Genito Christopher J, Beck Zoltan, Phares Timothy W, Kalle Fanta, Limbach Keith J, Stefaniak Maureen E, Patterson Noelle B, Bergmann-Leitner Elke S, Waters Norman C, Matyas Gary R, Alving Carl R, Dutta Sheetij
Laboratory of Structural Vaccinology, Malaria Vaccine Branch, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.
Laboratory of Adjuvant and Antigen Research, US Military HIV Research Program, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.
Vaccine. 2017 Jul 5;35(31):3865-3874. doi: 10.1016/j.vaccine.2017.05.070. Epub 2017 Jun 7.
Malaria caused by Plasmodium falciparum continues to threaten millions of people living in the tropical parts of the world. A vaccine that confers sterile and life-long protection remains elusive despite more than 30years of effort and resources invested in solving this problem. Antibodies to a malaria vaccine candidate circumsporozoite protein (CSP) can block invasion and can protect humans against malaria. We have manufactured the Falciparum Malaria Protein-013 (FMP013) vaccine based on the nearly full-length P. falciparum CSP 3D7 strain sequence. We report here immunogenicity and challenge data on FMP013 antigen in C57BL/6 mice formulated with two novel adjuvants of the Army Liposome Formulation (ALF) series and a commercially available adjuvant Montanide ISA 720 (Montanide) as a control. ALF is a liposomal adjuvant containing a synthetic monophosphoryl lipid A (3D-PHAD®). In our study, FMP013 was adjuvanted with ALF alone, ALF containing aluminum hydroxide (ALFA) or ALF containing QS-21 (ALFQ). Adjuvants ALF and ALFA induced similar antibody titers and protection against transgenic parasite challenge that were comparable to Montanide. ALFQ was superior to the other three adjuvants as it induced higher antibody titers with improved boosting after the third immunization, higher serum IgG2c titers, and enhanced protection. FMP013+ALFQ also augmented the numbers of splenic germinal center-derived activated B-cells and antibody secreting cells compared to Montanide. Further, FMP013+ALFQ induced antigen-specific IFN-γ ELISPOT activity, CD4 T-cells and a T1-biased cytokine profile. These results demonstrate that soluble CSP can induce a potent and sterile protective immune response when formulated with the QS-21 containing adjuvant ALFQ. Comparative mouse immunogenicity data presented here were used as the progression criteria for an ongoing non-human primate study and a regulatory toxicology study in preparation for a controlled human malaria infection (CHMI) trial.
由恶性疟原虫引起的疟疾继续威胁着生活在世界热带地区的数百万人。尽管投入了30多年的努力和资源来解决这个问题，但能提供无菌和终身保护的疫苗仍然难以实现。针对疟疾候选疫苗环子孢子蛋白（CSP）的抗体可以阻断感染，并能保护人类免受疟疾侵害。我们基于近乎全长的恶性疟原虫CSP 3D7株序列制备了恶性疟原虫蛋白-013（FMP013）疫苗。我们在此报告了用陆军脂质体制剂（ALF）系列的两种新型佐剂和市售佐剂Montanide ISA 720（Montanide）作为对照配制的FMP013抗原在C57BL/6小鼠中的免疫原性和攻毒数据。ALF是一种含有合成单磷酰脂质A（3D-PHAD®）的脂质体佐剂。在我们的研究中，FMP013分别与单独的ALF、含氢氧化铝的ALF（ALFA）或含QS-21的ALF（ALFQ）佐剂联用。佐剂ALF和ALFA诱导的抗体滴度以及对转基因寄生虫攻击的保护作用与Montanide相当。ALFQ优于其他三种佐剂，因为它在第三次免疫后诱导出更高的抗体滴度和更好的增强效果、更高的血清IgG2c滴度以及更强的保护作用。与Montanide相比，FMP013+ALFQ还增加了脾生发中心来源的活化B细胞和抗体分泌细胞的数量。此外，FMP013+ALFQ诱导了抗原特异性IFN-γ ELISPOT活性、CD4 T细胞和偏向T1的细胞因子谱。这些结果表明，可溶性CSP与含QS-21的佐剂ALFQ联用时可诱导强效的无菌保护性免疫反应。此处呈现的比较小鼠免疫原性数据被用作正在进行的非人灵长类动物研究和监管毒理学研究的进展标准，为受控人类疟疾感染（CHMI）试验做准备。
