The candidate tuberculosis vaccine Mtb72F/AS02A Tolerability and immunogenicity in humans
The candidate tuberculosis vaccine Mtb72F/AS02A Tolerability and immunogenicity in humans
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DOI：
10.4161/hv.8570
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发表时间：
2009-07-01
期刊：
影响因子：
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通讯作者：
Ballou, W. Ripley
中科院分区：
文献类型：
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作者：
Von Eschen, Kenneth;Morrison, Royce;Ballou, W. Ripley
结核病（TB）在世界许多地方仍然不受控制，并且针对TB的有效疫苗的开发代表高度优先的未满足的医疗需求。在一项开放标签I期研究（NCT 00730795）中，年龄为18-40岁的健康PPD（结核菌素纯化蛋白衍生物）阴性成人志愿者根据0-1-2个月的时间表接受了3剂候选Mtb 72 F/AS 02 A疫苗。评估了征集性、非征集性和严重不良事件（AE）、血液学和生化实验室参数。通过ELISA评估Mtb 72 F特异性体液应答，并通过细胞内细胞因子染色（ICS）和短期ELISPOT测定评估细胞介导的免疫（CMI）应答。还通过ICS评估了对组分肽（Mtb 39 a和Mtb 32a C-和N-末端抗原结构域，Mtb 32 C和Mtb 32 N）的CMI应答。Mtb 72 F/AS 02 A疫苗似乎主要是局部反应原性的，但这被认为是可接受的，因为这些AE通常是一过性的，并在1-2天内消退。报告的大多数AE的严重程度为轻度，未发生严重AE，未测量到与疫苗接种相关的具有医学意义的生化或血液学异常，所有AE均消退且无后遗症。疫苗诱导体液和CMI反应指标发生统计学显著变化。在ELISPOT测定中，Mtb 72 F抗原诱导了IL-2和IFN γ的良好产生，并且用ICS观察到表达至少两种活化标志物（主要是CD 40-L和IL-2）的CD 4（+）T细胞。用Mtb 39 a和Mtb 32 N观察到类似的CMI曲线。诱导的CMI应答在接种后持续至少6个月。所有受试者在第2次给药后1个月和第3次给药后6个月均为抗Mtb 72 F抗体血清阳性。这项首次人体试验发现Mtb 72 F/AS 02 A具有可接受的耐受性，在健康成人中具有免疫原性，并保证了疫苗的进一步开发。
Tuberculosis ( TB) remains uncontrolled in many parts of the world and the development of an effective vaccine against TB represents a high priority unmet medical need. Healthy PPD ( tuberculin purified protein derivative)-negative adult volunteers, aged 18-40 years received three doses of the candidate Mtb72F/AS02A vaccine according to a 0-1-2 months schedule in an open-label Phase I study ( NCT00730795). Solicited, unsolicited and serious adverse events ( AEs), hematological and biochemical laboratory parameters were assessed. Mtb72F-specific humoral responses were assessed by ELISA and cell-mediated immune ( CMI) responses by intracellular cytokine staining ( ICS) and short-term ELISPOT assays. CMI responses to the component peptides ( Mtb39a and the Mtb32a C-and N-terminal antigen domains, Mtb32C and Mtb32N) were also assessed by ICS. The Mtb72F/AS02A vaccine appeared to be mainly locally reactogenic but this was considered acceptable, since these AEs were usually transient and resolved within 1-2 days. Most AEs reported were mild in intensity, no serious AEs occurred, no medically significant biochemical or hematological abnormalities related to vaccination were measured and all AEs resolved without sequelae. The vaccine induced statistically significant changes in humoral and CMI response measures. The Mtb72F antigen induced good production of IL-2 and IFN gamma in the ELISPOT assay and CD4(+) T cells expressing at least two activation markers ( mainly CD40-L and IL-2) were observed with ICS. A similar CMI profile was observed with Mtb39a and Mtb32N. The induced CMI responses persisted for at least 6 months post-vaccination. All subjects were seropositive for anti-Mtb72F antibodies one month post-dose 2 and 6 months post-dose 3. This first trial in humans found Mtb72F/AS02A to have an acceptable tolerability, to be immunogenic in healthy adults and warrants further development of the vaccine.