A Study of Two Doses of WRAIR Dengue Vaccine Administered Six Months Apart to Healthy Adults and Children

Phase II, Randomized, Double-blind, Placebo-controlled Study of Two Doses of WRAIR Live Attenuated Tetravalent Dengue Vaccine Formulations, Administered Six Months Apart, to Healthy Adults and Children

The purpose of this study is to evaluate the safety and effectiveness of two different formulations of an investigational dengue vaccine (T-DEN) against a placebo vaccine when two doses are given six months apart to adults and children.

Study Overview

• Status: Completed
• Conditions: Dengue Fever; Dengue Hemorrhagic Fever; Dengue Shock Syndrome
• Intervention / Treatment: Biological: T-DEN-Post-Transfection F17; Biological: T-DEN-Post-Transfection F19; Other: Placebo

Detailed Description

In this study, children and adults at multiple sites in Puerto Rico will be randomly allocated to receive one of two T-DEN formulations or placebo. Subjects will be stratified by age group (a specific number of subjects in each of 4 age groups [12 months to 50 years of age] will be enrolled). The study includes 6 scheduled visits and 4 scheduled venipunctures. Safety follow-up for dengue may require unscheduled visits and venipunctures.> Multiple DEN virus serotypes are endemic in Puerto Rico and all residents are considered to be at risk for dengue. The results of this phase II study will provide a basis for identifying the vaccine formulations which elicit neutralizing antibodies to all four dengue virus serotypes in a high proportion of vaccine recipients. The most immunogenic and well tolerated candidate formulation identified in this study will be considered for advancement to phase III development.>

• Study Type: Interventional
• Enrollment (Actual): 636
• Phase: Phase 2

Contacts and Locations

Study Locations

• Puerto Rico
  • Caguas, Puerto Rico, 00725
    • San Juan Batista Medical School
  • Carolina, Puerto Rico, 00983
    • Private Practice
  • Ponce, Puerto Rico, 00733
    • St Luke's Memorial Hospital
  • Rio Grande, Puerto Rico, 00745
    • Caparra Internal Medicine Research Center
  • Rio Piedras, Puerto Rico, 00926
    • Private Practice
  • Rio Piedras, Puerto Rico, 00935
    • RCMI Clinical Research Center
  • San German, Puerto Rico, 00683
    • Torre Medica San Vicente de Paul
  • San Juan, Puerto Rico, 00909-1711
    • Clinical Research PR
  • San Juan, Puerto Rico, 00917
    • Centro de Neumologia Pediatricia
  • San Juan, Puerto Rico, 00921
    • Private Practice
  • San Juan, Puerto Rico, 00936-5067
    • Dept Pediatria, Esc. De Medicina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 50 years (Child, Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:>

• Subjects who the investigator believes that they and/or their parents/guardians 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.>
• A healthy male or non-pregnant female between 12 months (mths) and 50 years (yrs) of age at the time of the first vaccination;>
• Free of obvious health problems as established by medical history and physical examination before entering into the study;>
• For children: 23mths of age, full compliance with the United States Advisory Committee on Immunization Practices (U.S. ACIP) recommended childhood immunization schedule;>
• Written informed consent obtained from the subject or a parent/guardian and assent for subjects 7-20 yrs of age;>
• If the subject is female, she must be of non-childbearing potential, i.e. either pre-menarcheal, 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; condom and spermicide combination, oral contraceptives or other equivalent hormonal contraception, e.g. progestin implantable, cutaneous hormonal patch or injectable contraceptives) for 30 days (dys) prior to vaccination, have a negative pregnancy test within 48 hrs prior to vaccination and must agree to continue such precautions for 60 dys after completion of the vaccination series. Any child who begins menarche during the study period must follow the same precautions listed above, from menarche until 60 dys after the second vaccine dose.>

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 allergic disease/reaction likely to be exacerbated by any component of the vaccine;>
• 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;>
• Acute disease at the time of enrollment (acute disease is defined as the presence of a moderate or severe illness with or without fever); note that 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., equivalent to an 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 dys preceding the first dose of study vaccine/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 dys before each dose of the study vaccine and ending 30 dys after; with the exception of standard infant and children "inactivated" vaccines or the inactivated influenza vaccine administered to adults or children; >
• A planned move to a location that will prohibit participating in the trial for the 12 mth duration;>
• Chronic administration (defined as more than 14 dys) of immunosuppressants or other immune-modifying drugs within 90 dys 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 dys preceding the first dose or planned administration during the study period;>
• Hypertension;>
• Chest pain, palpitations, dizziness, shortness of breath unrelated to asthma, arrhythmias or friction rubs;>
• Any chronic systemic drug therapy to be continued during the study period (except for vitamin/mineral supplements, routine treatment for gastro-esophageal reflux);>
• Potential adult volunteers, or parents of potential child volunteers, who do not have easy access to a fixed or mobile telephone;>
• History of chronic alcohol consumption and/or drug abuse.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Control	Other: Placebo; Lyophilized, single dose vials and sterile water for > injection; 0.5 mL dose; Vaccination schedule: 0, 6 months
Experimental: T-DEN-Post-Transfection F17; Post-Transfection F17, full dose	Biological: T-DEN-Post-Transfection F17; Lyophilized, single dose vials and sterile water for injection; 0.5 mL dose at 0 and 6 months
Experimental: T-DEN-Post-Transfection F19; Post-Transfection F19, full dose	Biological: T-DEN-Post-Transfection F19; Lyophilized, single dose vials and sterile water for injection; 0.5 mL dose at 0 and 6 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety: Incidence of All and Grade 3 Solicited Local Symptoms	Incidence of all and grade 3 (prevents normal, everyday activities) solicited local and general symptoms within the 21-day follow-up period (Total vaccinated cohort)	Within 21 days (days 0-20) f/up period after each vaccine dose
Safety: Summary of Unsolicited Adverse Events Within the 31-day Post-vaccination Period	Summary of unsolicited Adverse Events within the 31-day post-vaccination period by age group (total vaccinated cohort)	Within the 31-day (days 0-30) follow-up period after each vaccine dose
Safety: Occurrence of Serious Adverse Events (SAEs)	Summary of SAEs, 6 months + 30 day follow-up period after last vaccine dose	6 months + 30 day follow-up period after last vaccine dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Suspected and Laboratory Confirmed Dengue	Incidence of suspected and confirmed dengue reported during the 31-day (Days 0-30) post-vaccination period and after the 31-day period	31-day (days 0-30) post-vaccination period and after 31-day period
GMTs for Antibody Titer Above the Assay Cut Off to Each DEN Serotype for Unprimed and Primed Subjects	Comparison of F17 and F19 formulations in terms of GMTs at month 7 (one month post dose 2) for each DEN type, -unprimed and primed subjects	at month 7 (one month post dose 2)
Percent of Subjects With Neut. Antibody Titer Above the Assay Cut-off to All Dengue Serotypes	Monovalent, bivalent, trivalent and tetravalent response for DEN neut. antibodies for unprimed and primed subjects	Pre-vaccination, at post dose 1, months 3 and 6 and post dose 2, month 7
Percent of Subjects With Neut. Sero-response to Each DEN Serotype	Seropositivity rates for DEN neut. antibodies for unprimed and primed subjects	Pre-accination, at post dose 1, months 3 and 6 and post dose 2, month 7
Vaccine Response to DEN Antibody at Post Dose 1, Month 3	Vaccine response for DEN-1, DEN-2, DEN-3 and DEN-4 antibody S- = seronegative subjects (antibody titer <10 ED50 for DEN-1, 2, 3, and 4 prior to vaccination; S+ = Seropositive subjects (antibody titer >10 ED50 for DEN-1, 2, 3 and 4 prior to vaccination; Total = subjects either seropositive or seronegative at pre-vaccination Vaccine response defined as: For initially seronegative subjects, antibody titer >10 ED50 at PI(M3) and for initially seropositive subjects: antibody titer at PI(m3) >4 fold the pre-vaccination antibody titer	at month 3, post dose 1
Vaccine Response to DEN Antibody at Post Dose 2, Month 7	Vaccine response for DEN-1, DEN2, DEN-3, DEN-4 antibody at post dose 2, month 7	at month 7, post dose 2

Collaborators and Investigators

• Sponsor: U.S. Army Medical Research and Development Command
• Collaborators: GlaxoSmithKline
• Investigators: Principal Investigator: Jorge Bertran-Pasarell, MD, Dept Medicina Interna Seccion Enfermedades Infecciosas; Principal Investigator: Clemente Diaz-Perez, MD, University of PR; Principal Investigator: Ines O. Esquilin-Rivera, MD, University of PR; Principal Investigator: Evelyn Matta-Fontanet, MD, Caparra Internal Medicine Research Center; Principal Investigator: Domingo Chardon-Feliciano, MD, Ponce School of Medicine; Principal Investigator: Javier Morales-Ramirez, MD, Clinical Research PR; Principal Investigator: Luis Rodriguez-Carrasquillo, MD, Private Practice, PR; Principal Investigator: Jose Rodriguez-Santana, MD, Centro de Neumologia Pediatrica; Principal Investigator: Miguel Sosa-Padilla, MD, Private Practice PR; Principal Investigator: Jose Tavarez-Valle, MD, Private Practice, PR; Principal Investigator: Alberto Santiago-Cornier, MD, Department of Molecular Medicine; Principal Investigator: Anna Quintero, MD, San Juan Batista Medical School

Publications and helpful links

General Publications

• Bauer K, Esquilin IO, Cornier AS, Thomas SJ, Quintero Del Rio AI, Bertran-Pasarell J, Morales Ramirez JO, Diaz C, Carlo S, Eckels KH, Tournay E, Toussaint JF, De La Barrera R, Fernandez S, Lyons A, Sun W, Innis BL. A Phase II, Randomized, Safety and Immunogenicity Trial of a Re-Derived, Live-Attenuated Dengue Virus Vaccine in Healthy Children and Adults Living in Puerto Rico. Am J Trop Med Hyg. 2015 Sep;93(3):441-453. doi: 10.4269/ajtmh.14-0625. Epub 2015 Jul 14.

Study record dates

Study Major Dates

• Study Start: July 1, 2007
• Primary Completion (Actual): April 1, 2010
• Study Completion (Actual): April 1, 2010

Study Registration Dates

• First Submitted: May 1, 2007
• First Submitted That Met QC Criteria: May 1, 2007
• First Posted (Estimate): May 3, 2007

Study Record Updates

• Last Update Posted (Actual): July 2, 2017
• Last Update Submitted That Met QC Criteria: June 5, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Vaccine; Dengue; Virus; Dengue Vaccine; Live-attenuated; Dengue viral infection
• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Infections; Arbovirus Infections; Vector Borne Diseases; Flavivirus Infections; Flaviviridae Infections; Body Temperature Changes; Shock; Fever; Hemorrhagic Fevers, Viral; Dengue; Severe Dengue
• Other Study ID Numbers: A-14040; WIRB number 20070071 (Other Identifier: Western Institutional Review Boards (WIRB)); 106405 (Other Identifier: GSK); T-DEN-003 (Other Identifier: MRMC/WRAIR)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: GlaxoSmithKline