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首页> 外文期刊>Applied Microbiology and Biotechnology >High titer MVA and influenza A virus production using a hybrid fed-batch/perfusion strategy with an ATF system
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High titer MVA and influenza A virus production using a hybrid fed-batch/perfusion strategy with an ATF system

机译：高滴度MVA和流感使用具有ATF系统的杂交Fed批次/灌注策略的病毒生产

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摘要

A cultivation strategy to increase the productivity of Modified Vaccinia Ankara (MVA) virus in high-cell density processes is presented. Based on an approach developed in shake flask cultures, this strategy was established in benchtop bioreactors, comprising the growth of suspension AGE1.CR.pIX cells to high cell densities in a chemically defined medium before infection with the MVA-CR19 virus strain. First, a perfusion regime was established to optimize the cell growth phase. Second, a fed-batch regime was chosen for the initial infection phase to facilitate virus uptake and cell-to-cell spreading. Afterwards, a switch to perfusion enabled the continuous supply of nutrients for the late stages of virus propagation. With maximum infectious titers of 1.0x10(10)IU/mL, this hybrid fed-batch/perfusion strategy increased product titers by almost one order of magnitude compared to conventional batch cultivations. Finally, this strategy was also applied to the production of influenza A/PR/8/34 (H1N1) virus considered for manufacturing of inactivated vaccines. Using the same culture system, a total number of 3.8x10(10) virions/mL was achieved. Overall, comparable or even higher cell-specific virus yields and volumetric productivities were obtained using the same cultivation systems as for the conventional batch cultivations. In addition, most viral particles were found in the culture supernatant, which can simplify further downstream operations, in particular for MVA viruses. Considering the current availability of well-described perfusion/cell retention technologies, the present strategy may contribute to the development of new approaches for viral vaccine production.
机译：提高了提高高细胞密度工艺改性痘苗病毒（MVA）病毒的栽培策略。基于摇瓶培养物中发展的方法，该策略在Benchtop生物反应器中建立，包括在用MVA-CR19病毒菌株感染之前将悬浮液12.Cr.pix细胞生长到化学定义的培养基中的高细胞密度。首先，建立灌注制度以优化细胞生长阶段。其次，选择初始感染阶段的美联储方案以促进病毒吸收和细胞对细胞扩散。之后，开关灌注的开关使得病毒传播的晚期营养成分的连续供应。对于1.0×10（10）IU / mL的最大传染性滴度，与常规分批培养相比，该杂交喂食/灌注策略通过几乎一大阶数增加了产物滴度。最后，该策略也适用于制造灭活疫苗的流感A / PR / 8/34（H1N1）病毒的生产。使用相同的培养系统，实现了3.8x10（10）个病毒粒子/ mL的总数。总体而言，使用与常规分批培养的相同培养系统获得相同的细胞特异性病毒产量和体积效率。此外，在培养上清液中发现大多数病毒颗粒，其可以简化进一步的下游操作，特别是用于MVA病毒。考虑到目前纯粹的灌注/细胞保留技术的可用性，目前的策略可能有助于开发病毒疫苗生产的新方法。

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