TLR7/8 adjuvant overcomes newborn hyporesponsiveness to pneumococcal conjugate vaccine at birth
TLR7/8 adjuvant overcomes newborn hyporesponsiveness to pneumococcal conjugate vaccine at birth
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DOI：
10.1172/jci.insight.91020
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发表时间：
2017-03-01
期刊：
影响因子：
8
通讯作者：
Levy, Ofer
中科院分区：
文献类型：
--
作者：
Dowling, David J.;van Haren, Simon D.;Levy, Ofer
感染是生命早期死亡的最常见原因，免疫接种是减少这一负担的最有希望的生物医学干预措施。然而，新生儿未能对大多数疫苗作出最佳反应。佐剂是增强疫苗免疫原性的关键方法，但人类新生儿白细胞对大多数候选佐剂（包括大多数TLR激动剂）的反应在功能上是不同的。在本文中，我们证明3 M-052是小鼠中的局部作用的脂质化咪唑并喹啉TLR 7/8激动剂佐剂，当适当配制时，其可以单独地和与明矾佐剂化的肺炎球菌缀合物疫苗13（PCV 13）协同地在体外诱导人新生儿白细胞产生稳健的Th 1细胞因子。当与PCV 13混合并i.m.在恒河猴出生的第一天，3 M-052显著增强了Th 1 CRM-197特异性新生儿CD 4（+）细胞的产生、新生儿和婴儿肺炎链球菌多糖特异性（PnPS特异性）B细胞的活化以及链球菌型特异性抗体滴度和调理吞噬细胞杀伤。值得注意的是，出生时单次剂量的PCV 13加0.1 mg/kg 3 M-052诱导的PnPS特异性IgG应答比单次出生剂量的单独PCV 13高约10-100倍，迅速超过保护的血清学相关性，早在出生后28天。这种有效的免疫策略，可能有效的一个出生剂量，可以代表一个新的模式，在生命早期的疫苗开发。
Infection is the most common cause of mortality in early life, and immunization is the most promising biomedical intervention to reduce this burden. However, newborns fail to respond optimally to most vaccines. Adjuvantation is a key approach to enhancing vaccine immunogenicity, but responses of human newborn leukocytes to most candidate adjuvants, including most TLR agonists, are functionally distinct. Herein, we demonstrate that 3M-052 is a locally acting lipidated imidazoquinoline TLR7/8 agonist adjuvant in mice, which, when properly formulated, can induce robust Th1 cytokine production by human newborn leukocytes in vitro, both alone and in synergy with the alum-adjuvanted pneumococcal conjugate vaccine 13 (PCV13). When admixed with PCV13 and administered i.m. on the first day of life to rhesus macaques, 3M-052 dramatically enhanced generation of Th1 CRM-197-specific neonatal CD4(+) cells, activation of newborn and infant Streptococcus pneumoniae polysaccharide-specific (PnPS-specific) B cells as well as serotype-specific antibody titers, and opsonophagocytic killing. Remarkably, a single dose at birth of PCV13 plus 0.1 mg/kg 3M-052 induced PnPS-specific IgG responses that were approximately 10-100 times greater than a single birth dose of PCV13 alone, rapidly exceeding the serologic correlate of protection, as early as 28 days of life. This potent immunization strategy, potentially effective with one birth dose, could represent a new paradigm in early life vaccine development.