Phase III Trial to Evaluate Efficacy and Safety of a Tetravalent Dengue Vaccine

Phase III, Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Efficacy, Safety, and Immunogenicity of the Dengue 1, 2, 3, 4 (Attenuated) Vaccine From Instituto Butantan

This is a randomized, multicenter, double-blind, placebo-controlled Phase III study that will evaluate efficacy and safety of a live attenuated, tetravalent, lyophilized dengue vaccine produced by Butantan Institute.

The study will be carried out in multiple sites in Brazil. The study will be community-based in select urban areas where there's dengue transmission.

Study's intervention will be a single dose of the tetravalent dengue vaccine or placebo in a ratio 2:1. For efficacy analysis will be considered all dengue cases occurring after 28 days post-vaccination in the entire population of 16944 participants.

For safety analysis participants will be divided in three age groups: 18 to 59 ys, 7-17 ys and 2 to 6 ys. In each of these age groups there will be a minimum of 4992 participants. The age groups of 18 to 59 ys and 7 to 17 ys will start first. Once safety data for the first 21 days after vaccination is analysed for 450 participants in 7-to17-ys age group, the following group, of 2 to 6 ys, will start.

The study's hypothesis is that the vaccine under investigation and produced by Butantan Institute is safe and provides protection against dengue symptomatic disease of 80% or more with a lower bound of the 95% confidence interval of 25%. This way, the expected number of dengue cases virologically confirmed is 24 or more which will provide a response in terms of vaccine efficacy.

All participants will be followed up for five years to verify dengue incidence, regardless severity.

Inclusion Criteria:

1. Children who have completed 24 months of age, adolescents and adults who have not completed 60 years of age;
2. Agree with periodic contacts, either/or by phone, electronic means, and home visits.
3. Show voluntary intention to participate in the study, documented by the participant's or participant's legal representative's signature of the informed consent form.

Exclusion Criteria:

1. For women: Pregnancy (confirmed by positive beta-hCG test) or breastfeeding;
2. Evidence of active neurological, cardiac, pulmonary, hepatic or renal disease as per clinical history and/or physical examination;
3. Compromised immune system diseases including: decompensated diabetes mellitus, cancer (except basal cell carcinoma), congenital or acquired immune deficiencies and not controlled autoimmune, as per clinical history and/or physical examination;
4. 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;
5. Abusive usage of alcohol or drugs in the past 12 months that has caused medical, professional or family problems, indicated by clinical history;
6. History of severe allergic reactions or anaphylaxis to the vaccine or to components of the vaccine in study;
7. History of asplenia;
8. Use of any investigational product within 28 days before or after receiving this study vaccination;
9. Has participated in another clinical trial six months prior to inclusion in the study or planning to participate in another clinical trial within 2 years following inclusion;
10. Use of immunosuppressant drugs such as: antineoplastic chemotherapy, radiation therapy, immunosuppressants to induce tolerance to transplants, and corticosteroids use (except topical or nasal). For this protocol will be considered for exclusion use of corticosteroids 3 months prior to the inclusion in the study and 6 months prior to the inclusion for the other therapies mentioned, and planned use of any immunosuppressant therapy within 2 years following inclusion in the study. It will be considered immunosuppressive dose of corticosteroids the equivalent to a dose ≥20 mg of prednisone per day for adults and the equivalent of prednisone at 2 mg/kg/day for children for over 7 days;
11. Have received blood products in the past three months, including transfusions or immunoglobulin, or scheduled administration of blood products or immunoglobulin for the following 2 years after vaccination;
12. Fever or suspected fever within 72 hours prior to vaccination or axillary temperature greater than 37,8°C on the day of vaccination (inclusion might be postponed until participant has completed 72 hours of no fever);
13. 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 28 days after receiving the investigational product;
14. 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.