H5N1 Priming and Boosting Strategies

Study Overview
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Brief Summary
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Severe disease in humans due to bird influenza viruses (H5N1) has led to concern that this virus may result in a widespread outbreak of bird flu. The purpose of this study is to evaluate the dose and dosing schedule for 2 different types of H5N1 vaccine. Participants will be randomly assigned to 1 of 9 possible vaccine groups. All participants will receive 2 doses of Clade 1, Clade 2, or combination Clade 1 and 2 on Day 0. All participants will receive a second dose of the same vaccine or a different vaccine type on study day 7, 14, 28 or 180. Study participants will include about 500 healthy adult subjects, ages 18-49 years old, who have no history of prior H5 flu exposure or vaccination. Study procedures may include medical history, physical exam, and blood sampling. Subject participation may last up to 372 days. Several DMID studies have recently evaluated H5N1 vaccines in healthy adults, 04-063, 05-0090, 05-0015, and 05-0043.

Detailed Description
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Severe disease in humans due to avian influenza viruses of the H5N1 subtype has raised concern regarding the potential emergence of these viruses in pandemic form. Results of earlier studies suggest that previous priming can significantly affect the responses to subsequent booster doses, even if these booster doses represent an antigenic variant. Both the length of time between priming and revaccination, as well as the antigenic relatedness of the priming and revaccination antigens, may impact the response. These issues could have an important impact on pre-vaccination strategies prior to the emergence of a pandemic. This study will evaluate immunogenicity with the same or with different H5 variants. In this study, different will be defined as clade 1 followed by clade 1, clade 1 followed by clade 2, clade 2 followed by clade 2, or a combination of clades 1 & 2 followed by a combination of clades 1 & 2. In addition, the study will evaluate the effect of the interval between doses on the subsequent response, with ultra-short intervals defined as 7 or 14 days, a short interval defined as 28 days and a long interval defined as 180 days. The study will evaluate whether the use of a longer duration between doses or cross-clade priming will result in enhanced immunogenicity. Primary objectives are: evaluate the dose and schedules of unadjuvanted inactivated subvirion H5N1 vaccines belonging to the same or different clades in H5-naïve, healthy adults; determine if boosting of subjects given the inactivated influenza rg A/Vietnam/1203/04 vaccine with a heterologous antigen inactivated influenza rg A/Indonesia/05/05 results in broader or higher immune responses compared with boosting with the homologous antigen; and evaluate the immune response to 2 doses of H5 vaccine given at times < 1 month apart. Secondary objectives are: determine the safety of 2 doses of inactivated H5 vaccines in healthy adults given at different schedules and antigen combinations; obtain additional information regarding the antibody response to a single dose and to ultra-short immunization schedules; and evaluate the effect on antibody levels after receiving an antigenic variant to the priming virus given as a booster or simultaneously. The study will be conducted as a randomized, prospective controlled, multi-center trial. Approximately 500 healthy adult subjects, aged 18-49, who have no history of prior H5 influenza exposure or vaccination will be enrolled. Subjects will be randomized to receive varying schedules, (2 doses separated by 7, 14, 28 or 180 days), and clades of unadjuvanted inactivated subvirion H5N1 vaccine.

Official Title
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A Phase II Randomized Study of the Safety and Immunogenicity of Vaccination Strategies Using One or Two Clades and Different Schedules of H5N1 Unadjuvanted, Inactivated Subvirion Influenza Vaccines in H5 Naïve Healthy Adults

Conditions
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Influenza

Intervention / Treatment
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* Biological: A/Vietnam/1203/04
* Biological: A/Indonesia/05/05


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women, 18 through 49 years old, who deny exposure to H5 virus or participation in an H5 vaccine study. In good health, as determined by vital signs (heart rate less than 100 bpm; blood pressure: systolic less than or equal to 140 mm Hg; diastolic less than or equal to 90 mm Hg; oral temperature less than 100.0 degrees Fahrenheit), medical history to ensure stable medical condition and a targeted physical examination, as indicated, based on medical history. A stable medical condition is defined as no recent change in prescription medication, dose, or frequency of medication in the last 3 months and health outcomes of the specific disease are considered to be within acceptable limits in the last 6 months. Any change that is due to change of health care provider, insurance company, etc, or is done for financial reasons, as long as in the same class of medication, will not be considered a violation of the inclusion criterion. Any change to prescription medication due to improvement of a disease outcome will not be considered a violation of the inclusion criterion. Women of childbearing potential (not surgically sterile or postmenopausal for greater than or equal to 1 year) must not be pregnant as indicated by a negative pregnancy test (urine or serum) within 24 hours prior to vaccine administration. Women of childbearing potential who are at risk of becoming pregnant must agree to practice adequate contraception (i.e., barrier methods, abstinence, monogamous relationship with vasectomized partner, intrauterine devices, Depo-Provera, Norplant, oral contraceptives, contraceptive patches or other licensed, effective methods) until 30 days following receipt of the last dose of vaccine. Able to understand and comply with planned study procedures. Able to provide informed consent prior to initiation of any study procedures and be available for all study visits. Exclusion Criteria: Has occupational exposure to poultry, to include but is not limited to chicken, turkey, or duck farmer, factory worker in poultry processing plant, veterinary staff that handles poultry; has recreational exposure to poultry, e.g. raising poultry in 4-H club, duck hunter that slaughters/handles the kill or history of previous H5N1 vaccination or exposure. Has a known allergy to eggs, egg products or other components of the vaccine (including gelatin, formaldehyde, octoxinol, thimerosal and egg or chicken protein). Is female of child-bearing potential who is breastfeeding or intends to become pregnant during the study period up to 30 days following receipt of the last dose of vaccine. Has immunosuppression as a result of an underlying illness or treatment with immunosuppressive or cytotoxic drugs, or use of anticancer chemotherapy or radiation therapy within the preceding 36 months. Has an active neoplastic disease (excluding non-melanoma skin cancer or prostate cancer that is stable in the absence of therapy) or a history of any hematologic malignancy. Active neoplastic disease is defined as no neoplastic disease or treatment for neoplastic disease within the past 5 years. Has long-term use (greater than 2 weeks) of oral or parenteral steroids (glucocorticoids), or high-dose inhaled steroids (>800 mcg/day of beclomethasone dipropionate or equivalent) within the preceding 6 months (nasal and topical steroids are allowed). Has a history of receiving immunoglobulin or other blood products within the 3 months prior to enrollment in this study. Has received any other licensed vaccines within 2 weeks (for inactivated vaccines) or 4 weeks (for live vaccines) prior to enrollment in this study, or plans to receive any other licensed vaccines within 2 weeks (for inactivated vaccines) or 4 weeks (for live vaccines) following each study vaccine. Has an acute or chronic medical condition that would render vaccination unsafe or would interfere with the evaluation of responses. This includes, but is not limited to solicited reactogenicity symptoms, known chronic liver disease, significant renal disease, unstable or progressive neurological disorders, diabetes mellitus, and transplant recipients. Has a history of severe reactions following vaccination with contemporary influenza virus vaccines. Has an acute illness or has an oral temperature greater than 99.9 degrees Fahrenheit (37.7 degrees Celsius) within 3 days prior to enrollment. Has received an experimental agent (vaccine, drug, biologic, device, blood product, or medication) within 1 month prior to enrollment in this study, or expects to receive an experimental agent during the study period. Has any condition that would, in the opinion of the site principal investigator place the subject at an unacceptable risk of injury or render the subject unable to meet the requirements of the protocol. Has a diagnosis of schizophrenia, bipolar disease or other severe (disabling) chronic psychiatric diagnosis. Has been hospitalized for psychiatric illness, history of suicide attempt or confinement for danger to self or others. Is receiving psychiatric drugs. Subjects who are receiving a single antidepressant drug and are stable for at least 3 months prior to enrollment without decompensating are allowed enrollment into the study. Has known human immunodeficiency virus, hepatitis B, or hepatitis C infection. Has a history of alcohol or drug abuse in the 5 years prior to enrollment. Has a history of Guillain-Barré syndrome. Has any condition that the investigator believes may interfere with successful completion of the study. Plans to enroll in another clinical trial (that has a study intervention in the form of drug, biologic or device that could interfere with safety assessment of H5N1 vaccine) at any time during the study period.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>25 subjects: Day 0, A/Vietnam/04 90 mcg; Day 7, A/Vietnam/04 90 mcg. | Biological: A/Vietnam/1203/04<br>* Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine; dosages 45 mcg and 90 mcg.<br>|
| Experimental: Group 9<br>100 subjects: Day 0, A/Vietnam/04 90 mcg; Day 28, A/Vietnam/04 90 mcg. | Biological: A/Vietnam/1203/04<br>* Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine; dosages 45 mcg and 90 mcg.<br>|
| Experimental: Group 8<br>100 subjects: Day 0, A/Vietnam/04 90 mcg. | Biological: A/Vietnam/1203/04<br>* Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine; dosages 45 mcg and 90 mcg.<br>|
| Experimental: Group 7<br>50 subjects: Day 0, A/Indonesia/05 90 mcg; Day 180, A/Indonesia/05 90 mcg. | Biological: A/Indonesia/05/05<br>* Inactivated subvirion influenza rg A/Indonesia/05/05 (clade 2) x PR8 A/H5N1 vaccine; dosages 45 mcg and 90 mcg.<br>|
| Experimental: Group 6<br>50 subjects: Day 0, A/Vietnam/04 90 mcg; Day 180, A/Indonesia/05 90 mcg. | Biological: A/Vietnam/1203/04<br>* Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine; dosages 45 mcg and 90 mcg.<br>Biological: A/Indonesia/05/05<br>* Inactivated subvirion influenza rg A/Indonesia/05/05 (clade 2) x PR8 A/H5N1 vaccine; dosages 45 mcg and 90 mcg.<br>|
| Experimental: Group 5<br>50 subjects: Day 0, A/Vietnam/04 45 mcg + A/Indonesia/05 45 mcg; Day 28, A/Vietnam/04 45 mcg + A/Indonesia/05 45 mcg. | Biological: A/Vietnam/1203/04<br>* Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine; dosages 45 mcg and 90 mcg.<br>Biological: A/Indonesia/05/05<br>* Inactivated subvirion influenza rg A/Indonesia/05/05 (clade 2) x PR8 A/H5N1 vaccine; dosages 45 mcg and 90 mcg.<br>|
| Experimental: Group 4<br>50 subjects: Day 0, A/Vietnam/04 90 mcg; Day 28, A/Indonesia/05 90 mcg. | Biological: A/Vietnam/1203/04<br>* Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine; dosages 45 mcg and 90 mcg.<br>Biological: A/Indonesia/05/05<br>* Inactivated subvirion influenza rg A/Indonesia/05/05 (clade 2) x PR8 A/H5N1 vaccine; dosages 45 mcg and 90 mcg.<br>|
| Experimental: Group 3<br>50 subjects: Day 0, A/Indonesia/05 90 mcg; Day 28, A/Indonesia/05 90 mcg. | Biological: A/Indonesia/05/05<br>* Inactivated subvirion influenza rg A/Indonesia/05/05 (clade 2) x PR8 A/H5N1 vaccine; dosages 45 mcg and 90 mcg.<br>|
| Experimental: Group 2<br>25 subjects: Day 0, A/Vietnam/04 90 mcg; Day 14, A/Vietnam/04 90 mcg. | Biological: A/Vietnam/1203/04<br>* Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine; dosages 45 mcg and 90 mcg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemagglutination Inhibition (HAI) Geometric Mean Titer (GMT) Against A/Vietnam/04 Antigen | The GMTs are as assessed by the HAI assay against the A/Vietnam/04 antigen at 28 days following the last vaccination. One group (VN, Day 0) receives only one vaccination, all other groups receive two vaccinations. | 28 days post last vaccination. | 
| Hemagglutination Inhibition (HAI) Geometric Mean Titer (GMT) Against A/Indonesia/05 Antigen | The GMTs are as assessed by the HAI assay against the A/Indonesia/05 antigen at 28 days following the last vaccination. One group (VN, Day 0) receives only one vaccination, all other groups receive two vaccinations. | 28 days post last vaccination. | 
| Number of Subjects Achieving a 4-fold or Greater HAI Antibody Titer Increase Against A/Vietnam/04 Antigen | The number of subjects who achieve a 4-fold or greater rise in titer, relative to the baseline (Day 0) titer, assessed by the HAI assay against the A/Vietnam/04 antigen at 28 days following the last vaccination. One group (VN, Day 0) receives only one vaccination, all other groups receive two vaccinations. Subjects whose baseline titer is <10 must have a post vaccination titer of at least 1:40 to be considered a 4-fold rise. | 28 days post last vaccination. | 
| Number of Subjects Achieving a 4-fold or Greater HAI Antibody Titer Increase Against A/Indonesia/05 Antigen | The number of subjects who achieve a 4-fold or greater rise in titer, relative to the baseline (Day 0) titer, assessed by the HAI assay against the A/Indonesia/05 antigen at 28 days following the last vaccination. One group (VN, Day 0) receives only one vaccination, all other groups receive two vaccinations. Subjects whose baseline titer is <10 must have a post vaccination titer of at least 1:40 to be considered a 4-fold rise. | 28 days post last vaccination. | 
| Number of Subjects Achieving a HAI Antibody Titer of 1:40 or Greater Against A/Vietnam/04 Antigen | The number of subjects who achieve a HAI antibody titer of 1:40 or greater as assessed by the HAI assay against the A/Vietnam/04 antigen at 28 days following the last vaccination. One group (VN, Day 0) receives only one vaccination, all other groups receive two vaccinations. | 28 days post last vaccination. | 
| Number of Subjects Achieving a HAI Antibody Titer of 1:40 or Greater Against A/Indonesia/05 Antigen | The number of subjects who achieve a HAI antibody titer of 1:40 or greater as assessed by the HAI assay against the A/Indonesia/05 antigen at 28 days following the last vaccination. One group (VN, Day 0) receives only one vaccination, all other groups receive two vaccinations. | 28 days post last vaccination. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Serious Adverse Events | Serious adverse events were collected at each study visit from the time of first vaccination through the final study visit at 180 days after the last vaccination. | Duration of study | 
| Number of Subjects Reporting Solicited Symptoms Within 7 Days of First Vaccination | Subjects record the occurrence of solicited symptoms on a Memory Aid for 7 days after first vaccination and review the Memory Aid with clinic staff at follow a up visit on Day 8. Subjects are counted if they indicated experiencing the symptom at any severity during the reporting period. The symptoms of redness and swelling were solicited as both functional grading as impact on daily activies as well as collected as a measured value in mm. The number reported for all symptoms is the number reporting greater than none. | 7 days after first vaccination | 
| Number of Subjects Reporting Solicited Symptoms Within 7 Days of Second Vaccination | Subjects record the occurrence of solicited symptoms on a Memory Aid for 7 days after the second vaccination and review the Memory Aid with clinic staff at a follow up visit on Day 8. Subjects are counted if they indicated experiencing the symptom at any severity during the reporting period. The symptoms of redness and swelling were solicited as both functional grading as impact on daily activies as well as collected as a measured value in mm. The number reported for all symptoms is the number reporting greater than none. | 7 days after second vaccination | 
| Neutralizing Geometric Mean Titer (GMT) Against A/Vietnam/04 Antigen | The GMTs are as assessed by the microneutralization assay against the A/Vietnam/04 antigen at 1 month following the last vaccination. One group (VN, Day 0) receives only one vaccination, all other groups receive two vaccinations. | 28 days post last vaccination. | 
| Neutralizing Geometric Mean Titer (GMT) Against A/Indonesia/05 Antigen | The GMTs are as assessed by the microneutralization assay against the A/Indonesia/05 antigen at 1 month following the last vaccination. One group (VN, Day 0) receives only one vaccination, all other groups receive two vaccinations. | 28 days post last vaccination. | 
| Number of Subjects Achieving a 4-fold or Greater Neutralizing Antibody Titer Increase Against A/Vietnam/04 Antigen | The number of subjects who achieve a 4-fold or greater rise in titer, relative to the baseline (Day 0) titer, assessed by the microneutralization assay against the A/Vietnam/04 antigen at 28 days following the last vaccination. One group (VN, Day 0) receives only one vaccination, all other groups receive two vaccinations. Subjects whose baseline titer is <10 must have a post vaccination titer of at least 1:40 to be considered a 4-fold rise. | 28 days post last vaccination. | 
| Number of Subjects Achieving a 4-fold or Greater Neutralizing Antibody Titer Increase Against A/Indonesia/05 Antigen | The number of subjects who achieve a 4-fold or greater rise in titer, relative to the baseline (Day 0) titer, assessed by the microneutralization assay against the A/Indonesia/05 antigen at 28 days following the last vaccination. One group (VN, Day 0) receives only one vaccination, all other groups receive two vaccinations. Subjects whose baseline titer is <10 must have a post vaccination titer of at least 1:40 to be considered a 4-fold rise. | 28 days post last vaccination. | 
| Number of Subjects Achieving Neutralizing Antibody Titer of 1:40 or Greater Against A/Vietnam/04 Antigen | The number of subjects who achieve a titer of 1:40 or greater as assessed by the microneutralization assay against the A/Vietnam/04 antigen at 28 days following the last vaccination. One group (VN, Day 0) receives only one vaccination, all other groups receive two vaccinations. | 28 days post last vaccination. | 
| Number of Subjects Achieving Neutralizing Antibody Titer of 1:40 or Greater Against A/Indonesia/05 Antigen | The number of subjects who achieve a titer of 1:40 or greater as assessed by the microneutralization assay against the A/Indonesia/05 antigen at 28 days following the last vaccination. One group (VN, Day 0) receives only one vaccination, all other groups receive two vaccinations. | 28 days post last vaccination. | 
| Hemagglutination Inhibition (HAI) Geometric Mean Titer (GMT) Against A/Vietnam/04 Antigen at 6 Months Post Last Vaccination | The GMTs are as assessed by the HAI assay against the A/Vietnam/04 antigen at 6 months following the last vaccination. One group (VN, Day 0) receives only one vaccination, all other groups receive two vaccinations. | Six months post last vaccination | 
| Hemagglutination Inhibition (HAI) Geometric Mean Titer (GMT) Against A/Indonesia/05 Antigen at 6 Months Post Last Vaccination | The GMTs are as assessed by the HAI assay against the A/Indonesia/05 antigen at 6 months following the last vaccination. One group (VN, Day 0) receives only one vaccination, all other groups receive two vaccinations. The CI shown as 5.0 to 5.0 reflect that all subjects had a titer of 5.0 for the VN,VN, Day 0,14 and VN, Day 0 groups. | Six months after last vaccination | 
| Neutralizing Geometric Mean Titer (GMT) Against A/Vietnam/04 Antigen at 6 Months Post Last Vaccination | The GMTs are as assessed by the microneutralization assay against the A/Vietnam/04 antigen at 6 months following the last vaccination. One group (VN, Day 0) receives only one vaccination, all other groups receive two vaccinations. | Six months post last vaccination | 
| Neutralizing Geometric Mean Titer (GMT) Against A/Indonesia/05 Antigen at 6 Months Post Last Vaccination | The GMTs are as assessed by the microneutralization assay against the A/Indonesia/05 antigen at 6 months following the last vaccination. One group (VN, Day 0) receives only one vaccination, all other groups receive two vaccinations. | Six months post last vaccination | 
| Hemagglutination Inhibition (HAI) Geometric Mean Titer (GMT) Against A/Vietnam/04 Antigen at 1, 2, 3 and 4 Weeks After 2 Doses | The kinetics of the antibody response to vaccination with A/Vietnam/04 is evaluated by the HAI GMT against the A/Vietnam/04 antigen at weekly intervals after receipt of 2 doses 7, 14 and 28 days apart | Weeks 1, 2, 3 and 4 after the second dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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influenza, H5N1, vaccine, avian influenza, parent protocol