Moores Cancer Center, University of California San Diego, La Jolla, CA 92093-0809.
Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA 92093-0901.
Proc Natl Acad Sci U S A. 2021 Jun 8;118(23). doi: 10.1073/pnas.2025718118.
Vaccine adjuvants enhance and prolong pathogen-specific protective immune responses. Recent reports indicate that host factors-such as aging, pregnancy, and genetic polymorphisms-influence efficacies of vaccines adjuvanted with Toll-like receptor (TLR) or known pattern-recognition receptor (PRR) agonists. Although PRR independent adjuvants (e.g., oil-in-water emulsion and saponin) are emerging, these adjuvants induce some local and systemic reactogenicity. Hence, new TLR and PRR-independent adjuvants that provide greater potency alone or in combination without compromising safety are highly desired. Previous cell-based high-throughput screenings yielded a small molecule 81 [-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide], which enhanced lipopolysaccharide-induced NF-κB and type I interferon signaling in reporter assays. Here compound 81 activated innate immunity in primary human peripheral blood mononuclear cells and murine bone marrow-derived dendritic cells (BMDCs). The innate immune activation by 81 was independent of TLRs and other PRRs and was significantly reduced in mitochondrial antiviral-signaling protein (MAVS)-deficient BMDCs. Compound 81 activities were mediated by mitochondrial dysfunction as mitophagy inducers and a mitochondria specific antioxidant significantly inhibited cytokine induction by 81. Both compound 81 and a derivative obtained via structure-activity relationship studies, 2F52 [-benzyl--(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide] modestly increased mitochondrial reactive oxygen species and induced the aggregation of MAVS. Neither 81 nor 2F52 injected as adjuvants caused local or systemic toxicity in mice at effective concentrations for vaccination. Furthermore, vaccination with inactivated influenza virus adjuvanted with 2F52 demonstrated protective effects in a murine lethal virus challenge study. As an unconventional and safe adjuvant that does not require known PRRs, compound 2F52 could be a useful addition to vaccines.
疫苗佐剂增强和延长了病原体特异性的保护性免疫反应。最近的报告表明，宿主因素，如衰老、妊娠和遗传多态性，会影响 Toll 样受体（TLR）或已知模式识别受体（PRR）激动剂佐剂的疫苗效力。虽然出现了 PRR 非依赖性佐剂（例如，油包水乳剂和皂苷），但这些佐剂会引起一些局部和全身的不良反应。因此，人们非常希望能够发现新的 TLR 和 PRR 非依赖性佐剂，这些佐剂在不影响安全性的前提下单独或联合使用时能够提供更高的效力。以前的基于细胞的高通量筛选产生了一种小分子 81 [-(4-氯-2,5-二甲氧基苯基）-4-乙氧基苯磺酰胺]，它在报告基因检测中增强了脂多糖诱导的 NF-κB 和 I 型干扰素信号传导。在这里，化合物 81 在原代人外周血单核细胞和小鼠骨髓来源的树突状细胞（BMDC）中激活了固有免疫。81 的固有免疫激活不依赖于 TLR 和其他 PRR，并且在缺失线粒体抗病毒信号蛋白（MAVS）的 BMDC 中显著减少。化合物 81 的活性是通过线粒体功能障碍介导的，作为自噬诱导剂，一种线粒体特异性抗氧化剂可显著抑制 81 诱导的细胞因子产生。化合物 81 和通过结构活性关系研究获得的衍生物 2F52 [苄基-（4-氯-2,5-二甲氧基苯基）-4-乙氧基苯磺酰胺]，都适度增加了线粒体活性氧，并诱导 MAVS 聚集。在有效的疫苗接种浓度下，81 或 2F52 作为佐剂注射到小鼠体内均不会导致局部或全身毒性。此外，用 2F52 佐剂的灭活流感病毒进行疫苗接种在小鼠致命病毒攻毒研究中显示出保护作用。作为一种非传统且安全的佐剂，不需要已知的 PRR，化合物 2F52 可能是疫苗的有用添加物。
