title: Maternal vaccination with a fimbrial tip adhesin and passive protection of neonatal mice against lethal human enterotoxigenic Escherichia coli challenge.
abstract: Globally, enterotoxigenic Escherichia coli (ETEC) is a leading cause of childhood and travelers' diarrhea, for which an effective vaccine is needed. Prevalent intestinal colonization factors (CFs) such as CFA/I fimbriae and heat-labile enterotoxin (LT) are important virulence factors and protective antigens. We tested the hypothesis that donor strand-complemented CfaE (dscCfaE), a stabilized form of the CFA/I fimbrial tip adhesin, is a protective antigen, using a lethal neonatal mouse ETEC challenge model and passive dam vaccination. For CFA/I-ETEC strain H10407, which has been extensively studied in volunteers, an inoculum of 2 × 10(7) bacteria resulted in 50% lethal doses (LD50) in neonatal DBA/2 mice. Vaccination of female DBA/2 mice with CFA/I fimbriae or dscCfaE, each given with a genetically attenuated LT adjuvant (LTK63) by intranasal or orogastric delivery, induced high antigen-specific serum IgG and fecal IgA titers and detectable milk IgA responses. Neonates born to and suckled by dams antenatally vaccinated with each of these four regimens showed 78 to 93% survival after a 20× LD50 challenge with H10407, compared to 100% mortality in pups from dams vaccinated with sham vaccine or LTK63 only. Crossover experiments showed that high pup survival rates after ETEC challenge were associated with suckling but not birthing from vaccinated dams, suggesting that vaccine-specific milk antibodies are protective. In corroboration, preincubation of the ETEC inoculum with antiadhesin and antifimbrial bovine colostral antibodies conferred a dose-dependent increase in pup survival after challenge. These findings indicate that the dscCfaE fimbrial tip adhesin serves as a protective passive vaccine antigen in this small animal model and merits further evaluation.
authors.affiliation: Laboratory for Vaccine Development, Department of Microbiology, Biomedical Sciences Institute, University of São Paulo, São Paulo, Brazil Department of Biological Sciences, State University of Santa Cruz, Ilhéus Bahia, Brazil.
authors.forename: Wilson B
authors.initials: WB
authors.lastname: Luiz
authors.affiliation: Laboratory for Vaccine Development, Department of Microbiology, Biomedical Sciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Juliana F
authors.initials: JF
authors.lastname: Rodrigues
authors.affiliation: ImmuCell Corporation, Portland, Maine, USA.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Crabb
authors.affiliation: Enteric Diseases Department, Infectious Diseases Directorate, Naval Medical Research Center, Silver Spring, Maryland, USA Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA stephen.j.savarino.mil@mail.mil lcsf@usp.br.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Savarino
authors.affiliation: Laboratory for Vaccine Development, Department of Microbiology, Biomedical Sciences Institute, University of São Paulo, São Paulo, Brazil stephen.j.savarino.mil@mail.mil lcsf@usp.br.
authors.forename: Luis C S
authors.initials: LC
authors.lastname: Ferreira
mesh_terms: D018829:Adhesins, Bacterial / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis*; D002417:Cattle; D004306:Dose-Response Relationship, Immunologic; D054307:Enterotoxigenic Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D004927:Escherichia coli Infections / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D029968:Escherichia coli Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D022361:Escherichia coli Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D005260:Female; D036781:Fimbriae Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D010861:Fimbriae, Bacterial / Q000737:chemistry / Q000276:immunology; D015870:Gene Expression; D007106:Immune Sera / Q000737:chemistry; D007116:Immunization, Passive; D007070:Immunoglobulin A / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000096:biosynthesis; D051379:Mice; D008811:Mice, Inbred DBA; D008892:Milk / Q000737:chemistry / Q000276:immunology*; D011247:Pregnancy; D016019:Survival Analysis; D014613:Vaccines, Attenuated
chemical_list: D018829:Adhesins, Bacterial; D000907:Antibodies, Bacterial; C559939:CfaE protein, E coli; D029968:Escherichia coli Proteins; D022361:Escherichia coli Vaccines; D007106:Immune Sera; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D014613:Vaccines, Attenuated; D036781:Fimbriae Proteins