Novel Recombinant Streptococcus mitis as an Oral Vaccine against HIV/AIDS

新型重组轻症链球菌作为抗艾滋病毒/艾滋病的口服疫苗

• 批准号: 10210254
• 负责人: Mark Cayabyab
• 金额: $ 71.82万
• 依托单位: NOVA SOUTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10210254
• 关键词: AIDS Vaccines; AIDS/HIV problem; Accounting; Address; Adenovirus Vector; Adherence; Adult; Animals; Antibody Response; Antigens; Attenuated; Bacteria; Cell Wall; Childhood; Collaborations; Cytoplasm; Cytotoxic T-Lymphocytes; Data; Development; Epithelial Cells; Gastrointestinal tract structure; Genome; Goals; HIV; HIV Infections; HIV envelope protein; HIV vaccine; HIV-1; Human; Immune response; Immunity; Infant; Laboratory Animals; Lead; Location; Macaca mulatta; Mediating; Microbe; Modeling; Modified Vaccinia Virus Ankara; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Nasopharynx; Oral; Oral cavity; Organism; Pathogenicity; Pharyngeal structure; Phase; Population; Property; Protein Subunits; Proteins; Public Health; Recombinant modified vaccinia virus Ankara; Recombinants; Role; Route; SIV; Streptococcus mitis; System; T cell response; Technology; Testing; Vaccination; Vaccine Antigen; Vaccines; Vagina; Viral Vector; base; capsule; efficacy trial; env Gene Products; host colonization; immunogenic; immunogenicity; innovation; mucosal vaccine; neutralizing antibody; nonhuman primate; novel; oral bacteria; oral vaccine; pathogen; pre-clinical; preclinical efficacy; preclinical safety; preclinical study; prevent; safety assessment; simian human immunodeficiency virus; transmission process; vaccine delivery; vaccine development; vector; vector vaccine

Vaccine strategies that elicit robust mucosal immunity may potentially be effective in preventing mucosal transmission of HIV and other pathogens. We will develop Streptococcus mitis, as a potential vaccine vector for the induction of protective mucosal immunity against HIV. S. mitis has important features that makes it an attractive mucosal vaccine vector. It is a commensal nonpathogenic bacterium in pediatric and adult populations and it is genetically tractable for expression of vaccine immunogens. The organism is most abundant in the mouth and efficiently colonizes the throat and nasopharynx and this microbe has been shown to induce durable mucosal immunity. Importantly, this oral bacterium can be delivered easily and safely via the oral route. The main objective of this proposal is to exploit these advantages to generate a safe recombinant oral vector that will effectively induce anti-HIV mucosal immune responses. We have generated a stable recombinant S. mitis expressing a HIV/SIV and we found that oral delivery of this vaccine vector was safe and in a heterologous rSmitis prime attenuated viral vector/Env protein induced robust mucosal and systemic cytotoxic T cell (CTL) response and neutralizing antibody response. In this proposal, we will further develop rS. mitis vaccine vectors by performing extensive immunogenicity studies, preclinical safety assessments and determine bacterial factors that impact immunogenicity with the goal of refining the vaccine vector. The Thai RV144 human trial and current preclinical studies show that the most promising vaccine strategies may involve combining various vaccine delivery systems with different immunogenic properties in a heterologous prime- boost strategy that utilizes HIV/SIV envelope protein immunogens and pox or adenoviral vectors. Therefore, we will develop a heterologous rSmitis-prime rMVA and Env protein boost vaccine strategy. The central hypothesis is that our heterologous prime-boost strategy will induce high magnitude and durable mucosal and systemic CTLs and neutralizing antibodies against HIV-1.The Specific Aims of this project are: 1) Conduct preclinical immunogenicity assessment of rSmitis prime- recombinant MVA vector and Env protein boost strategy in small laboratory animals. 2) Determine the role of bacterial factors on anti-HIV/SIV mucosal immune responses with the goal of fine-tuning vector immunogenicity. 3) Conduct preclinical immunogenicity assessment of rSmitis prime- recombinant MVA vector and Env protein boost strategy in non-human primates. There is a critical need for an effective HIV vaccine and the proposed studies could lead to the development of a novel and innovative rSmitis-based vaccine strategy as a mucosal AIDS vaccine. Promising findings from our preclinical immunogenicity studies would warrant further preclinical efficacy trials in nonhuman primates, which is a critical step towards human trials.

引起强粘膜免疫的疫苗策略可能有效地预防粘膜免疫。 艾滋病毒和其他病原体的传播。我们将开发缓症链球菌作为潜在的疫苗载体 用于诱导针对HIV的保护性粘膜免疫。S. mitis具有重要的功能，使其成为 有吸引力的粘膜疫苗载体。它是一种非致病性细菌，在儿童和成人 群体，并且其在遗传上易于表达疫苗免疫原。有机体是最 大量存在于口腔中，并有效地定植于喉咙和鼻咽，并且这种微生物已被证明 以诱导持久的粘膜免疫。重要的是，这种口腔细菌可以通过 口服途径。本提案的主要目的是利用这些优点来产生安全的重组体 口服载体，将有效地诱导抗HIV粘膜免疫应答。我们已经生成了一个稳定的 重组变异链球菌表达HIV/SIV的缓解症，我们发现口服这种疫苗载体是安全的， 在异源rSmitisprime减毒病毒载体/Env蛋白中诱导了稳健的粘膜和系统性 细胞毒性T细胞（CTL）应答和中和抗体应答。在本提案中，我们将进一步开发rS。 通过进行广泛的免疫原性研究、临床前安全性评估和 确定影响免疫原性的细菌因素，目的是改进疫苗载体。泰国 RV 144人体试验和目前的临床前研究表明，最有前途的疫苗策略可能涉及 将具有不同免疫原性的各种疫苗递送系统组合在异源引发剂中， 加强策略，利用HIV/SIV包膜蛋白免疫原和痘病毒或腺病毒载体。因此，我们认为， 我们将开发异源rSmitis-prime rMVA和Env蛋白加强疫苗策略。中央 假设是我们异源初免-加强策略将诱导高强度和持久的粘膜， 本项目的具体目标是：1）开展 rSmitis prime-重组MVA载体和Env蛋白的临床前免疫原性评估 在小型实验室动物中的加强策略。2)确定细菌因子在抗HIV/SIV中的作用 粘膜免疫应答，目的是微调载体免疫原性。3)进行临床前研究 rSmitis prime-重组MVA载体和Env蛋白加强策略免疫原性评估 在非人类灵长类动物中。目前迫切需要一种有效的艾滋病毒疫苗，拟议的研究可以 导致一种新的和创新的基于rSmitis的疫苗策略作为粘膜艾滋病疫苗的发展。 我们的临床前免疫原性研究的有希望的结果将保证进一步的临床前疗效试验， 这是迈向人体试验的关键一步。