Hyperimmune Bovine Colostral Anti-CS17 Antibodies Protect Against Enterotoxigenic Escherichia coli Diarrhea in a Randomized, Doubled-Blind, Placebo-Controlled Human Infection Model

Abstract

Background Enterotoxigenic Escherichia coli (ETEC) commonly cause diarrhea in children living in developing countries and in travelers to those regions. ETEC are characterized by colonization factors (CFs) that mediate intestinal adherence. We assessed if bovine colostral IgG (bIgG) antibodies against a CF, CS17, or antibodies against CsbD, the minor tip subunit of CS17, would protect subjects against diarrhea following challenge with a CS17-expressing ETEC strain. Methods Adult subjects were randomized (1:1:1) to receive oral bIgG against CS17, CsbD, or placebo. Two days prior to challenge, subjects began dosing 3 times daily with the bIgG products (or placebo). On day 3, subjects ingested 5 × 109 cfu ETEC strain LSN03-016011/A in buffer. Subjects were assessed for diarrhea for 120 hours postchallenge. Results A total of 36 subjects began oral prophylaxis and 35 were challenged with ETEC. While 50.0% of the placebo recipients had watery diarrhea, none of the subjects receiving anti-CS17 had diarrhea (P = .01). In contrast, diarrhea rates between placebo and anti-CsbD recipients (41.7%) were comparable (P = 1.0). Conclusions This is the first study to demonstrate anti-CS17 antibodies provide significant protection against ETEC expressing CS17. More research is needed to better understand why anti-CsbD was not comparably efficacious. Clinical Trials Registration. NCT00524004

Oral delivery of Hyperimmune bovine serum antibodies against CS6-expressing enterotoxigenicEscherichia colias a prophylactic against diarrhea

“…The products were safe and welltolerated, similar to other studies with orally administered bovine antibodies. [9][10][11][12]18 Additionally, antibodies targeting the B7A whole cell yielded a 50% reduction in MSD and a reduced disease severity score; however, anti-CS6 yielded no significant protection against MSD. There are several potential reasons for the lack of observed efficacy.…”

“…It is also possible that serum derived antibodies are incapable of providing robust protection compared to the colostral antibodies we have utilized previously. 11,18 To our knowledge, this is the first attempt to utilize orally delivered bovine serum antibodies to protect against an enteric infection. It may be that colostrum-derived antibodies, due to their intrinsic nature, are able to survive the orogastric delivery route better, thereby providing more active antibody to the gut.…”

“…Subjects were actively monitored for adverse events including signs and symptoms of gastrointestinal illness, rehydrated as needed, and all stools were collected and assessed as previously described. [19][20][21] Stool (or rectal swab) was plated directly on MacConkey (Mac) agar or Mac agar supplemented with 25ug/ml chloramphenicol (Mac+CM) as strain B7A is resistant to chloramphenicol. Lactose positive colonies were screened for agglutination in anti-B7A whole cell antiserum.…”

“…Using recombinant CS6, hyperimmune bovine serum IgG (BSIgG) targeting CS6 was derived and assessed for efficacy using previously established models for immunoprophylaxis against ETEC in a CHIM. 11,18 Methods Passive vaccination-challenge trial design Healthy non-pregnant adult subjects aged 18-50 years were recruited from the Mid-Atlantic area. Consented subjects were evaluated to assure good health and eligibility through medical history, physical examination, and screening laboratory tests.…”

Inhibition of invasive salmonella by orally administered IgA and IgG monoclonal antibodies

“…In the case of STm, that would be in the proximal small intestine, while for Shigella species the antibodies would need to reach the colon to exert their effects. Nonetheless, in spite of these barriers, specific oral IgG preparations from HBC have seen success therapeutically in clinical trials of children with rotavirus diarrhea [50], prophylactically in rotavirus-infected mice [51] and ETEC challenged humans [52,53], suggesting the goal of using passive immunization to combat enteric disease is not far from reach.…”