title: Adenovirus vector expressing Stx1/Stx2-neutralizing agent protects piglets infected with Escherichia coli O157:H7 against fatal systemic intoxication.
abstract: Hemolytic-uremic syndrome (HUS), caused by Shiga toxin (Stx)-producing Escherichia coli (STEC), remains untreatable. Production of human monoclonal antibodies against Stx, which are highly effective in preventing Stx sequelae in animal models, is languishing due to cost and logistics. We reported previously that the production and evaluation of a camelid heavy-chain-only VH domain (VHH)-based neutralizing agent (VNA) targeting Stx1 and Stx2 (VNA-Stx) protected mice from Stx1 and Stx2 intoxication. Here we report that a single intramuscular (i.m.) injection of a nonreplicating adenovirus (Ad) vector carrying a secretory transgene of VNA-Stx (Ad/VNA-Stx) protected mice challenged with Stx2 and protected gnotobiotic piglets infected with STEC from fatal systemic intoxication. One i.m. dose of Ad/VNA-Stx prevented fatal central nervous system (CNS) symptoms in 9 of 10 animals when it was given to piglets 24 h after bacterial challenge and in 5 of 9 animals when it was given 48 h after bacterial challenge, just prior to the onset of CNS symptoms. All 6 placebo animals died or were euthanized with severe CNS symptoms. Ad/VNA-Stx treatment had no impact on diarrhea. In conclusion, Ad/VNA-Stx treatment is effective in protecting piglets from fatal Stx2-mediated CNS complications following STEC challenge. With a low production cost and further development, this could presumably be an effective treatment for patients with HUS and/or individuals at high risk of developing HUS due to exposure to STEC.
authors.affiliation: Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA.
authors.forename: Abhineet S
authors.initials: AS
authors.lastname: Sheoran
authors.affiliation: Department of Radiation Oncology, Washington University, St. Louis, Missouri, USA.
authors.forename: Igor P
authors.initials: IP
authors.lastname: Dmitriev
authors.affiliation: Department of Radiation Oncology, Washington University, St. Louis, Missouri, USA.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Kashentseva
authors.affiliation: Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA.
authors.forename: Ocean
authors.initials: O
authors.lastname: Cohen
authors.affiliation: Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Mukherjee
authors.affiliation: Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Debatis
authors.affiliation: Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Shearer
authors.affiliation: Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Tremblay
authors.affiliation: Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA.
authors.forename: Gillian
authors.initials: G
authors.lastname: Beamer
authors.affiliation: Department of Radiation Oncology, Washington University, St. Louis, Missouri, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.affiliation: Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Shoemaker
authors.affiliation: Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, USA saul.tzipori@tufts.edu.
authors.forename: Saul
authors.initials: S
authors.lastname: Tzipori
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000235:genetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D019453:Escherichia coli O157 / Q000235:genetics / Q000276:immunology*; D005260:Female; D005822:Genetic Vectors; D006463:Hemolytic-Uremic Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D007273:Injections, Intramuscular; D051379:Mice; D022622:Shiga Toxin 1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D022641:Shiga Toxin 2 / Q000037:antagonists & inhibitors* / Q000276:immunology; D016019:Survival Analysis; D013552:Swine; D013997:Time Factors
chemical_list: D057134:Antibodies, Neutralizing; D004337:Drug Carriers; D022622:Shiga Toxin 1; D022641:Shiga Toxin 2