Department of Microbiology and Immunology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA.
TurboVax Inc., Philadelphia, PA.
Immunohorizons. 2024 Aug 1;8(8):527-537. doi: 10.4049/immunohorizons.2400040.
Many bacterial polysaccharide vaccines, including the typhoid Vi polysaccharide (ViPS) and tetravalent meningococcal polysaccharide conjugate (MCV4) vaccines, do not incorporate adjuvants and are not highly immunogenic, particularly in infants. I found that endotoxin, a TLR4 ligand in ViPS, contributes to the immunogenicity of typhoid vaccines. Because endotoxin is pyrogenic, and its levels are highly variable in vaccines, I developed monophosphoryl lipid A, a nontoxic TLR4 ligand-based adjuvant named Turbo. Admixing Turbo with ViPS and MCV4 vaccines improved their immunogenicity across all ages and eliminated booster requirement. To understand the characteristics of this adjuvanticity, I compared Turbo with alum. Unlike alum, which polarizes the response toward the IgG1 isotype, Turbo promoted Ab class switching to all IgG isotypes with affinity maturation; the magnitude of this IgG response is durable and accompanied by the presence of long-lived plasma cells in the mouse bone marrow. In striking contrast with the pathways employed by alum, Turbo adjuvanticity is independent of NLPR3, pyroptotic cell death effector Gasdermin D, and canonical and noncanonical inflammasome activation mediated by Caspase-1 and Caspase-11, respectively. Turbo adjuvanticity is primarily dependent on the MyD88 axis and is lost in mice deficient in costimulatory molecules CD86 and CD40, indicating that Turbo adjuvanticity includes activation of these pathways. Because Turbo formulations containing either monophosphoryl lipid A or TLR2 ligands, Pam2CysSerLys4, and Pam3CysSerLys4 help generate Ab response of all IgG isotypes, as an adjuvant Turbo can improve the immunogenicity of glycoconjugate vaccines against a wide range of bacterial pathogens whose elimination requires appropriate IgG isotypes.
许多细菌多糖疫苗，包括伤寒 Vi 多糖（ViPS）和四价脑膜炎球菌多糖结合疫苗（MCV4），都不包含佐剂，免疫原性也不高，尤其是在婴儿中。我发现，ViPS 中的内毒素是 TLR4 配体，有助于伤寒疫苗的免疫原性。由于内毒素是发热原，而且其在疫苗中的水平变化很大，因此我开发了单磷酰脂质 A，一种基于非毒性 TLR4 配体的佐剂，名为 Turbo。将 Turbo 与 ViPS 和 MCV4 疫苗混合使用可提高其在所有年龄段的免疫原性，并消除加强针的需求。为了了解这种佐剂的特性，我将 Turbo 与明矾进行了比较。与明矾不同，明矾使反应偏向 IgG1 同型，Turbo 促进了所有 IgG 同型的 Ab 类别转换，并伴有亲和力成熟；这种 IgG 反应的强度持久，并伴有长寿浆细胞存在于小鼠骨髓中。与明矾所采用的途径形成鲜明对比的是，Turbo 佐剂性独立于 NLPR3、致细胞裂解Gasdermin D、Caspase-1 和 Caspase-11 介导的经典和非经典炎症小体激活，分别。Turbo 佐剂性主要依赖于 MyD88 轴，在缺乏共刺激分子 CD86 和 CD40 的小鼠中丧失，表明 Turbo 佐剂性包括这些途径的激活。因为含有单磷酰脂质 A 或 TLR2 配体 Pam2CysSerLys4 和 Pam3CysSerLys4 的 Turbo 配方有助于产生所有 IgG 同型的 Ab 反应，因此作为佐剂，Turbo 可以提高针对广泛细菌病原体的糖缀合物疫苗的免疫原性，这些病原体的消除需要适当的 IgG 同型。
