Delivery of Powdered Vaccines for Improving Newborn Vaccination

摘要 本提案的目的是设计一种粉末状、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应答， 诱导保护性免疫。延长疫苗接种时间表，同时快速接种疫苗， 出生后母体抗体下降，留下几个月的脆弱期， 每个新生儿都有各种感染，这是疫苗接种率高的唯一主要因素， 可预防的新生儿疾病。消除或大大缩短脆弱的 期间，我们确定了一种有效的佐剂cGAMP，一种IFN基因刺激物的激动剂 （STING），其可以有力地支持新生小鼠的适应性免疫应答。我们将 联合收割机结合这种有效的佐剂和基于粉末的表皮疫苗接种， Hib疫苗，并将Hib疫苗剂量从目前的4剂减少到2剂。我们 将首先制造用Hib缀合的PRP-T疫苗和cGAMP包封的PLD-MNA， 表征其在新生小鼠和仔猪中的负载能力和递送效率。我们 还将最小化小猪模型中的皮肤刺激（如果有的话），并优化 新生小鼠的免疫。Aim 2将验证是否在出生时预充并在10天后加强 与包装有PRP-T/cGAMP的PLD-MNA相比， 反应比PRP-T疫苗的四次明矾/肌内免疫在存在 母源抗体这种无针的，可能家庭使用的疫苗接种，如果成功， 代表了一种范式转变技术，可以为新生儿和婴儿增加许多疫苗， 由于目前大多数婴儿疫苗是以粉末形式制成的， 装载到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.