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Inactivated or damaged? Comparing the effect of inactivation methods on influenza virions to optimize vaccine production
•β-propiolactone (BPL) and formaldehyde (FA) were used to inactivate several influenza virus strains.•BPL abolished the infectivity, FA was unable to completely inactivate the virus.•All methods damaged the binding and fusion capacity; BPL caused greater loss than FA.•FA treatments caused the highes...
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Published in: | Vaccine 2019-03, Vol.37 (12), p.1630-1637 |
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description | •β-propiolactone (BPL) and formaldehyde (FA) were used to inactivate several influenza virus strains.•BPL abolished the infectivity, FA was unable to completely inactivate the virus.•All methods damaged the binding and fusion capacity; BPL caused greater loss than FA.•FA treatments caused the highest reduction in TLR-7 stimulation.•All the observed effects were strain-dependent.
The vast majority of commercially available inactivated influenza vaccines are produced from egg-grown or cell-grown live influenza virus. The first step in the production process is virus inactivation with β-propiolactone (BPL) or formaldehyde (FA). Recommendations for production of inactivated vaccines merely define the maximal concentration for both reagents, leaving the optimization of the process to the manufacturers. We assessed the effect of inactivation with BPL and FA on 5 different influenza virus strains. The properties of the viral formulation, such as successful inactivation, preservation of hemagglutinin (HA) binding ability, fusion capacity and the potential to stimulate a Toll-like receptor 7 (TLR7) reporter cell line were then assessed and compared to the properties of the untreated virus. Inactivation with BPL resulted in undetectable infectivity levels, while FA-treated virus retained very low infectious titers. Hemagglutination and fusion ability were highly affected by those treatments that conferred higher inactivation, with BPL-treated virus binding and fusing at a lower degree compared to FA-inactivated samples. On the other hand, BPL-inactivated virus induced higher levels of activation of TLR7 than FA-inactivated virus. The alterations caused by BPL or FA treatments were virus strain dependent. This data shows that the inactivation procedures should be tailored on the virus strain, and that many other elements beside the concentration of the inactivating agent, such as incubation time and temperature, buffer and virus concentration, have to be defined to achieve a functional product. |
doi_str_mv | 10.1016/j.vaccine.2019.01.086 |
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The vast majority of commercially available inactivated influenza vaccines are produced from egg-grown or cell-grown live influenza virus. The first step in the production process is virus inactivation with β-propiolactone (BPL) or formaldehyde (FA). Recommendations for production of inactivated vaccines merely define the maximal concentration for both reagents, leaving the optimization of the process to the manufacturers. We assessed the effect of inactivation with BPL and FA on 5 different influenza virus strains. The properties of the viral formulation, such as successful inactivation, preservation of hemagglutinin (HA) binding ability, fusion capacity and the potential to stimulate a Toll-like receptor 7 (TLR7) reporter cell line were then assessed and compared to the properties of the untreated virus. Inactivation with BPL resulted in undetectable infectivity levels, while FA-treated virus retained very low infectious titers. Hemagglutination and fusion ability were highly affected by those treatments that conferred higher inactivation, with BPL-treated virus binding and fusing at a lower degree compared to FA-inactivated samples. On the other hand, BPL-inactivated virus induced higher levels of activation of TLR7 than FA-inactivated virus. The alterations caused by BPL or FA treatments were virus strain dependent. This data shows that the inactivation procedures should be tailored on the virus strain, and that many other elements beside the concentration of the inactivating agent, such as incubation time and temperature, buffer and virus concentration, have to be defined to achieve a functional product.</description><identifier>ISSN: 0264-410X</identifier><identifier>EISSN: 1873-2518</identifier><identifier>DOI: 10.1016/j.vaccine.2019.01.086</identifier><identifier>PMID: 30765167</identifier><language>eng</language><publisher>Netherlands: Elsevier Ltd</publisher><subject>Animals ; Antigens ; Binding ; Binding sites ; Cell Line ; Conflicts of interest ; Deactivation ; Foot & mouth disease ; Formaldehyde ; Formaldehyde - pharmacology ; Hemagglutination ; Hemagglutinin Glycoproteins, Influenza Virus - immunology ; Hemagglutinins ; Humans ; Immunization ; Inactivation ; Infectivity ; Influenza ; Influenza A virus - drug effects ; Influenza A virus - immunology ; Influenza A virus - isolation & purification ; Influenza Vaccines - immunology ; Lipids ; Manufacturers ; Manufacturing ; Optimization ; Preservation ; Proteins ; Reagents ; TLR7 protein ; Toll-like receptors ; Vaccine ; Vaccines ; Vaccines, Inactivated - immunology ; Virion - drug effects ; Virion - immunology ; Virion - isolation & purification ; Virions ; Virus Inactivation ; Viruses ; β-propiolactone</subject><ispartof>Vaccine, 2019-03, Vol.37 (12), p.1630-1637</ispartof><rights>2019 The Author(s)</rights><rights>Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.</rights><rights>2019. The Author(s)</rights><rights>2019 The Author(s) 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c561t-23aa76561443261d2f4daca29cdfed432eedb7612286368ca1140e31e39458283</citedby><cites>FETCH-LOGICAL-c561t-23aa76561443261d2f4daca29cdfed432eedb7612286368ca1140e31e39458283</cites><orcidid>0000-0002-2646-5143</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30765167$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Herrera-Rodriguez, José</creatorcontrib><creatorcontrib>Signorazzi, Aurora</creatorcontrib><creatorcontrib>Holtrop, Marijke</creatorcontrib><creatorcontrib>de Vries-Idema, Jacqueline</creatorcontrib><creatorcontrib>Huckriede, Anke</creatorcontrib><title>Inactivated or damaged? Comparing the effect of inactivation methods on influenza virions to optimize vaccine production</title><title>Vaccine</title><addtitle>Vaccine</addtitle><description>•β-propiolactone (BPL) and formaldehyde (FA) were used to inactivate several influenza virus strains.•BPL abolished the infectivity, FA was unable to completely inactivate the virus.•All methods damaged the binding and fusion capacity; BPL caused greater loss than FA.•FA treatments caused the highest reduction in TLR-7 stimulation.•All the observed effects were strain-dependent.
The vast majority of commercially available inactivated influenza vaccines are produced from egg-grown or cell-grown live influenza virus. The first step in the production process is virus inactivation with β-propiolactone (BPL) or formaldehyde (FA). Recommendations for production of inactivated vaccines merely define the maximal concentration for both reagents, leaving the optimization of the process to the manufacturers. We assessed the effect of inactivation with BPL and FA on 5 different influenza virus strains. The properties of the viral formulation, such as successful inactivation, preservation of hemagglutinin (HA) binding ability, fusion capacity and the potential to stimulate a Toll-like receptor 7 (TLR7) reporter cell line were then assessed and compared to the properties of the untreated virus. Inactivation with BPL resulted in undetectable infectivity levels, while FA-treated virus retained very low infectious titers. Hemagglutination and fusion ability were highly affected by those treatments that conferred higher inactivation, with BPL-treated virus binding and fusing at a lower degree compared to FA-inactivated samples. On the other hand, BPL-inactivated virus induced higher levels of activation of TLR7 than FA-inactivated virus. The alterations caused by BPL or FA treatments were virus strain dependent. This data shows that the inactivation procedures should be tailored on the virus strain, and that many other elements beside the concentration of the inactivating agent, such as incubation time and temperature, buffer and virus concentration, have to be defined to achieve a functional product.</description><subject>Animals</subject><subject>Antigens</subject><subject>Binding</subject><subject>Binding sites</subject><subject>Cell Line</subject><subject>Conflicts of interest</subject><subject>Deactivation</subject><subject>Foot & mouth disease</subject><subject>Formaldehyde</subject><subject>Formaldehyde - pharmacology</subject><subject>Hemagglutination</subject><subject>Hemagglutinin Glycoproteins, Influenza Virus - immunology</subject><subject>Hemagglutinins</subject><subject>Humans</subject><subject>Immunization</subject><subject>Inactivation</subject><subject>Infectivity</subject><subject>Influenza</subject><subject>Influenza A virus - drug effects</subject><subject>Influenza A virus - immunology</subject><subject>Influenza A virus - isolation & purification</subject><subject>Influenza Vaccines - immunology</subject><subject>Lipids</subject><subject>Manufacturers</subject><subject>Manufacturing</subject><subject>Optimization</subject><subject>Preservation</subject><subject>Proteins</subject><subject>Reagents</subject><subject>TLR7 protein</subject><subject>Toll-like receptors</subject><subject>Vaccine</subject><subject>Vaccines</subject><subject>Vaccines, Inactivated - immunology</subject><subject>Virion - drug effects</subject><subject>Virion - immunology</subject><subject>Virion - isolation & purification</subject><subject>Virions</subject><subject>Virus Inactivation</subject><subject>Viruses</subject><subject>β-propiolactone</subject><issn>0264-410X</issn><issn>1873-2518</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNqFkU9v1DAQxS0EokvhI4AsceGS4HESJ7lQoRV_KlXiAhI3y7Unu14l9mI7EfTT42i3FXDhZMvze88z8wh5CawEBuLtoVyU1tZhyRn0JYOSdeIR2UDXVgVvoHtMNoyLuqiBfb8gz2I8MMaaCvqn5KJirWhAtBvy89opneyiEhrqAzVqUjs0V3Trp6MK1u1o2iPFYUCdqB-oveetd3TCtPcm0ny1bhhndHeKLjbkWqTJU39MdrJ3SM-90mPwZtar9jl5Mqgx4ovzeUm-ffzwdfu5uPny6Xr7_qbQjYBU8Eqp3KuAuq64AMOH2iiteK_NgCa_IZrbVgDnnahEpxVAzbACrPq66XhXXZJ3J9_jfDuh0ehSUKM8Bjup8Et6ZeXfFWf3cucX2QI0eUnZ4M3ZIPgfM8YkJxs1jqNy6OcoOXR9I3jdioy-_gc9-Dm4PN5KtY3o236lmhOlg48x4PDQDDC5ZisP8rwvuWYrGcicbda9-nOSB9V9mBm4OgGY97lYDDJqi06jsSGnJ423__niN9ClupQ</recordid><startdate>20190314</startdate><enddate>20190314</enddate><creator>Herrera-Rodriguez, José</creator><creator>Signorazzi, Aurora</creator><creator>Holtrop, Marijke</creator><creator>de Vries-Idema, Jacqueline</creator><creator>Huckriede, Anke</creator><general>Elsevier Ltd</general><general>Elsevier Limited</general><general>The Author(s). 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Comparing the effect of inactivation methods on influenza virions to optimize vaccine production</title><author>Herrera-Rodriguez, José ; Signorazzi, Aurora ; Holtrop, Marijke ; de Vries-Idema, Jacqueline ; Huckriede, Anke</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c561t-23aa76561443261d2f4daca29cdfed432eedb7612286368ca1140e31e39458283</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Antigens</topic><topic>Binding</topic><topic>Binding sites</topic><topic>Cell Line</topic><topic>Conflicts of interest</topic><topic>Deactivation</topic><topic>Foot & mouth disease</topic><topic>Formaldehyde</topic><topic>Formaldehyde - pharmacology</topic><topic>Hemagglutination</topic><topic>Hemagglutinin Glycoproteins, Influenza Virus - immunology</topic><topic>Hemagglutinins</topic><topic>Humans</topic><topic>Immunization</topic><topic>Inactivation</topic><topic>Infectivity</topic><topic>Influenza</topic><topic>Influenza A virus - drug effects</topic><topic>Influenza A virus - immunology</topic><topic>Influenza A virus - isolation & purification</topic><topic>Influenza Vaccines - immunology</topic><topic>Lipids</topic><topic>Manufacturers</topic><topic>Manufacturing</topic><topic>Optimization</topic><topic>Preservation</topic><topic>Proteins</topic><topic>Reagents</topic><topic>TLR7 protein</topic><topic>Toll-like receptors</topic><topic>Vaccine</topic><topic>Vaccines</topic><topic>Vaccines, Inactivated - immunology</topic><topic>Virion - drug effects</topic><topic>Virion - immunology</topic><topic>Virion - isolation & purification</topic><topic>Virions</topic><topic>Virus Inactivation</topic><topic>Viruses</topic><topic>β-propiolactone</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Herrera-Rodriguez, José</creatorcontrib><creatorcontrib>Signorazzi, Aurora</creatorcontrib><creatorcontrib>Holtrop, Marijke</creatorcontrib><creatorcontrib>de Vries-Idema, Jacqueline</creatorcontrib><creatorcontrib>Huckriede, Anke</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>ProQuest Nursing & Allied Health Database</collection><collection>Health and Safety Science Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>ProQuest Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Healthcare Administration Database (Alumni)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Biological Sciences</collection><collection>Family Health Database (Proquest)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Healthcare Administration Database</collection><collection>Medical Database</collection><collection>ProQuest research library</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Vaccine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Herrera-Rodriguez, José</au><au>Signorazzi, Aurora</au><au>Holtrop, Marijke</au><au>de Vries-Idema, Jacqueline</au><au>Huckriede, Anke</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inactivated or damaged? Comparing the effect of inactivation methods on influenza virions to optimize vaccine production</atitle><jtitle>Vaccine</jtitle><addtitle>Vaccine</addtitle><date>2019-03-14</date><risdate>2019</risdate><volume>37</volume><issue>12</issue><spage>1630</spage><epage>1637</epage><pages>1630-1637</pages><issn>0264-410X</issn><eissn>1873-2518</eissn><abstract>•β-propiolactone (BPL) and formaldehyde (FA) were used to inactivate several influenza virus strains.•BPL abolished the infectivity, FA was unable to completely inactivate the virus.•All methods damaged the binding and fusion capacity; BPL caused greater loss than FA.•FA treatments caused the highest reduction in TLR-7 stimulation.•All the observed effects were strain-dependent.
The vast majority of commercially available inactivated influenza vaccines are produced from egg-grown or cell-grown live influenza virus. The first step in the production process is virus inactivation with β-propiolactone (BPL) or formaldehyde (FA). Recommendations for production of inactivated vaccines merely define the maximal concentration for both reagents, leaving the optimization of the process to the manufacturers. We assessed the effect of inactivation with BPL and FA on 5 different influenza virus strains. The properties of the viral formulation, such as successful inactivation, preservation of hemagglutinin (HA) binding ability, fusion capacity and the potential to stimulate a Toll-like receptor 7 (TLR7) reporter cell line were then assessed and compared to the properties of the untreated virus. Inactivation with BPL resulted in undetectable infectivity levels, while FA-treated virus retained very low infectious titers. Hemagglutination and fusion ability were highly affected by those treatments that conferred higher inactivation, with BPL-treated virus binding and fusing at a lower degree compared to FA-inactivated samples. On the other hand, BPL-inactivated virus induced higher levels of activation of TLR7 than FA-inactivated virus. The alterations caused by BPL or FA treatments were virus strain dependent. This data shows that the inactivation procedures should be tailored on the virus strain, and that many other elements beside the concentration of the inactivating agent, such as incubation time and temperature, buffer and virus concentration, have to be defined to achieve a functional product.</abstract><cop>Netherlands</cop><pub>Elsevier Ltd</pub><pmid>30765167</pmid><doi>10.1016/j.vaccine.2019.01.086</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0002-2646-5143</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Animals Antigens Binding Binding sites Cell Line Conflicts of interest Deactivation Foot & mouth disease Formaldehyde Formaldehyde - pharmacology Hemagglutination Hemagglutinin Glycoproteins, Influenza Virus - immunology Hemagglutinins Humans Immunization Inactivation Infectivity Influenza Influenza A virus - drug effects Influenza A virus - immunology Influenza A virus - isolation & purification Influenza Vaccines - immunology Lipids Manufacturers Manufacturing Optimization Preservation Proteins Reagents TLR7 protein Toll-like receptors Vaccine Vaccines Vaccines, Inactivated - immunology Virion - drug effects Virion - immunology Virion - isolation & purification Virions Virus Inactivation Viruses β-propiolactone |
title | Inactivated or damaged? Comparing the effect of inactivation methods on influenza virions to optimize vaccine production |
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