Macete Eusebio V, Sacarlal Jahit, Aponte John J, Leach Amanda, Navia Margarita M, Milman Jessica, Guinovart Caterina, Mandomando Inacio, López-Púa Yolanda, Lievens Marc, Owusu-Ofori Alex, Dubois Marie-Claude, Cahill Conor P, Koutsoukos Marguerite, Sillman Marla, Thompson Ricardo, Dubovsky Filip, Ballou W Ripley, Cohen Joe, Alonso Pedro L
Centro de Investigação em Saúde de Manhiça, Manhiça, Mozambique.
Trials. 2007 Mar 26;8:11. doi: 10.1186/1745-6215-8-11.
BACKGROUND: Previous trials of the RTS, S malaria candidate vaccine have shown that this vaccine is safe, tolerated and immunogenic. The development plan for this vaccine aims at administering it in the first year of life through the Expanded Program on Immunization (EPI). The objective was to evaluate the safety and reactogenicity of RTS, S/AS02D (0.5 ml dose), a pediatric formulation of GlaxoSmithKline Biologicals' current malaria candidate vaccine RTS, S/AS02A (0.25 ml dose). A 0.5 ml dose of AS02D is composed of the same active ingredients in the same quantities as in a 0.25 ml dose of AS02A and has been developed to be easily introduced into routine EPI practices. METHODS: We performed a phase I/IIb randomized double-blind bridging study in a malaria-endemic region of Mozambique, to compare the safety and immunogenicity of both candidate vaccines with the aim of replacing RTS, S/AS02A with RTS, S/AS02D as the candidate pediatric vaccine. 200 Mozambican children aged 3 to 5 years were randomized 1:1 to receive one of the 2 vaccines according to a 0, 1, 2 month schedule. RESULTS: Both vaccines were safe and had similar reactogenicity profiles. All subjects with paired pre and post-vaccination samples showed a vaccine response with respect to anti-circumsporozoite (CS) antibodies irrespective of initial anti-CS serostatus. Geometric mean titers (GMTs) were 191 EU/ml (95% CI 150-242) in recipients of RTS, S/AS02D compared to 180 EU/ml (95% CI 146-221) in recipients of RTS, S/AS02A. For the anti-hepatitis B surface antigen (HBsAg), all subjects were seroprotected at day 90, and the GMTs were 23,978 mIU/ml (95% CI 17,896-32,127) in RTS, S/AS02D recipients and 17,410 mIU/ml (95% CI 13,322-22,752) in RTS, S/AS02A recipients. There was a decrease in anti-CS GMTs between months 3 and 14 in both groups (191 vs 22 EU/mL in RTS, S/AS02D group and 180 vs 29 EU/mL in RTS, S/AS02A group). CONCLUSION: Our data show that the RTS, S/AS02D is safe, well tolerated, and demonstrates non-inferiority (defined as upper limit of the 95% confidence interval of the anti-CS GMT ratio of RTS, S/AS02A to RTS, S/AS02D below 3.0) of the antibody responses to circumsporozoite and HBsAg induced by the RTS, S/AS02D as compared to the RTS, S/AS02A.
背景：此前对RTS,S疟疾候选疫苗的试验表明，该疫苗安全、耐受性良好且具有免疫原性。该疫苗的开发计划旨在通过扩大免疫规划（EPI）在生命的第一年进行接种。目的是评估葛兰素史克生物制品公司目前的疟疾候选疫苗RTS,S/AS02A（0.25毫升剂量）的儿科制剂RTS,S/AS02D（0.5毫升剂量）的安全性和反应原性。0.5毫升剂量的AS02D与0.25毫升剂量的AS02A含有相同的活性成分，且数量相同，其开发目的是便于引入常规EPI实践。 方法：我们在莫桑比克的一个疟疾流行地区进行了一项I/IIb期随机双盲桥接研究，以比较两种候选疫苗的安全性和免疫原性，目的是用RTS,S/AS02D替代RTS,S/AS02A作为候选儿科疫苗。200名3至5岁的莫桑比克儿童按1:1随机分组，根据0、1、2个月的接种程序接受两种疫苗中的一种。 结果：两种疫苗均安全，且反应原性特征相似。所有接种前和接种后配对样本的受试者均显示出针对抗环子孢子（CS）抗体的疫苗反应，无论初始抗CS血清状态如何。RTS,S/AS02D接种者的几何平均滴度（GMT）为191 EU/ml（95%CI 150 - 242），而RTS,S/AS02A接种者为180 EU/ml（95%CI 146 - 221）。对于抗乙型肝炎表面抗原（HBsAg），所有受试者在第90天均获得血清保护，RTS,S/AS02D接种者的GMT为23,978 mIU/ml（95%CI 17,896 - 32,127），RTS,S/AS02A接种者为17,410 mIU/ml（95%CI 13,322 - 22,752）。两组在第3个月至第14个月期间抗CS GMT均有所下降（RTS,S/AS02D组为191 vs 22 EU/mL，RTS,S/AS02A组为180 vs 29 EU/mL）。 结论：我们的数据表明，RTS,S/AS02D安全、耐受性良好，并且与RTS,S/AS02A相比，RTS,S/AS02D诱导的针对环子孢子和HBsAg的抗体反应具有非劣效性（定义为RTS,S/AS02A与RTS,S/AS02D的抗CS GMT比值的95%置信区间上限低于3.0）。
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