Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Department of Epidemiology, University of North Carolina Gillings School of Public Health, Chapel Hill, NC, USA.
Nat Commun. 2021 Feb 17;12(1):1102. doi: 10.1038/s41467-021-21384-0.
The four-dengue virus (DENV) serotypes infect several hundred million people annually. For the greatest safety and efficacy, tetravalent DENV vaccines are designed to stimulate balanced protective immunity to all four serotypes. However, this has been difficult to achieve. Clinical trials with a leading vaccine demonstrated that unbalanced replication and immunodominance of one vaccine component over others can lead to low efficacy and vaccine enhanced severe disease. The Laboratory of Infectious Diseases at the National Institutes of Health has developed a live attenuated tetravalent DENV vaccine (TV003), which is currently being tested in phase 3 clinical trials. Here we report, our study to determine if TV003 stimulate balanced and serotype-specific (TS) neutralizing antibody (nAb) responses to each serotype. Serum samples from twenty-one dengue-naive individuals participated under study protocol CIR287 (ClinicalTrials.gov NCT02021968) are analyzed 6 months after vaccination. Most subjects (76%) develop TS nAbs to 3 or 4 DENV serotypes, indicating immunity is induced by each vaccine component. Vaccine-induced TS nAbs map to epitopes known to be targets of nAbs in people infected with wild type DENVs. Following challenge with a partially attenuated strain of DENV2, all 21 subjects are protected from the efficacy endpoints. However, some vaccinated individuals develop post challenge nAb boost, while others mount post-challenge antibody responses that are consistent with sterilizing immunity. TV003 vaccine induced DENV2 TS nAbs are associated with sterilizing immunity. Our results indicate that nAbs to TS epitopes on each serotype may be a better correlate than total levels of nAbs currently used for guiding DENV vaccine development.
四种登革热病毒(DENV)血清型每年感染数亿人。为了最大程度的安全和有效性,四价登革热疫苗旨在刺激对所有四种血清型的平衡保护免疫。然而,这一直很难实现。一项领先疫苗的临床试验表明,一种疫苗成分的不平衡复制和免疫优势超过其他成分会导致低疗效和疫苗增强的严重疾病。美国国立卫生研究院传染病实验室开发了一种减毒四价登革热疫苗(TV003),目前正在进行 3 期临床试验。在这里,我们报告了一项研究,以确定 TV003 是否能刺激对每种血清型的平衡和血清型特异性(TS)中和抗体(nAb)反应。根据研究方案 CIR287(ClinicalTrials.gov NCT02021968),对 21 名登革热初治个体的血清样本进行了分析,这些样本在接种后 6 个月采集。大多数受试者(76%)对 3 种或 4 种 DENV 血清型产生了 TS nAb,表明每种疫苗成分都能诱导免疫。疫苗诱导的 TS nAb 针对的表位与感染野生型 DENVs 的人群中 nAb 的靶标已知。在接受部分减毒的 DENV2 株攻击后,所有 21 名受试者均免受疗效终点的影响。然而,一些接种个体在挑战后出现 nAb 增强,而其他个体则出现与绝育免疫一致的抗体反应。TV003 疫苗诱导的 DENV2 TS nAb 与绝育免疫有关。我们的结果表明,针对每种血清型 TS 表位的 nAb 可能比目前用于指导登革热疫苗开发的总 nAb 水平更好地作为相关指标。