Prolonged Prophylactic Protection from Botulism with a Single Adenovirus Treatment Promoting Serum Expression of a VHH-Based Antitoxin Protein
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{"title"=>"Prolonged prophylactic protection from botulism with a single adenovirus treatment promoting serum expression of a VHH-based antitoxin protein", "type"=>"journal", "authors"=>[{"first_name"=>"Jean", "last_name"=>"Mukherjee", "scopus_author_id"=>"57198346889"}, {"first_name"=>"Igor", "last_name"=>"Dmitriev", "scopus_author_id"=>"7005895851"}, {"first_name"=>"Michelle", "last_name"=>"Debatis", "scopus_author_id"=>"6507288603"}, {"first_name"=>"Jacqueline M.", "last_name"=>"Tremblay", "scopus_author_id"=>"7202646780"}, {"first_name"=>"Gillian", "last_name"=>"Beamer", "scopus_author_id"=>"10739204300"}, {"first_name"=>"Elena A.", "last_name"=>"Kashentseva", "scopus_author_id"=>"16688803600"}, {"first_name"=>"David T.", "last_name"=>"Curiel", "scopus_author_id"=>"22134188600"}, {"first_name"=>"Charles B.", "last_name"=>"Shoemaker", "scopus_author_id"=>"7102870428"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "sgr"=>"84919484445", "pui"=>"373867561", "scopus"=>"2-s2.0-84919484445", "issn"=>"19326203", "pmid"=>"25170904", "doi"=>"10.1371/journal.pone.0106422"}, "id"=>"d9a0ae06-c2d4-3040-b3c2-de6dccfd9e1a", "abstract"=>"Current therapies for most acute toxin exposures are limited to administration of polyclonal antitoxin serum. We have shown that VHH-based neutralizing agents (VNAs) consisting of two or more linked, toxin-neutralizing heavy-chain-only VH domains (VHHs), each binding distinct epitopes, can potently protect animals from lethality in several intoxication models including Botulinum neurotoxin serotype A1 (BoNT/A1). Appending a 14 amino acid albumin binding peptide (ABP) to an anti-BoNT/A1 heterodimeric VNA (H7/B5) substantially improved serum stability and resulted in an effective VNA serum half-life of 1 to 2 days. A recombinant, replication-incompetent, adenoviral vector (Ad/VNA-BoNTA) was engineered that induces secretion of biologically active VNA, H7/B5/ABP (VNA-BoNTA), from transduced cells. Mice administered a single dose of Ad/VNA-BoNTA, or a different Ad/VNA, via different administration routes led to a wide range of VNA serum levels measured four days later; generally intravenous > intraperitoneal > intramuscular > subcutaneous. Ad/VNA-BoNTA treated mice were 100% protected from 10 LD50 of BoNT/A1 for more than six weeks and protection positively correlated with serum levels of VNA-BoNTA exceeding about 5 ng/ml. Some mice developed antibodies that inhibited VNA binding to target but these mice displayed no evidence of kidney damage due to deposition of immune complexes. Mice were also successfully protected from 10 LD50 BoNT/A1 when Ad/VNA-BoNTA was administered up to 1.5 hours post-intoxication, demonstrating rapid appearance of the protective VNA in serum following treatment. Genetic delivery of VNAs promises to be an effective method of providing prophylactic protection and/or acute treatments for many toxin-mediated diseases.", "link"=>"http://www.mendeley.com/research/prolonged-prophylactic-protection-botulism-single-adenovirus-treatment-promoting-serum-expression-vh", "reader_count"=>38, "reader_count_by_academic_status"=>{"Researcher"=>2, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>2, "Student > Postgraduate"=>2, "Student > Master"=>2, "Other"=>1, "Student > Bachelor"=>26, "Professor"=>2}, "reader_count_by_user_role"=>{"Researcher"=>2, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>2, "Student > Postgraduate"=>2, "Student > Master"=>2, "Other"=>1, "Student > Bachelor"=>26, "Professor"=>2}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>1, "Medicine and Dentistry"=>33, "Agricultural and Biological Sciences"=>2, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>33}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}}, "reader_count_by_country"=>{"Germany"=>1, "Russia"=>1}, "group_count"=>16}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1655481"], "description"=>"<p>All mice that survived BoNT/A1 treatments in study 1 were bled 10–11 days following intoxication. Serum from these terminal bleeds was assessed for serum VNA-BoNTA levels as described in Methods and Materials. The VNA concentration (ng/ml) from each individual mouse serum is represented as a black dot shown at the indicated time of collection, post-treatment. Dots within the shaded area all represent mice with VNA levels below the level at which the signals are at least two-fold over background and cannot be confidently distinguished from serum from control mice.</p>", "links"=>[], "tags"=>["gt", "prophylactic protection", "VNA binding", "bont", "2 days", "transduced cells", "Single Adenovirus Treatment Promoting Serum Expression", "acid albumin binding peptide", "kidney damage", "10 LD 50", "serum levels", "serum stability", "intoxication models", "toxin exposures", "Genetic delivery", "adenoviral vector", "polyclonal antitoxin serum", "vhh", "Botulinum neurotoxin serotype", "vh", "abp", "administration routes", "VNA serum levels"], "article_id"=>1155968, "categories"=>["Biological Sciences"], "users"=>["Jean Mukherjee", "Igor Dmitriev", "Michelle Debatis", "Jacqueline M. Tremblay", "Gillian Beamer", "Elena A. Kashentseva", "David T. Curiel", "Charles B. Shoemaker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0106422.g003", "stats"=>{"downloads"=>6, "page_views"=>30, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Serum_levels_of_VNA_H7_B5_ABP_following_Ad_VNA_BoNTA_treatments_study_1_/1155968", "title"=>"Serum levels of VNA-H7/B5/ABP following Ad/VNA-BoNTA treatments- study 1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-29 03:03:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655484"], "description"=>"<p>Groups of five mice (60 mice in total) were treated and challenged as for study 1 (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106422#pone-0106422-g002\" target=\"_blank\">Figure 2</a>) although the timeframe was extended to four months. Black bars indicate % survival of mice treated with Ad/VNA-BoNTA and later intoxicated at the indicated times. White bars indicate % survival of mice treated with Ad/VNA-control. Groups with no survival show a short bar ending at 0. An asterisk indicates a significant difference (p<0.05) from the control group.</p>", "links"=>[], "tags"=>["gt", "prophylactic protection", "VNA binding", "bont", "2 days", "transduced cells", "Single Adenovirus Treatment Promoting Serum Expression", "acid albumin binding peptide", "kidney damage", "10 LD 50", "serum levels", "serum stability", "intoxication models", "toxin exposures", "Genetic delivery", "adenoviral vector", "polyclonal antitoxin serum", "vhh", "Botulinum neurotoxin serotype", "vh", "abp", "administration routes", "VNA serum levels"], "article_id"=>1155971, "categories"=>["Biological Sciences"], "users"=>["Jean Mukherjee", "Igor Dmitriev", "Michelle Debatis", "Jacqueline M. Tremblay", "Gillian Beamer", "Elena A. Kashentseva", "David T. Curiel", "Charles B. Shoemaker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0106422.g004", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Ad_VNA_BoNTA_treatment_provides_long_term_protection_from_botulism_in_mice_study_2_/1155971", "title"=>"Ad/VNA-BoNTA treatment provides long term protection from botulism in mice- study 2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-29 03:03:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655487"], "description"=>"<p>Mice were treated with Ad/VNA-BoNTA and intoxicated as in study 1. Here, mice were bled one week prior to intoxication and survivors were also bled one week post-intoxication. VNA-BoNTA serum levels were quantified as described in Methods and Materials. The VNA concentration (ng/ml) from a single mouse serum is represented as a black dot. Lines connecting two dots show repeated measurements (pre- and post- intoxication) from surviving mice in the final two groups. The two circles indicate the VNA levels from the three mice that did not survive BoNT/A1 intoxication. Dots within the shaded area represent VNA serum levels below detection.</p>", "links"=>[], "tags"=>["gt", "prophylactic protection", "VNA binding", "bont", "2 days", "transduced cells", "Single Adenovirus Treatment Promoting Serum Expression", "acid albumin binding peptide", "kidney damage", "10 LD 50", "serum levels", "serum stability", "intoxication models", "toxin exposures", "Genetic delivery", "adenoviral vector", "polyclonal antitoxin serum", "vhh", "Botulinum neurotoxin serotype", "vh", "abp", "administration routes", "VNA serum levels"], "article_id"=>1155974, "categories"=>["Biological Sciences"], "users"=>["Jean Mukherjee", "Igor Dmitriev", "Michelle Debatis", "Jacqueline M. Tremblay", "Gillian Beamer", "Elena A. Kashentseva", "David T. Curiel", "Charles B. Shoemaker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0106422.g005", "stats"=>{"downloads"=>1, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Serum_levels_of_VNA_BoNTA_following_Ad_VNA_BoNTA_treatments_study_2_/1155974", "title"=>"Serum levels of VNA-BoNTA following Ad/VNA-BoNTA treatments- study 2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-29 03:03:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655488"], "description"=>"<p>Groups of five mice (10 mice in total) were treated with 3×10<sup>10</sup> vp of Ad/VNA-BoNTA (<b>A</b>) or Ad/VNA-control (<b>B</b>) on day 0 and bled two weeks later and then monthly for four months. The VNA concentrations (ng/ml) over time for individual mice are represented by the different symbols. Symbols within the shaded area represent VNA serum levels below detection.</p>", "links"=>[], "tags"=>["gt", "prophylactic protection", "VNA binding", "bont", "2 days", "transduced cells", "Single Adenovirus Treatment Promoting Serum Expression", "acid albumin binding peptide", "kidney damage", "10 LD 50", "serum levels", "serum stability", "intoxication models", "toxin exposures", "Genetic delivery", "adenoviral vector", "polyclonal antitoxin serum", "vhh", "Botulinum neurotoxin serotype", "vh", "abp", "administration routes", "VNA serum levels"], "article_id"=>1155976, "categories"=>["Biological Sciences"], "users"=>["Jean Mukherjee", "Igor Dmitriev", "Michelle Debatis", "Jacqueline M. Tremblay", "Gillian Beamer", "Elena A. Kashentseva", "David T. Curiel", "Charles B. Shoemaker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0106422.g006", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Persistence_of_serum_VNAs_/1155976", "title"=>"Persistence of serum VNAs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-29 03:03:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655490"], "description"=>"<p>Serum from mice treated with Ad/VNA-BoNTA or Ad/VNA-control was collected monthly from weeks 2 through 18 post-treatment and VNA levels were assessed (data shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106422#pone-0106422-g006\" target=\"_blank\">Figure 6</a>). <b>A–C.</b> Development of blocking Abs was investigated in the three Ad/VNA-BoNTA mice with low serum VNA levels (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106422#pone-0106422-g006\" target=\"_blank\">Figure 6A</a>; square, circle and diamond symbols). The presence of blocking Abs was assayed by measuring the potency of mouse serum, 1∶100, to inhibit the binding of serially diluted recombinant VNA-BoNTA (Trx/H7/B5/ABP) to BoNT/A1. The presence of blocking Abs shifts the curve to the left. Each box represents sera collected from the same mice at the indicated times post-treatment with Ad/VNA-BoNTA. <b>D.</b> VNA-BoNTA blocking assays were performed as above in A–C employing serum from mice 18 weeks following treatment with Ad/VNA-control to detect VNA cross-specific blocking Abs elicited by expression of the control VNA. The serum source was the terminal bleed of the five mice in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106422#pone-0106422-g006\" target=\"_blank\">Figure 6B</a>.</p>", "links"=>[], "tags"=>["gt", "prophylactic protection", "VNA binding", "bont", "2 days", "transduced cells", "Single Adenovirus Treatment Promoting Serum Expression", "acid albumin binding peptide", "kidney damage", "10 LD 50", "serum levels", "serum stability", "intoxication models", "toxin exposures", "Genetic delivery", "adenoviral vector", "polyclonal antitoxin serum", "vhh", "Botulinum neurotoxin serotype", "vh", "abp", "administration routes", "VNA serum levels"], "article_id"=>1155977, "categories"=>["Biological Sciences"], "users"=>["Jean Mukherjee", "Igor Dmitriev", "Michelle Debatis", "Jacqueline M. Tremblay", "Gillian Beamer", "Elena A. Kashentseva", "David T. Curiel", "Charles B. Shoemaker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0106422.g007", "stats"=>{"downloads"=>1, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Some_mice_treated_with_Ad_VNA_BoNTA_develop_blocking_antibodies_/1155977", "title"=>"Some mice treated with Ad/VNA-BoNTA develop blocking antibodies.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-29 03:03:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655492"], "description"=>"<p>A 10 LD<sub>50</sub> dose of BoNT/A1 was administered by intraperitoneal injection to groups of five mice. Mice were then administered 3×10<sup>10</sup> vp of Ad/VNA-BoNTA by intravenous injection at 5 minutes, 1.5, 3 or 4.5 hours later. A control group was given a mock treatment (PBS alone) 5 minutes following intoxication (dashed line). Symptoms of BoNT/A intoxication and survival were monitored and are shown as a survival curve for each group. The mock treated group is represented by a dashed line. An asterisk indicates a significant difference (p<0.05) from the control group. Surviving mice all showed moderate to severe abdominal breathing symptoms of botulism before recovering. In a prior study using the same doses, mice treated immediately following BoNT/A challenge with Ad/VNA-BoNTA, unlike those treated with Ad/VNA-control (0% survival after 24 hours), were fully protected and did not display any symptoms of botulism.</p>", "links"=>[], "tags"=>["gt", "prophylactic protection", "VNA binding", "bont", "2 days", "transduced cells", "Single Adenovirus Treatment Promoting Serum Expression", "acid albumin binding peptide", "kidney damage", "10 LD 50", "serum levels", "serum stability", "intoxication models", "toxin exposures", "Genetic delivery", "adenoviral vector", "polyclonal antitoxin serum", "vhh", "Botulinum neurotoxin serotype", "vh", "abp", "administration routes", "VNA serum levels"], "article_id"=>1155979, "categories"=>["Biological Sciences"], "users"=>["Jean Mukherjee", "Igor Dmitriev", "Michelle Debatis", "Jacqueline M. Tremblay", "Gillian Beamer", "Elena A. Kashentseva", "David T. Curiel", "Charles B. Shoemaker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0106422.g008", "stats"=>{"downloads"=>2, "page_views"=>28, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_BoNT_A1_lethality_in_mice_is_prevented_by_rapid_post_exposure_treatment_with_Ad_VNA_BoNTA_/1155979", "title"=>"BoNT/A1 lethality in mice is prevented by rapid post-exposure treatment with Ad/VNA-BoNTA.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-29 03:03:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655493"], "description"=>"<p>ND- not determined.</p>a<p>Routes by which Ad was administered; iv-intravenous, ip-intraperitoneal, im-intramuscular, sq-subcutaneous.</p>b<p>Serum was collected 4 days post-treatment and VNA levels estimated by dilution ELISA for binding to toxin targets.</p><p>Serum VNA-BoNTA levels following Ad/VNA-BoNTA administration via different routes.</p>", "links"=>[], "tags"=>["gt", "prophylactic protection", "VNA binding", "bont", "2 days", "transduced cells", "Single Adenovirus Treatment Promoting Serum Expression", "acid albumin binding peptide", "kidney damage", "10 LD 50", "serum levels", "serum stability", "intoxication models", "toxin exposures", "Genetic delivery", "adenoviral vector", "polyclonal antitoxin serum", "vhh", "Botulinum neurotoxin serotype", "vh", "abp", "administration routes", "VNA serum levels"], "article_id"=>1155980, "categories"=>["Biological Sciences"], "users"=>["Jean Mukherjee", "Igor Dmitriev", "Michelle Debatis", "Jacqueline M. Tremblay", "Gillian Beamer", "Elena A. Kashentseva", "David T. Curiel", "Charles B. Shoemaker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0106422.t001", "stats"=>{"downloads"=>1, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Serum_VNA_BoNTA_levels_following_Ad_VNA_BoNTA_administration_via_different_routes_/1155980", "title"=>"Serum VNA-BoNTA levels following Ad/VNA-BoNTA administration via different routes.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-08-29 03:03:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655494"], "description"=>"a<p>Routes by which Ad was administered; iv-intravenous, ip-intraperitoneal, im-intramuscular, sq-subcutaneous.</p>b<p>Serum was collected 4 days post-treatment and VNA levels estimated by dilution ELISA for binding to toxin targets.</p><p>Serum VNA-Stx levels following Ad/VNA-Stx administration via different routes.</p>", "links"=>[], "tags"=>["gt", "prophylactic protection", "VNA binding", "bont", "2 days", "transduced cells", "Single Adenovirus Treatment Promoting Serum Expression", "acid albumin binding peptide", "kidney damage", "10 LD 50", "serum levels", "serum stability", "intoxication models", "toxin exposures", "Genetic delivery", "adenoviral vector", "polyclonal antitoxin serum", "vhh", "Botulinum neurotoxin serotype", "vh", "abp", "administration routes", "VNA serum levels"], "article_id"=>1155981, "categories"=>["Biological Sciences"], "users"=>["Jean Mukherjee", "Igor Dmitriev", "Michelle Debatis", "Jacqueline M. Tremblay", "Gillian Beamer", "Elena A. Kashentseva", "David T. Curiel", "Charles B. Shoemaker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0106422.t002", "stats"=>{"downloads"=>0, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Serum_VNA_Stx_levels_following_Ad_VNA_Stx_administration_via_different_routes_/1155981", "title"=>"Serum VNA-Stx levels following Ad/VNA-Stx administration via different routes.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-08-29 03:03:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655469"], "description"=>"<p>(<b>A</b>) Protection from BoNT/A1 in mice treated with Trx/H7/B5 or Trx/H7/B5/ABP at various times prior to intoxication. Groups of five mice each (60 mice total) were treated with a known protective dose of 2 µg (40 pm) VNA and later challenged with 10 LD<sub>50</sub> of BoNT/A1 at the indicated times post-treatment. Bars indicate the % survival: Trx/H7/B5, white bar; Trx/H7/B5/ABP, black bar. Groups with no survival show a short bar ending at 0. A delta (Δ) indicates that all mice in this group displayed discernable abdominal breathing symptoms of botulism. An asterisk indicates a significant difference (p<0.05) from the control group. Results reported are representative of three similar studies. (<b>B</b>) Minimum dose of Trx/H7/B5/ABP that protects from 10 LD<sub>50</sub> BoNT/A1. Groups of five mice (25 mice total) were treated with the indicated dose of Trx/H7/B5/ABP and then challenged 6 hours later with 10 LD<sub>50</sub> BoNT/A1. Black bars indicate % survival and a delta (Δ) indicates that surviving mice displayed severe abdominal breathing symptoms of botulism. An asterisk indicates a significant difference (p<0.05) from the control group. Results reported are representative of three similar studies.</p>", "links"=>[], "tags"=>["gt", "prophylactic protection", "VNA binding", "bont", "2 days", "transduced cells", "Single Adenovirus Treatment Promoting Serum Expression", "acid albumin binding peptide", "kidney damage", "10 LD 50", "serum levels", "serum stability", "intoxication models", "toxin exposures", "Genetic delivery", "adenoviral vector", "polyclonal antitoxin serum", "vhh", "Botulinum neurotoxin serotype", "vh", "abp", "administration routes", "VNA serum levels"], "article_id"=>1155959, "categories"=>["Biological Sciences"], "users"=>["Jean Mukherjee", "Igor Dmitriev", "Michelle Debatis", "Jacqueline M. Tremblay", "Gillian Beamer", "Elena A. Kashentseva", "David T. Curiel", "Charles B. Shoemaker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0106422.g001", "stats"=>{"downloads"=>1, "page_views"=>22, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Albumin_binding_peptide_ABP_extends_the_serum_persistence_of_VNA_bioactivity_/1155959", "title"=>"Albumin binding peptide (ABP) extends the serum persistence of VNA bioactivity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-29 03:03:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655514", "https://ndownloader.figshare.com/files/1655516", "https://ndownloader.figshare.com/files/1655518"], "description"=>"<div><p>Current therapies for most acute toxin exposures are limited to administration of polyclonal antitoxin serum. We have shown that VHH-based neutralizing agents (VNAs) consisting of two or more linked, toxin-neutralizing heavy-chain-only V<sub>H</sub> domains (VHHs), each binding distinct epitopes, can potently protect animals from lethality in several intoxication models including Botulinum neurotoxin serotype A1 (BoNT/A1). Appending a 14 amino acid albumin binding peptide (ABP) to an anti-BoNT/A1 heterodimeric VNA (H7/B5) substantially improved serum stability and resulted in an effective VNA serum half-life of 1 to 2 days. A recombinant, replication-incompetent, adenoviral vector (Ad/VNA-BoNTA) was engineered that induces secretion of biologically active VNA, H7/B5/ABP (VNA-BoNTA), from transduced cells. Mice administered a single dose of Ad/VNA-BoNTA, or a different Ad/VNA, via different administration routes led to a wide range of VNA serum levels measured four days later; generally intravenous > intraperitoneal > intramuscular > subcutaneous. Ad/VNA-BoNTA treated mice were 100% protected from 10 LD<sub>50</sub> of BoNT/A1 for more than six weeks and protection positively correlated with serum levels of VNA-BoNTA exceeding about 5 ng/ml. Some mice developed antibodies that inhibited VNA binding to target but these mice displayed no evidence of kidney damage due to deposition of immune complexes. Mice were also successfully protected from 10 LD<sub>50</sub> BoNT/A1 when Ad/VNA-BoNTA was administered up to 1.5 hours post-intoxication, demonstrating rapid appearance of the protective VNA in serum following treatment. Genetic delivery of VNAs promises to be an effective method of providing prophylactic protection and/or acute treatments for many toxin-mediated diseases.</p></div>", "links"=>[], "tags"=>["gt", "prophylactic protection", "VNA binding", "bont", "2 days", "transduced cells", "Single Adenovirus Treatment Promoting Serum Expression", "acid albumin binding peptide", "kidney damage", "10 LD 50", "serum levels", "serum stability", "intoxication models", "toxin exposures", "Genetic delivery", "adenoviral vector", "polyclonal antitoxin serum", "vhh", "Botulinum neurotoxin serotype", "vh", "abp", "administration routes", "VNA serum levels"], "article_id"=>1155993, "categories"=>["Biological Sciences"], "users"=>["Jean Mukherjee", "Igor Dmitriev", "Michelle Debatis", "Jacqueline M. Tremblay", "Gillian Beamer", "Elena A. Kashentseva", "David T. Curiel", "Charles B. Shoemaker"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0106422.s001", "https://dx.doi.org/10.1371/journal.pone.0106422.s002", "https://dx.doi.org/10.1371/journal.pone.0106422.s003"], "stats"=>{"downloads"=>0, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Prolonged_Prophylactic_Protection_from_Botulism_with_a_Single_Adenovirus_Treatment_Promoting_Serum_Expression_of_a_VHH_Based_Antitoxin_Protein_/1155993", "title"=>"Prolonged Prophylactic Protection from Botulism with a Single Adenovirus Treatment Promoting Serum Expression of a VHH-Based Antitoxin Protein", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-08-29 03:03:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/1655476"], "description"=>"<p>Groups of five mice (80 mice in total) were treated with 3×10<sup>10</sup> vp of Ad/VNA-BoNTA or Ad/VNA-control on day 0 and one group treated with each of the two Ad/VNAs were administered 10 LD<sub>50</sub> of BoNT/A1 at the various times post-treatment. Black bars indicate % survival of mice treated with Ad/VNA-BoNTA and later intoxicated at the indicated times. White bars indicate % survival of mice treated with Ad/VNA-control. Groups with no survival show a short bar ending at 0. An asterisk indicates a significant difference (p<0.05) from the control group.</p>", "links"=>[], "tags"=>["gt", "prophylactic protection", "VNA binding", "bont", "2 days", "transduced cells", "Single Adenovirus Treatment Promoting Serum Expression", "acid albumin binding peptide", "kidney damage", "10 LD 50", "serum levels", "serum stability", "intoxication models", "toxin exposures", "Genetic delivery", "adenoviral vector", "polyclonal antitoxin serum", "vhh", "Botulinum neurotoxin serotype", "vh", "abp", "administration routes", "VNA serum levels"], "article_id"=>1155964, "categories"=>["Biological Sciences"], "users"=>["Jean Mukherjee", "Igor Dmitriev", "Michelle Debatis", "Jacqueline M. Tremblay", "Gillian Beamer", "Elena A. Kashentseva", "David T. Curiel", "Charles B. Shoemaker"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0106422.g002", "stats"=>{"downloads"=>1, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Ad_VNA_BoNTA_treatment_provides_long_term_protection_from_botulism_in_mice_study_1_/1155964", "title"=>"Ad/VNA-BoNTA treatment provides long term protection from botulism in mice- study 1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-08-29 03:03:40"}

PMC Usage Stats | Further Information

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