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. We conclude that the DENV2 component in the vaccine is immunodominant because of the high levels of serum neutralizing antibodies targeting type-specific epitopes. We also conclude that DENV1, 3 and 4 vaccine components are less immunogenic because most study subjects did not develop type-specific serum neutralizing antibodies to these serotypes. While DENV vaccine development has been guided by the presence of neutralizing antibodies to each serotype as a benchmark, our results indicate that the presence of neutralizing antibodies alone are not a reliable indicator of the immunogenicity of each vaccine component.Author summaryThe development of tetravalent dengue vaccines has been guided by neutralizing antibodies to each serotype as a correlate of safe and effective vaccine induced immunity. However, the absolute levels of neutralizing antibodies to each serotype has proven to be an unreliable correlate of protection. Levels of antibodies to epitopes that are unique to each serotype, which are measures of immunity independently stimulated by each vaccine component, rather than total quantity of neutralizing antibodies, are likely to be better correlates of protection. Here, we mapped the specificity of antibodies induced by the Takeda tetravalent dengue vaccine TAK-003 in monkeys and humans with no prior immunity to dengue. The TAK-003 vaccine induces high levels of serotype 2 specific neutralizing antibodies that map to known protective epitopes. In contrast, the serotype 1, 3 and 4 neutralizing antibody responses are lower and mainly consist of cross-reactive antibodies binding to epitopes conserved between serotypes. These heterotypic antibodies, which are most likely derived from the serotype 2 component, may not provide long term protection in vivo.

‘Mix and Match’ vaccination: Is dengue next?

“…Consistently, antibody depletion assays, which remove cross-neutralizing antibodies to identify type-specific antibodies, have revealed that TAK-003 recipients develop type-specific antibodies primarily against DENV2 while Dengvaxia recipients develop these against DENV4. These antibody responses correlate strongly with the serotype-specific efficacy of each vaccine [44] , [45] . Additionally, the two vaccines have different parent strains and backbones.…”

Current status and perspectives on vaccine development against dengue virus infection

“…Recently, type-specific Abs were characterized using samples from human and non-human primates vaccinated with TAK-003, and those against DENV2 were strongly induced. However, typespecific Abs against other DENV serotypes were inefficiently induced, and most of the neutralizing Abs against DENV1, DENV3, and DENV4 were cross-reactive (White et al, 2021).…”

“…First, the Abs produced by the dengue vaccine must induce type-specific Abs against all serotypes (Swaminathan and Khanna, 2019). Both the existing Dengvaxia ® and TAK-003 vaccines cannot generate type-specific Abs for all DENV serotypes and induce a skewed Ab response to one serotype (Thomas and Yoon, 2019;White et al, 2021). The TV003/005 induced high levels of type-specific Abs against all DENV serotypes compared with other live-attenuated vaccines (Nivarthi et al, 2021).…”

Controlled Human Infection Models To Accelerate Vaccine Development

“…In particular, like Butantan-DV (aka TV-003) described above, TAK-003 stimulates a relatively balanced profile of neutralizing antibodies (166) and memory B cells (167) against the four DENV serotypes, and also stimulates a CD8 + T-cell response against DENV non-structural proteins NS1, NS3, and NS5, which are associated with a protective immune response (168)(169)(170). In contrast, a recent publication highlighted the difference between type-specific neutralizing antibodies against DENV-2 as compared to cross-reactive DENV-1, DENV-3, and DENV-4 neutralizing antibodies (171).…”