Maternal Vaccination with a Fimbrial Tip Adhesin and Passive Protection of Neonatal Mice against Lethal Human Enterotoxigenic Escherichia coli Challenge

Abstract

e 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 (LD 50 ) 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؋ LD 50 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.

Antibodies derived from an enterotoxigenic Escherichia coli (ETEC) adhesin tip MEFA (multiepitope fusion antigen) against adherence of nine ETEC adhesins: CFA/I, CS1, CS2, CS3, CS4, CS5, CS6, CS21 and EtpA

“…Abundance of major subunits makes it easy for derived antibodies to target against adhesins, leading to effective protection against bacterial adherence and ETEC diarrhea. But recent studies suggested that adhesin tips play a key role in bacteria attaching to host receptors, and antibodies against tips are thought critical for protection against ETEC adherence and colonization [49, 50]. Data from this study indicated that antibodies derived from ETEC adhesin tips inhibited adherence of E. coli or ETEC bacteria expressing CFA/I, CS1-CS6, CS21 and EtpA to Caco-2 cells.…”

Immunogenicity of a prototype enterotoxigenic Escherichia coli adhesin vaccine in mice and nonhuman primates

“…Because ETEC cause disease while presumably being confined to the intestinal lumen, greater importance is placed on intestinal antibodies where abrogation of ETEC adhesion and colonization is tantamount to disease prevention. Elsewhere, however, we have shown that mouse vaccination with dscCfaE or CFA/I co-administered with an LT-based adjuvant elicited vaccine-specific coproantibody responses (37).…”

Mecanismos de virulencia de Escherichia coli enteropatógena

“…ADN y, recientemente, una mezcla celular completa inactivada de patotipos de E. coli [133][134][135][136][137] . Algunos de estos estudios están en la fase preclínica y otros con un grado de avance mayor en los estudios clínicos.…”

“…Los mayores avances en vacunas han sido en ECET. Se han investigado diferentes modelos con resultados variables en su efectividad, proteínas de algunos factores de virulencia expresados por ECET como CFs, subunidades de LT, ST, entre otros 133,137,138 . Para el control de las cepas de ECEP, desde hace varios años, con algunas de estas moléculas más conservadas, entre éstas la intimina, EspB, EspA y BfpA se han adelantado estudios para el desarrollo de vacunas en diversos modelos.…”