HIV/AIDS Vaccine and Antibody Development

在过去的一年里，我们已经创建并测试了几种候选疫苗，包括包膜三聚体蛋白和在载体蛋白上显示的融合肽。此外，我们继续开展工作，测试不同的给药方法和途径以及主要/加强组合，以进一步优化艾滋病毒疫苗战略。蛋白质免疫原与不同的佐剂和纳米颗粒的形式也进行了测试。在初步研究中获得有希望的免疫原性数据的几种候选疫苗正在进一步测试。在包括小鼠、豚鼠和非人灵长类动物（NHP）在内的多种疫苗试验动物模型中，广泛地激发了针对融合肽（FP）的HIV-1中和活性，融合肽是HIV融合机制的重要组成部分。基于这些临床前数据，两种新的HIV免疫原（结合载体蛋白的FP和C进化枝共识三聚体）被确定为候选疫苗，并已启动GMP生产。在这些研究中使用的佐剂，Adjuplex，也已开始GMP生产。

During the past year, we have created and tested several vaccine candidates including envelope trimer proteins and fusion peptides displayed on carrier proteins. In addition, we have continued our work testing different methods and routes of administration as well as prime/boost combinations to further optimize HIV vaccine strategies. Protein immunogens with different adjuvants and in the form of nanoparticles were also tested. Several candidate vaccines that elicited promising immunogenicity data in preliminary studies are being tested further. Broadly HIV-1 neutralizing activity directed to fusion peptide (FP), which is an essential component of HIV fusion machinery, was elicited in multiple vaccine-test animal models including mouse, guinea pig and non-human primate (NHP). Based on these preclinical data, two new HIV immunogens (FP conjugated to a carrier protein and a clade C consensus trimer) were identified as vaccine candidates and GMP manufactures have been initiated. GMP manufacture of the adjuvant used in these studies, Adjuplex, has also started. Studies to understand the development of broadly neutralizing antibodies using different human immunoglobulin knock-in mice are also ongoing. These studies are testing novel immunogens designed to generate neutralizing antibodies to multiple HIV-1 vulnerable sites: the CD4 binding site, V2 apex and membrane-proximal external region (MPER). For antibody development, we have applied targeted mutations to several broadly neutralizing anti-HIV-1 antibodies (bNAbs) that have been isolated from HIV+ donors. The mutations are designed to increase breadth, potency and half-life to improve potential efficacy for therapeutic application and to decrease immunogenicity to allow for more effective and longer lasting in vivo function. There are also structure-based mutations designed to improve affinity and neutralization potency. Additionally, mutations to improve biophysical properties and manufacturability have been designed in collaboration with Just Biotherapeutics, with plans for further development and use in clinical trials. We are also working with collaborators to develop tri-specific anti-HIV-1 antibodies that combine three different anti-HIV-1 specificities in one IgG-like molecule for both HIV-1 prevention and therapy, one of which has advanced to phase I clinical trials. In another collaborative effort, we are developing improved N6-like antibodies for use in HIV-1 therapy. The treatment of AIDS with combination antiretroviral therapy (cART) remains lifelong largely because the virus persists in latent reservoirs. Elimination of latently infected cells could therefore reduce treatment duration and facilitate immune reconstitution. We have developed immunomodulatory proteins referred to as T cell engagers (TCEs) that combines the specificity of a HIV-1 broadly neutralizing antibody with that of an antibody to the CD3 component of the T-cell receptor. These TCEs could potentially help to eliminate latently infected cells and deplete the viral reservoir in HIV-1-infected individuals. In addition, we have started collaborative work to develop TCEs that activate T cells to lyse HIV-1 infected cells.