Development of a maternal vaccine to protect infants against clade C HIV-1

开发母体疫苗以保护婴儿免受 C 型 HIV-1 感染

• 批准号: 9212530
• 负责人: Sallie R. Permar
• 金额: $ 29.73万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-10 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9212530
• 关键词: Active Immunization; Acute; Adherence; Adjuvant; Anti-Retroviral Agents; Antibodies; Antibody Response; Antigens; Autologous; B-Lymphocytes; Biological Assay; Breast Feeding; Caring; Child; Childhood; Cohort Studies; Development; Dose; Drug resistance; Effectiveness; Epidemic; Epitopes; Failure; Generations; HIV; HIV-1; HIV-1 vaccine; Human; Human Milk; Immunization; Immunoglobulin A; Immunoglobulin G; Immunologics; Infant; Infection; Intervention; Intramuscular; Lactation; Macaca mulatta; Maternal antibody; Methods; Milk; Modeling; Monkeys; Mothers; Neonatal; Oral; Passive Immunization; Pharmaceutical Preparations; Plague; Plasma; Pregnancy; Prevention; Prophylactic treatment; Proteins; Regimen; Risk; SIV; Safety; Source; Specificity; Testing; Time; Transcend; Vaccination; Vaccines; Variant; Vertical Disease Transmission; Viral; Virus; Woman; Work; base; cohort; drug resistant virus; env Gene Products; falls; high risk; immunogenicity; infancy; innovation; low and middle-income countries; mucosal vaccination; neutralizing antibody; placental transfer; postnatal; preclinical study; pregnant; prevent; programs; response; simian human immunodeficiency virus; tool; transmission process; vaccination strategy

ABSTRACT: Project 1 If an HIV-1-free generation is to be achieved, mother-to-child HIV-1 transmission (MTCT) of HIV-1 must be eradicated. While antiretroviral prophylaxis strategies effectively prevent MTCT, they do not eliminate transmission in high-risk settings such as acute maternal infection, development of maternal drug-resistant variants, and lack of antiretroviral drug access or adherence. An attractive solution is the development of immunologic interventions for MTCT, such as vaccines. Project 1 will focus on developing a maternal vaccination strategy to passively immunize the infant via placental transfer of IgG and mucosal delivery of breast milk antibody. The development of a maternal vaccine is supported by our recent findings, which show that reduced risk of MTCT can be predicted by high magnitude maternal antibody responses against the HIV-1 Envelope (Env) variable loop 3 (V3) and neutralization of tier 1 heterologous viruses. In addition, we showed that vaccination of pregnant and infant rhesus monkeys against Simian Immunodeficiency Virus (SIV) can partially protect against infant oral SIV acquisition. Finally, we demonstrated that HIV-1 Env MVA prime/protein boost immunization of lactating monkeys elicits both robust Env-specific IgA and neutralizing antibody responses in maternal breast milk. Importantly, these findings suggest that maternal vaccination to enhance easy-to-elicit Env-specific antibody responses could protect against oral HIV-1 acquisition via breastfeeding in early infancy, a time point when infant vaccination cannot offer protection. Thus, we hypothesize that maternal vaccination with an Env prime/boost strategy optimized to elicit robust, potentially- protective Env-specific maternal antibody responses will effectively reduce oral simian/human immunodeficiency virus (SHIV) acquisition in neonatal infant monkeys. In the first Aim of this proposal, we will compare the specificity and function of previously-identified breast milk-derived HIV-1 Env-specific IgG and IgA antibodies elicited by maternal MVA prime/Env T/F 1086.C boost immunization to define the potential benefits of breast milk antibody response induction. In Aim 2, we will determine whether maternal placentally transferred or breast milk-derived vaccine-elicited antibodies confer protection against acute oral SHIV challenge in infants, simulating acute maternal infection during lactation. Finally, in Aim 3, we will determine whether this maternal Env immunization strategy can enhance potentially protective maternal antibody responses in SHIV-infected, antiretroviral-treated pregnant monkeys and define their ability to reduce oral autologous SHIV acquisition in the SHIV-exposed infant. This preclinical study of the immunogenicity and effectiveness of maternal HIV-1 Env immunization for reduction of infant virus acquisition will define the feasibility of maternal HIV-1 immunization for elimination of pediatric HIV-1 infections.

摘要：项目1 如果要实现无HIV-1的生成，则HIV-1的母亲到儿童HIV-1传播（MTCT）必须为 根除。尽管抗逆转录病毒预防有效防止MTCT，但它们不会消除 在高风险环境中的传播，例如急性母亲感染，耐药性的发展 变体，缺乏抗逆转录病毒药物的获取或依从性。一个有吸引力的解决方案是开发 MTCT的免疫干预措施，例如疫苗。项目1将专注于开发母亲 疫苗接种策略，通过IgG的胎盘转移和粘膜输送来被动免疫婴儿 母乳抗体。我们最近的发现表明，产妇疫苗的开发得到了支持 降低的MTCT风险可以通过针对HIV-1的高幅度母体抗体反应来预测 包膜（Env）可变环3（V3）和1层异源病毒的中和。此外，我们显示了 怀孕和婴儿恒河猴针对猿猴免疫缺陷病毒（SIV）的疫苗接种可以 部分预防婴儿口服SIV获取。最后，我们证明了HIV-1 env MVA 哺乳猴的主要/蛋白质增强免疫，引起鲁棒的ENV特异性IGA和中和 母乳中的抗体反应。重要的是，这些发现表明母体疫苗接种 增强易于及时的ENV特异性抗体反应可以防止通过 婴儿早期母乳喂养，婴儿疫苗接种无法提供保护的时间。因此，我们 假设以Env Prime/Boost策略进行优化的孕产妇疫苗接种，以引起强大的，潜在的 保护性ENV特异性的母体抗体反应将有效地减少口服邻居/人 新生儿婴儿猴子中的免疫缺陷病毒（SHIV）获得。在该提议的第一个目的中，我们将 比较先前识别的母乳衍生的HIV-1 ENV特异性IgG和IgA的特异性和功能 母体MVA Prime/env T/F 1086.C促进免疫以定义潜在益处的抗体 母乳抗体反应诱导。在AIM 2中，我们将确定是否有母亲胎盘 转移或母乳衍生的疫苗引诱的抗体提供防止急性口服SHIV的保护 婴儿的挑战，模拟泌乳过程中的急性母体感染。最后，在AIM 3中，我们将确定 这种母体ENV免疫策略是否可以增强潜在的保护性母体抗体 SHIV感染，抗逆转录病毒治疗的孕妇的反应，并定义其降低口服的能力 在暴露于湿液的婴儿中自体湿夫。对免疫原性和的临床前研究 母体HIV-1环境免疫对减少婴儿病毒获取的有效性将定义 孕产妇HIV-1免疫以消除小儿HIV-1感染的可行性。