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

• 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?

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.