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

激发强大粘膜免疫力的疫苗策略可能在预防黏膜感染方面有效 艾滋病毒和其他病原体的传播。我们将开发微型链球菌作为一种潜在的疫苗载体 用于诱导对HIV的保护性粘膜免疫。S.mitis具有重要的特征，使其成为一种 诱人的黏膜疫苗载体。它是一种在儿童和成人中共生的非致病性细菌。 而且疫苗免疫原的表达在遗传上是可处理的。有机体是最 在口腔中丰富，并有效地定居在喉咙和鼻咽部，这种微生物已经被证明 诱导持久的粘膜免疫。重要的是，这种口腔细菌可以通过 口交路线。这项提议的主要目标是利用这些优势来产生安全的重组 可有效诱导抗HIV粘膜免疫反应的口服载体。我们已经建立了一个稳定的 重组链球菌表达HIV/SIV，我们发现口服该疫苗载体是安全的和 在异种rSmitis载体中，减毒病毒载体/env蛋白诱导强大的粘膜和系统 细胞毒性T细胞(CTL)应答和中和抗体应答。在这项建议中，我们将进一步发展RS。 通过执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，以改进疫苗载体。泰国人 RV144人体试验和目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不同疫苗递送系统组合在一个异种素材中- 利用HIV/SIV包膜蛋白免疫原和痘或腺病毒载体的Boost战略。因此， 我们将开发一种异源rSmitis-Prime rMVA和Env蛋白Boost疫苗策略。中环 假设我们的异源Prime-Boost策略将诱导高强度和持久的粘膜和 抗HIV-1的系统CTL和中和抗体本项目的具体目标是：1)开展 RSmitis重组MVA载体和Env蛋白临床前免疫原性评价 加强小型实验动物的策略。2)确定细菌因素在抗HIV/SIV中的作用 以微调载体免疫原性为目标的粘膜免疫反应。3)开展临床前工作 RSmitis重组MVA载体和Env蛋白Boost策略的免疫原性评价 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，拟议的研究可能 导致了一种基于rSmitis的新型和创新的疫苗策略的开发，作为一种粘膜艾滋病疫苗。 我们临床前免疫原性研究的有希望的发现将为进一步的临床前疗效试验提供保证 非人类灵长类动物，这是人类试验的关键一步。

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.