Walsh Douglas S, Gettayacamin Montip, Leitner Wolfgang W, Lyon Jeffrey A, Stewart V Ann, Marit Gary, Pichyangkul Sathit, Gosi Panita, Tongtawe Pongsri, Kester Kent E, Holland Carolyn A, Kolodny Nelly, Cohen Joe, Voss Gerald, Ballou W Ripley, Heppner D Gray
Department of Immunology & Medicine, US Army Medical Component, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.
Vaccine. 2006 May 8;24(19):4167-78. doi: 10.1016/j.vaccine.2006.02.041. Epub 2006 Mar 6.
RTS,S/AS02A, a recombinant Plasmodium falciparum vaccine based on the circumsporozoite protein (CSP) repeat and C-terminus regions, elicits strong humoral and Th1 cell-mediated immunity. In field studies, RTS,S/AS02A reduced malaria infection, clinical episodes, and disease severity. Heterologous prime-boost immunization regimens, optimally spaced, might improve the protective immunity of RTS,S/AS02A.
DNA plasmid encoding P. falciparum CSP (3D7) was administered to six experimental groups of rhesus monkeys (N = 5) by gene gun (coded as D), followed by a 1/5th human dose of RTS,S/AS02A (coded as R). Immunization regimens, including a numeral to denote weeks between immunizations, were D-4-R, D-16-R, D-4-D-4-R, D-4-D-16-R, D-16-D-4-R and D-16-D-16-R. A control group (N = 5) received a single 1/5th dose of RTS,S/AS02A. Endpoints were antibody (Ab) to homologous CSP repeat and C-terminus regions and delayed-type hypersensitivity (DTH) to CSP peptides.
Monkeys immunized twice with DNA, 16 weeks apart (D-16-D-4-R and D-16-D-16-R), developed higher levels of anti-C-terminus Abs than control monkeys (p<0.02). No CSP DNA priming regimen increased RTS,S/AS02A-induced Ab to CSP repeats. At 16 months after first immunization, D-R and D-D-R, but not control, monkeys had histologically confirmed DTH reactions against CSP C-terminus, which persisted at repeat testing 12 months later.
Two optimally spaced, particle-mediated epidermal deliveries of CSP DNA improved the humoral immunogenicity of a single dose of RTS,S/AS02A. Further, CSP DNA prime followed by one dose of RTS,S/AS02A gave biopsy proven DTH reactions against CSP C-terminus of up to 2 years duration, implying the induction of CD4+ memory T cells. Heterologous prime-boost strategies for malaria involving gene gun delivered DNA or more potent vectors, administered at optimal intervals, warrant further investigation.
RTS,S/AS02A是一种基于环子孢子蛋白（CSP）重复序列和C末端区域的重组恶性疟原虫疫苗，可引发强烈的体液免疫和Th1细胞介导的免疫反应。在现场研究中，RTS,S/AS02A可降低疟疾感染、临床发作和疾病严重程度。间隔时间最佳的异源初免-加强免疫方案可能会提高RTS,S/AS02A的保护性免疫力。
通过基因枪将编码恶性疟原虫CSP（3D7）的DNA质粒给予六组恒河猴（N = 5）（编码为D），随后给予1/5人剂量的RTS,S/AS02A（编码为R）。免疫方案包括一个数字，表示两次免疫之间的周数，分别为D-4-R、D-16-R、D-4-D-4-R、D-4-D-16-R、D-16-D-4-R和D-16-D-16-R。一个对照组（N = 5）接受单剂量1/5的RTS,S/AS02A。观察终点为针对同源CSP重复序列和C末端区域的抗体（Ab）以及对CSP肽的迟发型超敏反应（DTH）。
间隔16周用DNA免疫两次的猴子（D-16-D-4-R和D-16-D-16-R）产生的抗C末端抗体水平高于对照猴子（p<0.02）。没有CSP DNA初免方案能增加RTS,S/AS02A诱导的针对CSP重复序列的抗体。首次免疫后16个月，D-R和D-D-R组猴子（而非对照组）经组织学证实对CSP C末端有DTH反应，这种反应在12个月后的重复检测中仍然存在。
两次间隔时间最佳的颗粒介导的表皮递送CSP DNA可提高单剂量RTS,S/AS02A的体液免疫原性。此外，CSP DNA初免后再给予一剂RTS,S/AS02A可产生经活检证实的长达2年的针对CSP C末端的DTH反应，这意味着诱导了CD4+记忆T细胞。涉及基因枪递送DNA或更有效的载体、以最佳间隔给药的疟疾异源初免-加强策略值得进一步研究。
