UVM Vaccine Testing Center, Department of Microbiology and Molecular Genetics, University of Vermont Larner College of Medicine, Burlington, VT, USA; Department of Medicine, University of Vermont Larner College of Medicine, Burlington, VT, USA.
Infectious Diseases Division, iccdr,b, Dhaka, Bangladesh.
Lancet Infect Dis. 2024 Feb;24(2):150-160. doi: 10.1016/S1473-3099(23)00520-0. Epub 2023 Sep 27.
Morbidity and mortality from dengue virus (DENV) is rapidly growing in the large populations of south Asia. Few formal evaluations of candidate dengue vaccine candidates have been undertaken in India, Pakistan, or Bangladesh. Tetravalent vaccines must be tested for safety and immunogenicity in all age groups and in those previously exposed and naive to DENV infections. TV005 is a live, attenuated tetravalent dengue vaccine. We evaluated the safety and immunogenicity of a single dose of TV005 across age groups in dengue-endemic Bangladesh.
We performed a randomised, placebo-controlled age de-escalating clinical trial of TV005 at a single clinical site in dengue-endemic Dhaka, Bangladesh, following a technology transfer from the USA. Healthy (as determined by history, clinical examination, and safety laboratory test results) volunteers aged 1-50 years were randomly assigned 3:1 (stratified by four age groups) to receive a single dose of TV005 vaccine or placebo. Participants were followed up for 3 years. The study was double blind and was unmasked at day 180; outcome assessors, clinic staff, and volunteers remained blind throughout. Primary outcomes were safety, evaluated per-protocol as proportion of volunteers with solicited related adverse events of any severity through 28 days post dosing, and post-vaccination seropositivity by day 180 using serotype-specific neutralising antibodies (PRNT ≥10). Secondary outcomes included viremia, impact of past dengue exposure, and durability of antibody responses. This study is registered with Clinicaltrials.gov, NCT02678455, and is complete.
Between March 13, 2016, and Feb 14, 2017, 192 volunteers were enrolled into four age groups (adults [18-50 years; 20 male and 28 female], adolescents [11-17 years; 27 male and 21 female], children [5-10 years; 15 male and 33 female], and young children [1-4 years; 29 male and 19 female]) with 48 participant per group. All participants were Bangladeshi. Vaccination was well tolerated and most adverse events were mild. Rash was the most common vaccine-associated solicited adverse event, in 37 (26%) of 144 vaccine recipients versus six (12%) of 48 placebo recipients; followed by fever in seven (5% of 144) and arthralgias in seven (6% of 108), which were only observed in vaccine recipients. Post-vaccine, volunteers of all ages (n=142) were seropositive to most serotypes with 118 (83%) seropositive to DENV 1, 141 (99%) to DENV 2, 137 (96%) to DENV 3, and 124 (87%) to DENV 4, overall by day 180. Post-vaccination, viraemia was not consistently found and antibody titres were higher (10-15-fold for DENV 1-3 and 1·6-fold for DENV 4) in individuals with past dengue exposure compared with the dengue-naive participants (DENV 1 mean 480 [SD 4·0] vs 32 [2·4], DENV 2 1042 [3·2] vs 105 [3·1], DENV 3 1406 [2·8] vs 129 [4·7], and DENV 4 105 [3·3] vs 65 [3·1], respectively). Antibody titres to all serotypes remained stable in most adults (63-86%) after 3 years of follow-up. However, as expected for individuals without past exposure to dengue, titres for DENV 1, 3, and 4 waned by 3 years in the youngest (1-4 year old) cohort (69% seropositive for DENV 2 and 22-28% seropositive for DENV 1, 3, and 4).
With 3 years of follow-up, the single-dose tetravalent dengue vaccine, TV005, was well tolerated and immunogenic for all four serotypes in young children to adults, including individuals with no previous dengue exposure.
National Institutes of Health-National Institute of Allergy and Infectious Diseases Intramural Research Program and Johns Hopkins University.
For the Bangla translation of the abstract see Supplementary Materials section.
登革病毒（DENV）的发病率和死亡率在南亚的庞大人口中迅速上升。在印度、巴基斯坦和孟加拉国，对候选登革热疫苗进行了很少的正式评估。四价疫苗必须在所有年龄组中以及以前接触过和对 DENV 感染无免疫力的人群中进行安全性和免疫原性测试。TV005 是一种减毒的四价登革热疫苗。我们评估了在登革热流行的孟加拉国，TV005 在不同年龄组中单次剂量的安全性和免疫原性。
我们在登革热流行的孟加拉国达卡的一个单一临床地点进行了一项随机、安慰剂对照的年龄递减临床试验，该试验是从美国进行技术转让的。健康（通过病史、临床检查和安全实验室检测结果确定）志愿者年龄在 1-50 岁之间，按四个年龄组（1:3）随机分配接受 TV005 疫苗或安慰剂。参与者随访 3 年。该研究是双盲的，第 180 天揭盲；结果评估者、临床工作人员和志愿者在整个过程中均保持盲法。主要结局是安全性，按方案评估，通过 28 天的疫苗接种后，任何严重程度的志愿者中与疫苗相关的不良事件的比例，以及第 180 天的血清阳性率，通过血清型特异性中和抗体（PRNT≥10）来确定。次要结局包括病毒血症、过去登革热暴露的影响以及抗体反应的持久性。本研究在 Clinicaltrials.gov 注册，NCT02678455，现已完成。
2016 年 3 月 13 日至 2017 年 2 月 14 日期间，192 名志愿者被分为四个年龄组（成人[18-50 岁；男性 20 名，女性 28 名]、青少年[11-17 岁；男性 27 名，女性 21 名]、儿童[5-10 岁；男性 15 名，女性 33 名]和幼儿[1-4 岁；男性 29 名，女性 19 名]），每组 48 名参与者。所有参与者均为孟加拉国人。疫苗接种耐受性良好，大多数不良事件为轻度。皮疹是最常见的疫苗相关不良事件，在 144 名疫苗接种者中发生 37 例（26%），在 48 名安慰剂接种者中发生 6 例（12%）；其次是发热 7 例（5%）和关节痛 7 例（6%），仅在疫苗接种者中观察到。接种疫苗后，所有年龄组的志愿者（n=142）对大多数血清型均呈血清阳性，118 名志愿者（83%）对 DENV1 血清阳性，141 名志愿者（99%）对 DENV2 血清阳性，137 名志愿者（96%）对 DENV3 血清阳性，124 名志愿者（87%）对 DENV4 血清阳性，总体在第 180 天达到血清阳性。接种疫苗后，未发现病毒血症，与登革热无免疫力的参与者相比，过去有登革热暴露史的个体的抗体滴度更高（DENV1-3 为 10-15 倍，DENV4 为 1.6 倍）。DENV1 的平均血清滴度（480[4.0]与 32[2.4]，DENV2 为 1042[3.2]与 105[3.1]，DENV3 为 1406[2.8]与 129[4.7]，DENV4 为 105[3.3]与 65[3.1]）。在 3 年的随访后，大多数成年人（63-86%）的所有血清型抗体滴度仍保持稳定。然而，对于没有过去登革热暴露史的个体，在最年轻的（1-4 岁）队列中，DENV1、3 和 4 的抗体滴度在 3 年内下降（DENV2 血清阳性率为 69%，DENV1、3 和 4 的血清阳性率为 22-28%）。
TV005 是一种单价四价登革热疫苗，在孟加拉国进行的为期 3 年的随访中，该疫苗在幼儿至成年人中，包括无过去登革热暴露史的个体中，耐受性良好且具有免疫原性。
美国国立卫生研究院国家过敏和传染病研究所内部研究计划和约翰霍普金斯大学。
