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

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 group.

Interpretation: Our findings emphasise the acceptable tolerability and immunogenicity of the tetravalent DENVax formulations in healthy, flavivirus-naive adults. Further clinical testing of DENVax in different age groups and in dengue-endemic areas is warranted.

Funding: Takeda Vaccines.

Conflict of interest statement

Declaration of interests

JEO, CT, AAH, SS, JS, JA, JS, GSG, and DTS were employees of Inviragen (now Takeda Vaccines)—the trial sponsor. CY-HH has a patent (Avirulent, Immunogenic Flavivirus Chimeras) licensed to Takeda Vaccines and with royalties paid to the Centers for Disease Control and Prevention (CDC), a patent (Compositions and Methods for Dengue Virus Chimeric Constructs in Vaccines) pending to Takeda Vaccines and CDC, and a patent (Compositions, Methods and Uses for Dengue Virus Constructs) pending to Takeda Vaccines and CDC. IDV, LL, AJ, KLB, JLS, BEL, and MEB declare no competing interests.

Copyright © 2014 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Trial profile

Figure 2. Neutralising antibody titre induced by DENVax formulations in study participants

Low dose, subcutaneous (A); low dose, intradermal (B); high dose, subcutaneous (C); high dose, intradermal (D). Error bars show 95% CIs around the geometric mean titres. PRNT=plaque-reduction neutralisation test.

Figure 3. Seroconversion rates after dose one or dose two of DENVax

Low dose, subcutaneous (A); low dose, intradermal (B); high dose, subcutaneous (C); high dose, intradermal (D).