Bojang Kalifa A, Olodude Folasade, Pinder Margaret, Ofori-Anyinam Opokua, Vigneron Laurence, Fitzpatrick Steve, Njie Fanta, Kassanga Adams, Leach Amanda, Milman Jessica, Rabinovich Regina, McAdam Keith P W J, Kester Kent E, Heppner D Gray, Cohen Joe D, Tornieporth Nadia, Milligan Paul J M
Medical Research Council Laboratories, P.O. Box 273, Banjul, The Gambia.
Vaccine. 2005 Jul 14;23(32):4148-57. doi: 10.1016/j.vaccine.2005.03.019. Epub 2005 Apr 15.
RTS,S/AS02A is a pre-erythrocytic malaria vaccine candidate in which a portion of the circumsporozoite surface protein (CSP) of Plasmodium falciparum is genetically linked to hepatitis B surface antigen (HBsAg) coexpressed in yeast with unfused HBsAg. The resulting particulate antigen is formulated with the adjuvant system AS02A. We have initiated the paediatric clinical development of this vaccine by conducting two sequential Phase I studies in children: a study in older children (6--11 years), followed by a second study in younger children (1--5 years). In each study, a double-blind, randomised controlled, staggered, dose-escalation design was used to evaluate 10 microg RTS,S dose (10 microg RTS,S in 0.1mL AS02A), 25 microg dose (25 microg RTS,S in 0.25mL AS02A) and finally a 50 microg dose (50 microg RTS,S in 0.5mL AS02A) of the RTS,S/AS02A candidate malaria vaccine administered according to a 0-, 1- and 3-month vaccination schedule. Safety and reactogenicity were evaluated before moving to a higher dose level. The RTS,S/AS02A vaccine was safe at all dose levels, in both age groups. No serious adverse events related to vaccination were reported. The frequency of local Grade 3 symptoms was low but tended to increase with increasing dose level. Grade 3 general adverse events in the RTS,S/AS02A groups were infrequent and of short duration. The majority of local and general Grade 3 symptoms resolved or decreased in intensity within 48h. The pattern and intensity of reactogenicity seen in these studies are similar to those of previous studies with RTS,S/AS02A. All doses were highly immunogenic for anti-CSP and anti-HBsAg antibodies. The pooled anti-CSP antibody data from the two studies showed that the 25 microg dose and 50 microg dose anti-CSP antibody response were similar at both dose levels. However, the immunogenicity of the 10 microg dose anti-CSP response was significantly lower than that of either the 50 microg or 25 microg dose. The 25 microg dose was selected for future studies of RTS,S/AS02A in paediatric populations.
RTS,S/AS02A是一种红细胞前期疟疾候选疫苗，其中恶性疟原虫环子孢子表面蛋白（CSP）的一部分与乙肝表面抗原（HBsAg）通过基因连接，在酵母中与未融合的HBsAg共表达。所得的颗粒抗原与佐剂系统AS02A一起配制。我们通过在儿童中进行两项连续的I期研究启动了该疫苗的儿科临床开发：一项针对大龄儿童（6至11岁）的研究，随后是针对年幼儿童（1至5岁）的第二项研究。在每项研究中，采用双盲、随机对照、交错、剂量递增设计来评估按照0、1和3个月接种计划接种的10微克RTS,S剂量（0.1毫升AS02A中含10微克RTS,S）、25微克剂量（0.25毫升AS02A中含25微克RTS,S），最后是50微克剂量（0.5毫升AS02A中含50微克RTS,S）的RTS,S/AS02A候选疟疾疫苗。在升至更高剂量水平之前评估安全性和反应原性。RTS,S/AS02A疫苗在两个年龄组的所有剂量水平下均安全。未报告与疫苗接种相关的严重不良事件。局部3级症状的发生率较低，但有随剂量水平增加而升高的趋势。RTS,S/AS02A组中的3级一般不良事件不常见且持续时间短。大多数局部和一般3级症状在48小时内消退或强度降低。这些研究中观察到的反应原性模式和强度与先前RTS,S/AS02A研究的相似。所有剂量对针对CSP和HBsAg的抗体均具有高度免疫原性。两项研究汇总的抗CSP抗体数据表明，25微克剂量和50微克剂量的抗CSP抗体反应在两个剂量水平上相似。然而，10微克剂量的抗CSP反应的免疫原性明显低于50微克或25微克剂量。25微克剂量被选用于未来RTS,S/AS02A在儿科人群中的研究。
