COVID-19 vaccine development research

对抗COVID-19大流行的疫苗的迫切需求促使我们将数十年的HIV疫苗开发经验应用于SARS-CoV-2。我们假设，从过去的SARS疫苗研究（包括HIV疫苗研究）中吸取的经验教训可以应用于COVID-19疫苗的设计。基于高恢复率，人体免疫系统能够控制和消除病毒感染，因此疫苗很可能会起作用。来自几项临床试验的最新数据表明，不同的疫苗平台表明诱导体液免疫应答是可能的。为了支持这一点，据报道，SARS-CoV感染者产生了持久的病毒特异性（N，S，M，E）T细胞应答，并且靶向S的强T细胞应答与较高的中和Ab活性相关。基于其他病毒已知的持久性机制，我们假设SARS-CoV-2也可能发展了逃避宿主免疫系统的策略。因此，一种有效的疫苗可能需要设计超出使用天然蛋白质，我们正在探索这两种途径。免疫逃逸的一个常见机制是抗原靶标的快速突变，导致免疫逃逸。我们的疫苗策略旨在诱导针对SARS-CoV-2 S和N蛋白的结构保守部分的保护性免疫应答，这些部分对保护性免疫也很重要。这一战略是对正在进行的疫苗工作的重要补充，以防已经或正在进入第一阶段临床试验的第一代疫苗出现问题。这种疫苗的努力也可能通过诱导能够识别更广泛冠状病毒的更广泛免疫力来提供优势。我们正在开发基于DNA的疫苗，其基础是包含结构重要性区域，基于SARS 1和SARS-CoV-2结构的X射线晶体学数据，目的是诱导更有效的免疫反应。我们在DNA疫苗方案的开发和应用方面具有长期的实践经验。我们使用这种疫苗平台是因为它的多功能性、简单性、可扩展性和缺乏针对载体的免疫性。基于核酸的疫苗的使用提供了一种简单的方法，允许结构复杂的免疫原的有效表达和翻译后修饰，并导致体液免疫和细胞免疫的发展。免疫应答可以维持很长一段时间，并且可以通过相同或异源的加强策略来加强。多年来，我们成功地优化了不同的步骤，以获得改善的免疫原性，包括优化的疫苗方案，疫苗递送，免疫原选择，佐剂选择和联合疫苗方案。我们已经开发了一组CoV 2 DNA疫苗。在猕猴中的测试已经显示诱导稳健的Ab应答，包括与CoV-2感染的恢复期患者相当的Nab应答以及强的T细胞应答。我们正在测试我们最初候选疫苗的效力。

The urgent need for a vaccine to combat the COVID-19 pandemic prompted us to apply our decades of experience in developing HIV vaccines towards SARS-CoV-2. We hypothesize that lessons learned from past SARS vaccine research, including HIV vaccine research, could be applied to the design of a COVID-19 vaccine. Based on the high convalescence rate, the human immune system is able to control and eliminate the virus infection, thus it is likely that a vaccine will work. Recent data from several clinical trials showed that different vaccine platforms showed that induction of humoral immune responses is possible. In support of this, it was reported that SARS-CoV infected persons developed durable virus-specific (N, S, M, E) T cell responses and strong T cell responses targeting S correlated with higher neutralizing Ab activity. Based on the persistence mechanisms known for other viruses, we hypothesize that SARS-CoV-2 may also have developed strategies to evade the host's immune system. Thus, an effective vaccine may require design beyond the use of natural proteins and we are exploring both avenues. One common mechanism of immune evasion is rapid mutation of antigenic targets, leading to immune escape. Our vaccine strategy aims to induce protective immune responses targeting structurally conserved portions of the SARS-CoV-2 S and N proteins that are also important for protective immunity. This strategy is an important addition to the on-going vaccine efforts, in case there are problems with the first generation of vaccines that have moved or are moving to phase I clinical trials. This vaccine effort may also offer an advantage by inducing broader immunity able to recognize a broader range of coronaviruses. We are developing DNA-based vaccines based on inclusion of regions of structural importance, based on X-ray crystallographic data of SARS1 and SARS-CoV-2 structures, with the aim to induce more effective immune responses. We have long practical experience in the development and application of DNA vaccine regimens. We use this vaccine platform due its versatility, simplicity, scalability, and lack of eliciting immunity against the vector. The use of a nucleic acid-based vaccine provides a simple method allowing efficient expression and post-translational modifications of structurally complex immunogens and results in the development of both humoral and cellular immunity. Immune responses can be maintained for long periods and can be boosted by the same or heterologous boosting strategies. Over many years we have successfully optimized different steps to obtain improve immunogenicity including optimized vaccine regimens, vaccine delivery, immunogen selection, adjuvant selection, and combination vaccine regimens. We have developed a panel of CoV2 DNA vaccines. Testing in macaques has shown induction of robust Ab responses including Nab responses comparable of CoV-2 infected convalescent patients as well as strong T cell responses. We are in the process of testing efficacy of our initial vaccine candidates.