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The resulting threat of the Zika virus to human health has prompted the development of new vaccines, which have yet to be approved for human use. Vaccines based on the attenuated or chemically inactivated virus will require large\u2010scale production of the intact virus to meet potential global demands. Intact viruses are produced by infecting cultures of susceptible cells, a dynamic process that spans from hours to days and has yet to be optimized. Here, we infected Vero cells adhesively cultured in well\u2010plates with two Zika virus strains: a recently isolated strain from the Asian lineage, and a cell\u2010culture\u2010adapted strain from the African lineage. At different time points post\u2010infection, virus particles in the supernatant were quantified; further, microscopy images were used to quantify cell density and the proportion of cells expressing viral protein. These measurements were performed across multiple replicate samples of one\u2010step infections every four hours over 60\u2009h and for multi\u2010step infections every four to 24\u2009h over 144\u2009h, generating a rich data set. For each set of data, mathematical models were developed to estimate parameters associated with cell infection and virus production. The African\u2010lineage strain was found to produce a 14\u2010fold higher yield than the Asian\u2010lineage strain in one\u2010step growth and a sevenfold higher titer in multi\u2010step growth, suggesting a benefit of cell\u2010culture adaptation for developing a vaccine strain. We found that image\u2010based measurements were critical for discriminating among different models, and different parameters for the two strains could account for the experimentally observed differences. An exponential\u2010distributed delay model performed best in accounting for multi\u2010step infection of the Asian strain, and it highlighted the significant sensitivity of virus titer to the rate of viral degradation, with implications for optimization of vaccine production. More broadly, this study highlights how image\u2010based measurements can contribute to the discrimination of virus\u2010culture models for the optimal production of inactivated and attenuated whole\u2010virus vaccines.<\/jats:p>","DOI":"10.1002\/bit.27892","type":"journal-article","created":{"date-parts":[[2021,7,16]],"date-time":"2021-07-16T09:30:34Z","timestamp":1626427834000},"page":"4231-4245","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Kinetics of Asian and African Zika virus lineages over single\u2010cycle and multi\u2010cycle growth in culture: Gene expression, cell killing, virus production, and mathematical modeling"],"prefix":"10.1002","volume":"118","author":[{"given":"Huicheng","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Chemical and Biological Engineering, Wisconsin Institute for Discovery University of Wisconsin\u2010Madison  Madison Wisconsin USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6146-0594","authenticated-orcid":false,"given":"John","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering, Wisconsin Institute for Discovery University of Wisconsin\u2010Madison  Madison Wisconsin USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,7,28]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1109\/TAC.1974.1100705"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00807-16"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0005168"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1039\/b908197f"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00292-17"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.3201\/eid2304.161549"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.16-0969"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01623-05"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtbi.2008.05.031"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01640"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1127\/entomologia\/2017\/0496"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/v12050547"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1008564"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1704011114"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12687"},{"key":"e_1_2_7_17_1","unstructured":"Bidot C. 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