Mandaric Sanja, Friberg Heather, Saez-Llorens Xavier, Borja-Tabora Charissa, Biswal Shibadas, Escudero Ian, Faccin Alice, Gottardo Raphael, Brose Manja, Roubinis Nicholas, Fladager Darlene, DeAntonio Rodrigo, Dimero Julie Anne L, Montenegro Nathali, Folschweiller Nicolas, Currier Jeffrey R, Sharma Mayuri, Tricou Vianney
Takeda Pharmaceuticals International AG, Zurich, Switzerland.
Walter Reed Army Institute of Research, Silver Spring, MD, USA.
NPJ Vaccines. 2024 Oct 17;9(1):192. doi: 10.1038/s41541-024-00967-0.
As robust cellular responses are important for protection against dengue, this phase 2 study evaluated the kinetics and phenotype of T cell responses induced by TAK-003, a live-attenuated tetravalent dengue vaccine, in 4-16-year-old living in dengue-endemic countries (NCT02948829). Two hundred participants received TAK-003 on Days 1 and 90. Interferon-gamma (IFN-γ) enzyme-linked immunospot assay [ELISPOT] and intracellular cytokine staining were used to analyze T cell response and functionality, using peptide pools representing non-structural (NS) proteins NS3 and NS5 matching DENV-1, -2, -3, and -4 and DENV-2 NS1. One month after the second TAK-003 dose (Day 120), IFN-γ ELISPOT T cell response rates against any peptide pool were 97.1% (95% CI: 93.4% to 99.1%), and similar for baseline dengue seropositive (96.0%) and seronegative (98.6%) participants. IFN-γ ELISPOT T cell response rates at Day 120 were 79.8%, 90.2%, 77.3%, and 74.0%, against DENV-1, -2, -3, and -4, respectively, and remained elevated through 3 years post-vaccination. Multifunctional CD4 and CD8 T cell responses against DENV-2 NS peptides were observed, independent of baseline serostatus: CD8 T cells typically secreted IFN-γ and TNF-α whereas CD4 T cells secreted ≥ 2 of IFN-γ, IL-2 and TNF-α cytokines. NAb titers and seropositivity rates remained substantially elevated through 3 years post-vaccination. Overall, TAK-003 was well tolerated and elicited durable T cell responses against all four DENV serotypes irrespective of baseline serostatus in children and adolescents aged 4-16 years living in dengue-endemic countries. TAK-003-elicited CD4 and CD8 T cells were multifunctional and persisted up to 3 years post-vaccination.
由于强大的细胞反应对于预防登革热很重要，这项2期研究评估了减毒活四价登革热疫苗TAK-003在登革热流行国家4至16岁人群中诱导的T细胞反应的动力学和表型（NCT02948829）。200名参与者在第1天和第90天接种了TAK-003。使用干扰素-γ（IFN-γ）酶联免疫斑点试验[ELISPOT]和细胞内细胞因子染色，使用代表与登革病毒1、2、3和4以及登革病毒2 NS1匹配的非结构（NS）蛋白NS3和NS5的肽池来分析T细胞反应和功能。在第二次接种TAK-003剂量后1个月（第120天），针对任何肽池的IFN-γ ELISPOT T细胞反应率为97.1%（95%CI：93.4%至99.1%），基线登革热血清阳性（96.0%）和血清阴性（98.6%）参与者的反应率相似。在第120天，针对登革病毒1、2、3和4的IFN-γ ELISPOT T细胞反应率分别为79.8%、90.2%、77.3%和74.0%，并且在接种疫苗后3年内一直保持升高。观察到针对登革病毒2 NS肽的多功能CD4和CD8 T细胞反应，与基线血清状态无关：CD8 T细胞通常分泌IFN-γ和TNF-α，而CD4 T细胞分泌≥2种IFN-γ、IL-2和TNF-α细胞因子。中和抗体滴度和血清阳性率在接种疫苗后3年内仍大幅升高。总体而言，TAK-003耐受性良好，并且在生活在登革热流行国家的4至16岁儿童和青少年中，无论基线血清状态如何，都能引发针对所有四种登革热血清型的持久T细胞反应。TAK-003诱导产生的CD4和CD8 T细胞具有多功能性，并且在接种疫苗后持续长达3年。
