Design and proof of concept for targeted phage-based COVID-19 vaccination strategies with a streamlined cold-free supply chain.
Design and proof of concept for targeted phage-based COVID-19 vaccination strategies with a streamlined cold-free supply chain.
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DOI：
10.1073/pnas.2105739118
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发表时间：
2021-07-27
影响因子：
11.1
通讯作者：
Pasqualini R
中科院分区：
文献类型：
--
作者：
Staquicini DI;Tang FHF;Markosian C;Yao VJ;Staquicini FI;Dodero-Rojas E;Contessoto VG;Davis D;O'Brien P;Habib N;Smith TL;Bruiners N;Sidman RL;Gennaro ML;Lattime EC;Libutti SK;Whitford PC;Burley SK;Onuchic JN;Arap W;Pasqualini R
COVID-19疫情带来前所未有的影响。尽管有几种疫苗已经获得紧急使用授权，但需求带来了巨大的后勤挑战，包括供应、获取和分配，这证明研究替代策略是合理的。噬菌体是一种只感染细菌的病毒，可以安全地施用于人类。在这里，作为一个概念验证的研究，我们证明，气雾剂疫苗接种肺靶向噬菌体颗粒展示短SARS-CoV-2 S蛋白表位和皮下接种靶向AAVP颗粒携带整个S蛋白基因都引发免疫活性小鼠全身和特异性免疫反应。鉴于其独特的属性，包括坚固，易于工程设计的平台，快速大规模生产的成本效益以及室温下的稳定性，这些基于噬菌体的方法可能成为COVID-19疫苗开发的有吸引力的工具。开发针对2019年冠状病毒病（COVID-19）的有效疫苗是全球当务之急。针对广泛的、持续进化的和高致病性的病毒对整个人类群体进行快速免疫是一个前所未有的挑战，并且正在追求不同的疫苗方法。工程化的丝状噬菌体（噬菌体）颗粒由于其固有的免疫原性、遗传可塑性、稳定性、大规模生产的成本效益以及在人类中被证明的安全性而在疫苗开发中具有独特的潜力。在此，我们报告的发展和初步评估的两个有针对性的噬菌体为基础的疫苗接种方法对SARS-CoV-2：双配体肽靶向噬菌体和腺相关病毒/噬菌体（AAVP）颗粒。对于肽靶向噬菌体，我们进行了结构指导的抗原设计，以选择SARS-CoV-2刺突（S）蛋白的六个溶剂暴露表位。其中一个展示在噬菌体的主要衣壳蛋白pVIII上的表位在注射小鼠时诱导特异性和持续的体液应答。这些噬菌体被进一步工程化以在次要衣壳蛋白pIII上同时展示肽CAKSMGDIVC，以使它们能够从肺上皮转运到体循环中。将这些“双重展示”噬菌体雾化到小鼠的肺中产生了全身性和特异性抗体应答。在第二种方法中，靶向AAVP颗粒被工程化以在组成型CMV启动子的控制下递送整个S蛋白基因。这诱导了组织特异性转基因表达，刺激了小鼠的全身性S蛋白特异性抗体应答。通过这些概念验证的临床前实验，我们表明，基于靶向噬菌体和AAVP的颗粒都是强大而通用的平台，可以迅速产生用于翻译开发的COVID-19疫苗原型。
The COVID-19 pandemic has had an unprecedented impact. Although several vaccines have received emergency use authorization, demand has created enormous logistical challenges—including supply, access, and distribution—that justify research for alternative strategies. Phage are viruses that only infect bacteria and can be safely administered to humans. Here, as a proof-of-concept study, we demonstrate that aerosol vaccination with lung-targeted phage particles displaying short SARS-CoV-2 S protein epitopes and subcutaneous vaccination with targeted AAVP particles carrying the entire S protein gene both elicit systemic and specific immune responses in immunocompetent mice. Given their unique attributes, including sturdiness, simple-to-engineer platform, cost-effectiveness for rapid large-scale production, and stability at room temperature, these phage-based approaches may become attractive tools for COVID-19 vaccine development. Development of effective vaccines against coronavirus disease 2019 (COVID-19) is a global imperative. Rapid immunization of the entire human population against a widespread, continually evolving, and highly pathogenic virus is an unprecedented challenge, and different vaccine approaches are being pursued. Engineered filamentous bacteriophage (phage) particles have unique potential in vaccine development due to their inherent immunogenicity, genetic plasticity, stability, cost-effectiveness for large-scale production, and proven safety profile in humans. Herein we report the development and initial evaluation of two targeted phage-based vaccination approaches against SARS-CoV-2: dual ligand peptide-targeted phage and adeno-associated virus/phage (AAVP) particles. For peptide-targeted phage, we performed structure-guided antigen design to select six solvent-exposed epitopes of the SARS-CoV-2 spike (S) protein. One of these epitopes displayed on the major capsid protein pVIII of phage induced a specific and sustained humoral response when injected in mice. These phage were further engineered to simultaneously display the peptide CAKSMGDIVC on the minor capsid protein pIII to enable their transport from the lung epithelium into the systemic circulation. Aerosolization of these “dual-display” phage into the lungs of mice generated a systemic and specific antibody response. In the second approach, targeted AAVP particles were engineered to deliver the entire S protein gene under the control of a constitutive CMV promoter. This induced tissue-specific transgene expression, stimulating a systemic S protein-specific antibody response in mice. With these proof-of-concept preclinical experiments, we show that both targeted phage- and AAVP-based particles serve as robust yet versatile platforms that can promptly yield COVID-19 vaccine prototypes for translational development.
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影响因子：
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作者：
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作者：
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影响因子：
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作者：
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DOI：
10.1126/science.abe2402
发表时间：
2020-11-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Baum A;Ajithdoss D;Copin R;Zhou A;Lanza K;Negron N;Ni M;Wei Y;Mohammadi K;Musser B;Atwal GS;Oyejide A;Goez-Gazi Y;Dutton J;Clemmons E;Staples HM;Bartley C;Klaffke B;Alfson K;Gazi M;Gonzalez O;Dick E Jr;Carrion R Jr;Pessaint L;Porto M;Cook A;Brown R;Ali V;Greenhouse J;Taylor T;Andersen H;Lewis MG;Stahl N;Murphy AJ;Yancopoulos GD;Kyratsous CA
通讯作者：
Kyratsous CA