Oral Vaccination for AIDS Prevention in Rhesus Macaques

描述(申请人提供)：发展中世界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迫切。当在猕猴身上进行测试时，到目前为止开发的候选疫苗主要通过肌肉内途径进行评估，不能预防慢性感染，但可以降低病毒血症的设定点，并延缓向艾滋病的进展。病毒血症的控制和无病感染的持续时间取决于用于非人类灵长类动物疫苗评估的感染模式。由于除淋巴器官外，胃肠道也有大量的病毒复制，因此预防艾滋病毒感染和艾滋病可能需要疫苗在粘膜和全身诱导免疫的能力。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，这种疫苗由一个携带SIV前病毒基因组的单一质粒组成，该基因组产生非传染性颗粒，无论疫苗是通过直肠还是鼻腔途径进行的。我们有适当的工具来测量粘膜分泌物中SIV特异性IgA水平、粘膜细胞介导的反应和SIV特异性全身反应。因此，我们相信我们在确定口服DNA疫苗的有效性以及对病毒特异性粘膜反应的刺激如何影响HIV/SIV疫苗的效力方面处于独特的地位。探索通过口服途径给药的疫苗接种方案对于建立能够提供对胃肠道病毒复制的实质性控制的方案可能很重要。为了达到这一目标，我们提出了1.评价表达丙型肝炎病毒70kD E2外膜蛋白的DNA质粒与PLG微粒联合口服给猕猴时，是否在系统和粘膜上激发了显著的抗丙型肝炎病毒70kD E2免疫应答。2.评价DNA-MVA SIV疫苗的脂质体或微颗粒制剂在口服后是否能刺激更广泛的粘膜和全身反应。3.评价上述两种方案中哪种方案对阴道SIV攻击的保护效果最好。4.评价上述两种方案中较好的一种是否可以通过同时给予相同配方的DNA-MVA皮内免疫来进一步提高其预防进展为艾滋病的能力。项目简介：艾滋病疫苗可能需要产生比其他疫苗更高的免疫水平和免疫广度。重要的是探索可以提高免疫反应质量而不仅仅是免疫反应数量的方法，因为有效的疫苗必须在免疫反应高峰期以外的时间提供保护。黏膜免疫和系统免疫的同时存在对于防止慢性艾滋病毒/SIV感染的建立和在感染发生时控制疾病进展可能是重要的。口服疫苗可能最适合于提供驻留在胃肠道中的病毒特异性反应，在感染期间，胃肠道中会发生大量的艾滋病毒和SIV复制。为了实现这一目标，我们打算研究最大限度地提高我们的SIV DNA疫苗在免疫系统所有部分产生的免疫反应的质量和数量的策略。本文提出的研究目的是评估两种不同剂型的DNA/MVA疫苗中哪一种在口服时提供最多样化的免疫反应，以及在病毒攻击后对疾病进展的最显著保护作用。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可能在防止垂直传播方面发挥作用。这些研究的结果应该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.