Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, 6700B Rockledge Drive, Bethesda, MD 20892-7630, USA.
Sci Transl Med. 2012 Sep 12;4(151):151ra126. doi: 10.1126/scitranslmed.3004073.
Because clinical trials to assess the efficacy of vaccines against anthrax are not ethical or feasible, licensure for new anthrax vaccines will likely involve the Food and Drug Administration's "Animal Rule," a set of regulations that allow approval of products based on efficacy data only in animals combined with immunogenicity and safety data in animals and humans. U.S. government-sponsored animal studies have shown anthrax vaccine efficacy in a variety of settings. We examined data from 21 of those studies to determine whether an immunological bridge based on lethal toxin neutralization activity assay (TNA) can predict survival against an inhalation anthrax challenge within and across species and genera. The 21 studies were classified into 11 different settings, each of which had the same animal species, vaccine type and formulation, vaccination schedule, time of TNA measurement, and challenge time. Logistic regression models determined the contribution of vaccine dilution dose and TNA on prediction of survival. For most settings, logistic models using only TNA explained more than 75% of the survival effect of the models with dose additionally included. Cross-species survival predictions using TNA were compared to the actual survival and shown to have good agreement (Cohen's κ ranged from 0.55 to 0.78). In one study design, cynomolgus macaque data predicted 78.6% survival in rhesus macaques (actual survival, 83.0%) and 72.6% in rabbits (actual survival, 64.6%). These data add support for the use of TNA as an immunological bridge between species to extrapolate data in animals to predict anthrax vaccine effectiveness in humans.
由于评估炭疽疫苗疗效的临床试验在伦理或实际操作上不可行，新炭疽疫苗的许可可能涉及食品和药物管理局的“动物规则”，这是一套规定，允许仅根据动物的疗效数据以及动物和人体的免疫原性和安全性数据批准产品。美国政府资助的动物研究已经在各种环境中证明了炭疽疫苗的疗效。我们检查了其中 21 项研究的数据，以确定基于致死毒素中和活性测定（TNA）的免疫桥是否可以预测对吸入性炭疽挑战的生存能力，以及在物种和属内和跨物种的生存能力。这 21 项研究被分为 11 种不同的环境，每种环境都有相同的动物物种、疫苗类型和配方、接种时间表、TNA 测量时间和挑战时间。逻辑回归模型确定了疫苗稀释剂量和 TNA 对生存预测的贡献。对于大多数环境，仅使用 TNA 的逻辑模型解释了生存效应模型中包含剂量的 75%以上。使用 TNA 进行跨物种生存预测与实际生存情况进行了比较，结果表明具有良好的一致性（Cohen's κ 范围为 0.55 至 0.78）。在一项研究设计中，食蟹猴数据预测恒河猴的生存率为 78.6%（实际生存率为 83.0%），兔的生存率为 72.6%（实际生存率为 64.6%）。这些数据进一步支持了 TNA 作为物种间免疫桥的使用，以推断动物数据，从而预测人类炭疽疫苗的有效性。
