Oral Reovirus-Based Vaccines for Prevention of HIV-1 Disease

用于预防 HIV-1 疾病的口服呼肠孤病毒疫苗

• 批准号: 8141076
• 负责人: TERENCE S. DERMODY
• 金额: $ 21.87万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-03 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8141076
• 关键词: Acquired Immunodeficiency Syndrome; Antibodies; Antibody Formation; Attenuated; Binding; Capsid Proteins; Cell Culture Techniques; Chimera organism; Communicable Diseases; Development; Disease; Disease Progression; Engineering; Epitopes; Fostering; Future; Generations; Genetic Drift; Glycoproteins; Goals; HIV Infections; HIV-1; Human; Immune response; In Vitro; Infection; Infection Control; Infection prevention; International; Intestinal Mucosa; Knowledge; Lead; Life; Macaca; Macaca mulatta; Membrane; Modeling; Molecular Conformation; Monoclonal Antibodies; Morbidity - disease rate; Mucosal Immune Responses; Mucosal Immunity; Oral; Oryctolagus cuniculus; Peptides; Prevention; Process; Proteins; Recombinants; Reovirus; Reovirus 3; Research; Serial Passage; Serum; Surface; System; Testing; Vaccine Antigen; Vaccines; Virus; Work; base; cell mediated immune response; design; human monoclonal antibodies; immunogenicity; improved; mortality; mucosal site; neutralizing antibody; neutralizing monoclonal antibodies; nonhuman primate; novel vaccines; oral vaccine; prevent; research study; simian human immunodeficiency virus; vaccine candidate; vector; vector vaccine; vector-induced

DESCRIPTION (provided by applicant): Most current HIV-1 vaccine candidates are replication-defective, administered intramuscularly, and unlikely to induce immune responses at mucosal surfaces. The goal of the proposed research is to develop an orally administered replication-competent reovirus-based HIV-1 vaccine that stimulates mucosal and systemic humoral immune responses against broadly neutralizing epitopes of HIV-1. Reovirus infects intestinal mucosa to stimulate potent immune responses, is naturally attenuated in humans, and can be manipulated to express vaccine antigens. These key features make reovirus an ideal HIV-1 vaccine vector. The new vaccine vector will harbor HIV-1 sequences encoding the membrane-proximal external region (MPER) of HIV-1 envelope glycoprotein gp41, which form a-helical coiled coils at the base of the gp41 trimer. Importantly, monoclonal antibodies (MAbs) directed against MPER neutralize infection by HIV-1 primary isolates in vitro and protect against HIV-1 infection in passively immunized non-human primates. The central hypothesis of this proposal is that MPER sequences inserted into a-helical regions of trimeric reovirus attachment protein s1 will retain native immunogenicity and elicit neutralizing antibody responses against HIV-1. Three specific aims are proposed to test the central hypothesis and develop reovirus-based HIV-1 vaccines. In Specific Aim 1, recombinant reoviruses will be generated that display MPER sequences in native trimeric conformation within surface-exposed regions of reovirus s1. MPER-expressing reoviruses will be tested for replication efficiency, stability during serial passage, and interactions with MPER-specific mAbs. A first-generation reovirus vector has been engineered in which MPER sequences incorporated into s1 retain the native MPER-specific mAb epitope, indicating that the proposed approach is feasible. In Specific Aim 2, recombinant reovirus vectors will be tested for induction of humoral immune responses after inoculation into rabbits. Sera from immunized rabbits will be tested for the presence of MPER-specific antibodies and the capacity to neutralize infection by HIV-1 Env-pseudotyped viruses and primary isolates. Second-generation vectors will be designed based on results of the initial immunogenicity studies. In Specific Aim 3, the reovirus vector that induces the most potent HIV-1 neutralizing humoral immune responses in rabbits will be tested for induction of humoral immune responses in rhesus macaques. Sera from immunized macaques will be tested for MPER-specific antibodies and HIV-1 neutralizing capacity. This research will lead to a better understanding of vaccine requirements for the induction of potent mucosal immune responses against HIV-1 and foster development of a new class of HIV-1 vaccines that target mucosal sites. PUBLIC HEALTH RELEVANCE: HIV-1 infection is a leading cause of infectious disease morbidity and mortality worldwide, and vaccines to prevent HIV-1 infection are not available. The proposed research will develop new orally administered reovirus-based HIV-1 vaccines that display neutralizing epitopes in native conformation. This work will advance knowledge about induction of mucosal immunity and establish the feasibility for challenge studies in non-human primates and immunogenicity trials in humans.

描述(申请人提供)：大多数目前的HIV-1候选疫苗是复制缺陷的，肌肉注射，不太可能在粘膜表面诱导免疫反应。这项拟议研究的目标是开发一种口服复制能力强的呼肠孤病毒HIV-1疫苗，该疫苗能够刺激针对HIV-1广谱中和表位的粘膜和系统体液免疫反应。呼肠孤病毒感染肠道粘膜以刺激强大的免疫反应，在人类体内自然减弱，并可被操纵以表达疫苗抗原。这些关键特征使呼肠孤病毒成为理想的HIV-1疫苗载体。新的疫苗载体将含有编码HIV-1包膜糖蛋白gp41膜近端外区(MPER)的HIV-1序列，该序列在gp41三聚体的底部形成a螺旋卷曲。重要的是，针对MPER的单抗在体外可以中和HIV-1初级分离株的感染，并在被动免疫的非人类灵长类动物中保护HIV-1感染。这一建议的中心假设是，插入到三聚呼肠孤病毒附着蛋白S1的a-螺旋区域的MPER序列将保持天然的免疫原性，并诱导针对HIV-1的中和抗体反应。提出了三个具体目标来检验中心假设和开发基于呼肠孤病毒的HIV-1疫苗。在特定目标1中，将产生重组呼肠孤病毒，其在呼肠孤病毒S1的表面暴露区域内以天然三聚体构象显示MPER序列。将测试表达MPER的呼肠孤病毒的复制效率、在连续传代过程中的稳定性以及与MPER特异性单抗的相互作用。第一代呼肠孤病毒载体已经被设计出来，其中MPER序列被掺入到S1中，其中保留了天然的MPER特异性mAb表位，表明所提出的方法是可行的。在特定目的2中，将检测重组呼肠孤病毒载体接种兔后诱导体液免疫应答。将测试免疫兔子的血清中是否存在MPER特异性抗体，以及中和HIV-1环境假型病毒和初级分离株感染的能力。第二代载体将根据最初的免疫原性研究结果进行设计。在具体目标3中，将测试能够在兔体内诱导最强的HIV-1中和体液免疫反应的呼肠孤病毒载体，以诱导恒河猴的体液免疫反应。将对免疫猕猴的血清进行MPER特异性抗体和HIV-1中和能力的测试。这项研究将有助于更好地了解疫苗对诱导针对HIV-1的有效粘膜免疫反应的需求，并促进针对粘膜部位的新型HIV-1疫苗的开发。 公共卫生相关性：艾滋病毒-1感染是全世界传染病发病率和死亡率的主要原因，目前还没有预防艾滋病毒-1感染的疫苗。这项拟议的研究将开发新的口服呼肠孤病毒HIV-1疫苗，这种疫苗以天然构象显示中和表位。这项工作将促进对粘膜免疫诱导的了解，并为在非人类灵长类动物中进行挑战研究和在人类进行免疫原性试验奠定可行性。