DENGVAXIA(Dengue Tetravalent Vaccine, Live)Suspension for Subcutaneous Injection(九)
cent proteinaceous particles may be present). [See Dosage and Administration(2.3).]
After reconstitution, each 0.5 mL dose of DENGVAXIA contains 4.5 - 6.0 log10 CCID50 of eachof the chimeric yellow fever dengue (CYD) virus serotypes 1, 2, 3, and 4. Each 0.5 mL dose isformulated to contain 2 mg sodium chloride and the following ingredients as stabilizers: 0.56 mgessential amino acids (including L-phenylalanine), 0.2 mg non-essential amino acids, 2.5 mgL-arginine hydrochloride, 18.75 mg sucrose, 13.75 mg D-trehalose dihydrate, 9.38 mgD-sorbitol, 0.18 mg trometamol, and 0.63 mg urea.
Each of the four CYD viruses (CYD-1, CYD-2, CYD-3, and CYD-4) in DENGVAXIA wasconstructed using recombinant DNA technology by replacing the sequences encoding the
pre-membrane (prM) and envelope (E) proteins in the yellow fever (YF) 17D204 vaccine virusgenome with those encoding for the homologous sequences of dengue virus serotypes 1, 2, 3,and 4, respectively. Each CYD virus is cultured separately in Vero cells (African Green Monkeykidney) under serum-free conditions, harvested from the supernatant of the Vero cells andpurified by membrane chromatography and ultrafiltration. The purified and concentrated harvestof each CYD virus is then diluted in a stabilizer solution to produce the four monovalent drugsubstances. The final bulk product is a mixture of the four monovalent drug substances diluted inthe stabilizer solution. The final bulk product is sterilized by filtration at 0.22 µm, filled intovials and freeze-dried.
DENGVAXIA does not contain preservative.
The vial stoppers for the Lyophilized Vaccine Antigen and Diluent vials of DENGVAXIA arenot made with natural rubber latex.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Following administration, DENGVAXIA elicits dengue-specific immune responses against thefour dengue virus serotypes. The exact mechanism of protection has not been determined.
12.3 Pharmacokinetics
Viremia
In studies that eva luated the occurrence of vaccine viremia systematically at pre-specified timepoints,vaccine viremia (measured by genomic amplification methods) was observed followingvaccination with DENGVAXIA in 5.6% of subjects, with 90% of these occurrences documentedafter the first injection. Vaccine viremia was observed 7 to 14 days after DENGVAXIAvaccination with a duration of <7 days.
13 NON-CLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
DENGVAXIA has not been eva luated for carcinogenic or mutagenic potential or impairment ofmale fertility. Exposure of female rabbits to DENGVAXIA prior to and during gestation did notimpair fertility. [See Use in Specific Populations (8.1).]
14 CLINICAL STUDIES
14.1 Efficacy
The efficacy of DENGVAXIA was eva luated in two randomized, observer-blind, placebocontrolled,multi-center studies. Study 1 (N=20,869) was conducted in individuals 9 through 16years of age in four Latin American countries and Puerto Rico; and Study 2 (N=10,275) wasconducted in individuals 2 through 14 years of age in five Asia-Pacific countries. A subset ofsubjects in each study (10% in Study 1; 20% in Study 2) was eva luated for antibodies to denguevirus at the time of enrollment and at later time points. Both studies enrolled subjects irrespectiveof evidence of previous dengue infection. Subjects were randomized 2:1 to receive either
DENGVAXIA or saline placebo and were monitored for symptomatic virologically-c |
