for Group 3 | Day 169 through Day 176 |
| Percentage of subjects with positive B cell responses by plasmablast assays on peripheral blood mononuclear cells | Day 29 |
| Percentage of subjects with positive B cell responses by plasmablast assays on peripheral blood mononuclear cells for Group 2 | Day 113 |
| Percentage of subjects with positive B cell responses by plasmablast assays on peripheral blood mononuclear cells for Group 3 | Day 197 |
| Percentage of subjects with positive B cell responses by plasmablast assays on peripheral blood mononuclear cells for Groups 1, 5 | Day 209 |
Secondary
| Measure | Time frame |
|---|---|
| Percentage of subjects achieving a serum NtAb titer of 1:40 or greater against the H7N9 antigen contained in the study vaccines for Groups 1, 5 | Day 209 |
| Percentage of subjects achieving seroconversion (a pre-vaccination HAI titer <1:10 and a post-vaccination HAI titer = / > 1:40 or a pre-vaccination HAI titer = / > 1:10 and a minimum 4-fold rise in post-vaccination HAI antibody titer) | Day 29 |
| Percentage of subjects achieving seroconversion (a pre-vaccination HAI titer <1:10 and a post-vaccination HAI titer = / > 1:40 or a pre-vaccination HAI titer = / > 1:10 and a minimum 4-fold rise in post-vaccination HAI antibody titer) for Group 2 | Day 141 |
| Percentage of subjects achieving seroconversion (a pre-vaccination HAI titer <1:10 and a post-vaccination HAI titer = / > 1:40 or a pre-vaccination HAI titer = / > 1:10 and a minimum 4-fold rise in post-vaccination HAI antibody titer) for Group 3 | Day 225 |
| Geometric mean titers of serum HAI antibody for Group 3 | Day 197 |
| Percentage of subjects achieving seroconversion (a pre-vaccination NtAb titer <1:10 and a post-vaccination NtAb titer = / > 1:40 or a pre-vaccination NtAb titer = / > 1:10 and a minimum 4-fold rise in post-vaccination NtAb titer) | Day 29 |
| Percentage of subjects achieving seroconversion (a pre-vaccination NtAb titer <1:10 and a post-vaccination NtAb titer = / > 1:40 or a pre-vaccination NtAb titer = / > 1:10 and a minimum 4-fold rise in post-vaccination NtAb titer) for Group 2 | Day 113 |
| Percentage of subjects achieving seroconversion (a pre-vaccination NtAb titer <1:10 and a post-vaccination NtAb titer = / > 1:40 or a pre-vaccination NtAb titer = / > 1:10 and a minimum 4-fold rise in post-vaccination NtAb titer) for Group 3 | Day 197 |
| Percentage of subjects achieving seroconversion (a pre-vaccination NtAb titer <1:10 and a post-vaccination NtAb titer = / > 1:40 or a pre-vaccination NtAb titer = / > 1:10 and a minimum 4-fold rise in post-vaccination NtAb titer) for Groups 1, 5 | Day 209 |
| Percentage of subjects achieving seroconversion (a pre-vaccination HAI titer <1:10 and a post-vaccination HAI titer = / > 1:40 or a pre-vaccination HAI titer = / > 1:10 and a minimum 4-fold rise in post-vaccination HAI antibody titer) for Groups 1, 5 | Day 209 |
| Geometric mean titers of serum HAI antibody for Groups 1, 5 | Day 209 |
| Geometric mean titers of serum NtAb antibody | Day 1 |
| Geometric mean titers of serum NtAb antibody for Group 2 | Day 113 |
| Geometric mean titers of serum HAI antibody | Day 1 |
| Geometric mean titers of serum HAI antibody for Group 2 | Day 113 |
| Geometric mean titers of serum NtAb antibody for Group 3 | Day 197 |
| Geometric mean titers of serum NtAb antibody for Groups 1, 5 | Day 209 |
| Occurrence of adverse events of special interest following pIIV vaccination | Day 1 through Day 366 |
| Occurrence of adverse events of special interest following pIIV vaccination for Group 5 | Day 1 through Day 394 |
| Occurrence of local reactogenicity following pIIV vaccination | Day 1 through Day 8 |
| Occurrence of local reactogenicity following pIIV vaccination for Group 5 | Day 29 through Day 36 |
| Occurrence of new-onset chronic medical conditions for Group 2 | Day 1 through Day 265 |
| Occurrence of new-onset chronic medical conditions for Group 3 | Day 1 through Day 349 |
| Occurrence of new-onset chronic medical conditions for Group 4 | Day 1 through Day 181 |
| Occurrence of new-onset chronic medical conditions for Groups 1, 5 | Day 1 through Day 209 |
| Occurrence of study vaccine-related serious adverse events following pIIV vaccination | Day 1 through Day 366 |
| Occurrence of study vaccine-related serious adverse events following pIIV vaccination for Group 5 | Day 29 through Day 394 |
| Occurrence of study vaccine-related unsolicited non-serious adverse events following pIIV vaccination | Day 29 |
| Occurrence of study vaccine-related unsolicited non-serious adverse events following pIIV vaccination for Group 5 | Day 57 |
| Occurrence of systemic reactogenicity following pIIV vaccination | Day 1 through Day 8 |
| Occurrence of systemic reactogenicity following pIIV vaccination for Group 5 | Day 29 through Day 36 |
| Percentage of subjects achieving a serum HAI antibody titer of 1:40 or greater against the H7N9 antigen contained in the study vaccine | Day 1 |
| Percentage of subjects achieving a serum HAI antibody titer of 1:40 or greater against the H7N9 antigen contained in the study vaccine for Group 1, 5 | Day 209 |
| Percentage of subjects achieving a serum HAI antibody titer of 1:40 or greater against the H7N9 antigen contained in the study vaccine for Group 2 | Day 141 |
| Percentage of subjects achieving a serum HAI antibody titer of 1:40 or greater against the H7N9 antigen contained in the study vaccine for Group 3 | Day 225 |
| Percentage of subjects achieving a serum NtAb titer of 1:40 or greater against the H7N9 antigen contained in the study vaccines | Day 1 |
| Percentage of subjects achieving a serum NtAb titer of 1:40 or greater against the H7N9 antigen contained in the study vaccines for Group 2 | Day 113 |
| Percentage of subjects achieving a serum NtAb titer of 1:40 or greater against the H7N9 antigen contained in the study vaccines for Group 3 | Day 197 |
Countries
United States
Outcome results
None listed