Killed whole-genome reduced-bacteria surface-expressed coronavirus fusion peptide vaccines protect against disease in a porcine model.
Killed whole-genome reduced-bacteria surface-expressed coronavirus fusion peptide vaccines protect against disease in a porcine model.
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DOI：
10.1073/pnas.2025622118
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发表时间：
2021-05-04
影响因子：
11.1
通讯作者：
Zeichner SL
中科院分区：
文献类型：
--
作者：
Maeda DLNF;Tian D;Yu H;Dar N;Rajasekaran V;Meng S;Mahsoub HM;Sooryanarain H;Wang B;Heffron CL;Hassebroek A;LeRoith T;Meng XJ;Zeichner SL
我们报告了一种疫苗平台，在基因组减少的细菌表面表达疫苗抗原以增强疫苗免疫原性。我们通过在大肠杆菌表面表达SARS-CoV-2和猪流行性腹泻病毒的高度保守融合肽（FP）来生产灭活的全细胞细菌疫苗，从而证明了该疫苗平台的实用性。该疫苗引发有效的记忆应答，增强干扰素-γ应答，并在病毒攻击后为猪提供显著的疾病保护。FP可能是广泛保护性冠状病毒疫苗的靶点，因为β冠状病毒SARS-CoV-2 FP疫苗提供了对猪流行性腹泻病毒的交叉保护。当使用适合疫苗的细菌载体时，这种廉价的疫苗平台具有在发展中国家使用的潜力。随着2019年冠状病毒病（COVID-19）大流行的肆虐，探索新的抗进化疫苗抗原和新的疫苗平台非常重要，这些疫苗可以生产易于扩展的廉价疫苗，更容易储存和运输。我们在这里报告了一种基于合成生物学的疫苗平台，该平台采用具有诱导性革兰氏阴性自转运蛋白的表达载体在基因组减少的细菌表面表达疫苗抗原，以增强疫苗抗原与免疫系统的相互作用。作为原理验证，我们利用基因组减少的大肠杆菌在细胞表面表达SARS-CoV-2和猪流行性腹泻病毒（PEDV）融合肽（FP），并评估其作为灭活全细胞疫苗的用途。FP序列在冠状病毒中高度保守; 6个FP核心氨基酸残基，沿着核心上游的4个相邻残基和核心下游的3个残基，在SARS-CoV-2和PEDV之间是相同的。我们在PEDV攻击猪模型中测试了PEDV FP和SARS-CoV-2 FP疫苗的功效。我们证明，两种疫苗在病毒攻击后诱导有效的记忆应答，增强干扰素-γ应答，降低空肠组织中的病毒RNA载量，并提供针对临床疾病的显著保护。然而，这两种疫苗都没有引起杀菌免疫。由于SARS-CoV-2 FP和PEDV FP疫苗提供了相似的临床保护，因此冠状病毒FP可以成为使用任何平台的广泛保护性疫苗的靶标。重要的是，基因组减少的细菌表面表达的疫苗平台，当使用疫苗合适的细菌载体时，具有作为用于其他病原体的廉价、容易制造和快速疫苗平台的潜在效用。
We report a vaccine platform to express vaccine antigens on the surface of genome-reduced bacteria to enhance vaccine immunogenicity. We demonstrate the utility of this vaccine platform by expressing the highly conserved fusion peptide (FP) of SARS-CoV-2 and porcine epidemic diarrhea virus on the surface of Escherichia coli to produce killed whole-cell bacterial vaccines. The vaccine primes a potent anamnestic response, potentiates interferon-γ responses, and provides significant protection in pigs against disease following virus challenge. The FP could be a target for a broadly protective coronavirus vaccine since a betacoronavirus SARS-CoV-2 FP vaccine provided cross-protection against alphacoronavirus porcine epidemic diarrhea virus. When using a vaccine-appropriate bacteria vector, this inexpensive vaccine platform offers the potential for use in developing countries. As the coronavirus disease 2019 (COVID-19) pandemic rages on, it is important to explore new evolution-resistant vaccine antigens and new vaccine platforms that can produce readily scalable, inexpensive vaccines with easier storage and transport. We report here a synthetic biology-based vaccine platform that employs an expression vector with an inducible gram-negative autotransporter to express vaccine antigens on the surface of genome-reduced bacteria to enhance interaction of vaccine antigen with the immune system. As a proof-of-principle, we utilized genome-reduced Escherichia coli to express SARS-CoV-2 and porcine epidemic diarrhea virus (PEDV) fusion peptide (FP) on the cell surface, and evaluated their use as killed whole-cell vaccines. The FP sequence is highly conserved across coronaviruses; the six FP core amino acid residues, along with the four adjacent residues upstream and the three residues downstream from the core, are identical between SARS-CoV-2 and PEDV. We tested the efficacy of PEDV FP and SARS-CoV-2 FP vaccines in a PEDV challenge pig model. We demonstrated that both vaccines induced potent anamnestic responses upon virus challenge, potentiated interferon-γ responses, reduced viral RNA loads in jejunum tissue, and provided significant protection against clinical disease. However, neither vaccines elicited sterilizing immunity. Since SARS-CoV-2 FP and PEDV FP vaccines provided similar clinical protection, the coronavirus FP could be a target for a broadly protective vaccine using any platform. Importantly, the genome-reduced bacterial surface-expressed vaccine platform, when using a vaccine-appropriate bacterial vector, has potential utility as an inexpensive, readily manufactured, and rapid vaccine platform for other pathogens.
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