The primary objective is to determine, among dengue-naïve adults in an endemic population, the protective efficacy of TetraVax-DV TV005 vaccine against dengue infection induced by a live recombinant attenuated rDEN2∆30-7169 attenuated virus strain administered 6, 12, or 24 months after vaccination. Secondary objectives are: 1. Determine the durability of protection of TetraVax-DV TV005. 2. Evaluate the safety of TetraVax-DV TV005 in dengue-naïve volunteers in a dengue endemic population. 3. Evaluate the safety of the rDEN2∆30-7169 attenuated virus strain in a dengue endemic population.
This is a single center, Phase II, placebo-controlled, double-blind study to evaluate the ability of a single dose of TetraVax-DV TV005 vaccine to protect against infection induced by a live recombinant attenuated rDEN2∆30-7169 attenuated virus strain administered 6, 12, and 24 months after vaccination. TetraVax-DV TV005 will contain 103 PFU of rDEN1∆30, 104 PFU of rDEN2/4∆30(ME), 103 PFU of rDEN3∆30/31-7164 and 103 of rDEN4∆30. The dose of rDEN2∆30-7169 attenuated virus strain (DENV-2) will be 103 PFU. The placebo group will receive Plasma-Lyte A Injection pH 7.4. The study population will be comprised of 192 healthy male and healthy non-pregnant, non-lactating female dengue-naïve adult volunteers aged 18-45 years, inclusive, from dengue-endemic Dhaka, Bangladesh. After providing written informed consent, volunteers will undergo eligibility screening, including medical history, physical examination, hematology testing, liver function testing, hepatitis B and C screening, and serology screening for previous dengue infection. Pregnancy testing will be performed on females with childbearing potential. All screening tests must be performed within 60 days prior to vaccination. Eligible volunteers will be enrolled to receive TetraVax-DV TV005 or placebo (2:1) on an outpatient basis in one of three cohorts based on intended treatment with the attenuated virus strain timepoint (6, 12 or 24 months). The sequence of treatment assignments to either TV005 or placebo will be generated using block randomization. Randomization will occur sequentially at the time of study enrollment (vaccination) using a pre-generated list. All enrolled volunteers will be followed for 3 years post-vaccination for safety. At 6, 12, and 24 months post-vaccination, volunteers will be re-screened for treatment with the attenuated virus strain with a live recombinant attenuated DENV-2 virus strain (rDEN2Δ30-7169). Volunteers will receive treatment with the attenuated virus strain in three separate treatment groups each consisting of 33 randomly-selected, eligible vaccine and placebo recipients (2:1) from the three independently vaccinated cohorts. Following treatment with the attenuated virus strain, designated study staff will make home visits to study participants to collect fever and AE information once per day up to day 16. A total of 66 vaccine and 33 placebo recipients (52% of enrolled population) will receive the attenuated virus strain. Administration of the attenuated virus strain to volunteers at 12 and 24 months is contingent upon DSMB approval following review of all cumulative safety data from those volunteers treated with the attenuated virus strain at 6 months. Volunteers who receive placebo and are subsequently treated with the attenuated virus strain will be offered the TetraVax-DV TV005 vaccination 2 months after their attenuated virus strain dose. All volunteers who receive treatment with the attenuated virus strain will be followed for a minimum of one year post-treatment with the attenuated virus strain for safety (included in the overall 3 years of safety follow up). Volunteers receiving treatment with the attenuated virus strain will be closely monitored following treatment with the attenuated virus strain and will be admitted to a local hospital for closer observation should they meet admission criteria. Administration of the attenuated virus strain to volunteers at 12 and 24 months is contingent upon DSMB approval following review of all cumulative safety data from those volunteers treated with the attenuated virus strain at 6 months. Volunteers who receive placebo and are subsequently treated with the attenuated virus strain will be offered the TetraVax-DV TV005 vaccination 2 months after their attenuated virus strain dose. All volunteers who receive treatment with the attenuated virus strain will be followed for a minimum of one year post-treatment with the attenuated virus strain for safety (included in the overall 3 years of safety follow up).
The TV005 admixture is comprised of four monovalent dengue vaccine candidates representing each of the four DENV serotypes: rDEN1Δ30, rDEN2/4Δ30(ME), rDEN3Δ30/31, and rDEN4Δ30.
based on a cDNA derived DENV-2 virus (strain Tonga/74) in which the 3´ UTR of DENV-2 contains a 30 (nt) deletion (nt 173 - 143) homologous to the ∆30 deletion in the 3´ UTR of rDEN4Δ30 (named Δ30 for consistency). A plasmid was constructed to encode the entire genome of DENV-2 Tonga/74. The cDNA of the 3´ UTR of DENV-2 Tonga/74 was then modified to introduce a 31-nucleotide deletion homologous to the DEN4Δ30 deletion (∆30). Genome-length, capped, RNA transcripts were synthesized from the plasmid p2Δ30-7169 and purified
Icddr,B
Dhaka, Bangladesh
Frequency of viremia
Proportion of volunteers with viremia following treatment with the attenuated virus strain among those who received TV005 versus placebo at vaccination. Viremia will be measured by qRT-PCR.
Time frame: 28 days following challenge.
Quantity of Viremia
Quantity of viremia following treatment with the attenuated virus strain. Quantity of viremia will be measured by qRT-PCR.
Time frame: 28 days following challenge
Duration of viremia
Number of days viremic following treatment with the attenuated virus strain.
Time frame: 28 days following challenge
Frequency of volunteers with adverse events
Proportion of volunteers in each arm experiencing adverse events.
Time frame: 28-days post receipt of TV005 or placebo
Frequency of volunteers with adverse events
Proportion of volunteers in each arm experiencing adverse events.
Time frame: 28-days post receipt of challenge
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Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
192