Delivery of Powdered Vaccines for Improving Newborn Vaccination

摘要 该方案的目标是设计一种装满粉末、可溶解的微针阵列 (PLD-MNA)，以改善新生儿Hib疫苗接种。由于免疫系统不成熟，大多数 新生儿疫苗诱导次优免疫反应，需要多个增强剂才能 诱导一种保护性免疫。延长的疫苗接种时间表，与快速 母体抗体在出生后下降，留下几个月的脆弱时期 每个新生儿的各种感染，这是疫苗接种率高的唯一主要因素- 新生儿中发生的可预防的疾病。消灭或大大缩短弱势群体 期间，我们确定了一种有效的佐剂cGAMP，它是干扰素基因刺激物的激动剂。 (刺痛)可以有力地增强新生小鼠的适应性免疫反应。我们会 将这种强效佐剂与粉状表皮疫苗相结合，大力增强 并在这项提议中将Hib疫苗的剂量从目前的4剂减少到2剂。我们 将首先制备用Hib结合的PRP-T疫苗和cGAMP包裹的PLD-MNA，并 研究其在新生小鼠和仔猪体内的承载能力和传递效率。我们 还将最大限度地减少对小猪模型的皮肤刺激性，如果有的话，并优化 新生小鼠的免疫接种。目标2将在出生时验证最佳状态，并在10天后增强 用PRP-T/cGAMP包装的PLD-MNA可诱导相当或更好的免疫 四种明胶/肌肉注射PRP-T疫苗的免疫效果比较 母体抗体。如果成功，这种无针头、有可能在家中使用的疫苗接种将 代表着一种范式转变的技术，以增强许多新生儿和婴儿的疫苗， 因为目前大多数婴儿疫苗都是以粉末的形式制成，可以直接 加载到PLD-MNAs中并应用于新生儿。

Abstract Objective of this proposal is to engineer a Powder-Laden, Dissolvable MicroNeedle Array (PLD-MNA) to improve newborn Hib vaccination. Due to the immature immune system, most of the newborn vaccines induce suboptimal immune responses and require multiple boosters to induce a protective immunity. The lengthened vaccination schedule, in conjunction with a rapid decline of maternal antibodies after birth, leaves a few months of a vulnerability period to various infections for every newborn, which is the single major factor for a high rate of vaccine- preventable diseases occurring in newborns. To eliminate or greatly shorten the vulnerable period, we identified a potent adjuvant cGAMP, an agonist of the stimulator of IFN genes (STING) that could robustly bolster adaptive immune responses in neonatal mice. We will combine this potent adjuvant and powder-based epidermic vaccination to vigorously augment Hib vaccine and reduce Hib vaccine dosage from the current 4 to 2 doses in this proposal. We will first fabricate PLD-MNA encapsulated with Hib conjugated PRP-T vaccine and cGAMP and characterize its loading capacity and delivery efficiency in both newborn mice and piglets. We will also minimize skin irritation, if there is any, in a piglet model and optimize the dosage of immunization in newborn mice. Aim 2 will validate whether prime at birth and boost 10 days later with PLD-MNA packaged with PRP-T/cGAMP can induce a comparable or superior immune response than four alum/intramuscular immunizations of PRP-T vaccine in the presence of maternal antibodies. This needle-free, potentially home-use vaccination, if successful, would represent a paradigm-shifting technology to augment many vaccines for newborns and infants, because most of current infant vaccines are made in a form of powder and can be directly loaded into the PLD-MNAs and applied to newborns.