Molecular engineering improves antigen quality and enables integrated manufacturing of a trivalent subunit vaccine candidate for rotavirus
- Autores
- Dalvie, Neil C.; Brady, Joseph R.; Crowell, Laura E.; Tracey, Mary Kate; Biedermann, Andrew M.; Kaur, Kawaljit; Hickey, John M.; Kristensen II, D. Lee; Bonnyman, Alexandra D.; Rodriguez-Aponte, Sergio A.; Whittaker, Charles A.; Bok, Marina; Vega, Celina Guadalupe; Mukhopadhyay, Tarit K.; Joshi, Sangeeta B.; Volkin, David B.; Parreño, Gladys; Love, Kerry R.; Love, J. Christopher
- Año de publicación
- 2021
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Background: Vaccines comprising recombinant subunit proteins are well-suited to low-cost and high-volume production for global use. The design of manufacturing processes to produce subunit vaccines depends, however, on the inherent biophysical traits presented by an individual antigen of interest. New candidate antigens typically require developing custom processes for each one and may require unique steps to ensure sufficient yields without product-related variants. Results: We describe a holistic approach for the molecular design of recombinant protein antigens—considering both their manufacturability and antigenicity—informed by bioinformatic analyses such as RNA-seq, ribosome profiling, and sequence-based prediction tools. We demonstrate this approach by engineering the product sequences of a trivalent non-replicating rotavirus vaccine (NRRV) candidate to improve titers and mitigate product variants caused by N-terminal truncation, hypermannosylation, and aggregation. The three engineered NRRV antigens retained their original antigenicity and immunogenicity, while their improved manufacturability enabled concomitant production and purification of all three serotypes in a single, end-to-end perfusion-based process using the biotechnical yeast Komagataella phaffii. Conclusions: This study demonstrates that molecular engineering of subunit antigens using advanced genomic methods can facilitate their manufacturing in continuous production. Such capabilities have potential to lower the cost and volumetric requirements in manufacturing vaccines based on recombinant protein subunits.
Instituto de Virología
Fil: Dalvie, Neil C. Massachusetts Institute of Technology. Department of Chemical Engineering; Estados Unidos
Fil: Dalvie, Neil C. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados Unidos
Fil: Brady, Joseph R. Massachusetts Institute of Technology. Department of Chemical Engineering; Estados Unidos
Fil: Brady, Joseph R. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados Unidos
Fil: Crowell, Laura E. Massachusetts Institute of Technology. Department of Chemical Engineering; Estados Unidos
Fil: Crowell, Laura E. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados Unidos
Fil: Tracey, Mary Kate. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados Unidos
Fil: Biedermann, Andrew M. Massachusetts Institute of Technology. Department of Chemical Engineering; Estados Unidos
Fil: Biedermann, Andrew M. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados Unidos
Fil: Kaur, Kawaljit. University of Kansas. Vaccine Analytics and Formulation Center. Department of Pharmaceutical Chemistry; Estados Unidos
Fil: Hickey, John M. University of Kansas. Vaccine Analytics and Formulation Center. Department of Pharmaceutical Chemistry; Estados Unidos
Fil: Kristensen II, D. Lee. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados Unidos
Fil: Bonnyman, Alexandra D. Massachusetts Institute of Technology. Department of Chemical Engineering; Estados Unidos
Fil: Bonnyman, Alexandra D. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados Unidos
Fil: Rodriguez-Aponte, Sergio A. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados Unidos
Fil: Rodriguez-Aponte, Sergio A. Massachusetts Institute of Technology. Department of Biological Engineering; Estados Unidos
Fil: Whittaker, Charles A. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados Unidos
Fil: Bok, Marina. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; Argentina
Fil: Bok, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Vega, Celina Guadalupe. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; Argentina
Fil: Vega, Celina Guadalupe. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Mukhopadhyay, Tarit K. University College London. Department of Biochemical Engineering; Reino Unidos
Fil: Joshi, Sangeeta B. University of Kansas. Vaccine Analytics and Formulation Center. Department of Pharmaceutical Chemistry; Estados Unidos
Fil: Volkin, David B. University of Kansas. Vaccine Analytics and Formulation Center. Department of Pharmaceutical Chemistry; Estados Unidos
Fil: Parreño, Gladys Viviana. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; Argentina
Fil: Parreño, Gladys Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Love, Kerry R. Massachusetts Institute of Technology. Department of Chemical Engineering; Estados Unidos
Fil: Love, Kerry R. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados Unidos
Fil: Love, J. Christopher. Massachusetts Institute of Technology. Department of Chemical Engineering; Estados Unidos
Fil: Love, J. Christopher. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados Unidos - Fuente
- Microbial Cell Factories 20 : Article number: 94 (2021)
- Materia
-
Vacuna
Antígenos
Genética Molecular
Pichia pastoris
Vaccines
Rotavirus
Antigens
Molecular Genetics - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- http://creativecommons.org/licenses/by-nc-sa/4.0/
- Repositorio
.jpg)
- Institución
- Instituto Nacional de Tecnología Agropecuaria
- OAI Identificador
- oai:localhost:20.500.12123/10760
Ver los metadatos del registro completo
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Molecular engineering improves antigen quality and enables integrated manufacturing of a trivalent subunit vaccine candidate for rotavirusDalvie, Neil C.Brady, Joseph R.Crowell, Laura E.Tracey, Mary KateBiedermann, Andrew M.Kaur, KawaljitHickey, John M.Kristensen II, D. LeeBonnyman, Alexandra D.Rodriguez-Aponte, Sergio A.Whittaker, Charles A.Bok, MarinaVega, Celina GuadalupeMukhopadhyay, Tarit K.Joshi, Sangeeta B.Volkin, David B.Parreño, GladysLove, Kerry R.Love, J. ChristopherVacunaAntígenosGenética MolecularPichia pastorisVaccinesRotavirusAntigensMolecular GeneticsBackground: Vaccines comprising recombinant subunit proteins are well-suited to low-cost and high-volume production for global use. The design of manufacturing processes to produce subunit vaccines depends, however, on the inherent biophysical traits presented by an individual antigen of interest. New candidate antigens typically require developing custom processes for each one and may require unique steps to ensure sufficient yields without product-related variants. Results: We describe a holistic approach for the molecular design of recombinant protein antigens—considering both their manufacturability and antigenicity—informed by bioinformatic analyses such as RNA-seq, ribosome profiling, and sequence-based prediction tools. We demonstrate this approach by engineering the product sequences of a trivalent non-replicating rotavirus vaccine (NRRV) candidate to improve titers and mitigate product variants caused by N-terminal truncation, hypermannosylation, and aggregation. The three engineered NRRV antigens retained their original antigenicity and immunogenicity, while their improved manufacturability enabled concomitant production and purification of all three serotypes in a single, end-to-end perfusion-based process using the biotechnical yeast Komagataella phaffii. Conclusions: This study demonstrates that molecular engineering of subunit antigens using advanced genomic methods can facilitate their manufacturing in continuous production. Such capabilities have potential to lower the cost and volumetric requirements in manufacturing vaccines based on recombinant protein subunits.Instituto de VirologíaFil: Dalvie, Neil C. Massachusetts Institute of Technology. Department of Chemical Engineering; Estados UnidosFil: Dalvie, Neil C. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados UnidosFil: Brady, Joseph R. Massachusetts Institute of Technology. Department of Chemical Engineering; Estados UnidosFil: Brady, Joseph R. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados UnidosFil: Crowell, Laura E. Massachusetts Institute of Technology. Department of Chemical Engineering; Estados UnidosFil: Crowell, Laura E. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados UnidosFil: Tracey, Mary Kate. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados UnidosFil: Biedermann, Andrew M. Massachusetts Institute of Technology. Department of Chemical Engineering; Estados UnidosFil: Biedermann, Andrew M. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados UnidosFil: Kaur, Kawaljit. University of Kansas. Vaccine Analytics and Formulation Center. Department of Pharmaceutical Chemistry; Estados UnidosFil: Hickey, John M. University of Kansas. Vaccine Analytics and Formulation Center. Department of Pharmaceutical Chemistry; Estados UnidosFil: Kristensen II, D. Lee. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados UnidosFil: Bonnyman, Alexandra D. Massachusetts Institute of Technology. Department of Chemical Engineering; Estados UnidosFil: Bonnyman, Alexandra D. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados UnidosFil: Rodriguez-Aponte, Sergio A. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados UnidosFil: Rodriguez-Aponte, Sergio A. Massachusetts Institute of Technology. Department of Biological Engineering; Estados UnidosFil: Whittaker, Charles A. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados UnidosFil: Bok, Marina. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; ArgentinaFil: Bok, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Vega, Celina Guadalupe. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; ArgentinaFil: Vega, Celina Guadalupe. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mukhopadhyay, Tarit K. University College London. Department of Biochemical Engineering; Reino UnidosFil: Joshi, Sangeeta B. University of Kansas. Vaccine Analytics and Formulation Center. Department of Pharmaceutical Chemistry; Estados UnidosFil: Volkin, David B. University of Kansas. Vaccine Analytics and Formulation Center. Department of Pharmaceutical Chemistry; Estados UnidosFil: Parreño, Gladys Viviana. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; ArgentinaFil: Parreño, Gladys Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Love, Kerry R. Massachusetts Institute of Technology. Department of Chemical Engineering; Estados UnidosFil: Love, Kerry R. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados UnidosFil: Love, J. Christopher. Massachusetts Institute of Technology. Department of Chemical Engineering; Estados UnidosFil: Love, J. Christopher. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados UnidosBMC2021-11-12T13:55:22Z2021-11-12T13:55:22Z2021-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfhttp://hdl.handle.net/20.500.12123/10760https://microbialcellfactories.biomedcentral.com/articles/10.1186/s12934-021-01583-61475-2859https://doi.org/10.1186/s12934-021-01583-6Microbial Cell Factories 20 : Article number: 94 (2021)reponame:INTA Digital (INTA)instname:Instituto Nacional de Tecnología Agropecuariaenginfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-sa/4.0/Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)2025-09-29T13:45:24Zoai:localhost:20.500.12123/10760instacron:INTAInstitucionalhttp://repositorio.inta.gob.ar/Organismo científico-tecnológicoNo correspondehttp://repositorio.inta.gob.ar/oai/requesttripaldi.nicolas@inta.gob.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:l2025-09-29 13:45:24.945INTA Digital (INTA) - Instituto Nacional de Tecnología Agropecuariafalse |
| dc.title.none.fl_str_mv |
Molecular engineering improves antigen quality and enables integrated manufacturing of a trivalent subunit vaccine candidate for rotavirus |
| title |
Molecular engineering improves antigen quality and enables integrated manufacturing of a trivalent subunit vaccine candidate for rotavirus |
| spellingShingle |
Molecular engineering improves antigen quality and enables integrated manufacturing of a trivalent subunit vaccine candidate for rotavirus Dalvie, Neil C. Vacuna Antígenos Genética Molecular Pichia pastoris Vaccines Rotavirus Antigens Molecular Genetics |
| title_short |
Molecular engineering improves antigen quality and enables integrated manufacturing of a trivalent subunit vaccine candidate for rotavirus |
| title_full |
Molecular engineering improves antigen quality and enables integrated manufacturing of a trivalent subunit vaccine candidate for rotavirus |
| title_fullStr |
Molecular engineering improves antigen quality and enables integrated manufacturing of a trivalent subunit vaccine candidate for rotavirus |
| title_full_unstemmed |
Molecular engineering improves antigen quality and enables integrated manufacturing of a trivalent subunit vaccine candidate for rotavirus |
| title_sort |
Molecular engineering improves antigen quality and enables integrated manufacturing of a trivalent subunit vaccine candidate for rotavirus |
| dc.creator.none.fl_str_mv |
Dalvie, Neil C. Brady, Joseph R. Crowell, Laura E. Tracey, Mary Kate Biedermann, Andrew M. Kaur, Kawaljit Hickey, John M. Kristensen II, D. Lee Bonnyman, Alexandra D. Rodriguez-Aponte, Sergio A. Whittaker, Charles A. Bok, Marina Vega, Celina Guadalupe Mukhopadhyay, Tarit K. Joshi, Sangeeta B. Volkin, David B. Parreño, Gladys Love, Kerry R. Love, J. Christopher |
| author |
Dalvie, Neil C. |
| author_facet |
Dalvie, Neil C. Brady, Joseph R. Crowell, Laura E. Tracey, Mary Kate Biedermann, Andrew M. Kaur, Kawaljit Hickey, John M. Kristensen II, D. Lee Bonnyman, Alexandra D. Rodriguez-Aponte, Sergio A. Whittaker, Charles A. Bok, Marina Vega, Celina Guadalupe Mukhopadhyay, Tarit K. Joshi, Sangeeta B. Volkin, David B. Parreño, Gladys Love, Kerry R. Love, J. Christopher |
| author_role |
author |
| author2 |
Brady, Joseph R. Crowell, Laura E. Tracey, Mary Kate Biedermann, Andrew M. Kaur, Kawaljit Hickey, John M. Kristensen II, D. Lee Bonnyman, Alexandra D. Rodriguez-Aponte, Sergio A. Whittaker, Charles A. Bok, Marina Vega, Celina Guadalupe Mukhopadhyay, Tarit K. Joshi, Sangeeta B. Volkin, David B. Parreño, Gladys Love, Kerry R. Love, J. Christopher |
| author2_role |
author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Vacuna Antígenos Genética Molecular Pichia pastoris Vaccines Rotavirus Antigens Molecular Genetics |
| topic |
Vacuna Antígenos Genética Molecular Pichia pastoris Vaccines Rotavirus Antigens Molecular Genetics |
| dc.description.none.fl_txt_mv |
Background: Vaccines comprising recombinant subunit proteins are well-suited to low-cost and high-volume production for global use. The design of manufacturing processes to produce subunit vaccines depends, however, on the inherent biophysical traits presented by an individual antigen of interest. New candidate antigens typically require developing custom processes for each one and may require unique steps to ensure sufficient yields without product-related variants. Results: We describe a holistic approach for the molecular design of recombinant protein antigens—considering both their manufacturability and antigenicity—informed by bioinformatic analyses such as RNA-seq, ribosome profiling, and sequence-based prediction tools. We demonstrate this approach by engineering the product sequences of a trivalent non-replicating rotavirus vaccine (NRRV) candidate to improve titers and mitigate product variants caused by N-terminal truncation, hypermannosylation, and aggregation. The three engineered NRRV antigens retained their original antigenicity and immunogenicity, while their improved manufacturability enabled concomitant production and purification of all three serotypes in a single, end-to-end perfusion-based process using the biotechnical yeast Komagataella phaffii. Conclusions: This study demonstrates that molecular engineering of subunit antigens using advanced genomic methods can facilitate their manufacturing in continuous production. Such capabilities have potential to lower the cost and volumetric requirements in manufacturing vaccines based on recombinant protein subunits. Instituto de Virología Fil: Dalvie, Neil C. Massachusetts Institute of Technology. Department of Chemical Engineering; Estados Unidos Fil: Dalvie, Neil C. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados Unidos Fil: Brady, Joseph R. Massachusetts Institute of Technology. Department of Chemical Engineering; Estados Unidos Fil: Brady, Joseph R. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados Unidos Fil: Crowell, Laura E. Massachusetts Institute of Technology. Department of Chemical Engineering; Estados Unidos Fil: Crowell, Laura E. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados Unidos Fil: Tracey, Mary Kate. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados Unidos Fil: Biedermann, Andrew M. Massachusetts Institute of Technology. Department of Chemical Engineering; Estados Unidos Fil: Biedermann, Andrew M. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados Unidos Fil: Kaur, Kawaljit. University of Kansas. Vaccine Analytics and Formulation Center. Department of Pharmaceutical Chemistry; Estados Unidos Fil: Hickey, John M. University of Kansas. Vaccine Analytics and Formulation Center. Department of Pharmaceutical Chemistry; Estados Unidos Fil: Kristensen II, D. Lee. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados Unidos Fil: Bonnyman, Alexandra D. Massachusetts Institute of Technology. Department of Chemical Engineering; Estados Unidos Fil: Bonnyman, Alexandra D. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados Unidos Fil: Rodriguez-Aponte, Sergio A. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados Unidos Fil: Rodriguez-Aponte, Sergio A. Massachusetts Institute of Technology. Department of Biological Engineering; Estados Unidos Fil: Whittaker, Charles A. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados Unidos Fil: Bok, Marina. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; Argentina Fil: Bok, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Vega, Celina Guadalupe. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; Argentina Fil: Vega, Celina Guadalupe. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Mukhopadhyay, Tarit K. University College London. Department of Biochemical Engineering; Reino Unidos Fil: Joshi, Sangeeta B. University of Kansas. Vaccine Analytics and Formulation Center. Department of Pharmaceutical Chemistry; Estados Unidos Fil: Volkin, David B. University of Kansas. Vaccine Analytics and Formulation Center. Department of Pharmaceutical Chemistry; Estados Unidos Fil: Parreño, Gladys Viviana. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Virología; Argentina Fil: Parreño, Gladys Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Love, Kerry R. Massachusetts Institute of Technology. Department of Chemical Engineering; Estados Unidos Fil: Love, Kerry R. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados Unidos Fil: Love, J. Christopher. Massachusetts Institute of Technology. Department of Chemical Engineering; Estados Unidos Fil: Love, J. Christopher. Massachusetts Institute of Technology. The Koch Institute for Integrative Cancer Research; Estados Unidos |
| description |
Background: Vaccines comprising recombinant subunit proteins are well-suited to low-cost and high-volume production for global use. The design of manufacturing processes to produce subunit vaccines depends, however, on the inherent biophysical traits presented by an individual antigen of interest. New candidate antigens typically require developing custom processes for each one and may require unique steps to ensure sufficient yields without product-related variants. Results: We describe a holistic approach for the molecular design of recombinant protein antigens—considering both their manufacturability and antigenicity—informed by bioinformatic analyses such as RNA-seq, ribosome profiling, and sequence-based prediction tools. We demonstrate this approach by engineering the product sequences of a trivalent non-replicating rotavirus vaccine (NRRV) candidate to improve titers and mitigate product variants caused by N-terminal truncation, hypermannosylation, and aggregation. The three engineered NRRV antigens retained their original antigenicity and immunogenicity, while their improved manufacturability enabled concomitant production and purification of all three serotypes in a single, end-to-end perfusion-based process using the biotechnical yeast Komagataella phaffii. Conclusions: This study demonstrates that molecular engineering of subunit antigens using advanced genomic methods can facilitate their manufacturing in continuous production. Such capabilities have potential to lower the cost and volumetric requirements in manufacturing vaccines based on recombinant protein subunits. |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021-11-12T13:55:22Z 2021-11-12T13:55:22Z 2021-05 |
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info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
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article |
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publishedVersion |
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http://hdl.handle.net/20.500.12123/10760 https://microbialcellfactories.biomedcentral.com/articles/10.1186/s12934-021-01583-6 1475-2859 https://doi.org/10.1186/s12934-021-01583-6 |
| url |
http://hdl.handle.net/20.500.12123/10760 https://microbialcellfactories.biomedcentral.com/articles/10.1186/s12934-021-01583-6 https://doi.org/10.1186/s12934-021-01583-6 |
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1475-2859 |
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eng |
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application/pdf |
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BMC |
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BMC |
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Microbial Cell Factories 20 : Article number: 94 (2021) reponame:INTA Digital (INTA) instname:Instituto Nacional de Tecnología Agropecuaria |
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