TAK-003 elicits cellular immune response against all dengue serotypes in paediatric cohort

Audrey Abella
24 May 2023
TAK-003 elicits cellular immune response against all dengue serotypes in paediatric cohort
Sanja Manjaric presenting the findings of a phase II study evaluating a tetravalent dengue vaccine in a paediatric cohort.

TAK-003, a live-attenuated, recombinant tetravalent dengue vaccine covering all four dengue virus (DENV) strains, elicited a cell-mediated immune (CMI) response in healthy children and adolescents aged 4–16 years, the phase II DEN-313 study has shown.

“[This response occurred] irrespective of DENV baseline serostatus [and] was maintained through day 270,” noted Sanja Mandaric from Takeda Pharmaceuticals International AG, Zürich, Switzerland at ESPID 2023.

Two-hundred participants from Panama and the Philippines (mean age 6.7 years, 50 percent female) received the vaccine on days 1 and 90. About 60 percent were seropositive at baseline. Participants were followed for up to 3 years. [ESPID 2023, abstract O0083]

At day 120, IFN-γ ELISPOT* positive responder rates to any peptide pool were comparable between seronegative and seropositive participants at baseline (83 percent vs 76 percent).

The magnitude of IFN-γ ELISPOT response rate was higher in the seropositive vs seronegative subgroup at day 30 (mean SFCs**/106 PBMCs**, 3,044.2 vs 1,666.1). This was sustained at a steady state up to month 9 (mean SFCs/106 PBMCs, 2,121.4 vs 1,544.5).

“[TAK-003] was not only specific for DENV-2. It is also cross-reactive towards DENV-1, 3, and 4. This pattern was observed in both seronegative and seropositive participants at baseline,” she continued.

TAK-003 also elicited CD8 and CD4 T-cell responses against DENV-2 NS1, NS3, and NS5 regardless of baseline serostatus. “The CD8 and CD4 T cells were functional. They were producing all three cytokines – IFN-γ, interleukin(IL)-2, and tumour necrosis factor-alpha (TNF-ɑ), and there were no differences according to serostatus,” noted Mandaric. “[These cytokines] have been shown to have a protective role in dengue natural infection.”

TAK-003 also elicited multifunctional CD8 and CD4 T-cell responses against dengue NS proteins. These were seen in the heatmaps of magnitude of responses at day 120 for the different cytokine combinations in NS1-, NS3-, and NS5-specific T cells.

“What’s interesting to note is that CD8 T-cell responses were typically characterized by the secretion of IFN-γ with and without TNF-ɑ in a hierarchical manner,” said Mandaric. Furthermore, CD4 T-cell responses were polyfunctional and are basically characterized by the secretion of ≥2 cytokines (ie, IL-2 in combination with IFN-y and TNF-ɑ).

A little over 40 percent reported unsolicited adverse events (AEs) within 28 days post vaccine, the most common being nasopharyngitis and upper respiratory tract infection. Nonetheless, most were mild, and only 1.5 percent were vaccine-related. There were no deaths, discontinuations due to AEs, or TAK-003-related serious AEs.

Twelve participants had virologically confirmed dengue (mostly DENV-3), but none met the WHO criteria for dengue haemorrhagic fever. All were observed after the second TAK-003 dose and resolved within 2–7 days. Only one case required hospitalization.

“TAK-003 was well tolerated, with no important safety risks identified,” said Mandaric.

No correlate of protection yet

“Dengue is a painful, potentially life-threatening disease affecting many people all over the world,” said Mandaric. About 400 million dengue infections are reported every year across 128 countries. [Nature 2013;496:504-507; PLoS Negl Trop Dis 2012;8:e1760]

“The TAK-003 backbone has been designed to elicit immune responses against DENV-specific non-structural proteins, which are important for protective CMI response. Previous studies have shown that TAK-003 elicits a broad CMI response to both structural and non-structural proteins,” Mandaric explained.

The NS1, NS3, and NS5 non-structural proteins of all DENV serotypes have been mapped as immunodominant targets of the TAK-003-mediated T-cell response. “These three proteins play an important role in viral replication. Some of them are involved in host evasion. NS1 is involved in the pathogenesis of severe dengue,” she said.

Mandaric underscored that there is no correlate of protection for dengue yet, “but what we know … is that the multifunctional dengue-specific T-cells are associated with a protective immune response against dengue.”

More investigations are underway to better understand the CMI response elicited by TAK-003.

TAK-003 has been approved in the EU and other dengue-endemic countries*** for dengue prevention regardless of serostatus.


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