Phase II Trial to Evaluate Safety and Immunogenicity of a Dengue 1,2,3,4 (Attenuated) Vaccine

Phase 2

• Conditions: Dengue
• Interventions: Biological: Dengue 1,2,3,4 (attenuated) vaccine; Other: Placebo; Biological: TetraVax-DV Vaccine - Admixture TV003

• Registration Number: NCT01696422
• Lead Sponsor: Butantan Institute

Brief Summary

This is a phase II step-wise, randomized, multicenter, double-blind and controlled clinical trial to evaluate the safety and immunogenicity of a attenuated tetravalent lyophilized dengue vaccine manufactured by Butantan Institute. Three Clinical Sites at University of Sao Paulo - Brazil will participate in the study. A total of 300 volunteers will be recruited and divided into two steps: Step A (with no previous exposure to dengue) and Step B (with and without previous exposure to dengue). In step A the participants will be assigned to receive either the lyophilized vaccine, or the liquid vaccine(developed at NIH and produced and formulated at Butantan according to the NIH-Protocol), or the placebo. In Step B participants will be assigned to receive either the lyophilized vaccine, or the placebo. Both vaccine formulations (lyophilized and liquid) are composed of the same attenuated viruses: rDEN1∆30, rDEN2/4∆30(ME), rDEN3∆30/31, and rDEN4∆30. At the end of the study, 20 volunteers will have received the liquid formulation (NIH), 210 the lyophilized formulation (Butantan), and 70 will have received the placebo. All participants included in both steps will be followed by a period of five years after their inclusion in the study. The study hypothesis is that the investigational lyophilized dengue vaccine manufactured by Butantan Institute is safe and confers balanced immune response, after one dose of 1000PFU, to all for vaccine viruses.

Detailed Description

This is a phase II step-wise, randomized, multicenter, double-blind and controlled clinical trial to evaluate the safety and immunogenicity of an attenuated tetravalent lyophilized dengue vaccine manufactured by Butantan Institute. A total of 300 volunteers will be recruited including men and no pregnant/breastfeeding women between 18 and 59 years of age complete, with and without previous exposure to dengue that will be randomized into Step A and Step B. Step A will include 50 volunteers with no previous exposure and they will be randomly assigned to receive one dose of either the lyophilized formulation (Butantan), or the liquid formulation (TetraVax-DV Vaccine - Admixture TV003 developed by NIH/NIAID and produced and formulated at Butantan according the NIH-Protocol), or the placebo. A second dose will be administered six months after the first vaccination as part of an exploratory assessment. Step B will include 250 participants(50 without previous exposure to dengue,and 200 with previous exposure to dengue) who will be randomly assigned to receive one dose of either the lyophilized formulation (Butantan),or the placebo. All participants included in both steps will be followed by a period of five years after their inclusion in the study. The vaccines will be administered at dose of 1000 PFU (for each of the vaccine viruses),and both vaccines and the placebo will be administered subcutaneously.

Study Timeline

• Study First Submitted: 2012-09-27
• Study First Submitted QC: 2012-09-27
• Study First Posted: 2012-10-01
• Study Start: 2013-10
• Primary Completion: 2016-04
• Status Verified: 2019-01
• Last Update Submitted: 2019-01-15
• Last Update Posted: 2019-01-16
• Study Completion: 2020-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 300

Inclusion Criteria

• Healthy adults (men and non-pregnant women), from 18 to 59 years old;
• Willingness to participate throughout the study period (approximately five years);
• Willingness to participate documented by the signature of ICF;
• Females with childbearing potential must be willing to avoid pregnancies up to three weeks after the last vaccine dose. All female volunteers will be considered with childbearing potential unless they have documented history of hysterectomy, tubal ligation or are postmenopausal (12 months of amenorrhea after the last menstrual period).

Exclusion Criteria

• Pregnancy (confirmed by positive beta-hCG test) or breastfeeding;
• Evidence of active neurological, cardiac, pulmonary, hepatic or renal disease as clinical history, physical examination and/or laboratory results;
• Compromised immune system diseases including: diabetes mellitus, cancer (except basal cell carcinoma) and autoimmune diseases;
• Behavioral, cognitive or psychiatric disease that in the opinion of the principal investigator or his representative physician, affects the participant ability to understand and cooperate with all study protocol requirements;
• Values of absolute neutrophil, alanine aminotransferase (ALT) or serum creatinine count greater than or equal to Grade 1, as defined in the protocol;
• Abusive usage of alcohol or drugs in the past 12 months that has caused medical, professional or family problems, indicated by clinical history;
• History of severe allergic reactions or anaphylaxis;
• Diagnosis of asthma with a history of hospitalization in the last six months due to illness;
• Fever or suspect fever within 72 hours prior to vaccination or axillary temperature greater than 37,8°C on the day of vaccination;
• Positive result of HIV-1 serology by screening or confirmed tests;
• Screening or confirmed positive test for hepatitis C virus (HCV);
• Positive test of hepatitis B virus antigen surface (AgHBs) alone or against hepatitis B "core" antigen antibody (anti-HBc);
• Use of corticosteroids (except topical or nasal) or other immunosuppressive drugs within 42 days before study initiation/baseline. It will be considered immunosuppressive dose of corticosteroids the equivalent to a dose ≥10 mg of prednisone per day for over 14 days;
• Use of anticoagulant medication;
• Have received live virus vaccine within 28 days or killed virus vaccine in the last 14 days prior to vaccination, or have a scheduled immunization during the first 42 days after receiving the investigational product;
• History of asplenia;
• Have received blood products in the past six months, including transfusions or immunoglobulin, or scheduled administration of blood products or immunoglobulin for the first 42 days after vaccination;
• Use of any investigational product within 42 days before or after receiving this study vaccination;
• Has participated in another clinical trial six months prior to vaccination;
• Denies permission for biological material storage for future research as defined in ICF;
• Any other condition that might put in risk the safety/rights of a potential participant or hurdle his/her compliance with this protocol in investigator's opinion or his representative physician.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Step A: dengue lyophilized vaccine	Dengue 1,2,3,4 (attenuated) vaccine	Dengue 1,2,3,4 (attenuated) vaccine Two doses with a six-months interval, SC
Step B: Placebo	Placebo	Placebo comparator Single dose, SC
Step A: Placebo	Placebo	Placebo comparator Two doses with a six-months interval, SC
Step B: dengue lyophilized vaccine	Dengue 1,2,3,4 (attenuated) vaccine	Dengue 1,2,3,4 (attenuated) vaccine Single dose, SC
Step A:dengue liquid vaccine	TetraVax-DV Vaccine - Admixture TV003	TetraVax-DV Vaccine - Admixture TV003 Two doses with a six-months interval, SC

Primary Outcome Measures

Name	Time	Method
Safety	Up to day 21 after vaccination	Frequency of solicited and unsolicited local and systemic adverse reactions up to Day 21 after vaccination.
Immunogenicity	Up to day 91 after vaccination	Seroconversion rate for each of the four vaccine viruses defined by PRNT50 ≥1:10 for each vaccine virus serotype on Days 28, 56 or 91.

Secondary Outcome Measures

Name	Time	Method
Immunogenicity	Annualy up to five years	1. Response rates of monovalent, bivalent, trivalent or tetravalent, at Day 28, 56 and 91 and annually after vaccination, as measured by PRNT50 for each one of the four vaccine viruses; 2. The difference between the geometric means, pre and post vaccination, serum level of neutralizing antibodies measured by PRNT50 for each of the four vaccine viruses evaluated until five years after the first vaccination.
Safety	up to Day 182 after the first vaccination	1. Unsolicited adverse events after Day 21 and up to Day 182 after the first vaccination; 2. Viremia for each of the four vaccine virus on Days 3, 6, 9, 12, 15 and 21 after the first vaccination of all volunteers in Step A of study and 40 volunteers with previous exposure to Dengue of Step B. For other volunteers from Step B, viremia only is measured on Day 12.; 3. Cases of suspected and confirmed dengue in five years after the first vaccination;

Trial Locations

Locations (2)

Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo; 🇧🇷 São Paulo, Brazil

Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da USP; 🇧🇷 Sao Paulo, Brazil