Oral Vaccination for AIDS Prevention in Rhesus Macaques

描述（由申请人提供）：发展中国家艾滋病流行的严重性，加上其中一些国家可用于卫生保健的资源有限，使得对艾滋病疫苗的需求日益紧迫。当在恒河猴中进行测试时，迄今为止开发的候选疫苗主要通过肌内途径进行评估，不能保护免受慢性感染，但可以降低病毒血症设定点并延缓进展为AIDS。病毒血症的控制和无病感染的持续时间取决于用于非人灵长类动物疫苗评价的感染模型。由于除淋巴器官外，大量病毒复制还发生在胃肠道中，因此预防HIV感染和AIDS可能需要疫苗在粘膜和全身隔室中诱导免疫的能力。我们已经建立了用SIV DNA疫苗刺激粘膜反应的疫苗接种方案，SIV DNA疫苗由携带SIV前病毒基因组的单个质粒组成，该基因组产生非感染性颗粒，无论疫苗接种是通过直肠还是鼻途径进行。我们有适当的工具来测量粘膜分泌物中SIV特异性伊加水平，粘膜细胞介导的反应和SIV特异性全身反应。因此，我们相信，我们处于独特的地位，以确定口服DNA疫苗的有效性和病毒特异性粘膜反应的刺激如何影响HIV/SIV疫苗的疗效。探索通过口服途径给予的疫苗接种方案对于建立能够实质性控制胃肠道中病毒复制的方案可能是重要的。为了实现这一目标，我们提出1。评价不同剂量的表达丙型肝炎病毒70 kD E2包膜蛋白并与PLG微粒组合的DNA质粒经口给予恒河猴时是否能全身和粘膜刺激显著的抗丙型肝炎病毒70 kD E2免疫应答。2.评价DNA-MVA SIV疫苗的脂质体或微粒制剂在口服给药后是否刺激更广泛的粘膜和全身反应。3.评价上述两种方案中哪一种对阴道SIV攻击提供最佳保护。4.评价是否可以通过同时给予类似配制的DNA-MVA皮内免疫，进一步改善上述两种方案中较好的方案对艾滋病进展的保护作用。项目说明：艾滋病疫苗可能需要产生比其他疫苗更大的免疫水平和免疫广度。重要的是要探索可以提高免疫应答的质量而不仅仅是数量的方法，因为有效的疫苗必须在免疫应答的高峰之外的时间提供保护。粘膜免疫和全身免疫的同时存在可能对预防慢性HIV/SIV感染的建立和在感染发生时控制疾病进展很重要。口服疫苗接种可能最适合于提供存在于胃肠道中的病毒特异性应答，在胃肠道中，在感染期间发生大量HIV和SIV复制。为了实现这一目标，我们打算研究策略，应最大限度地提高我们的SIV DNA疫苗在免疫系统的所有部分产生的免疫应答的质量和数量。本文提出的研究目的是评价两种不同的DNA/MVA疫苗制剂中哪一种在口服给药时提供最多样化的免疫应答，以及在病毒攻击后对疾病进展的最显著保护。生殖道中的抗病毒免疫至关重要，不仅因为这些反应在性接触艾滋病毒时可以发挥作用，而且还因为这些反应在预防垂直传播方面可能发挥作用。这些研究的结果对艾滋病疫苗的开发具有很高的价值。

DESCRIPTION (provided by applicant): The severity of the AIDS epidemic in the developing world combined with the limited resources that some of these countries have available for health care render the need of an AIDS vaccine more urgent every day. When tested in Rhesus macaques, the candidate vaccines developed thus far, evaluated predominantly via the intramuscular route, do not protect from chronic infection but provide a reduction in the viremia set point and a delay of progression to AIDS. The control of viremia and the length of disease-free infection depend on the model of infection used for the vaccine evaluation in non-human primates. As substantial virus replication occurs in the gastrointestinal tract in addition to the lymphoid organs, the ability of vaccines to induce immunity both in mucosal and systemic compartments may be required for prevention of HIV infection and AIDS. We have established vaccination regimens that stimulate mucosal responses with an SIV DNA vaccine, which consists of a single plasmid carrying an SIV proviral genome that produces noninfectious particles, whether the vaccination occurs via the rectal or nasal route. We have the appropriate tools to measure SIV-specific IgA levels in mucosal secretions, mucosal cell-mediated responses, and SIV-specific systemic responses. As a consequence, we believe that we are uniquely placed to determine the effectiveness of oral DNA vaccination and how stimulation of virus-specific mucosal responses can affect the efficacy of a HIV/SIV vaccine. Exploring vaccination regimens administered via the oral route may be important to establish regimens capable of providing substantial control of viral replication in the gastrointestinal tract. Towards this goal we propose 1. To evaluate whether different doses of a DNA plasmid expressing the Hepatitis C Virus 70 kD E2 Envelope protein and combined with PLG micro particles stimulate significant anti- Hepatitis C Virus 70 kD E2 immune responses systemically and mucosally when administered orally to Rhesus macaques. 2. To evaluate whether a liposome or a micro particle formulation of a DNA-MVA SIV vaccine stimulates broader mucosal and systemic responses after oral administration. 3. To evaluate which of the two above regimens provides the best protection from vaginal SIV challenge. 4. To evaluate whether the better of the two above regimens can be further improved in its protection from progression to AIDS by the simultaneous administration of a similarly formulated DNA-MVA intradermal immunization. Project Narrative: AIDS vaccines may need to engender a substantially greater level and breadth of immunity than other vaccines. It is important to explore approaches that may enhance the quality and not simply the quantity of the immune response because an efficacious vaccine will have to provide protection at times other than the peak of the immune response. The simultaneous presence of both mucosal and systemic immunity may be important in preventing the establishment of a chronic HIV/SIV infection and in controlling disease progression if infection occurs. Oral vaccination may be best suited at providing virus-specific responses that reside in the gastrointestinal tract where a significant amount of HIV and SIV replication occurs during the infection. Toward this goal we intend to investigate strategies that should maximize the quality and quantity of immune responses produced by our SIV DNA vaccine in all the compartments of the immune system. The objective of the studies proposed here is to evaluate which of two different formulations of the DNA/MVA vaccine provides the most diverse immune responses when administered orally and the most significant protection from disease progression after viral challenge. Antiviral immunity in the genital tract is not only critical because of the role that these responses can play at the time of sexual exposure to HIV but also because of the role that these responses may play in preventing vertical transmission. The results of such studies should be highly valuable for AIDS vaccine development.