Microneedle array delivered recombinant coronavirus vaccines: Immunogenicity and rapid translational development
Microneedle array delivered recombinant coronavirus vaccines: Immunogenicity and rapid translational development
复制标题
DOI：
10.1016/j.ebiom.2020.102743
复制
发表时间：
2020-05-01
期刊：
影响因子：
11.1
通讯作者：
Gambotto, Andrea
中科院分区：
文献类型：
--
作者：
Kim, Eun;Erdos, Geza;Gambotto, Andrea
背景资料：冠状病毒对全球健康构成严重威胁，如严重急性呼吸系统综合征（SARS）、中东呼吸系统综合征（MERS）和COVID-19。SARS冠状病毒（SARS-CoV），MERS冠状病毒（MERS-CoV）和新型冠状病毒，以前称为2019-nCoV，现在正式命名为SARS-CoV-2，分别是SARS，MERS和COVID-19疾病爆发的病原体。目前迫切需要安全的疫苗，能够迅速诱导针对这些传染性病原体的有效和持久的病毒特异性免疫应答。冠状病毒刺突蛋白（S）是病毒包膜的特征性结构成分，被认为是预防冠状病毒感染的疫苗的关键靶点。方法：我们首先构建了密码子优化的MERS-S1亚单位疫苗，该亚单位疫苗与折叠子三聚化结构域融合以模拟天然病毒结构。在变体构建体中，我们将免疫刺激剂（RS 09或鞭毛蛋白，分别作为TLR 4或TLR 5激动剂）工程化到该三聚体设计中。我们通过ELISA和病毒中和试验评估接种小鼠血清中的病毒特异性IgG抗体，全面测试了MERS-CoV疫苗在小鼠中的临床前免疫原性，其中MERS-CoV疫苗通过传统针注射皮下递送，或通过溶解微针阵列（MNAs）进行皮内递送。由于对COVID-19疫苗的迫切需求，我们利用这一策略快速开发了MNA SARS-CoV-2亚单位疫苗，并利用我们在MNA MERS-CoV疫苗方面的丰富经验在体内测试了其临床前免疫原性。具体而言，MNA递送的MERS-S1亚单位疫苗引起强烈且持久的抗原特异性抗体应答。基于我们正在努力开发MERS-CoV疫苗，MNA递送的MERS-CoV疫苗具有良好的免疫原性，以及我们在MNA制造和递送方面的经验，包括临床试验，我们在SARS-CoV-2 S1序列鉴定后4周内快速设计并生产了临床可翻译的MNA SARS-CoV-2亚单位疫苗。最重要的是，这些MNA递送的SARS-CoV-2 S1亚单位疫苗引发了有效的抗原特异性抗体应答，这种应答在免疫后2周开始明显。不断进步的科学和技术努力使我们能够更快地应对新出现的大流行病。我们正在努力开发MNA-MERS-S1亚单位疫苗，使我们能够快速设计和生产能够诱导有效病毒特异性抗体反应的MNA SARS-CoV-2亚单位疫苗。总的来说，我们的结果支持MNA递送的重组蛋白亚单位疫苗的临床开发，以对抗SARS，MERS，COVID-19和其他新兴传染病。(C)2020作者（S）由爱思唯尔公司出版
Background: Coronaviruses pose a serious threat to global health as evidenced by Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and COVID-19. SARS Coronavirus (SARS-CoV), MERS Coronavirus (MERS-CoV), and the novel coronavirus, previously dubbed 2019-nCoV, and now officially named SARS-CoV-2, are the causative agents of the SARS, MERS, and COVID-19 disease outbreaks, respectively. Safe vaccines that rapidly induce potent and long-lasting virus-specific immune responses against these infectious agents are urgently needed. The coronavirus spike (S) protein, a characteristic structural component of the viral envelope, is considered a key target for vaccines for the prevention of coronavirus infection.Methods: We first generated codon optimized MERS-S1 subunit vaccines fused with a foldon trimerization domain to mimic the native viral structure. In variant constructs, we engineered immune stimulants (RS09 or flagellin, as TLR4 or TLR5 agonists, respectively) into this trimeric design. We comprehensively tested the pre-clinical immunogenicity of MERS-CoV vaccines in mice when delivered subcutaneously by traditional needle injection, or intracutaneously by dissolving microneedle arrays (MNAs) by evaluating virus specific IgG antibodies in the serum of vaccinated mice by ELISA and using virus neutralization assays. Driven by the urgent need for COVID-19 vaccines, we utilized this strategy to rapidly develop MNA SARS-CoV-2 subunit vaccines and tested their pre-clinical immunogenicity in vivo by exploiting our substantial experience with MNA MERS-CoV vaccines.Findings: Here we describe the development of MNA delivered MERS-CoV vaccines and their pre-clinical immunogenicity. Specifically, MNA delivered MERS-S1 subunit vaccines elicited strong and long-lasting antigen-specific antibody responses. Building on our ongoing efforts to develop MERS-CoV vaccines, promising immunogenicity of MNA-delivered MERS-CoV vaccines, and our experience with MNA fabrication and delivery, including clinical trials, we rapidly designed and produced clinically-translatable MNA SARS-CoV-2 subunit vaccines within 4 weeks of the identification of the SARS-CoV-2 S1 sequence. Most importantly, these MNA delivered SARS-CoV-2 S1 subunit vaccines elicited potent antigen-specific antibody responses that were evident beginning 2 weeks after immunization.Interpretation: MNA delivery of coronaviruses-S1 subunit vaccines is a promising immunization strategy against coronavirus infection. Progressive scientific and technological efforts enable quicker responses to emerging pandemics. Our ongoing efforts to develop MNA-MERS-S1 subunit vaccines enabled us to rapidly design and produce MNA SARS-CoV-2 subunit vaccines capable of inducing potent virus-specific antibody responses. Collectively, our results support the clinical development of MNA delivered recombinant protein subunit vaccines against SARS, MERS, COVID-19, and other emerging infectious diseases. (C) 2020 The Author(s). Published by Elsevier B.V.