H5N1 Priming and Boosting Strategies | NCT00703053

ID	Type	Description	Link
N01AI80003C

Description Module

Detailed Description

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.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Group 1	Experimental	25 subjects: Day 0, A/Vietnam/04 90 mcg; Day 7, A/Vietnam/04 90 mcg.	Biological: A/Vietnam/1203/04
Group 9	Experimental	100 subjects: Day 0, A/Vietnam/04 90 mcg; Day 28, A/Vietnam/04 90 mcg.	Biological: A/Vietnam/1203/04
Group 8	Experimental	100 subjects: Day 0, A/Vietnam/04 90 mcg.	Biological: A/Vietnam/1203/04
Group 7	Experimental	50 subjects: Day 0, A/Indonesia/05 90 mcg; Day 180, A/Indonesia/05 90 mcg.	Biological: A/Indonesia/05/05
Group 6	Experimental	50 subjects: Day 0, A/Vietnam/04 90 mcg; Day 180, A/Indonesia/05 90 mcg.	Biological: A/Vietnam/1203/04 Biological: A/Indonesia/05/05
Group 5	Experimental	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.

Interventions

Name	Type	Description	Arm Group Labels	Other Names
A/Vietnam/1203/04	Biological	Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine; dosages 45 mcg and 90 mcg.	Group 1 Group 2

Outcomes Module

Primary Outcomes

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

Secondary Outcomes

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

Eligibility Module

Eligibility Criteria

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.

Facility	Status	City	State	ZIP	Country	Contacts
The Hope Clinic of the Emory Vaccine Center		Decatur	Georgia	30030	United States
Mayo Clinic, Rochester - Vaccine Research Group

PubMed Identifier	Type	Citation	Retractions
21282194	Result	Belshe RB, Frey SE, Graham I, Mulligan MJ, Edupuganti S, Jackson LA, Wald A, Poland G, Jacobson R, Keyserling HL, Spearman P, Hill H, Wolff M; National Institute of Allergy and Infectious Diseases-Funded Vaccine and Treatment Evaluation Units. Safety and immunogenicity of influenza A H5 subunit vaccines: effect of vaccine schedule and antigenic variant. J Infect Dis. 2011 Mar 1;203(5):666-73. doi: 10.1093/infdis/jiq093. Epub 2011 Jan 31.

Arm/Group Information

ID	Title	Description
FG000	VN/VN, Day 0, 7	Day 0, Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine (VN); 90 mcg dosage; Day 7, Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine (VN); 90 mcg dosage.
FG001	VN/VN, Day 0, 14	Day 0, Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine (VN); 90 mcg dosage; Day 14, Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine (VN); 90 mcg dosage.
FG002	I/I, Day 0, 28	Day 0, Inactivated subvirion influenza rg A/Indonesia/05/05 (clade 2) x PR8 A/H5N1 vaccine (I); 90 mcg dosage; Day 28, Inactivated subvirion influenza rg A/Indonesia/05/05 (clade 2) x PR8 A/H5N1 vaccine (I); 90 mcg dosage.
FG003	VN/I, Day 0, 28	Day 0, Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine (VN); 90 mcg dosage; Day 28, Inactivated subvirion influenza rg A/Indonesia/05/05 (clade 2) x PR8 A/H5N1 vaccine (I); 90 mcg dosage.
FG004	VN+I/VN+I, Day 0, 28	Day 0, Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine (VN); 45 mcg dosage and Inactivated subvirion influenza rg A/Indonesia/05/05 (clade 2) x PR8 A/H5N1 vaccine (I); 45 mcg dosage; Day 28, Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine (VN); 45 mcg dosage and Inactivated subvirion influenza rg A/Indonesia/05/05 (clade 2) x PR8 A/H5N1 vaccine (I); 45 mcg dosage.
FG005	VN/I, Day 0, 180	Day 0, Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine (VN); 90 mcg dosage; Day 180, Inactivated subvirion influenza rg A/Indonesia/05/05 (clade 2) x PR8 A/H5N1 vaccine (I); 90 mcg dosage.
FG006	I/I, Day 0, 180	Day 0, Inactivated subvirion influenza rg A/Indonesia/05/05 (clade 2) x PR8 A/H5N1 vaccine (I); 90 mcg dosage; Day 180, Inactivated subvirion influenza rg A/Indonesia/05/05 (clade 2) x PR8 A/H5N1 vaccine (I); 90 mcg dosage.
FG007	VN, Day 0	Day 0, Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine (VN); 90 mcg dosage.
FG008	VN/VN, Day 0, 28	Day 0, Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine (VN); 90 mcg dosage; Day 28, Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine (VN); 90 mcg dosage.

ID	Title	Description
BG000	VN/VN, Day 0, 7	Day 0, Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine (VN); 90 mcg dosage; Day 7, Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine (VN); 90 mcg dosage.
BG001	VN/VN, Day 0, 14

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical			Count of Participants

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

Analyses are based on a modified intent to treat population. 1 subject is excluded at all timepoints due to steroid receipt. 21 subjects not receiving vaccination 2 and one misdosed at vaccination 2 were dropped at timepoints post vaccination 2 only, as were 5 due to receipt of prohibited vaccines/steroids.

Posted

Geometric Mean

95% Confidence Interval

Titer

28 days post last vaccination.

ID	Title	Description
OG000	VN/VN, Day 0, 7	Day 0, Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine (VN); 90 mcg dosage; Day 7, Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine (VN); 90 mcg dosage.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	VN/VN, Day 0, 7	Day 0, Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine (VN); 90 mcg dosage; Day 7, Inactivated subvirion influenza rg A/Vietnam/1203/04 (clade 1) x PR8 A/H5N1 vaccine (VN); 90 mcg dosage.

ID	Term
D007251	Influenza, Human
D005585	Influenza in Birds

ID	Term
D012141	Respiratory Tract Infections
D007239	Infections
D009976	Orthomyxoviridae Infections
D012327	RNA Virus Infections