University of Saskatchewan, College of Pharmacy and Nutrition, 107 Wiggins Road, Saskatoon, Saskatchewan S7N 5E5, Canada.
Vaccine and Infectious Disease Organization, University of Saskatchewan, 120 Veterinary Road, Saskatoon, Saskatchewan S7N 5E3, Canada.
Mol Pharm. 2022 Jun 6;19(6):1814-1824. doi: 10.1021/acs.molpharmaceut.1c00852. Epub 2022 Mar 18.
Continuous outbreaks of pertussis around the world suggest inadequate immune protection in infants and weakened immune responses induced over time by the acellular pertussis vaccine. Vaccine adjuvants provide a means to improve vaccine immunogenicity and support long-term adaptive immunity against pertussis. An acellular pertussis vaccine was prepared with pertactin, pertussis toxin, and fimbriae 2/3 antigens combined with a triple-adjuvant system consisting of innate defense regulator peptide IDR 1002, a Toll-like receptor-3 agonist poly(I:C), and a polyphosphazene in a fixed combination. The vaccine was delivered intranasally in a cationic lipid nanoparticle formulation fabricated by simple admixture and two schema for addition of antigens (LT-A, antigens associated outside of L-TriAdj, and LAT, antigens associated inside of L-TriAdj) to optimize particle size and cationic surface charge. In the former, antigens were associated with the lipidic formulation of the triple adjuvant by electrostatic attraction. In the latter, the antigens resided in the interior of the lipid nanoparticle. Two dose levels of antigens were used with adjuvant comprised of the triple adjuvant with or without the lipid nanoparticle carrier. Formulation of vaccines with the triple adjuvant stimulated systemic and mucosal immune responses. The lipid nanoparticle vaccines favored a Th1 type of response with higher IgG2a and IgA serum antibody titers particularly for pertussis toxin and pertactin formulated at the 5 μg dose level in the admixed formulation. Additionally, the lipid nanoparticle vaccines resulted in high nasal SIgA antibodies and an early (4 weeks post vaccination) response after a single vaccination dose. The LT-A nanoparticles trended toward higher titers of serum antibodies compared to LAT. The cationic lipid-based vaccine nanoparticles formulated with a triple adjuvant showed encouraging results as a potential formulation for intranasally administered pertussis vaccines.
全球持续爆发百日咳表明婴儿的免疫保护不足，以及无细胞百日咳疫苗随时间推移诱导的免疫反应减弱。疫苗佐剂提供了一种提高疫苗免疫原性和支持百日咳长期适应性免疫的手段。一种无细胞百日咳疫苗由 pertactin、百日咳毒素和菌毛 2/3 抗原与三佐剂系统（先天防御调节剂肽 IDR 1002、Toll 样受体 3 激动剂聚（I:C）和聚磷腈）组合而成，固定组合。该疫苗以阳离子脂质纳米颗粒制剂经鼻给药，该制剂通过简单混合和两种抗原添加方案（LT-A，与 L-TriAdj 外关联的抗原和 LAT，与 L-TriAdj 内关联的抗原）来优化粒径和阳离子表面电荷。在前一种方案中，抗原通过静电吸引与三佐剂的脂质制剂相关联。在后一种方案中，抗原位于脂质纳米颗粒的内部。使用两种抗原剂量水平，佐剂由三佐剂组成，或包含或不包含脂质纳米颗粒载体。用三佐剂配制疫苗可刺激全身和粘膜免疫反应。脂质纳米颗粒疫苗有利于 Th1 型反应，特别是在混合配方中以 5μg 剂量水平配制的 pertussis 毒素和 pertactin 时，血清 IgG2a 和 IgA 抗体滴度更高。此外，脂质纳米颗粒疫苗可导致高鼻 SIgA 抗体，并在单次接种剂量后即可早期（接种后 4 周）产生反应。与 LAT 相比，LT-A 纳米颗粒趋向于更高的血清抗体滴度。用三佐剂配制的基于阳离子脂质的疫苗纳米颗粒作为经鼻给药的百日咳疫苗的潜在制剂显示出可喜的结果。
