Sheets Rebecca L, Stein Judith, Manetz T Scott, Andrews Charla, Bailer Robert, Rathmann John, Gomez Phillip L
U.S. Public Health Service, Vaccine Production Program, NIH/NIAID/Vaccine Research Center, Bethesda, Maryland 20892-7628, USA.
Toxicol Sci. 2006 Jun;91(2):620-30. doi: 10.1093/toxsci/kfj170. Epub 2006 Mar 28.
The Vaccine Research Center has developed a number of vaccine candidates for different diseases/infectious agents (HIV-1, Severe Acute Respiratory Syndrome virus, West Nile virus, and Ebola virus, plus a plasmid cytokine adjuvant-IL-2/Ig) based on a DNA plasmid vaccine platform. To support the clinical development of each of these vaccine candidates, preclinical studies were performed to screen for potential toxicities (intrinsic and immunotoxicities). All treatment-related toxicities identified in these repeated-dose toxicology studies have been confined primarily to the sites of injection and seem to be the result of both the delivery method (as they are seen in both control and treated animals) and the intended immune response to the vaccine (as they occur with greater frequency and severity in treated animals). Reactogenicity at the site of injection is generally seen to be reversible as the frequency and severity diminished between doses and between the immediate and recovery termination time points. This observation also correlated with the biodistribution data reported in the companion article (Sheets et al., 2006), in which DNA plasmid vaccine was shown to remain at the site of injection, rather than biodistributing widely, and to clear over time. The results of these safety studies have been submitted to the Food and Drug Administration to support the safety of initiating clinical studies with these and related DNA plasmid vaccines. Thus far, standard repeated-dose toxicology studies have not identified any target organs for toxicity (other than the injection site) for our DNA plasmid vaccines at doses up to 8 mg per immunization, regardless of disease indication (i.e., expressed gene-insert) and despite differences (strengths) in the promoters used to drive this expression. As clinical data accumulate with these products, it will be possible to retrospectively compare the safety profiles of the products in the clinic to the results of the repeated-dose toxicology studies, in order to determine the utility of such toxicology studies for signaling potential immunotoxicities or intrinsic toxicities from DNA vaccines. These data build on the biodistribution studies performed (see companion article, Sheets et al., 2006) to demonstrate the safety and suitability for investigational human use of DNA plasmid vaccine candidates for a variety of infectious disease prevention indications.
疫苗研究中心基于DNA质粒疫苗平台，针对不同疾病/感染源（HIV-1、严重急性呼吸综合征病毒、西尼罗河病毒和埃博拉病毒，外加一种质粒细胞因子佐剂——IL-2/Ig）研发了多种候选疫苗。为支持每种候选疫苗的临床开发，开展了临床前研究以筛查潜在毒性（内在毒性和免疫毒性）。在这些重复给药毒理学研究中确定的所有与治疗相关的毒性主要局限于注射部位，似乎是给药方式（因为在对照动物和受试动物中均可见）和对疫苗预期免疫反应（因为在受试动物中出现的频率和严重程度更高）共同作用的结果。注射部位的反应原性通常被认为是可逆的，因为剂量之间以及即时和恢复终止时间点之间的频率和严重程度会降低。这一观察结果也与配套文章（希茨等人，2006年）中报道的生物分布数据相关，其中显示DNA质粒疫苗会留在注射部位，而不是广泛分布，并会随时间清除。这些安全性研究的结果已提交给美国食品药品监督管理局，以支持使用这些及相关DNA质粒疫苗启动临床研究的安全性。到目前为止，标准的重复给药毒理学研究尚未确定我们的DNA质粒疫苗在每次免疫剂量高达8毫克时的任何毒性靶器官（注射部位除外），无论疾病指征（即表达的基因插入片段）如何，也不管用于驱动这种表达的启动子存在差异（强度不同）。随着这些产品临床数据的积累，将有可能回顾性地比较临床中产品的安全性概况与重复给药毒理学研究的结果，以确定此类毒理学研究对于提示DNA疫苗潜在免疫毒性或内在毒性的效用。这些数据建立在已开展的生物分布研究基础之上（见配套文章，希茨等人，2006年），以证明候选DNA质粒疫苗用于多种传染病预防指征的人体研究的安全性和适用性。
