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

基本信息

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
项目类别：
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

项目摘要

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.

引发强大粘膜免疫的疫苗策略可能有效预防粘膜疾病 HIV 和其他病原体的传播。我们将开发轻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 具有重要的特征，使其成为有吸引力的粘膜疫苗载体。它是儿童和成人中的共生非致病性细菌人群，并且它在遗传上易于表达疫苗免疫原。生物体是最这种微生物在口腔中含量丰富，并有效地定植于喉咙和鼻咽部，并且已被证明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。该提案的主要目标是利用这些优势来产生安全的重组体口服载体将有效诱导抗艾滋病毒粘膜免疫反应。我们已经生成了一个稳定的表达 HIV/SIV 的重组 S. mitis，我们发现这种疫苗载体的口服给药是安全且可靠的在异源 rSmitis prime 减毒病毒载体/Env 蛋白中诱导强健的粘膜和全身细胞毒性 T 细胞 (CTL) 反应和中和抗体反应。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，以完善疫苗载体。泰国人 RV144人体试验和当前的临床前研究表明，最有希望的疫苗策略可能包括将具有不同免疫原性的各种疫苗递送系统结合在异源初免中利用 HIV/SIV 包膜蛋白免疫原和痘或腺病毒载体的加强策略。所以，我们将开发异源 rSmitis 引发的 rMVA 和 Env 蛋白加强疫苗策略。中央假设我们的异源初免-加强策略将诱导高强度和持久的粘膜和系统性 CTL 和针对 HIV-1 的中和抗体。该项目的具体目标是： 1) 进行 rSmitis prime重组MVA载体和Env蛋白的临床前免疫原性评估小型实验动物的增强策略。 2）确定细菌因素对抗HIV/SIV的作用粘膜免疫反应，以微调载体免疫原性为目标。 3) 进行临床前研究 rSmitis prime 重组 MVA 载体和 Env 蛋白加强策略的免疫原性评估在非人类灵长类动物中。迫切需要一种有效的艾滋病毒疫苗，拟议的研究可以导致开发出一种新颖且创新的基于 rSmitis 的疫苗策略作为粘膜艾滋病疫苗。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非人类灵长类动物，这是迈向人体试验的关键一步。