Safety and Immunogenicity of Various Formulations of Live Attenuated Tetravalent Dengue Vaccine in Healthy US Adults

Study Overview
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Brief Summary
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This descriptive study will evaluate the safety and immunogenicity of 3 different formulations of the WRAIR dengue vaccine compared to a placebo.

Detailed Description
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Subjects will be randomized into one of 4 groups. One group will receive a placebo vaccine and the others will receive one of 3 different dengue vaccine formations. Each subject will receive two doses six months apart. Study subjects who elect to participate in a mosquito transmissibility component of the study will undergo mosquito feedings during each of the two assigned follow-up visits after vaccine dose 1. All subjects will have 11 venipunctures during 11 visits (i.e., screening plus 10 study visits) over a period of nine months. A third (booster) dose of post transfection F17 or F19 will be administered approximately 5 to 12 months after dose 2 to all subjects who received one of these formulation for their first two doses. Volunteers will return for a single visit 6 months after receiving their booster dose (long term follow-up)

Official Title
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Phase II, Randomized, Observer-Blind, Single Center, Controlled Study of Two Doses of Various Formulations of WRAIR Live Attenuated Tetravalent Dengue Vaccine Compared to Placebo Control Administered on 0-6-Month Schedule to Healthy Adults

Conditions
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Dengue

Intervention / Treatment
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* Biological: Pre-transfection F17
* Biological: Post-transfection F17
* Biological: Post-transfection F19
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A healthy male or female adult 18-45 years at the time of vaccination; Free of obvious health problems as established by medical history and physical examination before entering into the study; Written informed consent obtained from the subject; Able to read the Subject Information Sheet and Consent Form; Subjects who the investigator believes can and will comply with the requirements of the protocol (e.g., completion of the diary cards, return for follow-up visits) should be enrolled in the study; If the subject is female, she must be of non-childbearing potential, i.e. either surgically sterilized or one year post-menopausal; or, if of childbearing potential, she must be abstinent or have used adequate contraceptive precautions (i.e. intrauterine contraceptive device; oral contraceptives or other equivalent hormonal contraception, e.g. progestin implantable, cutaneous hormonal patch or injectable contraceptives) for 30 days prior to vaccination, have a negative pregnancy test within 48 hours prior to vaccination and must agree to continue such precautions for 60 days after completion of the vaccination series. Exclusion Criteria: Pregnant or lactating female; Female planning to become pregnant or planning to discontinue abstinence or contraceptive precautions; History of any neurological or behavioral disorder or seizures, with the exception of a single febrile seizure in childhood; History of drug abuse or alcohol consumption (more than 2 drinks per day); History of allergic disease/reaction likely to be exacerbated by any component of the vaccine; History of urticaria related to mosquito bites requiring medical attention; Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic, renal, hematologic or endocrine functional defect, as determined by physical examination or laboratory tests; Any confirmed or suspected immunosuppressive or immunodeficient condition; Subject seropositive for HBsAg, anti-HCV or anti-HIV; Acute disease at the time of enrollment (acute disease is defined as the presence of a moderate or severe illness with or without fever); (Vaccine can be administered to persons with a minor illness such as diarrhea, mild upper respiratory infection with or without low-grade febrile illness, i.e., oral temperature <37.5°C/<99.5°F.) Chronic hepatomegaly, right upper quadrant abdominal pain or tenderness; Chronic splenomegaly, left upper quadrant abdominal pain or tenderness; Use of any investigational or non-registered drug or vaccine other than the study vaccine within 30 days preceding the study vaccine (includes placebo) or planned use during the study period; Planned administration of a vaccine not foreseen by the study protocol during the period starting from 30 days before each dose of the study vaccine and ending 30 days after; A planned move to a location that will prohibit participating in the trial for 9 months after the initial vaccination; Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within 90 days preceding the first dose or planned administration during the study period. For corticosteroids, this will mean prednisone, or equivalent, 0.5 mg/kg/day. Inhaled and topical steroids are allowed; Administration of immunoglobulins and/or blood products within 90 days preceding the first dose or planned administration during the study period; Any chronic systemic drug therapy to be continued during the study period (except for vitamin/mineral supplements, a single anti-hypertension medication or routine treatment for gastro-esophageal reflux).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pre-transfection F17<br>4 monovalent vaccine lots: DEN type 1 45AZ5 PDK-27, Lot 1-1-90 DEN type 2 S16803 PDK-50, Lot 1-1-90 DEN type 3 CH53489 PDK-20 DEN type 4 341750 PDK-6, Lot 1-1-90 in 50% EMEM stabilizer, streptomycin, neomycin and vegetable-derived carbohydrates and amino acids stabilizers for injection. Freeze-dried monovalent dengue vaccines were rehydrated with sterile water for injection diluted to match viral concentration of the F17 Post vaccine | Biological: Pre-transfection F17<br>* Dengue tetravalent Vaccine F17 Pre transfection: 0.5 mL volume per dose, administered at 0 and 6 months via subcutaneous injection<br>|
| Experimental: Post-transfection F17<br>4 monovalent vaccine lots: DEN type 1: 4.9 log10 FFU/mL DEN type 2 : 5.3 log10 FFU/mL DEN type 3: 4.7 log10 FFU/mL DEN type 4: 5.0 log10 FFU/mL in 50% EMEM stabilizer, streptomycin, neomycin and vegetable-derived carbohydrates and amino acids stabilizers for injection. Lyophilized, single dose vials and sterile water for injection | Biological: Post-transfection F17<br>* Dengue tetravalent Vaccine F17 Post transfection: 0.5 mL volume per dose, administered at 0 and 6 months via subcutaneous injection. For the booster phase of the study, a booster dose was administered at five months to one year following the second dose.<br>|
| Experimental: Post-transfection F19<br>4 monovalent vaccine lots: DEN type 1: 4.9 log10 FFU/mL DEN type 2: 5.2 log10 FFU/mL DEN type 3: 4.6 log10 FFU/mL DEN type 4: 4.4 log10 FFU/mL (1:10 dilution) in 50% EMEM-stabilizer, streptomycin, neomycin and vegetable-derived carbohydrates and amino acids stabilizers for injection. Lyophilized, single dose vials and sterile water for injection | Biological: Post-transfection F19<br>* Dengue tetravalent Vaccine F19 Post transfection: 0.5 mL volume per dose, administered at 0 and 6 months via subcutaneous injection. For the booster phase of the study, a booster dose was administered at five months to one year following the second dose.<br>|
| Placebo Comparator: Placebo<br>A sterile solution of the same EMEM, with phenol red (1:1) and the same virus stabilizer contained in the vaccine. The phenol red dye (phenolsulfonphthalein) is an FDA-accepted vaccine excipient used in vaccines as a pH indicator. The placebo was identical in appearance to the dengue vaccine. | Other: Placebo<br>* Sterile solution of buffered water (0.9% NaCl), U.S. FDA accepted vaccine excipient, phenol red dye(phenolsulfonphthalein, used in vaccines as a pH indicator); 0.5 mL volume per dose, administered at 0 and 6 months via subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| N Antibody, Geometric Mean Titer(GMT) to Dengue Serotypes 1, 2, 3 and 4 | GMTs for DEN neut. antibodies -unprimed subjects (primary and booster ATP Cohort for immunogenicity) PRE = Pre dose PI(M1) = Post dose 1, month 1 PII(M7) = Post dose 2, month 7 PRE III = Pre dose 3 PIII(M1) = Post dose 3, month 1 | Pre dose 1, 1 month post dose 1, 7 months post dose 2, Pre dose 3 and 1 month post dose 3 | 
| Percentage of Subjects Seropositive for Dengue Serotypes 1, 2, 3 and 4 | Serpositivity rates for DEN neut. antibodies -unprimed subjects (primary and booster ATP Cohort for immunogenicity) PRE = Pre dose PI(M1) = Post dose 1, month 1 PII(M7) = Post dose 2, month 7 PRE III = Pre dose 3 PIII(M1) = Post dose 3, month 1 | Pre dose 1, 1 month post dose 1, 7 months post dose 2, Pre dose 3 and 1 month post dose 3 | 
| Occurrence of Any, and Grade 3 Solicited Adverse Events (AEs) Within 21 Days Follow-up After Dose 1 of Study Vaccine | Diary cards, digital thermometers, and small rulers were provided to subjects to record local and general solicited symptoms(pain, redness and swelling at the injection site, fatigue, headache, pain behind the eyes, abdominal pain, nausea, vomiting, muscle aches, joint aches, rash, photophobia and pruritis) and oral temperature taken daily for 21 days (days 0 through 20). The observations were to be recorded each evening and account for the previous 24 hours. If multiple temperature measurements were taken throughout the day, the maximum temperature was to be recorded. | 21 days following 1st vaccination dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Any, and Grade 3 Solicited Adverse Events (AEs) Within 21 Days Follow-up After Dose 2 of Study Vaccine; |  | within 21 days after vaccination | 
| Unsolicited Adverse Events Within 31 Days After Each Dose of Study Vaccine Dose | Summary of Unsolicited Adverse Events within 31 days after each dose of study vaccine dose (Primary total vaccinated cohort) | within 31 days of study vaccine | 
| Occurrence of Serious Adverse Events (SAEs) Throughout the Entire Study Period. | Serious adverse events will be recorded throughout the entire study period. Subjects instructed to contact the investigator immediately should they manifest any signs or symptoms they perceive as serious. An identification card and a set of phone numbers to contact study staff 24 hours a day, 7 days a week given to subjects. | Days 0 to 270 | 
| Occurrence of Abnormal Findings at Physical Examination After Each Vaccine Dose | Abnormal findings at DEN physical examination were defined as: rash, generalized rash, hemorrhages (skin, conjunctival or mucosal), conjunctival injection, hepatomegaly, splenomegaly or lymphadenopathy; generalized lymphadenopathy (palpable lymph nodes in 4 or more of the following locations: cervical, axillary, inguinal or other with right and left sides considered as separate locations) positive tourniquet test (WHO criterion of 20 or more petechiae per 2.5 cm square)Results were reported positive/negative using the WHO criterion. | throughout the 202 day study | 
| Percentage of Subjects With Suspected and Confirmed Dengue Reported During the 31-day Post-vaccination Period (Total Vaccinated Cohort) | The case definition of confirmed dengue used in this protocol requires fever (equivalent to an oral temperature ≥38.0ºC/≥ 100.4ºF) for three or more successive days, at least two of the signs or symptoms consistent with suspected dengue occurring during the period of fever, at least one clinical laboratory abnormality, and DEN viremia detected by RTqPCR. Cases not meeting all criteria were not considered confirmed dengue. The percentage of subjects with suspected or confirmed dengue were tabulated by group after each vaccination. | Days 0-30 post vaccination periods (total vaccinated cohort) | 
| Neutralizing Antibody Sero-response to Each Dengue Serotype After Each Dose | Sero-response defined as: For initially seronegative(S-) subjects, antibody titer >=10 DE50 at PI(M1) For initially seropositive(S+) subjects, antibody titer at PI(M1) >=4 fold the pre-vacciniation neut. antibody titer | Days 0 to 270 | 
| Neutralizing Antibody Sero-response to Each Dengue Serotype After Each Dose (Continued) | Sero-response defined as: For initially seronegative(S-) subjects, antibody titer >=10 DE50 at PI(M1) For initially seropositive(S+) subjects, antibody titer at PI(M1) >=4 fold the pre-vacciniation neut. antibody titer | Days 0 to 270 | 
| Occurrence of Measurable Dengue Viremia at Specified Time Points Following Each Vaccine Dose. | For vireimia: Negative = GEQ/µl result is equal to zero Undetermined = GEQ/µL result is below LOD Positive = GEQ/µL result is >= LOD | Days 0 to 270 |