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

This study has been completed.
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
U.S. Army Medical Research and Materiel Command
ClinicalTrials.gov Identifier:
NCT00322049
First received: May 3, 2006
Last updated: May 22, 2012
Last verified: May 2012
  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
Biological: Varicella vaccine and Haemophilus influenzae Type b Conjugate vaccine
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver)
Primary Purpose: Prevention
Official Title: A Phase I/II Trial of Tetravalent Live Attenuated Dengue Vaccine in Flavivirus Antibody Naive Infants

Resource links provided by NLM:


Further study details as provided by U.S. Army Medical Research and Materiel Command:

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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Assess the safety and reactogenicity of a booster dose of DEN vaccine given at Year 3 post primary vaccination [ Time Frame: Post booster day 5, day 10, day 21 and day 30 ] [ 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: Yes ]
  • Occurrence and relationship to vaccination of all serious adverse events (SAEs) occurring throughout the study period. [ Time Frame: Within 31 days of vaccine dose ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: Yes ]
  • 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. ] [ Designated as safety issue: Yes ]
  • Occurence of dengue viremia 10 days post booster dose [ Time Frame: 10 days post booster dose ] [ Designated as safety issue: Yes ]

Enrollment: 51
Study Start Date: February 2004
Study Completion Date: June 2009
Primary Completion Date: June 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dengue Vaccine
Dengue vaccine at Months 0 and 6 and booster follow-up at 3 years
Biological: Tetravalent live attenuated dengue vaccine

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).

Active Comparator: Control vaccines
Control vaccines: Hemophilus influenza type b (Hib) vaccine and varicella vaccine
Biological: Varicella vaccine and Haemophilus influenzae Type b Conjugate vaccine
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.

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 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:

  1. Is a 3rd dose of live virus tetravalent dengue vaccine safe in Thai toddlers/children?
  2. Is a 3rd dose of live virus tetravalent dengue vaccine required in toddlers/children to induce optimal immune (neutralizing antibody, cellular mediated immunity) responses?
  3. Is there evidence of T and B cell memory following a primary dengue vaccination series (dose 1 and 2)?
  4. 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. (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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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 Medical Research and Materiel Command
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

No publications provided by U.S. Army Medical Research and Materiel Command

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: U.S. Army Medical Research and Materiel Command
ClinicalTrials.gov Identifier: NCT00322049     History of Changes
Other Study ID Numbers: WRAIR 824, HSRRB Log A-10064, GSK CPMS7663310/001, DEN-001
Study First Received: May 3, 2006
Last Updated: May 22, 2012
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board
Thailand: Ethical Review Committee, Ministry of Public Health
Thailand: Ethical Review Committee, Royal Thai Army Medical Department

Keywords provided by U.S. Army Medical Research and Materiel Command:
Dengue, Vaccine, Thailand

Additional relevant MeSH terms:
Dengue
Arbovirus Infections
Virus Diseases
Flavivirus Infections
Flaviviridae Infections
RNA Virus Infections
Hemorrhagic Fevers, Viral

ClinicalTrials.gov processed this record on September 18, 2014