Safety and Immunogenicity of Escalating Dosages of a Single Oral Administration of Peru-15 pCTB, a Candidate Live, Attenuated Vaccine against Enterotoxigenic Escherichia coli and Vibrio cholerae

Abstract

c Enterotoxigenic Escherichia coli (ETEC) organisms are a leading cause of infectious diarrhea in developing countries. A live, attenuated cholera strain that expresses high levels of the nontoxic B subunit of cholera toxin, which might also serve as an ETEC protective antigen, was evaluated for safety, excretion, and immunogenicity in healthy volunteers. We enrolled four inpatient dose-escalation cohorts of 15 to 16 eligible subjects to randomly (3:1) receive a single oral dose of vaccine or placebo (buffer alone), evaluating 1 ؋10 7 , 1 ؋10 8 , 1 ؋10 9 , and 1 ؋10 10 CFU of the vaccine. The vaccine was well tolerated, although some subjects experienced moderate diarrhea. The serum Inaba vibriocidal antibody response appeared to display a dose-response relationship with increasing dosages of vaccine, plateauing at the 10 9 -CFU dosage. The serum antitoxin (cholera toxin and heat-labile enterotoxin) antibody seroconversion rate (4-fold increase over baseline) also appeared to display a dose-response relationship. The vaccine strain was excreted in stool cultures, displaying a dose-response relationship. A single oral dose of Peru-15 pCTB at dosages up to 1 ؋10 10 CFU was safe and immunogenic in this first-in-human trial. These encouraging data support the ongoing clinical development of this candidate combined cholera and ETEC vaccine. (This study has been registered at ClinicalTrials.gov under registration no. NCT00654108.) O ne of the most important etiologic agents causing diarrhea among travelers from industrialized countries who visit developing countries is the mucosally noninvasive bacterial pathogen enterotoxigenic Escherichia coli (ETEC) (1-3). ETEC infections are also a leading cause of serious diarrheal illness and death in infants and young children in developing countries (4). Cumulatively, ETEC is estimated to cause ϳ600 million total cases of diarrhea worldwide annually, including ϳ280 million cases and Ͼ400,000 deaths in children Ͻ5 years of age (5).After the ingestion of contaminated food or water, ETEC organisms colonize the upper intestinal tract by a variety of antigenically distinct colonization factors (6). Once an infection is established, the bacteria secrete either a heat-labile toxin (LT), heat-stable toxin (ST), or both. ETEC strains are antigenically diverse, and the existence of many different O:H serotypes, multiple fimbrial colonization factors, and three different enterotoxin phenotypes (LT only, ST only, and LT plus ST) (7) have complicated vaccine development.However, LT is an oligomeric protein that is structurally, functionally, and antigenically similar to the cholera toxin (CT) of Vibrio cholerae and consists of a single enzymatically active subunit (LTA) and a pentameric complex of five identical receptor binding subunits (LTB) similar to the corresponding cholera toxin subunits (CTA and CTB, respectively). Although LT and CT have many features in common, they are clearly distinct molecules with biochemical and immunologic differences that make them unique (8). However, sev...

Noninvasive vaccination against infectious diseases

“…Furthermore, the vaccine was safe up to 1 × 10 10 CFU. 70 Recently, an oral recombinant adenovirus influenza vaccine induced significant increases in haemagglutination inhibition and high titers of microneutralization antibodies with only mild adverse effects. 71 Moreover, Euvichol is an inactivated bivalent oral cholera vaccine tested during a phase I clinical trial in healthy South Korean adult males that induced a seroconversion rate of 95% and 45% for Vibrio cholera O1 and O139, respectively.…”

Dual-Use Vaccine for Diarrhoeal Diseases: Cross-Protective Immunogenicity of a Cold-Chain-Free, Live-Attenuated, Oral Cholera Vaccine against Enterotoxigenic Escherichia coli (ETEC) Challenge in BALB/c Mice

“…In contrast, the mice immunised with HaitiV elicited anti-CTB IgG (~30 ELISA units) and anti-CTB IgA (~300 ELISA units) on day 42 [55]. Distinctly, the mice immunised with Peru-15p CTB-a live-attenuated cholera vaccine-expressed high levels of CT-B (~30 fold) and recorded a high level of anti-CT-B titre with a geometric mean titre (GMT) of 3200 by day 42 [56].…”

Transient Intestinal Colonization by a Live-Attenuated Oral Cholera Vaccine Induces Protective Immune Responses in Streptomycin-Treated Mice

“…Furthermore, live OCVs appear to be more effective in children less than 5 years of age (9,10), a group that is highly susceptible to death from cholera and that is not adequately protected by killed OCVs. In volunteer studies, these vaccines have shown great promise (11,12), but none are approved for use in cholera endemic regions.…”