Jaikumar pareta: Dengue vaccine by Jaikumar pareta

Dengue vaccine enters phase 3 trial in Brazil by

Jaikumar pareta:

Dengue is a mosquito-borne flavivirus disease that has spread to most tropical and many subtropical areas. The disease is caused by four closely related viruses, the Dengue viruses 1-4. There are no specific dengue therapeutics and prevention is currently limited to vector control measures. A dengue vaccine would therefore represent a major advance in the control of the disease.

Status of vaccine development

The first dengue vaccine, Dengvaxia (CYD-TDV) by Sanofi Pasteur, was first registered in Mexico in December, 2015. CYD-TDV is a live recombinant tetravalent dengue vaccine that has been evaluated as a 3-dose series on a 0/6/12 month schedule in Phase III clinical studies. It has been registered for use in individuals 9-45 years of age living in endemic areas.

Challenges to vaccine development

Infection by one of the four dengue virus serotypes has been shown to confer lasting protection against homotypic re-infection, but only transient protection against a secondary heterotypic infection. Moreover, secondary heterotypic infection is associated with an increased risk of severe disease. This and other observations suggest an immunopathological component in dengue pathogenesis, which is referred to as immune enhancement of disease. Due to these dengue-specific complexities, vaccine development focuses on the generation of a tetravalent vaccine aimed at providing long-term protection against all virus serotypes. Additional challenges are posed by the lack of an adequate animal disease model and the resulting uncertainty around correlates of protection. In spite of these challenges, vaccine development has made remarkable progress in recent years, and the current dengue vaccine pipeline is advanced, diverse and overall promising.

A large-scale clinical trial to evaluate whether a candidate vaccine can prevent the mosquito-borne illness dengue fever has been launched in Brazil. The vaccine, TV003, was developed by scientists in the laboratory of Stephen Whitehead, Ph.D., at NIH’s National Institute of Allergy and Infectious Diseases (NIAID). The Butantan Institute, a non-profit producer of immunobiologic products for Brazil, licensed the NIAID dengue vaccine technology and is sponsoring the placebo-controlled, multi-center Phase 3 trial using test vaccine produced in Sao Paulo.

Dengue fever is common in many parts of the tropics and subtropics and about half the world’s population is at risk of infection. The World Health Organization estimates that up to 400 million dengue infections occur annually, resulting in 500,000 hospitalizations. More than 1.5 million cases of dengue were reported in Brazil in 2015.

Dengue is caused by any of four related viruses, termed serotypes DEN-1, DEN-2, DEN-3 and DEN-4, which are transmitted to people by Aedes aegypti mosquitoes. A person exposed to one dengue virus type gains immunity to that type, but not to the other three. In fact, a second infection with a virus type that differs from the first can lead to a more severe course of disease.

“Researchers in NIAID’s Laboratory of Infectious Diseases spent many years developing and testing dengue vaccine candidates designed to elicit antibodies against all four dengue virus serotypes,” said NIAID Director Anthony S. Fauci, M.D. “Earlier clinical trials of this candidate conducted in the United States by NIAID showed that it could elicit a robust antibody and cellular immune response after just one dose,” he added. “Because the impact of dengue fever in Brazil is especially large and the country has an excellent health infrastructure, it is an ideal location to test the vaccine candidate.”

The new trial aims to enroll almost 17,000 healthy people aged 2 to 59 years in 13 cities, beginning in Sao Paulo. Two-thirds of the volunteers will receive a single dose of the candidate vaccine, while one-third will receive an inactive placebo injection. Neither participants nor study staff will know which of the two groups a volunteer is in. All volunteers will be monitored for five years through a combination of in-person visits to the health clinic and telephone or text communications from the investigators. The goal of the trial is determine if the candidate vaccine prevents dengue fever and to provide additional information about its safety. Although the trial is scheduled to last five years, the investigators hope to have early indications of the potential efficacy of the vaccine in less than two years. The principal investigator is Alexander Precioso, M.D., Ph.D., of the Butantan Institute.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases.

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.

Study Type:InterventionalStudy Design:Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: PreventionOfficial Title:Phase III Trial to Evaluate Efficacy and Safety of a Dengue 1,2,3,4 (Attenuated) Vaccine

Primary Outcome Measures:

Efficacy (incidence density of symptomatic dengue cases, virologically confirmed) [ Time Frame: at 52 weeks post vaccination, all cases after 28 days post-vaccination ] [ Designated as safety issue: No ]
• The primary efficacy outcome is incidence density of symptomatic dengue cases, virologically confirmed, after 28 days post-vaccination. Virological confirmation might be done by viral isolation, RT-PCR and/or detection of NS1.
Safety (adverse reactions) [ Time Frame: in the first 21 days post-vaccination ] [ Designated as safety issue: Yes ]
• The primary safety outcome is the frequency of local and systemic adverse reactions, solicited and non-solicited in the three age groups, within the first 21 days post-vaccination. Adverse reactions are defined as adverse events that have a reasonable causal relationship with vaccination.

Estimated Enrollment:	16944
Study Start Date:	January 2016
Estimated Study Completion Date:	November 2021
Estimated Primary Completion Date:	January 2017 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Dengue 1,2,3,4 (attenuated) vaccine Dengue 1,2,3,4 (attenuated) vaccine Single dose, SC	Biological: Dengue 1,2,3,4 (attenuated) vaccine Dose 1000 PFU per virus (1,2,3,4) Route:subcutaneous Other Names: Butantan DV TetraVax-DV-TV003
Placebo Comparator: Placebo Placebo Single dose, SC	Other: Placebo Route:subcutaneous

Eligibility

Ages Eligible for Study:	24 Months to 59 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Children who have completed 24 months of age, adolescents and adults who have not completed 60 years of age;
Agree with periodic contacts, either/or by phone, electronic means, and home visits.
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:

For women: Pregnancy (confirmed by positive beta-hCG test) or breastfeeding;
Evidence of active neurological, cardiac, pulmonary, hepatic or renal disease as per clinical history and/or physical examination;
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;
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;
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 to the vaccine or to components of the vaccine in study;
History of asplenia;
Use of any investigational product within 28 days before or after receiving this study vaccination;
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;
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;
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;
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);
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;
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.