Efficacy of different AV7909 dose regimens in a nonclinical model of pulmonary anthrax

Pulmonary anthrax caused by exposure to inhaled <i>Bacillus anthracis</i>, the most lethal form of anthrax disease, is a continued military and public health concern for the United States. The vaccine AV7909, consisting of the licensed anthrax drug substance AVA adjuvanted with CpG7909, induces high levels of toxin neutralizing antibodies in healthy adults using fewer doses than AVA. This study compares the ability of one- or two-dose regimens of AV7909 to induce a protective immune response in guinea pigs challenged with a lethal dose of aerosolized <i>B. anthracis</i> spores 6 weeks after the last vaccine dose. The results indicated that AV7909 was less effective when delivered as a single dose compared to the two-dose regimen that resulted in dose-dependent protection against death. The toxin neutralizing assay (TNA) titer and anti-PA IgG responses were proportional to the protective efficacy, with a 50% TNA neutralizing factor (NF₅₀) greater than 0.1 associated with survival in animals receiving two doses of vaccine. The strong protection at relatively low TNA NF₅₀ titers in this guinea pig model supports the exploration of lower doses in clinical trials to determine if these protective levels of neutralizing antibodies can be achieved in humans; however, protection with a single dose may not be feasible.

吸入炭疽芽孢杆菌（*Bacillus anthracis*）引发的肺炭疽是炭疽病中致死性最强的类型，长期以来均为美国军方与公共卫生领域的重点关切问题。疫苗AV7909由获批上市的炭疽原料药AVA与CpG7909佐剂复配而成，仅需少于AVA的接种剂次，即可在健康成年人体内诱导出高水平的毒素中和抗体。本研究对比了AV7909单剂次与两剂次接种方案，在末次接种后6周，经致死剂量气溶胶化炭疽芽孢杆菌（*Bacillus anthracis*）孢子攻毒的豚鼠体内诱导保护性免疫应答的能力。研究结果显示，AV7909单剂次接种的保护效果弱于两剂次方案，后者可产生剂量依赖性的死亡防护效应。毒素中和试验（TNA）滴度与抗PA IgG抗体应答水平与保护效力呈正相关；在接种两剂疫苗的动物中，TNA 50%中和因子（NF₅₀）大于0.1与受试动物存活显著相关。该豚鼠模型中，即便TNA NF₅₀滴度相对较低仍可实现较强的保护效果，这一发现支持在临床试验中探索更低的接种剂量，以明确人类体内能否达到此类保护性中和抗体水平；不过单剂次接种的防护效果或难以实现。