Enhancing protective antibody responses for a GM-CSF adjuvanted HIV vaccine

描述(申请人提供)：艾滋病毒/艾滋病仍然是一个主要的健康问题，需要有效和持久的艾滋病毒疫苗。建立具有中和和非中和机制的有效和持久的抗体(Ab)有助于预防粘膜HIV感染。最近RV144试验的结果强调了保护性非中和抗体机制的重要作用。在RV144试验中也观察到，随着抗体反应减弱，疫苗效力减弱，从而强调了开发既耐用又耐用的艾滋病毒疫苗的重要性。因此，我们的主要目标是提高目前正在进行1/2a阶段临床测试的GeoVax HIV疫苗所激发的抗体反应的强度，同时保持其持久性和质量。GeoVax HIV疫苗是利用质粒DNA和改良的安卡拉牛痘(Vaccinia Ankara，MVA)载体表达的蛋白质，形成显示三聚体gp160外膜(DNA疫苗)或三聚体gp150外膜(MVAVLP)的非传染性病毒样颗粒(VLP)。为了增强疫苗的效力，粒细胞-巨噬细胞集落刺激因子(GM-CSF)作为佐剂与VLP通过DNA基元(DNAGM)共表达。我们的含有GM-CSF的SIV原型疫苗提高了抗膜(Env)抗体的亲和力和结合效价，并保护了71%的接种猕猴免受SIVsmE660的12次直肠暴露，而没有共表达GM-CSF的匹配疫苗仅提供了25%的保护。虽然这种带有佐剂的疫苗代表着朝着实现保护性艾滋病毒疫苗迈出的重要一步，但我们临床试验的数据表明，我们的艾滋病毒疫苗在人类身上诱导的环境特异性抗体水平比我们的SIV原型疫苗在猕猴身上诱导的水平要低得多。泰国的RV144试验显示，通过将一种蛋白质与痘病毒增强相结合，对感染具有适度的保护作用。因此，我们正在努力确定将在人类中实现更高效价的保护性环境抗体反应的条件。在这里，我们建议1)在我们目前的MVA Boost方案中添加可溶性低聚体gp140 Env，或2)用分泌可溶性gp140的MVA替代我们目前的MVA Boost，以增强我们的DNAGM/MVA疫苗诱导的抗体的强度并保持其持久性和质量。我们的合作者是HIV疫苗、体液免疫、MVA重组体领域的专家沈晓英博士、David Montefiori博士、Bernard Moss博士、Linda Wyatt博士和Hanne Elard博士。我们的目标是在第一阶段实现抗环境病毒结合抗体效价至少提高10倍。如果成功，我们计划提交第二阶段提案，测试使用最好的疫苗方案对新城疫病毒的保护。从这项研究中获得的数据对于提供IND提交所需的初步安全性和有效性数据以及在临床试验中进行的工作将非常重要。凭借我们在临床试验和MVA制造方面的经验，我们有能力将这些疫苗成分投入临床测试，申请IND批准，并逐步进入商业化。我们高度强调为艾滋病毒疫苗激发更高滴度和持久保护性抗体反应的重要性，并强调加强我们的DNAGM/MVAVLP疫苗是实现有效艾滋病毒疫苗的关键一步。

DESCRIPTION (provided by applicant): HIV/AIDS remains a major health problem and there is a need for effective and durable HIV vaccines. Establishing potent and durable antibodies (Ab) that have neutralizing and non-neutralizing mechanisms can contribute to the prevention of mucosal HIV infection. Findings from the recent RV144 trial have highlighted a significant role for protective non-neutralizing Ab mechanisms. It was also observed in the RV144 trial, that vaccine efficacy diminished as Ab responses waned thus underlining the importance of developing HIV vaccines that are also durable. Therefore our main goal is to improve the magnitude while maintaining the durability and quality of the Ab responses elicited by the GeoVax HIV vaccines that are currently undergoing Phase 1/2a clinical testing. GeoVax HIV vaccines are designed using plasmid DNA and Modified Vaccinia Ankara (MVA) vectors to express proteins that form non-infectious virus like-particles (VLP) displaying trimeric gp160 envelope (DNA vaccines) or trimeric gp150 envelope (MVAVLP). To augment vaccine potency, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) is co-expressed as an adjuvant with VLPs by the DNA prime (DNAGM). Our SIV prototype vaccine with GM-CSF enhanced the avidity, binding titers of anti-envelope (Env) Ab and protected 71% of vaccinated macaques against 12 repeat rectal exposures to SIVsmE660, whereas a matched vaccine without co-expressed GM-CSF provided only 25% protection. While this adjuvanted vaccine represents a significant step toward achieving a protective HIV vaccine, data from our clinical trials indicate that much lower levels of Env-specific Ab are elicited by our HIV vaccines in humans than our SIV prototype vaccines in macaques. The RV144 Thai trial showed moderate protection against infection by combining a protein with a poxvirus boost. Thus, we are working to identify conditions that will achieve higher titer of protective Env Ab responses in humans. Here, we are proposing to 1) add a soluble oligomeric gp140 Env to our current MVA boost regimen or 2) substitute our current MVA boost with an MVA that secretes soluble gp140, to enhance the magnitude and maintain the durability and quality, of Ab elicited by our DNAGM/MVA vaccine. Our collaborators are Drs Xiaoying Shen, David Montefiori, Bernard Moss, Linda Wyatt and Hanne Elyard who are experts in the field of HIV vaccines, humoral immunity, MVA recombinants. Our goal is to achieve at least a 10-fold enhancement of anti-Env binding Ab titers in Phase I. With success, we plan to submit a Phase II proposal testing protection against SHIV with the best vaccine regimen. The data gained from this study will be of great importance in providing the initial safety and efficacy data needed for an IND submission and the work to be carried out in clinical trials. With our experience in clinical trials and MVA manufacture, we are well positioned with the capability to move these vaccine components into clinical testing, apply for IND approval and ramp into commercialization. We highly stress the importance of eliciting higher titers and durable protective Ab responses for HIV vaccines and that enhancing our DNAGM/MVAVLP vaccine is a critical step forward to achieving an effective HIV vaccine.