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CDI varies greatly from asymptomatic carriage to life-threatening diarrhea, toxic megacolon, and toxemia. The incidence of community-acquired infection has increased due to the emergence of hypervirulent antibiotic-resistant strains. These new strains contribute to the frequent occurrence of disease relapse, complicating treatment, increasing hospital stays, and increasing morbidity and mortality among patients. Therefore, it is critical to develop new therapeutic approaches that bypass the development of antimicrobial resistance and avoid disruption of gut microflora. Here, we describe the construction of a single heteromultimeric VHH-based neutralizing agent (VNA) that targets the two primary virulence factors of\n            <jats:named-content content-type=\"genus-species\">Clostridium difficile<\/jats:named-content>\n            , toxins A (TcdA) and B (TcdB). Designated VNA2-Tcd, this agent has subnanomolar toxin neutralization potencies for both\n            <jats:named-content content-type=\"genus-species\">C. difficile<\/jats:named-content>\n            toxins in cell assays. When given systemically by parenteral administration, VNA2-Tcd protected against CDI in gnotobiotic piglets and mice and to a lesser extent in hamsters. Protection from CDI was also observed in gnotobiotic piglets treated by gene therapy with an adenovirus that promoted the expression of VNA2-Tcd.\n          <\/jats:p>","DOI":"10.1128\/cvi.00730-15","type":"journal-article","created":{"date-parts":[[2016,7,14]],"date-time":"2016-07-14T06:38:05Z","timestamp":1468478285000},"page":"774-784","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":48,"title":["A Tetraspecific VHH-Based Neutralizing Antibody Modifies Disease Outcome in Three Animal Models of Clostridium difficile Infection"],"prefix":"10.1128","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6606-4398","authenticated-orcid":false,"given":"Diane J.","family":"Schmidt","sequence":"first","affiliation":[{"name":"Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gillian","family":"Beamer","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline M.","family":"Tremblay","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer A.","family":"Steele","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeun Bum","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Animal Resources Science, Dankook University, Cheonan, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaunkai","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai Key Laboratory of Veterinary Biotechnology, Key Laboratory of Urban Agriculture (South) Ministry of Agriculture, Shanghai, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Debatis","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingmin","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease and Global Health, Cummings 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