Laser-based powder vaccine delivery for improved newborn immunization

描述（由申请人提供）：不成熟的免疫系统使新生儿易受感染，同时在接种疫苗后无法快速建立保护性免疫。目前，全世界每年有400万6个月以下的新生儿死于疫苗可预防的疾病，仅在美国，每年治疗受感染的新生儿和婴儿的费用就高达6.9亿美元。提高新生儿疫苗的免疫原性是降低新生儿早期感染相关的高发病率和死亡率的关键。提出了一种基于激光的粉末递送（LPD）与临床单磷酰脂质A （MPL）佐剂（MPL/LPD）联合用于改善新生儿免疫的方法。激光在皮肤表面产生可自我再生的微通道。局部应用粉末疫苗/MPL包被的阵列贴片后，疫苗/MPL可以有效地沉积到这些微通道中，就地溶解，并有效地被皮肤抗原呈递细胞（apc）吸收或激活。基于MPL/LPD的免疫预计将大大提高新生儿疫苗的免疫原性，因为LPD将疫苗输送到富含apc的皮肤组织；激光在每个微通道周围招募大量apc，从而更有效地摄取抗原；MPL通过刺激常驻和招募的apc成熟进一步增强疫苗诱导的免疫应答。在正常健康皮肤的包围下，这些暂时“打开”的微通道可以在24小时内被“重新封闭”并被新合成的组织所取代，以确保这项技术的安全性。基于LPD/ mpl的免疫也不需要针头注射，也不会引起疼痛，因为激光只影响表皮组织。这种基于MPL/ lpd的无针无痛免疫方法不仅显著提高了疫苗的免疫原性和安全性，而且有望克服母源抗体的干扰，通过将粉状疫苗递送到分离的微通道中，使其在皮肤内逐渐溶解并有效吸收。区隔化的疫苗递送和抗原摄取模式有望大大减少循环抗体对疫苗的系统性分布和灭活。多糖包裹的细菌，如b型流感嗜血杆菌（Hib），是婴儿严重感染的主要原因。因此，Hib疫苗将用于在新生小鼠（特异性目的1）和猪（特异性目的2）中探索基于MPL/ lpd的免疫。本研究将MPL/LPD初级/增强免疫与4种肌内免疫进行比较，在明矾佐剂存在或不存在母源抗体的情况下诱导保护性抗体反应。该应用响应了2010年NIAID组织的“婴儿免疫挑战”研讨会，提出了一种新的基于激光的递送和调节技术，用于改善新生儿免疫。这种新的免疫策略不仅将对Hib疫苗的递送和佐剂，而且将对临床中其他低免疫原性疫苗的递送和佐剂产生广泛的影响。

DESCRIPTION (provided by applicant): The immature immune system renders newborns vulnerable to infections and meanwhile unable to mount a rapid protective immunity after vaccination. Currently, 4 million newborns under the age of 6 months die of vaccine-preventable diseases each year worldwide and the annual cost to treat infected newborns and infants reaches $690 million in USA alone. Enhancing newborn vaccine immunogenicity is the key to reduce early infection-associated high morbidity and mortality in newborns. A laser-based powder delivery (LPD) in combination with a clinical monophosphoryl lipid A (MPL) adjuvant (MPL/LPD) is proposed for improved newborn immunization. Laser generates self-renewable microchannels in the skin surface. After topical application of powder vaccine/MPL-coated array patches, vaccine/MPL can be efficiently deposited into these microchannels, dissolved in situ, and efficiently taken up by or activate skin antigen-presenting cells (APCs). MPL/LPD-based immunization is expected to profoundly improve newborn vaccine immunogenicity because LPD delivers vaccines to APC-rich skin tissue; laser recruits a large number of APCs around each microchannel for more efficient antigen uptake; MPL further enhances vaccine-induced immune response by stimulation of maturation of resident and recruited APCs. Surrounded by normal healthy skin, these temporarily "opened" microchannels can be "resealed" and replaced with newly synthesized tissue within 24 hours to ensure the safety of this technology. LPD/MPL-based immunization also eliminates needle injection and causes no pain because laser only affects the epidermal tissue. Besides the significantly improved vaccine immunogenicity and the superior safety, the needle-free, painless MPL/LPD-based immunization is promising to overcome interference of maternal antibodies by delivery of powder vaccines to separated microchannels for gradual dissolution and efficient uptake inside the skin. The compartmentalized vaccine delivery and antigen uptake pattern is expected to greatly reduce systemic distribution and inactivation of vaccines by circulating antibodies. Polysaccharide-encapsulated bacteria, such as Haemophilus influenzae type b (Hib), are leading causes of serious infections in infants. Thus, Hib vaccine will be used to explore MPL/LPD-based immunization in newborn mice (specific aim 1) and pigs (specific aim 2). MPL/LPD prime/boost immunization will be compared with 4 intramuscular immunizations in the presence of Alum adjuvant to induce a protective antibody response in the presence or absence of maternal antibodies in this proposal. This application responds to "Challenges in infant immunity" workshop organized by NIAID in 2010 by presenting a novel laser-based delivery and adjuvantation technology for improved newborn immunization. The novel immunization strategy will have a broad impact on delivery and adjuvantation of not only Hib vaccine but also other vaccines with a low immunogenicity in the clinic.