A Lassa Vaccine in primates with AIDS

描述（由申请人提供）：针对患有艾滋病拉沙热病毒的灵长类动物的拉沙疫苗是西非啮齿动物传播的祸害，由于其致命性和气溶胶传播性，在美国被列为A类生物威胁。控制拉沙热的努力主要集中在疫苗开发上，因为这种疾病的病程非常迅速，有效的治疗通常为时已晚。我们开发了一种候选减毒疫苗MOP/LAS，它是Lassa Josiah毒株和无毒力Mopeia毒株之间的一种替代物。它是一种减毒的感染性疫苗，可保护豚鼠免受拉沙热病毒的致命攻击。作为我们疫苗开发计划的一部分，我们希望了解这种拉沙热疫苗和艾滋病毒之间的相互作用，因为这些病原体在撒哈拉以南非洲的同一地区流行。在这项研究中，我们采用艾滋病的SIV/猕猴模型来模拟艾滋病毒感染者的免疫抑制状态。我们的目标是确定减毒沙粒病毒疫苗在患有SIV疾病的猕猴中是否安全和具有免疫原性。这些研究将触及最近出现的一个更广泛的问题，即3名器官移植受者因移植组织的LCMV感染而死亡，从而提高了一种通常良性的沙粒病毒在免疫抑制宿主中可能变得有毒的可能性。我们的假设是减毒疫苗株在艾滋病免疫抑制的宿主中不会变得更毒.我们建议在完成的艾滋病研究中剩下的SIV感染猴中检验这一假设，我们将使用我们以前猕猴研究中开发的毒性和良性沙粒病毒感染的标准。我们的具体目标是：1）检验减毒拉沙疫苗（MOP/LAS）将在SIV获得性免疫缺陷综合征（AIDS）期间免疫受到抑制的猕猴中保持减毒的假设。2)检验艾滋病猴接种减毒沙粒病毒后会对疫苗抗原产生强烈免疫反应的假设。我们的长期目标是向西非提供拉沙热疫苗，并从这些研究中获得关于艾滋病疫苗接种免疫反应的基本信息。一个成功的拉沙热疫苗应该是安全的，并提供给艾滋病毒感染者，拉沙疫苗接种计划必须预测流行的艾滋病毒对疫苗性能的任何影响。公共卫生相关性：在患有艾滋病拉沙热病毒的灵长类动物中接种拉沙疫苗会导致人类患上一种致命疾病，是西非严重的公共卫生威胁。虽然它可能被用于生物战，但这种病毒家族在美国并不是一个严重的健康威胁（除了移植患者的致命污染的罕见发生率）。我们研制了一种疫苗，成功地保护了豚鼠。我们有机会在一次艾滋病实验中剩下的猴子身上测试疫苗，这项测试将解决我们的疫苗在艾滋病患者身上的安全性。这是一个重要的问题，因为西非拉沙流行地区也有很高的艾滋病发病率。

DESCRIPTION (provided by applicant): A Lassa vaccine in primates with AIDS Lassa fever virus is a rodent-borne scourge in West Africa and, less has been classified as a Category A biothreat in the US because of its lethality and aerosol-transmissibility. Efforts to control Lassa fever focus largely on vaccine development, because the disease course is exceptionally rapid and effective therapies are usually too late. We developed a candidate attenuated vaccine, MOP/LAS that is a reassortant between Lassa Josiah strain and the avirulent Mopeia strain. It is an attenuated, infectious vaccine that protects guinea pigs from lethal challenge with Lassa fever virus. As part of our vaccine development plan, we want to understand the interactions between this Lassa fever vaccine and HIV, since these pathogens are endemic in the same regions of sub-Saharan Africa. In this study, we employ the SIV/macaque model for AIDS to simulate the immune-suppressed state of persons living with HIV. Our goal is to determine whether an attenuated arenavirus vaccine could be safe and immunogenic in macaques with SIV disease. These studies will touch on a broader issue that arose recently when 3 organ transplant recipients died due to LCMV infection of the transplanted tissue, thus raising the possibility that an ordinarily benign arenavirus can become virulent in immune-suppressed hosts. Our hypothesis is that an attenuated vaccine strain will not become more virulent in an AIDS- immunosupressed host. We propose to test this hypothesis in SIV-infected monkeys remaining from completed AIDS studies, and we will use criteria for virulent and benign arenavirus infections developed in our previous macaque studies. Our specific aims are to: 1) Test the hypothesis that an attenuated Lassa vaccine (MOP/LAS) will remain attenuated in macaques where immunity is suppressed during SIV-acquired immunodeficiency syndrome (AIDS). 2) Test the hypothesis that AIDS monkeys given an attenuated arenavirus will develop robust immune responses to vaccine antigens. Our long-term goal is to deliver a vaccine against Lassa fever to West Africa, and to derive from these studies basic information on immune responses to vaccination in the context of AIDS. A successful Lassa fever vaccine should be safe and available to persons with HIV, and Lassa vaccination programs must anticipate any effect of endemic HIV on vaccine performance. PUBLIC HEALTH RELEVANCE: A Lassa vaccine in primates with AIDS Lassa fever virus causes a deadly disease in man and is a serious public health threat in West Africa. Though it can potentially be used in biowarfare, this family of viruses are not a serious health threat in the US (except for the rare incidence of lethal contamination for transplant patients). We developed a vaccine that successfully protected guinea pigs. We have the chance to test the vaccine in monkeys left over from an AIDS experiment, and this test will address the safety of our vaccines in people with AIDS. This is an important question since the Lassa endemic region of West Africa also has a high incidence of AIDS.