Pre-Clinical Development of a Intranasal Bivalent gD2/gB2 HSV-2 Mucosal Vaccine

摘要 生殖器单纯疱疹病毒-2（HSV-2）感染是影响超过4000万人的主要公共卫生问题 在美国，全球超过5亿。HSV-2感染的特点是疼痛复发，生殖器感染， 疼痛，这可能与相当大的心理痛苦相吻合。传播可发生在性行为期间 接触和从母亲到婴儿出生时致命的后果。虽然有几种疫苗 显示出对该病毒的强烈中和活性，目前还没有有效的疫苗来预防 HSV-2最近的研究表明，虽然全身性体液免疫是有益的，但粘膜免疫的共同诱导是有益的。 豁免是充分保护先决条件。BlueWillow Biologics已经建立了NanoVax®，一种专有的油包 水纳米乳剂（NE 01）佐剂技术，其设计用于鼻内免疫。我们 证实了NE 01增强抗原靶向免疫系统的能力，同时安全地诱导 有效的体液、粘膜和细胞免疫应答，包括Th 1、Th 2和Th 17的平衡诱导 细胞这一特征促进了诱导粘膜和细胞介导的免疫应答的有效疫苗的开发。 免疫力，对各种呼吸道和性传播病原体，包括HSV-2的全面保护。 为了解决这一未满足的医疗需求，BlueWillow Biologics正在开发一种新型的鼻内双价疫苗。 由NE 01中配制的两种HSV-2糖蛋白（gB 2和gD 2）组成。我们的临床前研究表明 得到的鼻内疫苗（IN）gB 2/gD 2-NE 01是一种有效的和商业上可行的预防剂 预防HSV-2感染的策略。我们已经优化了工艺，以扩大生产规模， 抗原，以实现高纯度gB 2和gD 2原料药的可重现生产，其规模足以 满足临床需求。重要的是，我们已经证明了药物的预防等效性 从已建立的规模扩大生产工艺制备的产品与我们之前在实验室规模制备的产品相比。 这表明我们有能力制造大量的纯材料，同时保持完整性和 关键疫苗成分的活动。 在该IIB期SBIR计划中，BlueWillow Biologics将执行IN的剩余开发工作。 gB 2/gD 2-NE 01 HSV-2疫苗是提交研究性新药（IND）申请所必需的。使用 根据第二阶段建立的规模扩大工艺，我们将完善gB 2表达工艺， 产量，每种抗原生产两批，沿着NE 01佐剂，并将材料 完成IND启动GLP毒理学研究，并制定稳定性临床材料 考核本材料的准备将使与FDA的IND前会议能够要求反馈 并批准我们的GLP毒理学研究设计。GLP毒理学研究完成后，BlueWillow将 准备提交IND申请并启动1期临床试验（不包括在此资助范围内）。

ABSTRACT Genital herpes simplex virus-2 (HSV-2) infections are a major public health problem affecting >40 million people in the United States and >500 million globally. HSV-2 infection is characterized by painful recurring, genital sores and this can coincide with considerable psychological distress. Transmission can occur during sexual contact and from mother to child during birth with fatal consequences. Although several vaccines have been shown to elicit strong neutralizing activity against the virus, there is currently no effective vaccine to prevent HSV-2. Recent research has shown that while systemic, humoral immunity is beneficial, co-induction of mucosal immunity is prerequisite for full protection. BlueWillow Biologics has established NanoVax®, a proprietary oil-in- water nanoemulsion (NE01) adjuvant technology, that is designed for intranasal immunization. We've demonstrated the ability of NE01 to augment the targeting of antigens to the immune system while safely eliciting potent humoral, mucosal and cellular immune responses, including balanced induction of Th1, Th2 and Th17 cells. This feature facilitates the development of efficacious vaccines that induce mucosal and cell mediated immunity for full protection against various respiratory and sexually transmitted pathogens, including HSV-2. To address this unmet medical need, BlueWillow Biologics is developing a novel, intranasal bivalent vaccine comprised of two HSV-2 glycoproteins (gB2 and gD2) formulated in NE01. Our preclinical studies have shown that the resulting intranasal vaccine (IN) gB2/gD2-NE01 is an effective and commercially viable prophylactic strategy to prevent HSV-2 infections. We have optimized the processes for scale-up manufacturing of the antigens to achieve reproducible production of highly pure gB2 and gD2 drug substances at a scale sufficient to meet clinical demand. Importantly, we've demonstrated the prophylactic equivalency of the drug substances prepared from the established scale-up manufacturing processes to those we previously prepared at lab scale. This demonstrates our ability to manufacture high quantity of pure material while preserving the integrity and activities of the key vaccine components. In this Phase IIB SBIR program, BlueWillow Biologics will execute the remaining development work on the IN gB2/gD2-NE01 HSV-2 vaccine necessary to submit an investigational new drug (IND) application. Using the established scale-up processes established under Phase II, we will refine the gB2 expression process to improve yield, manufacture two batches of each antigen, along with the NE01 adjuvant, and dedicate the material towards completing an IND-enabling GLP toxicology study and formulating clinical material for stability assessment. The preparation of this material will enable a pre-IND meeting with the FDA to request feedback and approval of our GLP toxicology study design. Upon completion of the GLP toxicology study, BlueWillow will be ready to file an IND application and initiate a Phase 1 clinical trial (not covered under this funding).