A Phase I/II Trial of Tetravalent Live Attenuated Dengue Vaccine in Flavivirus Antibody Naive Infants

Study Overview
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Brief Summary
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The main target populations for the tetravalent live attenuated dengue virus vaccine are indigenous populations, especially infants less than 2 years old, residing in areas of the world endemic for dengue and at risk of developing dengue hemorrhagic fever (DHF). The presence of maternal dengue antibody during the first year of life makes it unlikely that a vaccine given during that time will have long-term efficacy, as the vaccine virus would likely be neutralized prior to necessary replication. Children older than 18 months may have preexisting flavivirus antibody. Therefore, vaccination of infants living in Thailand early in the second year of life (between the ages of 12 and 18 months) seems most beneficial. The aim of this trial is to evaluate the safety and immunogenicity of a two-dose schedule of a tetravalent live attenuated dengue vaccine in flavivirus antibody naïve infants beginning at 12-15 months of age. To assess the kinetics of dengue neutralizing antibodies to each dengue virus serotype one and four years following dose 2 of dengue/control vaccination in the setting of potential wild-type dengue virus exposure. To assess the immunogenicity, the safety and reactogenicity of a booster dose of dengue vaccine administered at Year 3 following primary vaccination.

Detailed Description
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This is a Phase I/II, randomized, observer-blind, controlled trial. Thirty-four flavivirus naïve infants will be randomized to the vaccine group and 17 infants to the control group. Infants receive dengue vaccine at study months 0 and 6 or control vaccine (Varicella vaccine at study month 0 and Haemophilus influenzae Type b Conjugate vaccine at study month 6). Both are licensed for use in Thailand. All infants subsequently receive an inactivated JE vaccine approximately one and 1.5 months following dengue vaccine dose 2. Infants are monitored daily for 21 days following each dengue or control vaccination and 7 days after each JE vaccination for solicited adverse events. Unsolicited events will be recorded up to 31 days (days 0-30) after dengue/control vaccinations and each day after dose 1 of JE vaccine until the concluding study visit. Study duration (excluding screening) is approximately 8.5 months for each subject. Each enrollee is followed a four year period following dose 2 of dengue/control vaccination to assess for dengue-related hospitalizations and dengue antibody kinetics. Investigators will administer a 3rd dose of tetravalent dengue vaccine to all subjects who received 2 doses of dengue vaccine (0 and 6 months) during the primary phase of the study. The 3rd dose will be administered 3 years following the primary vaccination series. Peripheral blood mononuclear cells (PBMCs) and sera will be collected at the time of dose 3, and twice again at one month and one year following dose 3 from dengue group subjects. Investigators will address the following questions: Is a 3rd dose of live virus tetravalent dengue vaccine safe in Thai toddlers/children? Is a 3rd dose of live virus tetravalent dengue vaccine required in toddlers/children to induce optimal immune (neutralizing antibody, cellular mediated immunity) responses? Is there evidence of T and B cell memory following a primary dengue vaccination series (dose 1 and 2)? How does a 3rd dose of live virus tetravalent dengue vaccine impact B and T cell memory?

Official Title
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A Phase I/II Trial of Tetravalent Live Attenuated Dengue Vaccine in Flavivirus Antibody Naive Infants

Conditions
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Dengue

Intervention / Treatment
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* Biological: Tetravalent live attenuated dengue vaccine
* Biological: Varicella vaccine and Haemophilus influenzae Type b Conjugate vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female infants between 12 and 15 months (12 and <16 months) of age at the time of the first dengue vaccination Free of obvious health problems as established by medical history and clinical examination before entering into the study. As a marker of nutritional status, an infant's weight to height ratio will be above the 5th percentile compared to the standards for same sex and age children cared for at Phramongkutklao Hospital, Bangkok, Thailand Written informed consent obtained from the parent of the subject. Amendment 8 Inclusion Criteria: Completed the Dengue-001 study having previously received 2 doses of experimental dengue vaccine according to protocol. Written informed consent obtained from the parent or guardian of the subject. (obtained in amendment 5) Written informed consent obtained from the parent or guardian of the subject who agrees to their child's participation to receive a dengue booster dose and booster follow-up. Exclusion Criteria: Use of any investigational or non-registered drug or vaccine other than the protocol-specified vaccines within 30 days preceding the administration of the first dose of dengue/control vaccine or planned use during the study period Administration of a registered vaccine within 30 days preceding the first study vaccination or planned administration within 30 days prior to, or 30 days after any protocol-specified vaccine administration MMR vaccination given within 60 days prior to the first dose of dengue/control vaccine (added bullet point, or planned administration within 60 days prior to, or 30 days after any protocol-specified vaccine administration Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs during the study period. (For corticosteroids, this will mean prednisone, or equivalent, 0.5 mg/kg/day. Inhaled and topical steroids are allowed. Any confirmed or suspected immunosuppressive or immunodeficient condition Any clinically significant history, including any seizures or other serious medical condition as determined by the investigator A first order family member (parent or sibling) with a history of chronic headaches A first order family member (parent or sibling) with a history of a congenital or hereditary immunodeficiency Abnormal clinical laboratory screening test results (based on normal values set by the laboratory) that are deemed clinically significant by study investigators and/or the Medical Monitor The presence of HBsAg or antibodies against HIV or HCV at screening Pre-existing antibody to dengue 1-4 virus serotypes or Japanese encephalitis virus (JEV) by HAI or PRNT50 at screening Previous vaccination against yellow fever virus, JEV, tick-borne encephalitis virus (TBE), varicella virus or booster dose of Hib in the second year of life History of varicella disease or invasive Haemophilus Influenzae B disease Acute disease at time of enrollment (Acute illness is defined as the presence of a moderate or severe illness with or without fever). All vaccines can be administered to persons with a minor illness such as diarrhea or mild upper respiratory infection with or without low-grade febrile illness, i.e., axillary temperature <37.5°C (<99.5°F). Administration of immunoglobulins and/or blood products since birth or planned administration during the study period Known allergic or idiosyncratic reaction to neomycin or related antibiotics (including streptomycin, gentamicin, amikacin, , tobramycin, kanamycin and bacitracin) Allergy to dogs or monkeys or hypersensitivity to proteins of rodent or neural origin Allergy to gelatin or hypersensitivity to thimerosal Infant whose parent has no easy access to a fixed or mobile telephone Parental illiteracy Plans to leave Bangkok during the first 8.5 months after initial vaccination or definite plans to move from Bangkok during the 5 years following first dose dengue/control vaccination. Amendment 8 Exclusion Criteria: -Any subject with confirmed dengue hemorrhagic fever during the 2 to 3 year period before booster dose administration will not be eligible for enrollment for the booster.

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 15 Months

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: Cohort A: Dengue Vaccine- Full Dose (T-DEN F17 )<br>Dengue vaccine at Months 0 and 6 and booster follow-up at 3 years; DEN candidate vaccine: One dose of the tetravalent, live attenuated DEN vaccine candidate, F17, contains dengue serotype 1, 2, 3 and 4 vaccines. This formulation contains 50 mcg/mL neomycin base, 5.5% lactose, and 1.9 g/dL human serum albumin; for subcutaneous injection. All infants subsequently received an inactivated JE vaccine approximately one and 1.5 months following dengue vaccine dose 2. The licensed JE vaccine in liquid form, was dosed at 0.25 ml for subcutaneous injection. | Biological: Tetravalent live attenuated dengue vaccine<br>* DEN candidate vaccine: One dose of the tetravalent, live attenuated DEN vaccine candidate, F17, contains dengue serotype 1, 2, 3 and 4 vaccines. This formulation contains 50 mcg/mL neomycin base, 5.5% lactose, and 1.9 g/dL human serum albumin; for subcutaneous injection. Infants received dengue vaccine at study months 0 and 6 or control vaccine (varicella vaccine at study month 0 and Haemophilus influenzae Type b Conjugate vaccine at study month 6). Both control vaccines are licensed for use in Thailand. All infants subsequently received an inactivated JE vaccine approximately one and 1.5 months following dengue vaccine dose 2. The licensed JE vaccine in liquid form, was dosed at 0.25 ml for subcutaneous injection. A booster dose of DEN vaccine was given to all subjects previously vaccinated with DEN vaccine in Dengue -001. The booster dose was administered approximately 42 months after dose 2 (at the Year 3 visit).<br>|
| Active Comparator: Cohort B: Control vaccines<br>Control vaccines: Hemophilus influenza type b (Hib) vaccine and varicella vaccine | Biological: Varicella vaccine and Haemophilus influenzae Type b Conjugate vaccine<br>* Infants received dengue vaccine at study months 0 and 6 or control vaccine (varicella vaccine at study month 0 and Haemophilus influenzae Type b Conjugate vaccine at study month 6). Both control vaccines are licensed for use in Thailand.<br>|
| Experimental: Cohort C: Dengue Vaccine - 1/10 Dose (T-DEN F17 )<br>Dengue vaccine at Months 0 and 6 and booster follow-up at 3 years | Biological: Tetravalent live attenuated dengue vaccine<br>* DEN candidate vaccine: One dose of the tetravalent, live attenuated DEN vaccine candidate, F17, contains dengue serotype 1, 2, 3 and 4 vaccines. This formulation contains 50 mcg/mL neomycin base, 5.5% lactose, and 1.9 g/dL human serum albumin; for subcutaneous injection. Infants received dengue vaccine at study months 0 and 6 or control vaccine (varicella vaccine at study month 0 and Haemophilus influenzae Type b Conjugate vaccine at study month 6). Both control vaccines are licensed for use in Thailand. All infants subsequently received an inactivated JE vaccine approximately one and 1.5 months following dengue vaccine dose 2. The licensed JE vaccine in liquid form, was dosed at 0.25 ml for subcutaneous injection. A booster dose of DEN vaccine was given to all subjects previously vaccinated with DEN vaccine in Dengue -001. The booster dose was administered approximately 42 months after dose 2 (at the Year 3 visit).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reactogenicity in Terms of Solicited Symptoms After Dose 1 of the Dengue Vaccine vs. Control Vaccine. | Local and general solicited reactogenicity using diary cards for 21 days (days 0-20) after the first dose of dengue/control vaccine | 21-day follow-up period after Dose 1 | 
| Geometric Mean Titers (GMT) for N Antibody to All Four Serotypes and Japanese Encephalitis (JE) Vaccine | Assess the immunogenicity of the dengue vaccine in terms of GMTs 30 days post-Dose 2 of dengue vaccine for all four serotypes (DEN-1, 2, 3, 4 and JE (Japanese encephalitis)). Analysis of immunogenicity was performed on the ATP cohort. | 30 days post Dose 2 | 
| Percent of Participants With Seronegative Neutralizing (N) Antibody Titers to Each DEN Serotype After Dose 2 | Seronegative for N antibody against DEN 1, 2, 3 and 4 antibody after dengue dose 2. Seronegative (antibody titer <10 1/Dil for N lg to DEN-1, N lg to DEN-2, N lg to DEN-3, N lg) prior to vaccination. | month 7 after dose 2 | 
| Percent of Participants With Seronegative Neutralizing (N) Antibody Titers to Each DEN Serotype After Dengue Dose 2 (and 2 Doses of JE | Seropositivity for N antibody against DEN 1, 2, 3 and 4 antibody after dengue dose 2 (and 2 doses of JE). Seronegative (antibody titer <10 1/Dil for N lg to DEN-1, N lg to DEN-2, N lg to DEN-3, N lg) prior to vaccination. | month 8.5 | 
| JE Vaccine Response | Seropositivity rates and GMTs for N lg to JEV antibodies. Pre= Pre vaccination, blood sampling prior to the first vaccine dose; PI(M1)= Post 1, month 1, blood sampling one month after dose 1 at study month 1; PI(M6)= Post 1, month 6, blood sampling 6 months after dose 1 at study month 6; PII(M7)= Post II, month 7, blood sampling one month after dose 2 at study month 7; PIV(M8.5)= Post IV, month 8.5, blood sampling after 2 doses of dengue/control and 2 doses of JE vaccines at study month 8.5 | Pre-vaccination, 1, 6, 7 and 8.5 months after two doses of dengue vaccine | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dengue Specific Symptoms | Percentage of subjects showing incidence of dengue specific symptoms during the 30-day follow-up period after vaccinations | 30-day follow-up period after dose 1 and 2 | 
| Percentage of Subjects With a Dengue Viremia 10 Days Post Booster Dose | Percentage of subjects with a dengue viremia 10 days after each dose of vaccine. RT PCR = Reverse-transcriptase polymerase chain reaction Nested PCR - Nested polymerase chain reaction Per protocol, all participants receiving a Dengue Vaccine were combined for Dengue Viremia assessment via RT-PCR and Nested PCR | 10 days after post dose 1 and 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dengue, Vaccine, Thailand