Development of rationally designed HIV vaccines

开发合理设计的艾滋病毒疫苗

• 批准号: 10262240
• 负责人: Genoveffa Franchini
• 金额: $ 439.53万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10262240
• 关键词: AIDS prevention; Acquired Immunodeficiency Syndrome; Address; Adjuvant; Affect; Age; Animal Model; Animals; Antibodies; Antibody Response; Antibody titer measurement; Antigens; Blood; CD14 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Canarypox Vectors; Cells; Chinese People; Collaborations; Combined Vaccines; Communities; DNA; Data; Dependence; Development; Epigenetic Process; FCGR3B gene; Female; Frequencies; Futility; Future; Genes; Genetic Transcription; HIV; HIV Envelope Protein gp120; HIV Vaccine Trials Network; HIV vaccine; Homing; Human; Hypoxia; IL8 gene; Immune; Immune response; Immune system; Immunity; Immunize; Immunoglobulin G; Infection; Infection prevention; Infectious Agent; Inflammasome; Insulin-Like Growth Factor I; Integrin Binding; Interleukin-10; Interleukin-6; Intervention; Intramuscular; Joints; Knowledge; Legal patent; Life; Liposomes; Logistics; Lung; Lymphoid Cell; MF59; Macaca; Macaca mulatta; Malignant Neoplasms; Mediating; Memory; Metabolic; MicroRNAs; Modality; Modeling; Monoclonal Antibodies; Mucositis; Mucous Membrane; Myeloid Cells; National Institute of Allergy and Infectious Disease; Natural Immunity; Pathway interactions; Peripheral Blood Mononuclear Cell; Phase; Plasma; Political Factor; Population Genetics; Preventive; Proteins; Recombinant Vaccines; Regimen; Research; Research Personnel; Risk; Role; SIV; SIV Vaccines; STAT3 gene; South Africa; Specificity; T cell response; T-Lymphocyte; Testing; Th2 Cells; Thailand; Training; Uncertainty; United States National Institutes of Health; Universities; Vaccinated; Vaccines; Viral; Virus; Virus Diseases; Work; adaptive immune response; age related; aluminum sulfate; animal facility; animal model development; antiretroviral therapy; arm; base; cytotoxic CD8 T cells; design; efficacy testing; exosome; expectation; extracellular vesicles; gender difference; immunogenic; immunogenicity; insight; lymph nodes; macrophage; male; microbiome research; monocyte; natural killer cell protein 44-kDa; neonate; neutralizing antibody; neutrophil; next generation; novel; novel vaccines; nutrition; pathogen; predictive modeling; rectal; response; risk minimization; sex; simian human immunodeficiency virus; simian immunodeficiency virus gp120; vaccine candidate; vaccine efficacy; vaccine evaluation; vaccine trial; volunteer

Accomplishments 1: Assess which macaque model better predicts or recapitulates the efficacy of HIV vaccine candidates in humans. The SIVmac251 model has predicted and recapitulated RV144: In 2005, a collaborative study in neonates predicted the results of RV144. More recently we recapitulated the efficacy of the RV144 vaccine regimen in young (2-3 years) male and female macaques. The latter study has provided more value than just the evaluation of vaccine efficacy. Our integrated study of RNA expression in PBMCs and exosomes together with comprehensive analyses of innate and adaptive immune responses in blood, lymph nodes, and mucosa uncovered unexpected correlates of risk of virus acquisition such as mucosal innate lymphoid cells (ILCs) and the expression of 12 genes, ten of which are part of the RAS pathway. The usefulness of this model was validated by similar observations in another protective vaccine regimen that I developed in collaboration with Dr. Strbo and the late Dr. Eckhart Podack of Miami University. This approach was the subject of a joint patent. We have also performed a confirmatory study entirely supported by the Division of AIDS, NIAID, in other animal facilities wherein we compared the immunogenicity and efficacy of the ALVAC and NYVAC SIV-based vaccine regimens. The ALVAC-SIV based vaccine was also protective in Chinese macaques, whereas the "more immunogenic" NYVAC-based SIV recombinant vaccine was not. Of note, the NYVAC-based vaccine did not induce an early burst of IL-1B as was the case in the non-protective Ad26 prime regimen. Will the SIVmac251 model predict the results of HVTN-702? We tested the efficacy of the ALVAC-based SIV vaccines in the SIVmac251 model using the alum in parallel with the MF59 adjuvant in the gp120 boost. To our surprise, the MF59 based regimen in the SIV model was not efficacious, despite its higher immunogenicity. While this observation stirred debate in the scientific community, our findings did not influence the decision by the P5 Partnership to use MF59 as an adjuvant in the HVTN-702 study in South Africa. Instead, logistical and political factors likely influenced the decision to proceed as originally planned. Given the current uncertainty of how accurately the SIVmac251 animal model will predict human results, our study will provide crucial information to define the model's utility since we observed no efficacy in macaques. The preliminary analysis of futility in HVTN-702 will be made public in 2018 and will address this issue. SHIV-clade C Tier 1 in female Chinese rhesus macaques: In another study supported mostly by NIAID, macaques were immunized with the identical ALVAC-HIV-based vaccines used in HVTN702, combined with either the MF59 or the alum (Novartis) in the gp120 boost, and challenged with a SHIV clade C Tier 1 virus. The MF59 based regimen was protective, whereas the alumN was not. Protection was associated with neutralizing antibodies to the SHIV clade C Tier 1 virus. In its current state, I don't believe that this SHIV model will predict the results of HVTN-702 because only 1% of HIV clade C viruses in South Africa are sensitive to neutralization. However, the interim analysis of HVTN-702 for futility will further our knowledge of animal model predictability and will guide the choice and refinement of faithful animal models for the development of fully effective vaccines for HIV. 2. HIV vaccine candidate activation of hypoxia and inflammasome in CD14+ monocytes is associated with a decreased risk of SIVmac251 acquisition. This study demonstrated that CD14+ and CD16+ monocytes have a role in the risk of SIVmac251 acquisition and has contributed to the mechanistic insight on the role of IL-1B and IL-10 in the DNA/ALVAC/alum vaccine platform. We compared ALVAC-SIV, DNA-SIV, and Ad26-SIV prime modalities in combination with two ALVAC-SIV + gp120 protein boosts in young male macaques. We used the intramuscular DNA-SIV prime with the intent of increasing CD4+ T cells and antibody responses since we demonstrated in prior work that the CD4+ T cells elicited by the DNA prime influence the anti-envelope titers. The Ad26-SIV prime was chosen with the intent of increasing mucosal antibodies to Env and CD8+ T cell responses. The DNA prime protected against infection in the DNA prime regimen, and VE correlated with hypoxia and inflammasome activation in classical CD14+ CD16negative monocytes that in turn directly correlated with the gut-homing CCR5negative Th2 cell responses and with mucosal NKp44+ cells and IgG to V2. In the same group, the frequency of differentiated CD16+ monocytes correlated with reduced vaccine efficacy via STAT3 activation. The Ad26 prime regimen did not protect against SIV acquisition, despite its higher immunogenicity, and it was associated with a decrease in total CD14+ DR+ monocytes in blood, accumulation of de novo differentiated CX3CR1+ CD163+ macrophages in lymph nodes, mucosal inflammation, and skewing of CD4+ T cells toward Th17 cells in the rectal mucosa and lungs. Th17 cells are preferentially infected by HIV/SIV and negatively regulate NKp44+ cells. It is possible that vaccine-generated target cells for virus infection, may have decreased the efficacy of the Ad26 prime regimen, as was observed in other vaccine studies in macaques and humans. 3. A simplified vaccine regimen based on DNA/ALVAC-SIV / ALVAC-SIV + gp120 / alum affords 69% vaccine efficacy. With the intent of confirming the importance of monocyte-mediated innate immunity and investigating whether the DNA/ALVAC/gp120/alum approach was also effective in female macaques, we designed a study in young and old females. We tested a simplified version of the DNA prime ALVAC/gp120/alum vaccine approach using two intramuscular DNA primes (weeks 0 and 4), one ALVAC-SIV boost (week 8), and a single final boost with the combination ALVAC-SIV and gp120 in alum at week 13. Challenge exposure was started at week 17 and continued for 11 weeks. We found that this vaccine had 69% VE in young female macaques (average age 2.7 years), but failed to protect old female macaques (average age 7.5 years). Protection in young females correlated with the frequency of CD14+ classical monocytes, confirming the results of the previous study in young males. In old vaccinated females, however, we observed a correlation with the plasma level of IL-6 and IL-8 and increased virus acquisition. These data further support a role for monocytes in protection of both female and male macaques and uncovered an age-dependent factor. No difference in SIVmac251 acquisition was observed in young or old naive controls (data not shown). Current Research and Future Plans 1. Define the epigenetic signatures of CD14+ monocytes, neutrophils, and Th2 CCR5negative T cells and study the miRNA signatures in extracellular vesicles (EV) that track with protective immunity. 2. Define the specificity and mechanistic intersection between protective vaccine-induced V2-targeted humoral responses and innate immunity 3. Development of the next generation of ALVAC based HIV vaccine candidate leveraging innate immunity to elicit durable protective immune profiles 4. Investigate whether monoclonal antibodies to V2 that inhibit a4B7 integrin binding protect against SIVmac251 acquisition, alone or in combination with innate monocyte memory immunity 5. Durability 6. Investigate the basis for the age bias vaccine efficacy and test adjuvants that may overcome it, such as IGF-1 and an alum-based liposome ALFA adjuvant with respect to innate immunity. 7: Design an HIV clade B based optimal DNA/ALVAC/gp120/alum vaccine regimen and test it in a phase I HIV vaccine trial in young volunteers. We will also seek to understand the role of monocytes in COV-2 infection.

成就 1：评估哪种猕猴模型能够更好地预测或概括 HIV 候选疫苗对人类的功效。 SIVmac251 模型预测并概括了 RV144：2005 年，一项针对新生儿的合作研究预测了 RV144 的结果。最近，我们概括了 RV144 疫苗方案对年轻（2-3 岁）雄性和雌性猕猴的功效。后一项研究提供的价值不仅仅是评估疫苗功效。我们对 PBMC 和外泌体中 RNA 表达的综合研究，以及对血液、淋巴结和粘膜中先天性和适应性免疫反应的综合分析，发现了病毒感染风险的意想不到的相关性，例如粘膜先天性淋巴细胞 (ILC) 和 12 个基因的表达，其中 10 个基因是 RAS 途径的一部分。我与迈阿密大学的 Strbo 博士和已故的 Eckhart Podack 博士合作开发的另一种保护性疫苗方案中的类似观察结果验证了该模型的有用性。这种方法是一项联合专利的主题。我们还在其他动物设施中进行了一项完全由艾滋病司 (NIAID) 支持的验证性研究，其中我们比较了 ALVAC 和 NYVAC 基于 SIV 的疫苗方案的免疫原性和功效。基于 ALVAC-SIV 的疫苗对中国猕猴也具有保护作用，而“免疫原性更强”的基于 NYVAC 的 SIV 重组疫苗则不然。值得注意的是，基于 NYVAC 的疫苗不会像非保护性 Ad26 初免方案那样诱导 IL-1B 的早期爆发。 SIVmac251模型会预测HVTN-702的结果吗？我们在 SIVmac251 模型中测试了基于 ALVAC 的 SIV 疫苗的功效，同时使用明矾和 gp120 加强剂中的 MF59 佐剂。令我们惊讶的是，基于 MF59 的方案在 SIV 模型中并不有效，尽管其免疫原性较高。虽然这一观察结果在科学界引起了争论，但我们的发现并没有影响 P5 Partnership 在南非的 HVTN-702 研究中使用 MF59 作为佐剂的决定。相反，后勤和政治因素可能影响了按原计划进行的决定。鉴于目前 SIVmac251 动物模型预测人类结果的准确性尚不确定，我们的研究将为定义该模型的效用提供重要信息，因为我们在猕猴中没有观察到功效。 HVTN-702 无效性的初步分析将于 2018 年公开，并将解决这个问题。雌性中国恒河猴中的 SHIV 分支 C 1 级：在另一项主要由 NIAID 支持的研究中，猕猴使用与 HVTN702 中使用的相同的基于 ALVAC-HIV 的疫苗进行免疫，并结合 gp120 增强剂中的 MF59 或明矾（诺华），并用 SHIV 分支 C 1 级病毒进行攻击。基于 MF59 的方案具有保护性，而 alumN 则没有。保护作用与 SHIV 分支 C 1 级病毒的中和抗体有关。在目前的状态下，我不相信这个 SHIV 模型能够预测 HVTN-702 的结果，因为南非只有 1% 的 HIV C 分支病毒对中和敏感。然而，对 HVTN-702 无效性的中期分析将进一步加深我们对动物模型可预测性的了解，并将指导选择和完善忠实的动物模型，以开发完全有效的 HIV 疫苗。 2. HIV 候选疫苗激活 CD14+ 单核细胞中的缺氧和炎症小体与 SIVmac251 获得风险降低相关。这项研究证明 CD14+ 和 CD16+ 单核细胞在 SIVmac251 获得风险中发挥作用，并有助于深入了解 IL-1B 和 IL-10 在 DNA/ALVAC/明矾疫苗平台中的作用。我们在年轻雄性猕猴中比较了 ALVAC-SIV、DNA-SIV 和 Ad26-SIV Prime 模式与两种 ALVAC-SIV + gp120 蛋白加强的组合。我们使用肌内 DNA-SIV 引发剂的目的是增加 CD4+ T 细胞和抗体反应，因为我们在之前的工作中证明了 DNA 引发剂引发的 CD4+ T 细胞会影响抗包膜滴度。选择 Ad26-SIV prime 的目的是增加针对 Env 和 CD8+ T 细胞反应的粘膜抗体。在 DNA Prime 方案中，DNA Prime 可防止感染，VE 与经典 CD14+ CD16 阴性单核细胞中的缺氧和炎症小体激活相关，而后者又与肠道归巢 CCR5 阴性 Th2 细胞反应以及粘膜 NKp44+ 细胞和 V2 IgG 直接相关。在同一组中，分化的 CD16+ 单核细胞的频率与通过 STAT3 激活而降低的疫苗功效相关。尽管 Ad26 免疫原性较高，但 Ad26 Prime 方案并不能防止 SIV 获得，并且与血液中 CD14+ DR+ 单核细胞总数的减少、淋巴结中新生分化的 CX3CR1+ CD163+ 巨噬细胞的积累、粘膜炎症以及直肠粘膜和直肠粘膜中 CD4+ T 细胞向 Th17 细胞的倾斜有关。 肺。 Th17 细胞优先被 HIV/SIV 感染，并对 NKp44+ 细胞产生负调节。正如在猕猴和人类的其他疫苗研究中观察到的那样，疫苗产生的用于病毒感染的靶细胞可能会降低 Ad26 Prime 方案的功效。 3. 基于 DNA/ALVAC-SIV / ALVAC-SIV + gp120 / alum 的简化疫苗方案可提供 69% 的疫苗效力。为了确认单核细胞介导的先天免疫的重要性并研究 DNA/ALVAC/gp120/明矾方法是否对雌性猕猴也有效，我们设计了一项针对年轻和年老雌性猕猴的研究。我们测试了 DNA Prime ALVAC/gp120/alum 疫苗方法的简化版本，使用两次肌内 DNA Prime（第 0 周和第 4 周）、一次 ALVAC-SIV 加强（第 8 周）以及在第 13 周使用 ALVAC-SIV 和 gp120 组合在明矾中进行的单次最终加强。攻击暴露从第 17 周开始并持续 11 周。我们发现这种疫苗在年轻雌性猕猴（平均年龄 2.7 岁）中具有 69% VE，但未能保护年老雌性猕猴（平均年龄 7.5 岁）。年轻女性的保护作用与 CD14+ 经典单核细胞的频率相关，证实了之前在年轻男性中的研究结果。然而，在老年接种疫苗的雌性中，我们观察到血浆 IL-6 和 IL-8 水平与病毒获取增加的相关性。这些数据进一步支持单核细胞在保护雌性和雄性猕猴中的作用，并发现了年龄依赖性因素。在年轻或年老的初始对照中没有观察到 SIVmac251 获取的差异（数据未显示）。当前研究和未来计划 1. 定义 CD14+ 单核细胞、中性粒细胞和 Th2 CCR5 阴性 T 细胞的表观遗传特征，并研究跟踪保护性免疫的细胞外囊泡 (EV) 中的 miRNA 特征。 2. 定义保护性疫苗诱导的 V2 靶向体液反应与先天免疫之间的特异性和机制交叉 3. 开发下一代基于 ALVAC 的 HIV 候选疫苗，利用先天免疫引发持久的保护性免疫特征 4. 研究抑制 a4B7 整合素结合的 V2 单克隆抗体是否可以防止 SIVmac251 获得， 单独使用或与先天单核细胞记忆免疫相结合 5. 耐久性 6. 研究年龄偏差疫苗功效的基础，并测试可以克服它的佐剂，例如与先天免疫有关的 IGF-1 和基于明矾的脂质体 ALFA 佐剂。图 7：设计基于 HIV 进化枝 B 的最佳 DNA/ALVAC/gp120/alum 疫苗方案，并在年轻志愿者中进行 I 期 HIV 疫苗试验。我们还将寻求了解单核细胞在 COV-2 感染中的作用。