A Lassa Vaccine in primates with AIDS

描述(由申请人提供)：在携带艾滋病拉沙热病毒的灵长类动物中接种拉沙疫苗在西非是一种由啮齿动物传播的祸害，在美国，LITE因其致命性和气溶胶传播性而被归类为A类生物疫苗。控制拉沙热的努力主要集中在疫苗开发上，因为该病病程异常迅速，有效的治疗方法通常为时已晚。我们开发了一种候选减毒疫苗MOP/LAS，它是Lassa Josiah株和弱毒株Mopeia株之间的重配。这是一种减毒的传染性疫苗，可以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相同地区流行。在这项研究中，我们使用艾滋病的SIV/Macaque模型来模拟艾滋病毒携带者的免疫抑制状态。我们的目标是确定弱毒疫苗对患有SIV疾病的猕猴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，当时3名器官移植受者因移植组织感染LCMV而死亡，从而增加了一种通常良性的Arena病毒在免疫抑制的宿主中变得毒力的可能性。我们的假设是，在艾滋病免疫抑制的宿主中，减毒疫苗株不会变得更强。我们建议在完成艾滋病研究后剩下的感染SIV的猴子身上测试这一假设，我们将使用我们之前的猕猴研究中开发的毒力和良性ArenaVirus感染的标准。我们的具体目标是：1)测试假设，即在SIV获得性免疫缺陷综合征(AIDS)期间免疫抑制的猕猴中，减毒LASA疫苗(MOP/LAS)将保持减毒状态。2)测试这样一种假设，即给艾滋病猴子注射了减毒的Arena病毒后，它们会对疫苗抗原产生强大的免疫反应。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有关艾滋病疫苗接种免疫反应的基本信息。一种成功的拉沙热疫苗应该是安全的，艾滋病毒携带者可以获得，拉萨疫苗接种计划必须预见到地方性艾滋病毒对疫苗性能的任何影响。公共卫生相关性：在携带艾滋病拉沙热病毒的灵长类动物中接种拉沙疫苗会在人类中导致一种致命的疾病，并对西非的公共卫生构成严重威胁。尽管它可能被用于生物武器，但这一病毒家族在美国并不是一个严重的健康威胁(除了罕见的对移植患者的致命污染)。我们开发了一种疫苗，成功地保护了豚鼠。我们有机会在艾滋病实验遗留下来的猴子身上测试疫苗，这次测试将解决我们疫苗在艾滋病患者身上的安全性问题。这是一个重要的问题，因为西非的拉萨流行地区的艾滋病发病率也很高。

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.