title: Immunogenicity of a prototype enterotoxigenic Escherichia coli adhesin vaccine in mice and nonhuman primates.
abstract: Enterotoxigenic Escherichia coli (ETEC) are the most common cause of bacterial diarrhea in young children in developing countries and in travelers. Efforts to develop an ETEC vaccine have intensified in the past decade, and intestinal colonization factors (CFs) are somatic components of most investigational vaccines. CFA/I and related Class 5 fimbrial CFs feature a major stalk-forming subunit and a minor, antigenically conserved tip adhesin. We hypothesized that the tip adhesin is critical for stimulating antibodies that specifically inhibit ETEC attachment to the small intestine. To address this, we compared the capacity of donor strand complemented CfaE (dscCfaE), a stabilized form of the CFA/I fimbrial tip adhesin, and CFA/I fimbriae to elicit anti-adhesive antibodies in mice, using hemagglutination inhibition (HAI) as proxy for neutralization of intestinal adhesion. When given with genetically attenuated heat-labile enterotoxin LTR192G as adjuvant by intranasal (IN) or orogastric (OG) vaccination, dscCfaE exceeded CFA/I fimbriae in eliciting serum HAI titers and anti-CfaE antibody titers. Based on these findings, we vaccinated Aotus nancymaae nonhuman primates (NHP) with dscCfaE alone or admixed with one of two adjuvants, LTR192G and cholera toxin B-subunit, by IN and OG administration. Only IN vaccination with dscCfaE with either adjuvant elicited substantial serum HAI titers and IgA and IgG anti-adhesin responses, with the latter detectable a year after vaccination. In conclusion, we have shown that dscCfaE elicits robust HAI and anti-adhesin antibody responses in both mice and NHPs when given with adjuvant by IN vaccination, encouraging further evaluation of an ETEC adhesin-based vaccine approach.
authors.affiliation: Enteric Diseases Department, Naval Medical Research Center, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Sincock
authors.affiliation: Bacteriology Department, Naval Medical Research Unit No. 6, APO, AA 34031-3800, USA.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Hall
authors.affiliation: Enteric Diseases Department, Naval Medical Research Center, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Woods
authors.affiliation: Enteric Diseases Department, Naval Medical Research Center, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.
authors.forename: Aisling
authors.initials: A
authors.lastname: O'Dowd
authors.affiliation: Enteric Diseases Department, Naval Medical Research Center, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Poole
authors.affiliation: Enteric Diseases Department, Naval Medical Research Center, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.
authors.forename: Annette L
authors.initials: AL
authors.lastname: McVeigh
authors.affiliation: Bacteriology Department, Naval Medical Research Unit No. 6, APO, AA 34031-3800, USA.
authors.forename: Gladys
authors.initials: G
authors.lastname: Nunez
authors.affiliation: Bacteriology Department, Naval Medical Research Unit No. 6, APO, AA 34031-3800, USA.
authors.forename: Nereyda
authors.initials: N
authors.lastname: Espinoza
authors.affiliation: Enteric Diseases Department, Naval Medical Research Center, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.
authors.forename: Milagros
authors.initials: M
authors.lastname: Miller
authors.affiliation: Enteric Diseases Department, Naval Medical Research Center, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA; Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814 USA. Electronic address: s.j.savarino@gmail.com.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Savarino
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000281:Administration, Intranasal; D000284:Administration, Oral; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D016645:Aotidae; D004195:Disease Models, Animal; D054307:Enterotoxigenic Escherichia coli / Q000276:immunology*; D004927:Escherichia coli Infections / Q000517:prevention & control*; D029968:Escherichia coli Proteins / Q000276:immunology*; D022361:Escherichia coli Vaccines / Q000008:administration & dosage / Q000276:immunology*; D036781:Fimbriae Proteins / Q000276:immunology*; D006385:Hemagglutination Inhibition Tests; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D008807:Mice, Inbred BALB C; D016896:Treatment Outcome; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; C559939:CfaE protein, E coli; D029968:Escherichia coli Proteins; D022361:Escherichia coli Vaccines; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D022223:Vaccines, Subunit; C022924:colonization factor antigens; D036781:Fimbriae Proteins
keywords: CFA/I fimbriae; CfaE; Enterotoxigenic Escherichia coli; Mice; Nonhuman primates; Vaccine