资料来源：《已上市人用预防疫苗佐剂的研究进展》，《获批上市疫苗中佐剂的研究进展》

从全球研发趋势来看，新型疫苗佐剂向着Toll样受体激活剂、复合佐剂和纳米颗粒等多元化方向发展。Toll样受体（TLR）是天然免疫系统的重要成分，TLR受体激动剂被认为是一类非常有前途的疫苗佐剂。一系列研究证实，TLR4激动剂吡喃葡萄糖基脂质A（GLA-SE）作为H5N1流感疫苗佐剂[1]，在II期临床实验中免疫效果良好，并在结核疫苗[2]、肿瘤抗原疫苗[3]进行了测试。TLR7激动剂Imiquimod作为癌症疫苗佐剂用于头颈基底细胞癌[4]和黑色素瘤[5]的治疗，具有良好的耐受性和免疫原性。此外，TLR9激动剂MGN1703、IC31、SD-101也有望成为候选疫苗佐剂[6-8]。在复合佐剂领域，由磷脂、胆固醇和皂苷组成的复合物ISCOMATRIX能诱导广泛而有效的体液和细胞免疫应答，已在流感疫苗[9]、呼吸道合胞病毒[10]、生殖器疱疹病毒疫苗GEN-003 [11] 、新冠疫苗 [12]等多款疫苗中开展临床研究。另有研究表明，由双链RNA类似物及TLR配体组成的Poly I:C/PIKA佐剂可显著提高狂犬疫苗在成人体内的抗体水平和T细胞反应[13]。近年来，纳米颗粒作为疫苗佐剂和递送系统也发展较快。例如，阳离子脂质体VCL-HB01在DNA登革热疫苗I期临床试验中表现出良好的安全性和耐受性[14]。使用纳米凝胶作为递送系统的肺炎链球菌疫苗[15]，在动物模型中经鼻内免疫，证明纳米凝胶装在的疫苗有效且安全。

与此同时，国内也涌现出一批优秀企业，试图突破这一卡脖子领域。例如，瑞科生物对标葛兰素史克的AS01、AS03、AS04研发了三款新型佐剂，分别开展了针对带状疱疹疫苗、新冠疫苗、HPV疫苗的研发。迈科康生物自主研发的复合新型佐剂MA105佐剂系统，已被用于重组带状疱疹疫苗的研发。依生生物开发的皮卡佐剂已经在狂犬疫苗、乙肝疫苗上开展临床研究。此外，华泰诺、华普生物、沃森生物/上海泽润生物、智飞生物、三叶草生物也开始布局新型疫苗佐剂。

随着对先天免疫信号通路的认知不断加深，更多潜在的新型疫苗佐剂会不断被发现。我们有理由相信，疫苗佐剂将迎来新的黄金时代。

参考文献：

1.Pillet S, et al. Humoral and cell-mediated immune responses to H5N1 plant-made virus-like particle vaccine are differentially impacted by alum and GLA-SE adjuvants in a phase 2 clinical trial. NPJ vaccines 2018;3(1):1-9

2.Penn-Nicholson A, et al. Safety and immunogenicity of the novel tuberculosis vaccine ID93+ GLASE in BCG-vaccinated healthy adults in South Africa: a randomised, double-blind, placebo-controlled phase 1 trial. Lancet Respir Med 2018;6(4):287-298.

3.Bakos O, et al. Combining surgery and immunotherapy: turning an immunosuppressive effect into a therapeutic opportunity. J ImmuoTherapy of Cancer 2018; 6(1):1-11.

4.Singh S, et al. Topical imiquimod as a neo-adjuvant chemotherapy for cartilage salvage in the treatment of nodular basal cell carcinomas of the head and neck . Indian Journal of Dermatology, Venereology and Leprology 2021;87(3):1-4

5.Meneveau MO，et al.Immunogenicity in humans of a transdermal multipeptide melanoma vaccine administered with or without a TLR7 agonist.J Immunother Cancer 2021; 9:e002214.

6.Burghardt Wittig, et al. MGN1703, an immune-modulator and toll-like receptor 9 (TLR-9) agonist: From bench to bedside. Critical Reviews in Oncology/Hematology 2015; 94(1):31-44.

7.Norrby M, et al. Safety and immunogenicity of the novel H4: IC31 tuberculosis vaccine candidate in BCG-vaccinated adults: two phase I dose escalation trials. Vaccine 2017;35(12):1652-1661.

8.Suliman S, et al. Dose optimization of H56: IC31 vaccine for tuberculosis-endemic populations. A double-blind, placebo-controlled, dose-selection trial. Am J Respir Crit Care Med 2019;199(2): 220-231.

9.Windon RG ，et al. Local immune responses to influenza antigen are synergistically enhanced by the adjuvant ISCOMATRIX . Vaccine 2002; 20: 490–497.10.Morelli A,et al. ISCOMATRIX adjuvant in the development of prophylactic and therapeutic vaccines. In:Immunopotentiators in modern vaccines. Elsevier; 2017. p. 311-332.

11.Wagoner V, et al. Effects of Different Doses of GEN-003, a Therapeutic Vaccine for Genital Herpes Simplex Virus-2, on Viral Shedding and Lesions: Results of a Randomized Placebo-Controlled Trial. J Infec Diseases 2018; 12:1890-1899.

12. Heath PT, et al.Safety and Efficacy of NVX-CoV2373 Covid-19 Vaccine. N ENGL J MED 2021; 385(13) :1172-1183.

14.Danko JR, et al. Safety and immunogenicity of a tetravalent dengue DNA vaccine administered with a cationic lipid-based adjuvant in a phase 1 clinical trial. Am J Trop Med Hyg 2018;98(3): 849-856.

15. 杨雪华等. 纳米凝胶的研究进展[J]. 食品与药品, 2022年第2期, 183-187.返回搜狐，查看更多