Tameris M, Hokey D A, Nduba V, Sacarlal J, Laher F, Kiringa G, Gondo K, Lazarus E M, Gray G E, Nachman S, Mahomed H, Downing K, Abel B, Scriba T J, McClain J B, Pau M G, Hendriks J, Dheenadhayalan V, Ishmukhamedov S, Luabeya A K K, Geldenhuys H, Shepherd B, Blatner G, Cardenas V, Walker R, Hanekom W A, Sadoff J, Douoguih M, Barker L, Hatherill M
South African Tuberculosis Vaccine Initiative (SATVI), Department of Paediatrics and Child Health and Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Cape Town, South Africa.
Aeras, Rockville, MD, USA.
Vaccine. 2015 Jun 9;33(25):2944-54. doi: 10.1016/j.vaccine.2015.03.070. Epub 2015 Apr 28.
Several novel tuberculosis vaccines are currently in clinical trials, including AERAS-402, an adenovector encoding a fusion protein of Mycobacterium tuberculosis antigens 85A, 85B, and TB10.4. A multicentred trial of AERAS-402 safety and immunogenicity in healthy infants was conducted in three countries in sub-Saharan Africa, using an adaptive design.
In a double-blind, randomised, placebo-controlled, dose-finding trial, we enrolled BCG-vaccinated, HIV-uninfected infants aged 16-26 weeks. Infants in the safety/dose-finding phase received two doses of AERAS-402 across three dose levels, or placebo, intramuscularly on days 0 and 28. Infants in the expanded safety phase received three doses of the highest dose level, with the 3rd dose at day 280. Follow up for safety and immunogenicity was for up to two years.
We enrolled 206 infants (52 placebo and 154 AERAS-402 recipients) into the dose-finding phase and 281 (141 placebo and 140 AERAS-402 recipients) into the expanded safety phase. Safety data were acceptable across all dose levels. No vaccine-related deaths were recorded. A single serious adverse event of tachypnoea was deemed related to study vaccine. Antibodies directed largely against Ag85A and Ag85B were detected. Low magnitude CD4+ and CD8+ polyfunctional T cell responses were observed at all dose levels. The addition of a third dose of AERAS-402 at the highest dose level did not increase frequency or magnitude of antibody or CD8+ T cell responses.
AERAS-402 has an acceptable safety profile in infants and was well tolerated at all dose levels. Response rate was lower than previously seen in BCG vaccinated adults, and frequency and magnitude of antigen-specific T cells were not increased by a third dose of vaccine.
目前有几种新型结核病疫苗正在进行临床试验，包括AERAS-402，一种腺病毒载体，编码结核分枝杆菌抗原85A、85B和TB10.4的融合蛋白。在撒哈拉以南非洲的三个国家进行了一项关于AERAS-402在健康婴儿中的安全性和免疫原性的多中心试验，采用适应性设计。
在一项双盲、随机、安慰剂对照、剂量探索试验中，我们纳入了接种过卡介苗、未感染艾滋病毒的16-26周龄婴儿。在安全性/剂量探索阶段的婴儿在第0天和第28天通过肌肉注射接受两剂三种剂量水平的AERAS-402或安慰剂。在扩大安全性阶段的婴儿接受三剂最高剂量水平的疫苗，第三剂在第280天接种。对安全性和免疫原性的随访长达两年。
我们将206名婴儿（52名接受安慰剂，154名接受AERAS-402）纳入剂量探索阶段，将281名婴儿（141名接受安慰剂，140名接受AERAS-402）纳入扩大安全性阶段。所有剂量水平的安全性数据均可接受。未记录到与疫苗相关的死亡病例。有一例呼吸急促的严重不良事件被认为与研究疫苗有关。检测到主要针对Ag85A和Ag85B的抗体。在所有剂量水平均观察到低水平的CD4+和CD8+多功能T细胞反应。在最高剂量水平添加第三剂AERAS-402并未增加抗体或CD8+T细胞反应的频率或强度。
AERAS-402在婴儿中的安全性可接受，在所有剂量水平均耐受性良好。反应率低于先前在接种卡介苗的成年人中观察到的水平，第三剂疫苗并未增加抗原特异性T细胞的频率和强度。
