Department of Veterinary Medicine, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.
Structural Vaccinology Laboratory, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.
Vaccine. 2019 Jun 27;37(29):3793-3803. doi: 10.1016/j.vaccine.2019.05.059. Epub 2019 May 28.
Antibodies to Circumsporozoite protein (CSP) confer protection against controlled human malaria infection (CHMI) caused by the parasite Plasmodium falciparum. Although CSP is highly immunogenic, it does not induce long lasting protection and efforts to improve CSP-specific immunological memory and duration of protection are underway. We have previously reported that the clinical grade CSP vaccine FMP013 was immunogenic and protective against malaria challenge in mice when combined with the Army Liposomal Formulation adjuvant containing immune modulators 3D-PHAD™ and QS21 (ALFQ). To move forward with clinical evaluation, we now report the safety, toxicity and immunogenicity of clinical grade FMP013 and ALFQ in Rhesus macaques. Three groups of Rhesus (n = 6) received half or full human dose of FMP013 + ALFQ on a 0-1-2 month schedule, which showed mild local site reactions with no hematologic derangements in red blood cell homeostasis, liver function or kidney function. Immunization induced a transient systemic inflammatory response, including elevated white blood cell counts, mild fever, and a few incidences of elevated creatine kinase, receding to normal range by day 7 post vaccination. Optimal immunogenicity in Rhesus was observed using a 1 mL ALFQ + 20 µg FMP013 dose. Doubling the FMP013 antigen dose to 40 µg had no effect while halving the ALFQ adjuvant dose to 0.5 mL lowered immunogenicity. Similar to data generated in mice, FMP013 + ALFQ induced serum antibodies that reacted to all regions of the CSP molecule and a Th1-biased cytokine response in Rhesus. Rhesus antibody response to FMP013 + ALFQ was found to be non-inferior to historical benchmarks including that of RTS,S + AS01 in humans. A four-dose GLP toxicity study in rabbits confirmed no local site reactions and transient systemic inflammation associated with ALFQ adjuvant administration. These safety and immunogenicity data support the clinical progression and testing of FMP013 + ALFQ in a CHMI trial in the near future.
针对疟原虫恶性疟原虫引起的人体疟疾感染（CHMI），环状孢子蛋白（CSP）抗体可提供保护。尽管 CSP 具有高度免疫原性，但它不能诱导长期保护，因此正在努力改善 CSP 特异性免疫记忆和保护时间。我们之前报道过，临床级 CSP 疫苗 FMP013 与含有免疫调节剂 3D-PHAD™和 QS21（ALFQ）的陆军脂质体制剂联合使用时，在小鼠中具有免疫原性和抗疟作用。为了推进临床评估，我们现在报告临床级 FMP013 和 ALFQ 在恒河猴中的安全性、毒性和免疫原性。三组恒河猴（每组 6 只）在 0-1-2 个月的时间内接受了半剂量或全剂量的 FMP013+ALFQ，结果显示局部反应轻微，红细胞稳态、肝功能或肾功能无血液学紊乱。免疫接种诱导了短暂的全身炎症反应，包括白细胞计数升高、轻度发热和少数肌酸激酶升高，接种后 7 天恢复正常。在恒河猴中观察到最佳的免疫原性是使用 1ml ALFQ+20μg FMP013 剂量。将 FMP013 抗原剂量增加一倍至 40μg 没有效果，而将 ALFQ 佐剂剂量减半至 0.5ml 则降低了免疫原性。与在小鼠中生成的数据类似，FMP013+ALFQ 诱导的血清抗体可与 CSP 分子的所有区域反应，并在恒河猴中引起 Th1 偏向的细胞因子反应。恒河猴对 FMP013+ALFQ 的抗体反应被发现不劣于包括人类 RTS,S+AS01 在内的历史基准。在兔子中进行的一项四剂量 GLP 毒性研究证实，ALFQ 佐剂给药无局部反应和短暂的全身炎症。这些安全性和免疫原性数据支持 FMP013+ALFQ 在近期 CHMI 试验中的临床进展和测试。
