Laser-based powder vaccine delivery for improved newborn immunization

基于激光的粉末疫苗输送可改善新生儿免疫

• 批准号: 8569476
• 负责人: Xinyuan Chen
• 金额: $ 20.1万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8569476
• 关键词: Adjuvant; Adverse effects; Affect; Age; Anatomy; Animal Model; Antibodies; Antibody Formation; Antigen-Presenting Cells; Antigens; Area; Bacteria; Biological; Birth; Chemicals; Clinic; Clinical; Communicable Diseases; Conjugate Vaccines; Data; Deposition; Development; Disease; Dose; Economics; Educational workshop; Encapsulated; Ensure; Family suidae; Goals; Gray unit of radiation dose; Haemophilus influenzae type b bacteria; Hour; Human; Immune response; Immune system; Immunity; Immunization; In Situ; Infant; Infection; Injection of therapeutic agent; Intramuscular; Lasers; Left; Maternal antibody; Medical; Modeling; Molecular; Morbidity - disease rate; Mus; Muscle; National Institute of Allergy and Infectious Disease; Needles; Newborn Infant; Nicotine; One-Step dentin bonding system; Ovalbumin; Pain; Painless; Pattern; Pharmaceutical Preparations; Polysaccharides; Powder dose form; Reaction; Recovery; Recruitment Activity; Retinal Cone; Safety; Shapes; Skin; Skin Tissue; Surface; System; Technology; Time; Tissues; Topical application; Vaccination; Vaccine Antigen; Vaccines; aluminum sulfate; base; cost; immunogenicity; improved; infant death; intradermal injection; monophosphoryl lipid A; mortality; neonate; novel; pre-clinical; public health relevance; skin patch; success; uptake; vaccine delivery

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.

描述（申请人提供）：新生儿免疫系统不成熟，容易受到感染，同时接种疫苗后无法快速形成保护性免疫力。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新生儿和婴儿的费用就达到 6.9 亿美元。增强新生儿疫苗的免疫原性是降低新生儿早期感染相关高发病率和死亡率的关键。建议将基于激光的粉末输送 (LPD) 与临床单磷酰脂质 A (MPL) 佐剂 (MPL/LPD) 相结合，以改善新生儿免疫。激光在皮肤表面产生自我更新的微通道。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，原位溶解，并有效地被皮肤抗原呈递细胞（APC）吸收或激活。基于 MPL/LPD 的免疫有望显着提高新生儿疫苗的免疫原性，因为 LPD 将疫苗递送至富含 APC 的皮肤组织；激光在每个微通道周围招募大量 APC，以更有效地摄取抗原； 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反应。这些暂时“打开”的微通道被正常健康的皮肤包围，可以在24小时内“重新密封”并被新合成的组织取代，以确保这项技术的安全性。基于 LPD/MPL 的免疫还消除了针头注射，并且不会引起疼痛，因为激光只影响表皮组织。除了显着提高的疫苗免疫原性和卓越的安全性外，基于MPL/LPD的无针、无痛免疫通过将粉末疫苗输送到分离的微通道中逐渐溶解并在皮肤内有效吸收，有望克服母体抗体的干扰。分区化的疫苗递送和抗原摄取模式预计将大大减少循环抗体引起的疫苗的全身分布和灭活。多糖包膜细菌，例如 b 型流感嗜血杆菌 (Hib)，是婴儿严重感染的主要原因。因此，Hib 疫苗将用于探索新生小鼠（具体目标 1）和猪（具体目标 2）中基于 MPL/LPD 的免疫。在本提案中，MPL/LPD初免/加强免疫将与明矾佐剂存在下的 4 次肌内免疫进行比较，以在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 NIAID 于 2010 年举办的“婴儿免疫挑战”研讨会，提出了一种新颖的基于激光的递送和佐剂技术，用于改善新生儿免疫。这种新型免疫策略不仅将对 Hib 疫苗而且对临床上其他低免疫原性疫苗的递送和佐剂产生广泛影响。