Safety and immunogenicity of a recombinant live attenuated tetravalent dengue vaccine (DENVax) in flavivirus-naive healthy adults in Colombia: a randomised, placebo-controlled, phase 1 study

Abstract

Summary Background Dengue virus is the most serious mosquito-borne viral threat to public health and no vaccines or antiviral therapies are approved for dengue fever. The tetravalent DENVax vaccine contains a molecularly characterised live attenuated dengue serotype-2 virus (DENVax-2) and three recombinant vaccine viruses expressing the prM and E structural genes for serotypes 1, 3, and 4 in the DENVax-2 genetic backbone. We aimed to assess the safety and immunogenicity of tetravalent DENVax formulations. Methods We undertook a randomised, double-blind, phase 1, dose-escalation trial between Oct 11, 2011, and Nov 9, 2011, in the Rionegro, Antioquia, Colombia. The first cohort of participants (aged 18–45 years) were randomly assigned centrally, via block randomisation, to receive a low-dose formulation of DENvax, or placebo, by either subcutaneous or intradermal administration. After a safety assessment, participants were randomly assigned to receive a high-dose DENVax formulation, or placebo, by subcutaneous or intradermal administration. Group assignment was not masked from study pharmacists, but allocation was concealed from participants, nurses, and investigators. Primary endpoints were frequency and severity of injection-site and systemic reactions within 28 days of each vaccination. Secondary endpoints were the immunogenicity of DENVax against all four dengue virus serotypes, and the viraemia due to each of the four vaccine components after immunisation. Analysis was by intention to treat for safety and per protocol for immunogenicity. Because of the small sample size, no detailed comparison of adverse event rates were warranted. The trial is registered with ClinicalTrials.gov, number NCT01224639. Findings We randomly assigned 96 patients to one of the four study groups: 40 participants (42%) received low-dose vaccine and eight participants (8%) received placebo in the low-dose groups; 39 participants (41%) received high-dose vaccine, with nine (9%) participants assigned to receive placebo. Both formulations were well tolerated with mostly mild and transient local or systemic reactions. No clinically meaningful differences were recorded in the overall incidence of local and systemic adverse events between patients in the vaccine and placebo groups; 68 (86%) of 79 participants in the vaccine groups had solicited systemic adverse events compared with 13 (76%) of 17 of those in the placebo groups. By contrast, 67 participants (85%) in the vaccine group had local solicited reactions compared with five (29%) participants in the placebo group. Immunisation with either high-dose or low-dose DENVax formulations induced neutralising antibody responses to all four dengue virus serotypes; 30 days after the second dose, 47 (62%) of 76 participants given vaccine seroconverted to all four serotypes and 73 (96%) participants seroconverted to three or more dengue viruses. Infectious DENVax viruses were detected in only ten (25%) of 40 participants in the low-dose group and 13 (33%) of 39 participants in the high-dose ...

Dengue virus envelope protein domain I/II hinge: a key target for dengue virus vaccine design?

“…Furthermore, a recent Phase I trial of a tetravalent DENV vaccine candidate consisting of an attenuated DENV2 backbone containing prM/E genes of variant serotypes revealed similar problems. While demonstrating acceptable safety, neutralization titers to DENV2 predominated, while DENV4 titers were barely detectable under most inoculation conditions [19]. These results serve as a reminder that chimerization schemes must be carefully considered to preserve viral fitness necessary for induction of balanced immune responses against all four serotypes.…”

Advances in Dengue Vaccine: A Review Study

“…In a randomized controlled phase I study in Philippine, Capeding et al [30] reported that a vaccine regime of either 3 TDV vaccination administered over a year or two TDV vaccination given more than 8 months apart led to a balanced antibody response to all four dengue serotypes among flavivirus-exposed populace that included children [31]. The reactogenicity did not increase with successive vaccination and was not higher in children than in adults and adolescents.…”

“…There is data on safety and immunogenicity for individuals aged up to 45 but there is no efficacy data for individuals above the age of 1636, [37]. Osorio et al [31] reported that there is acceptable tolerability and immunogenicity of the tetravalent DENVAX formulation in healthy, flavivirus-naïve adults but more clinical studies are needed to test DENVAX in different age groups in DENV-endemic areas. Although TDV is safe, a number of adverse events have been reported.…”

Guiding dengue vaccine development using knowledge gained from the success of the yellow fever vaccine

“…The results showed that the vaccine was safe, generally well-tolerated, and immunogenic. 90,94 In subjects tested in the USA, the overall seroconversion rates and geometric mean titers at day 120 after two doses of the vaccine were highest for DENV-2 (92.1% and a PRNT 50 of 292.8), followed by DENV-1 and DENV-3 and were lowest for DENV-4 (71.1% and a PRNT 50 titer of 15.0). Further development of this vaccine is needed to induce a more balanced immune response among all four DENV serotypes.…”