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

Sponsors and Collaborators:	U.S. Army Office of the Surgeon General GlaxoSmithKline
Information provided by:	Walter Reed Army Institute of Research (WRAIR)
ClinicalTrials.gov Identifier:	NCT00322049

Purpose

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.

Condition	Intervention	Phase
Dengue	Biological: Tetravalent live attenuated dengue vaccine	Phase I Phase II

MedlinePlus related topics: Dengue Fever

Drug Information available for: Immunoglobulins Globulin, Immune

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Prevention, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety Study
Official Title:	A Phase I/II Trial of Tetravalent Live Attenuated Dengue Vaccine in Flavivirus Antibody Naive Infants

Further study details as provided by Walter Reed Army Institute of Research (WRAIR):

Primary Outcome Measures:

Compare the reactogenicity in terms of solicited symptoms within the 21-day follow-up period after Dose 1 of the dengue vaccine vs. control vaccine. [ Time Frame: 21-day follow-up period after Dose 1 ]
Assess the immunogenicity of the dengue vaccine in terms of seroconversion 30 days post-Dose 2 of dengue vaccine for all four serotypes. [ Time Frame: 30 days post Dose 2 ]
Neutralizing (N) antibody titers >= 1:10 to each DEN serotype, one year and four years after the second dose of dengue/control vaccine. [ Time Frame: One and four years after 2nd dose of vaccine ]
Neutralizing (N) antibody titers >=1:10 to each DEN serotype, at booster visit prior to vaccination and one month after the booster dose, and Year 4 after primary vaccination (dengue group only). [ Time Frame: Booster visit , 1 month after Booster dose and Year 4 ]

Secondary Outcome Measures:

Assess the safety and reactogenicity of two doses of the dengue vaccine; [ Designated as safety issue: Yes ]
Assess the immunogenicity of the dengue vaccine in terms of appearance of neutralizing antibodies to each of four dengue virus serotypes and Japanese encephalitis (JE), 30 days after each dose of dengue vaccine and 30 days after the second dose of JE; [ Time Frame: 30 days after dengue vaccine and 30 days after 2nd dose of JE ]
Assess the immunogenicity of the dengue vaccine in terms of appearance of neutralizing antibodies to all dengue virus serotypes 30 days after Dose 1 of dengue vaccine; [ Time Frame: 30 days after Dose 1 vaccine ]
Explore the effect of prior dengue vaccination on immunogenicity of two (of three required) doses of JE vaccine given four and six weeks after completion of the dengue vaccination course. [ Time Frame: 4 and 6 weeks after completion of vaccinations ]
Explore the effect of prior dengue vaccination on reactogenicity of two doses of JE vaccine given four and six weeks after completion of the dengue vaccination course. [ Time Frame: 4 and 6 weeks after completion of vaccinations ]
Occurrence, intensity and relationship to vaccination of solicited adverse events (AE) within 21 days and unsolicited AEs within 31 days (days 0-30) follow-up after the dengue vaccine booster dose. [ Time Frame: Sol AE (21days) and Unsol AEs(31days) after vaccine booster dose ]
Occurrence, intensity and relationship to vaccination of unsolicited AEs within 31 days (days 0-30) after the dengue vaccine booster dose [ Time Frame: 31 days after vaccine booster dose ]
Occurrence and relationship to vaccination of all serious adverse events (SAEs) occurring throughout the study period.
Occurrence of hematological and biochemical values within or outside the normal ranges at booster visit, 10 days post booster dose and one month post booster dose. [ Time Frame: 10 days and 1 month post booster dose ]
Occurrence of alert values for safety laboratory determinations within 31 days post booster dose. [ Time Frame: Within 31 days post booster dose ] [ Designated as safety issue: Yes ]
Occurence of suspected and confirmed dengue within 31 days post booster dose. [ Time Frame: Within 31 days post booster dose. ]
Occurence of dengue viremia 10.

Estimated Enrollment:	51
Study Start Date:	February 2004
Estimated Study Completion Date:	December 2009
Estimated Primary Completion Date:	July 2009 (Final data collection date for primary outcome measure)

Detailed Description:

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 administerd 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 two years following dose 3 from all 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?

Eligibility

Ages Eligible for Study:	12 Months to 15 Months
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

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.

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00322049

Locations

Thailand
USAMC-AFRIMS/Department of Pediatrics, Pharamongkutklao Hospital
Bangkok, Thailand, 10400

Sponsors and Collaborators

U.S. Army Office of the Surgeon General

GlaxoSmithKline

Investigators

Principal Investigator:	Robert V. Gibbons, MD	U.S. Army Medical Component Armed Forces Research Institute of Medical Sciences (USAMC-AFRIMS)
Principal Investigator:	Veerachai Watanaveeradej, MD	Infectious Disease Department of Pediatrics Phramongkutklao Hospital

More Information

Study ID Numbers:	WRAIR 824, HSRRB Log A-10064, GSK CPMS76610/001(Dengue-001)
Study First Received:	May 3, 2006
Last Updated:	September 9, 2008
ClinicalTrials.gov Identifier:	NCT00322049
Health Authority:	United States: Food and Drug Administration; United States: USAMMDA; Belgium: GSK

Keywords provided by Walter Reed Army Institute of Research (WRAIR):

Dengue, Vaccine, Thailand

Study placed in the following topic categories:

Virus Diseases
Fever
Antibodies
Hemorrhagic Fevers, Viral
Dengue
Hemorrhagic fever

Viral hemorrhagic fever
Dengue fever
Arbovirus Infections
Immunoglobulins
Dengue Hemorrhagic Fever

Additional relevant MeSH terms:

RNA Virus Infections
Flaviviridae Infections
Flavivirus Infections

ClinicalTrials.gov processed this record on January 14, 2009