Defining levels of dengue virus serotype-specific neutralizing antibodies induced by a live attenuated tetravalent dengue vaccine (TAK-003)

Abstract

The four dengue virus serotypes (DENV1-4) infect several hundred million people each year living in tropical and sub-tropical regions. Clinical development of DENV vaccines is difficult because immunity to a single serotype increases risk of severe disease during a second infection with a new serotype. Leading vaccines are based on tetravalent formulations to induce simultaneous and balanced protective immunity to all 4 serotypes. TAK-003 is a tetravalent live attenuated dengue vaccine candidate developed by Takeda Vaccines Inc, which is currently being evaluated in phase 3 efficacy trials. Here, we use antibody depletion methods and chimeric, epitope transplant DENVs to characterize the specificity of neutralizing antibodies in dengue-naïve adults and non-human primates immunized with TAK-003. Our results demonstrate that TAK-003 induced high levels of DENV2 neutralizing antibodies that recognized unique (type-specific) epitopes on DENV2. In contrast, most vaccinated subjects developed lower levels of DENV1, DENV3 and DENV4 neutralizing antibodies that mainly targeted epitopes that were conserved (cross-reactive) between serotypes. Trial Registration: ClinicalTrials.gov NCT02425098.

Current Development and Challenges of Tetravalent Live-Attenuated Dengue Vaccines

“…In contrast, 5%, 83%, 12% and 27% of TAK-003 vaccinees developed TS nAb to DENV1, DENV2, DENV3 and DENV4, respectively. Most of the anti-DENV2 TS nAb bind to DENV2 EDIII epitopes ( 95 ). To avoid the generation of anti-prM, a tetravalent subunit virus-like particle vaccine, DSV4, which expresses EDIII of all four DENVs but not prM, had been engineered.…”

Updates on Dengue Vaccine and Antiviral: Where Are We Heading?

“…The vaccine was proven to be immunogenic and well-tolerated in multiple phase I and II clinical studies, independent of the participants' age or serostatus. TAK-003 showed a DENV serotype-dependent protective effectiveness, similar to its predecessor Dengvaxia, but with higher levels of DENV2 neutralizing antibodies and lower DENV3 and DENV4 protection rates, consequently, its safety profile is not entirely known [38]. Although a previous clinical study indicated it triggers CD8+ T lymphocytes directed at NS1, NS3, and NS5 in patients that have never been infected with DENV [39], this data were not included in later clinical studies.…”

Envelope-dimer epitope-like broadly protective antibodies against dengue in children following natural infection and vaccination

“…There is an urgent need for dengue vaccines and vaccine strategies that elicit protection against all serotypes. Both licensed dengue vaccines, Dengvaxia and QDENGA, have shown limited or no protection in DENVnaive individuals, with evidence that vaccination increases the risk of disease caused by some of the DENV serotypes [5][6][7][8][9][10][11] . Each vaccine contains live-attenuated chimeric replicating viruses with the envelope and pre-membrane proteins of DENV1-4 in either the 17D yellow fever vaccine backbone (Dengvaxia) or an attenuated DENV2 strain (QDENGA) 12 .…”