Safety and Immunogenicity of Two Different Lots of the Oral, Killed Enterotoxigenic Escherichia coli-Cholera Toxin B Subunit Vaccine in Israeli Young Adults Oral, inactivated, whole cell enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine: results of the initial evaluation in children. PRIDE Study Group. A double-blind, placebo-controlled trial to evaluate the efficacy of PTL-003, an attenuated enterotoxigenic E. coli (ETEC) vaccine strain, in protecting against challenge with virulent ETEC. Lack of prophylactic efficacy of an enteric-coated bovine hyperimmune milk product against enterotoxigenic Escherichia coli challenge administered during a standard meal. Safety and efficacy of E coli enterotoxin adjuvant for urease-based rectal immunization against Helicobacter pylori. Safety and immunogenicity of an oral, inactivated enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine in Bangladeshi children 18-36 months of age. Calibrated serological techniques demonstrate significant different serum response rates to an oral killed cholera vaccine between Swedish and Nicaraguan children. Immunoprotective oral whole cell vaccine for enterotoxigenic Escherichia coli diarrhea prepared by in situ destruction of chromosomal and plasmid DNA with colicin E2. Transcutaneous immunization with the heat-labile toxin (LT) of enterotoxigenic Escherichia coli (ETEC): protective efficacy in a double-blind, placebo-controlled challenge study. Immunologic response to oral cholera vaccination in a crossover study: a novel placebo effect. Reduced doses of oral killed enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine is safe and immunogenic in Bangladeshi infants 6-17 months of age: dosing studies in different age groups. Enteral immunization and challenge of volunteers given enterotoxigenic E. coli CFA/II encapsulated in biodegradable microspheres. Dose-Dependent Circulating Immunoglobulin A Antibody-Secreting Cell and Serum Antibody Responses in Swedish Volunteers to an Oral Inactivated Enterotoxigenic Escherichia coli Vaccine A Combination Vaccine Consisting of Three Live Attenuated Enterotoxigenic Escherichia coli Strains Expressing a Range of Colonization Factors and Heat-Labile Toxin Subunit B Is Well Tolerated and Immunogenic in a Placebo-Controlled Double-Blind Phase I Trial in Healthy Adults The Oral, Live Attenuated Enterotoxigenic Escherichia coli Vaccine ACE527 Reduces the Incidence and Severity of Diarrhea in a Human Challenge Model of Diarrheal Disease Exclusion of clinically atypical or microbiologically mixed diarrhoeal episodes from outcome events in a field trial of oral cholera vaccines. Safety and immunogenicity of Escherichia coli O157 O-specific polysaccharide conjugate vaccine in 2-5-year-old children. Analysis of efficacy of CVD 103-HgR live oral cholera vaccine against all-cause travellers' diarrhoea in a randomised, double-blind, placebo-controlled study. Safety, Immunogenicity, and Protective Efficacy of the Whole-Cell/Recombinant B Subunit (WC/rBS) Oral Cholera Vaccine Against Travelers' Diarrhea. Comparative Safety and Immunogenicity of Two Attenuated Enterotoxigenic Escherichia coli Vaccine Strains in Healthy Adults Milk immunoglobulin with specific activity against purified colonization factor antigens can protect against oral challenge with enterotoxigenic Escherichia coli. Safety and immunogenicity of an oral recombinant cholera B subunit-whole cell vaccine in Swedish volunteers. Oral immunization of adult volunteers with microencapsulated enterotoxigenic Escherichia coli (ETEC) CS6 antigen. Randomised, double-blind, safety and efficacy of a killed oral vaccine for enterotoxigenic E. Coli diarrhoea of travellers to Guatemala and Mexico. Use of a patch containing heat-labile toxin from Escherichia coli against travellers' diarrhoea: a phase II, randomised, double-blind, placebo-controlled field trial Cross-protection by B subunit-whole cell cholera vaccine against diarrhea associated with heat-labile toxin-producing enterotoxigenic Escherichia coli: results of a large-scale field trial. IMMUNISATION OF VOLUNTEERS WITH A SYNTHETIC PEPTIDE VACCINE FOR ENTEROTOXIGENIC ESCHERICHIA COLI Double-blind, randomized, placebo controlled pilot study evaluating efficacy and reactogenicity of an oral ETEC B-subunit-inactivated whole cell vaccine against travelers' diarrhea (preliminary report). Construction and Phase I Clinical Evaluation of the Safety and Immunogenicity of a Candidate Enterotoxigenic Escherichia coli Vaccine Strain Expressing Colonization Factor Antigen CFA/I Introductory evaluation of an oral, killed whole cell enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine in Egyptian infants An oral B subunit: whole cell vaccine against cholera. Safety and immunogenicity of an oral, killed enterotoxigenic Escherichia coli-cholera toxin B subunit vaccine in Egyptian adults. Prevention of travellers' diarrhoea by oral B-subunit/whole-cell cholera vaccine Ability of SPI2 mutant of S. typhi to effectively induce antibody responses to the mucosal antigen enterotoxigenic E. coli heat labile toxin B subunit after oral delivery to humans Randomized Clinical Trial Assessing the Safety and Immunogenicity of Oral Microencapsulated Enterotoxigenic Escherichia coli Surface Antigen 6 with or without Heat-Labile Enterotoxin with Mutation R192G
ABSTRACT Enterotoxigenic Escherichia coli ( ETEC ) is one of the leading causes of diarrhea among Israeli soldiers serving in field units . Two double-blind placebo-controlled , r and omized trials were performed among 155 healthy volunteers to evaluate the safety and immunogenicity of different lots of the oral , killed ETEC vaccine consisting of two doses of whole cells plus recombinantly produced cholera toxin B subunit ( rCT B ) . The two doses of vaccine lot E005 and the first dose of vaccine lot E003 were well tolerated by the volunteers . However , 5 ( 17 % ) vaccinees reported an episode of vomiting a few hours after the second dose of lot E003 ; none of the placebo recipients reported similar symptoms . Both lots of vaccine stimulated a rate of significant antibody-secreting cell ( ASC ) response to CTB and to colonization factor antigen I ( CFA/I ) after one or two doses , ranging from 85 to 100 % and from 81 to 100 % , respectively . The rate of ASC response to CS2 , CS4 , and CS5 was slightly lower than the rate of ASC response induced to CTB , CFA/I , and CS1 . The second vaccine dose enhanced the response to CTB but did not increase the frequencies or magnitude of ASC responses to the other antigens . The two lots of the ETEC vaccine induced similar rates of serum antibody responses to CTB and CFA/I which were less frequent than the ASC responses to the same antigens . Based on these safety and immunogenicity data , an efficacy study of the ETEC vaccine is under way in the Israel Defense Force Two r and omized , double-blinded trials assessed the safety and immunogenicity of an oral , killed enterotoxigenic Escherichia coli ( ETEC ) plus cholera toxin B subunit vaccine in Egyptian children . Two doses of vaccine or E. coli K-12 were given 2 weeks apart to 105 6- to 12-year-olds and 97 2- to 5-year-olds .  Safety was monitored for 3 days after each dose . Blood was collected before immunization and 7 days after each dose to measure immune responses . Few children reported postdosing symptoms , with no differences in the frequency of symptoms between treatment groups . Most vaccinees had an IgA antibody-secreting cell response against colonization factor antigen I ( 100 % , 6 - 12 years ; 95 % , 2 - 5 years ) , coli surface antigen 2 ( 92 % , 6 - 12 years ; 83 % , 2 - 5 years ) , and coli surface antigen 4 ( 93 % , 6 - 12 years ) . Vaccination evoked a > /=4-fold rise in antitoxic IgA and IgG titers in 93 % and 81 % of children , respectively . In conclusion , the oral ETEC vaccine was safe and immunogenic in 2- to 12-year-old children , justifying further evaluation in infants Enterotoxigenic E. coli ( ETEC ) are an important cause of diarrhea in developing countries , especially among indigenous children and travelers . In this r and omized , double-blind , placebo-controlled trial , a live , attenuated CS1/CS3 ETEC strain , PTL-003 , was tested as a potential vaccine strain . Thirty-three subjects drank buffered solutions containing either PTL-003 or placebo on Days 0 and 10 and were challenged with virulent CS1/CS3 ETEC strain E24377A on Day 28 . The vaccine did not protect against moderate to severe ETEC illness ( the primary endpoint ) , but it did prime subjects for a rapid antibody response to CS1 and CS3 after challenge , suggesting that a dose of vaccine on Day 28 might improve the immune response to the vaccine . Higher serum anti-CS3 IgA titers at the time of challenge correlated with less severe diarrheal illness Orally administered bovine immunoglobulins with specific activity against colonization factors of enterotoxigenic Escherichia coli ( ETEC ) could provide passive protection against ETEC challenge in volunteers . Twenty healthy adult volunteers ingested either a placebo or a partially enteric-coated preparation of bovine immunoglobulins with activity against the colonization factor antigens CFA/I , CS3 , and CS6 and then were challenged with ETEC strain E24377A ( CS1 + , CS3 + ) administered with a st and ard meal . There was no difference in the incidence or severity of diarrhea among the 10 volunteers who received the bovine immunoglobulins and the 10 who received placebo . Either the specificity or titer of anti-colonization factor antibodies or the formulation of antibodies in this product was not adequate to provide passive protection against ETEC challenge Low dose E. coli heat-labile enterotoxin ( LT ) , delivered orally or enterically , has been used as an adjuvant for Helicobacter pylori ( H. pylori ) urease in healthy adults . In this study we aim to test the safety and adjuvant efficacy of LT delivered rectally together with recombinant H. pylori urease .  Eighteen healthy adults without present or past H. pylori infection were enrolled in a double blind , r and omized , ascending dose study to receive either urease ( 60 mg ) , or urease ( 60 mg ) + LT ( 5 or 25 microg ) . The immunization preparation was administered per rectum on days 0 , 14 and 28 . Serum , stool and saliva anti-urease and anti-LT IgG and IgA antibodies ( Abs ) were measured and urease-specific and LT-specific antigen secreting cells ( ASCs ) were counted in peripheral blood at baseline and 7 ( ASC counts ) or 14 days ( antibody levels ) after each dosing . Peripheral blood lymphoproliferation assays were also performed at baseline and at the end of the study . Rectally delivered urease and LT were well tolerated . Among the 12 subjects assigned to urease+LT , 2 ( 16.7 % ) developed anti-urease IgG Abs , 1 ( 8.3 % ) developed anti-urease IgA Abs , and 3 ( 25 % ) showed urease-specific IgA(+ ) ASCs . Immune responses to LT were more vigorous , especially in subjects exposed to 5 microg LT . In the urease+ 5 microg LT group , anti-LT IgG and IgA Abs developed in 60 and 80 % of the subjects , respectively , while LT-specific IgG(+ ) and IgA(+ ) ASCs were detected in all subjects . The magnitude of the anti-LT response was much higher than the response to urease . No IgA anti-urease or anti-LT Abs were detected in stool or saliva and lymphocyte proliferative responses to urease were unsatisfactory . In conclusion , rectal delivery of 5 microg LT is safe and induces vigorous systemic anti-LT immune responses . Further studies are needed to determine if LT can be an effective adjuvant for rectally delivered antigens A phase II safety and immunogenicity study of an oral-formalin inactivated enterotoxigenic Escherichia coli ( ETEC ) vaccine containing six colonization factors ( CFA/I , CS1 , CS2 , CS3 , CS4 , CS5 ) and 1 mg of recombinant cholera toxin B subunit ( the CF-BS-ETEC vaccine ) was carried out in an urban slum of Dhaka city in Bangladesh . The study was carried out in a double blinded , placebo controlled design in 158 children , 18 - 36 months of age . Children were given two doses of the CF-BS-ETEC vaccine or the placebo which consisted of E. coli K12 . The vaccine was well tolerated . The immune response was studied in 60 children ( 30 each in the placebo and vaccine group ) . Significant vaccine specific IgA antibody-secreting cell ( ASC ) responses were seen 7 days after ingestion of the first and second dose of the vaccine . The responses to CFA/I ( P < or=0.001 ) , CS2 ( P=0.021 ) , CS4 ( P=0.009 ) and rCT B ( P < or=0.001 ) were elevated in the vaccines in comparison to the pre-immune values and in comparison to those seen in the placebo recipients ( P=0.018 to < 0.001 ) . Vaccines but not placebo recipients also showed significantly increased IgM ASC responses to all three CF antigens that were tested ( P=0.012 to < 0.001 ) and IgG-ASCs to rCT B ( P<0.001 ) . Peak ASC levels were reached after one dose of the vaccine with no further increase or decrease after the second dose . The vaccine recipients also responded with IgA plasma antibodies to CFA/I , CS1 , CS2 , CS4 and rCT B after one or two doses of the vaccine ( P=0.01 to < 0.001 ) . Subjects in the placebo group failed to mount responses to any of the antigens . The vaccine also induced responses in mucosal IgA antibodies in feces to CFA/I , CS2 and rCT B ( 61 , 88 and 69 % responder frequency , respectively ) and the magnitude of the response was elevated in comparison to the pre-immune levels ( P=0.031 to < 0.001 ) and to the levels of the control group ( P=0.003 to < 0.001 ) . This study thus shows that the CF-BS-ETEC vaccine is well tolerated in children , 18 - 36 months of age and gives rise to significant systemic and mucosal IgA antibody responses Serum responses to oral cholera vaccines were assessed in three paediatric vaccine trials , two in León , Nicaragua and one in Stockholm , Sweden . A calibrated anti-cholera toxin B subunit ( CTB ) IgA ELISA was used together with an assay for vibriocidal antibodies . Swedish children had lower pre-vaccination levels of antibody , but serum responses were more pronounced in Swedish children than in Nicaraguan children .  Post-vaccination levels of anti-toxin antibody were generally above those found after natural infections with enterotoxigenic Escherichia coli , that cross-reacts serologically with Vibrio cholerae . Adverse events seen after vaccination were generally mild and of little clinical significance Vaccine regimens which mimic actual infection with bacterial enteropathogens should offer the best opportunity for successful long-term immunoprotection against diarrheal disease caused by enterotoxigenic Escherichia coli ( ETEC ) or Vibrio cholerae . Based on this principle , we design ed and tested an oral whole cell anti-ETEC vaccine consisting of intact cells of ETEC strain H-10407 ( ST+LT+ ; O78:H11:CFA/I ) which were rendered incapable of replication by treatment with a potent DNA endonuclease , colicin E2 . Young healthy volunteers were administered two oral doses of either placebo or approx . 3 X 10(10 ) vaccine cells . In a double-blind study , 9 of 10 vaccinees responded with an increase in CFA/I-specific intestinal IgA antibody , determined as percent of total IgA. Challenge with virulent strain H-10407 ( 5 X 10(9 ) living cells ) produced diarrhea in 8 of 9 ( 89 % ) of the placebo-treated volunteers and in 2 of 10 ( 20 % ) of the vaccinees . Thus , the colicin E2-killed whole cell vaccine afforded both a significant intestinal immune response and significant protection against challenge with the virulent organism . The data presented here suggest that for this vaccine preparation an intestinal anti-CFA/I IgA response is a good indicator of a protective immune response , which most likely involves antibody responses to a number of antigens in addition to CFA/I. We conclude that the colicin E2 method for preparing an oral anti-ETEC vaccine merits further study and that this method may also be applicable to other enteropathogens BACKGROUND An enterotoxigenic Escherichia coli ( ETEC ) vaccine could reduce diarrhea among children in developing countries and travelers to these countries . The heat-labile toxin ( LT ) of ETEC is immunogenic but too toxic for oral or nasal vaccines . METHODS In a double-blind , placebo-controlled trial , 59 adults were r and omized to receive 50 microg of LT or placebo in a patch applied to alternating arms on days 0 , 21 , and 42 . On day 56 , 27 vaccinees and 20 controls were challenged orally with 6x10(8 ) cfu of LT+/ST+ ETEC . RESULTS 100 and 97 % of vaccinees had 4-fold increases in anti-LT IgG and IgA , and 100 and 90 % developed IgG- and IgA-antibody-secreting cell responses . The study did not meet the primary endpoint : 82 % of vaccinees and 75 % of controls had moderate to severe ETEC illness . However , vaccinees with ETEC illness had lower numbers ( 6.8 versus 9.7 , p=0.04 ) and weights of loose stools ( 840 g versus 1147 g , p<0.05 ) , a decreased need for intravenous fluids ( 14 % versus 40 % , p=0.03 ) and a delayed onset of diarrhea ( 30 h versus 22 h , p=0.01 ) . CONCLUSIONS Transcutaneous LT vaccination induced anti-toxin immune responses that did not prevent but mitigated illness following a high-dose challenge with a virulent LT+/ST+ ETEC strain The authors conducted a two-period crossover study of the reactogenicity and immunogenicity of live oral cholera vaccine CVD 103-HgR  among US university students . Subjects ingested 5 x 10(8 ) colony forming units of either killed Escherichia coli K12 placebo or vaccine , followed by the opposite treatment one week later . Surprisingly , the dynamics of the immunologic response were influenced by prior ingestion of placebo . Subjects who received placebo first showed stronger vibriocidal antibody responses 2 weeks after vaccination compared with subjects who received vaccine first ; this same pattern was seen for antitoxin titers . The authors suggest that ingestion of E. coli K12 one week prior to immunization boosts the immunologic response to vaccine by an unknown mechanism . Future crossover studies that examine immunologic outcomes might be design ed to explore the ubiquity of such an effect The oral-formalin inactivated whole cell enterotoxigenic Escherichia coli ( ETEC ) vaccine needs to be further tested in developing countries in order to determine the dose at which it will be safe and immunogenic for infants who are the target population for the vaccine . To determine the immunogenicity of reduced doses , studies were first carried out in children , 2 - 12 years of age ( n = 60 ) . The full , half or a quarter doses of the vaccine were comparable in immunogenicity with similar frequency of responses seen to the different antigens ( P = NS ) . Following this result , a pilot study carried out in infants , 6 - 17 months of age ( n = 50 ) , showed that the frequency of episodes of vomiting was lowest when a quarter of the full dose was used . The infants however showed comparable immune responses to the half and quarter dose of vaccine that was tested ( P = NS ) . Based on these results in the infants , a r and omized double blind placebo-controlled Phase II study was carried out in 158 children , 6 - 17 months of age , where a quarter dose of the ETEC vaccine was tested .  Adverse events of mild vomiting were seen in only 4 % of vaccinees and in 2.5 % of placebo recipients . The IgA-antibody secreting cell ( ASC ) responses to CFA/I ( GM : 28.1 ASC/10(7 ) P BMC ) and BS ( GM : 55.7 ASC/10(7 ) P BMC ) were elevated compared to placebo recipients ( CFA/I-2.0 ; BS-4.8 ASC/10(7 ) P BMC ) ( P = 0.01 to < 0.001 ) . The plasma-IgA antibody titers in vaccinees were also significantly elevated to CFA/I ( GM-93.00 ) , CS1 ( GM-62.0 ) , CS2 ( GM-55.0 ) , CS4 ( GM-66.0 ) and BS ( 1057.0 ) compared to preimmune levels or responses or levels in placebo recipients ( P < or = 0.05 - 0.001 ) . This study thus demonstrates that reduced doses of the ETEC vaccine is immunogenic in children and infants as well as safe in infants down to 6 months of age The development of a safe and effective vaccine against enterotoxigenic Escherichia coli ( ETEC ) would be useful for travellers and for young children in endemic areas . A feasibility study of an enteral ETEC vaccine prototype consisting of colonization factor antigen II ( CFA/II ) , containing two component antigens CS1 and CS3 , encapsulated in biodegradable polymer microspheres ( BPM ) was conducted in healthy volunteers . Ten adult volunteers swallowed intestinal tubes on days 0 , 7 , 14 and 28 ; after collection of jejunal fluid sample s , 1 mg of CFA/II in BPM was administered via the tube . Volunteers kept a diary of symptoms after each dose . Secretory IgA in jejunal fluids , serum responses and circulating antibody-secreting cells ( ASC ) were measured before and after vaccination . The vaccine was well tolerated . Five of ten volunteers developed IgA anti-CFA/II ASC by 7 days after the last dose of vaccine ; these same five vaccinees had IgA anti-CS3 ASC , and three of these five vaccinees had IgA anti-CS1 ASC . Five of ten vaccinees developed rises in jejunal fluid sIgA anti-CFA/II with peak GMT of 1:42 . About 8 weeks after the first dose of vaccine , ten vaccinees and ten unvaccinated control volunteers underwent challenge with 10(9 ) c.f.u . ETEC E24377A ( O139:H28 LT+ST+CS1+CS3 + ) . Ten of ten controls and seven of ten vaccinees developed diarrhoea ( p = 0.11 , 30 % vaccine efficacy ) . Two of the three protected vaccinees had the highest numbers of ASC and highest sIgA titres during the course of immunization , suggesting that these responses were protective and that this vaccine development strategy has merit . Future studies with higher dosages and a different dosing schedule are planned ABSTRACT The immunogenicity of different preparations of an oral inactivated enterotoxigenic Escherichia coli ( ETEC ) vaccine was evaluated in Swedish volunteers previously unexposed to ETEC infection . The vaccine preparations consisted of recombinant cholera toxin B subunit ( CTB ) and various amounts of formalin-killed whole bacteria expressing the most prevalent colonization factor antigens ( CFAs ) . Significant immunoglobulin A ( IgA ) antibody-secreting cell ( ASC ) responses against CTB and the various CFA components were seen in a majority of volunteers after two doses of ETEC vaccine independent of the vaccine lot given . The IgA ASC responses against CTB were significantly higher after the second than after the first immunization , whereas the CFA-specific IgA ASC responses were almost comparable after the first and second doses of ETEC vaccine . Two immunizations with one-third of a full dose of CFA-ETEC bacteria induced lower frequencies of IgA ASC responses against all the different CFAs than two full vaccine doses , i.e. , 63 versus 80 % for CFA/I , 56 versus 70 % for CS1 , 31 versus 65 % for CS2 , and 56 versus 75 % for CS4 . The proportion of vaccinees responding with rises in the titer of serum IgA antibody against the various CFA antigens was also lower after immunization with the reduced dose of CFA-ETEC bacteria . These findings suggest that measurements of circulating IgA ASCs can be used not only for qualitative but also for quantitative assessment s of the immunogenicity of individual fimbrial antigens in various preparations of ETEC vaccine ABSTRACT Immune responses against colonization factors ( CFs ) and the nontoxic B component of the enterotoxigenic Escherichia coli ( ETEC ) heat-labile toxin ( LTB ) are considered to be important for immunity against diarrhea caused by ETEC . Individual live attenuated ETEC derivatives that have had their toxin genes removed and whose aroC , ompC , and ompF genes are deleted have shown promise as vaccines against ETEC . The development of such strains has culminated in the testing of a three-strain-combination live attenuated vaccine known as ACE527 , comprised of strains ACAM2025 expressing colonization factor antigen I ( CFA/I ) and LTB ; ACAM2022 , expressing CS5 , CS6 , and LTB ; and ACAM2027 , expressing CS1 , CS2 , CS3 , and LTB . The recombinant CF and LTB genes expressed in the three strains were inserted into the bacterial chromosome to ensure their stable inheritance and expression without the requirement for any selection . ACE527 has been tested in a r and omized placebo-controlled , double-blind , phase I safety and immunogenicity study in healthy adult volunteers and proved to be well tolerated and immunogenic at dose levels of 1010 and 1011 total CFU . There was no indication of strain interference on the basis of fecal shedding patterns , with all three being detected in the feces of 50 % and 83 % of low- and high-dose vaccine recipients , respectively . Similarly , strong immune responses to LTB and to CFs expressed on all three constituent strains were induced , with at least 50 % of subjects in the high-dose group responding to LTB , CFA/I , CS3 , and CS6 ABSTRACT An oral , live attenuated , three-strain recombinant bacterial vaccine , ACE527 , was demonstrated to generate strong immune responses to colonization factor and toxin antigens of enterotoxigenic Escherichia coli ( ETEC ) in human volunteers . The vaccine was safe and well tolerated at doses of up to 1011 CFU , administered in each of two doses given 21 days apart . These observations have now been extended in a phase 2b study with a total of 70 subjects . Fifty-six of these subjects were challenged 28 days after the second dose of vaccine with the highly virulent ETEC strain H10407 to obtain preliminary indicators of efficacy against disease and to support further development of the vaccine for both travelers and infants in countries where ETEC is endemic . The vaccine had a significant impact on intestinal colonization by the challenge strain , as measured by quantitative fecal culture 2 days after challenge , demonstrating the induction of a functional immune response to the CFA/I antigen . The incidence and severity of diarrhea were also reduced in vaccinees as measured by a number of secondary and ad hoc endpoints , although the 27 % reduction seen in the primary endpoint , moderate to severe diarrhea , was not statistically significant . Together , these observations support the hypothesis that the ACE527 vaccine has a dual mode of action , targeting both colonization factors and the heat-labile enterotoxin ( LT ) , and suggest that it should be further developed for more advanced trials to evaluate its impact on the burden of ETEC disease in field setting We investigated whether alternative clinical and microbiological criteria for outcome events affected estimates of vaccine efficacy in a r and omized , double-blind field trial of B subunit-killed whole cell ( BS-WC ) and killed whole cell-only ( WC ) oral cholera vaccines among 62,285 rural Bangladeshi participants . At one year of follow-up estimates of vaccine protective efficacy ( PE = 60 % , P less than 0.0001 for BS-WC ; PE = 54 % , P less than 0.0001 for WC ) against all treated diarrhoeal episodes associated with V. cholerae 01 were similar to estimates of efficacy against only those episodes which were clinical ly typical and unassociated with additional enteric pathogens ( PE = 62 % , P less than 0.0001 for BS-WC ; PE = 52 % , P less than 0.0001 for WC ) . In contrast , estimates of vaccine cross-protection against episodes associated with each of several agents antigenically related to V. cholerae 01 ( LT-ETEC , non-cholera Vibrio sp , Aeromonas sp ) were substantially reduced when mixed infections with V. cholerae 01 were excluded . We conclude that restrictive criteria intended to improve the specificity of the definition of cholera did not increase the detectability of vaccine efficacy against V. cholerae 01 , but that exclusion of mixed infections with V. cholerae 01 was necessary to avoid false-positive conclusions about vaccine cross-protection against other potential target pathogens BACKGROUND Escherichia coli O157:H7 causes severe enteritis and hemolytic-uremic syndrome , mostly in young children and older adults . Similar to the case with Shigella , serum IgG against the O-specific polysaccharide of E. coli O157:H7 may confer immunity by lysing the inoculum in the intestine . A phase 1 trial in adults showed that a vaccine of E. coli O157:H7 O-specific polysaccharide conjugated to recombinant exotoxin A of Pseudomonas aeruginosa ( O157-rEPA ) was safe and immunogenic . METHODS A phase 2 trial of the O157-rEPA vaccine was conducted in 49 children 2 - 5 years old who were divided r and omly into groups receiving 1 or 2 doses of vaccine .  Adverse reactions were monitored . Serum IgG lipopolysaccharide ( LPS ) antibodies were determined . RESULTS No significant adverse reactions were observed . At 1 week after the first dose was administered , most children ( 81 % ) responded with a > 4-fold increase in serum IgG LPS antibodies . At 6 weeks after the first dose was administered , all children responded with a > 8-fold increase ; a second dose did not elicit a booster response . At 26 weeks after the first dose was administered , the geometric mean titer of serum IgG LPS antibodies was ~20-fold higher than was the prevaccination titer . These serum sample s had high titers of bactericidal activity that were correlated roughly with serum IgG LPS antibody titers ( r = .78 ) . CONCLUSIONS The O157-rEPA vaccine was safe and immunogenic in young children . A phase 3 trial of the administration of this conjugate vaccine concurrently with routine immunization in infants is planned Enterotoxigenic Escherichia coli ( ETEC ) , which produces heat labile toxin ( LT ) and /or heat stable toxin ( ST ) , is considered to be the most common known cause of travellers ' diarrhoea ( TD ) . Owing to the antigenic similarity between cholera toxin and LT , immunization with inactivated oral B-subunit/whole-cell cholera vaccine ( BS-WC ) offers short term ( 3 months ) but significant ( > 67 % ) protection against TD caused by LT-related ETEC . Since it expresses the cholera toxin B ( CTB ) subunit , the live attenuated oral cholera vaccine strain CVD 103-HgR , may induce similar protection . A trial was performed to determine if CVD 103-HgR live oral cholera vaccine would provide a protective efficacy of at least 50 % against TD . In addition , the protective efficacy of the vaccine against TD specifically due to LT-ETEC and LT/ST-ETEC was determined . Volunteers ( n=134 ) travelling to Indonesia , India , Thail and or West-Africa were r and omised to receive either a placebo ( n=65 ) or the vaccine ( n=69 ) . In the placebo group , 46 % reported an episode of diarrhoea , compared to 52 % in the vaccine group . No significant group differences were found with regard to incidence , duration or severity of all caused TD or ETEC-associated TD . However , ETEC-associated TD occurred earlier in the placebo group ( median 5 days ) , compared to the vaccine group ( median 15 days ) . In conclusion , CVD 103-HgR live oral cholera vaccine failed to provide a 50 % protection against TD . This study does not exclude that the vaccine may offer a short-lived protection against ETEC-associated TD . However , the power of the study was limited by the unexpected low incidence of LT-ETEC-associated diarrhoea ( 9 % of all TD ) compared to ST-associated TD ( 24 % of all TD ) Background : A prospect i ve , r and omized , double-blind , placebo-controlled trial of WC/rBS oral cholera vaccine was conducted in 502 U.S. college students attending summer educational programs in Mexico . Methods : Two doses of vaccine ( or placebo ) were administered 10 days apart immediately after arrival in Mexico . Results : The vaccine was free of significant adverse side effects . Anticholera toxin seroconversion was demonstrated in 86.7 % of vaccinees compared to 8.2 % of controls ( p < .001 ) . Postvaccination titers varied according to disease status ( travelers ' diarrhea ) and enteropathogen isolated when disease developed . Protective efficacy ( PE ) against enterotoxigenic Escherichia coli ( ETEC ) diarrhea was 50 % ( 95 % CI , 14 - 71 % ) , beginning 7 days after the second dose of WC/rBS . However , 74 % of ETEC cases occurred within 7 days of the second dose , when no efficacy was demonstrated . Conclusions : Vaccines employed to prevent travelers ' diarrhea will likely need to be administered before arrival in a developing country to be predictably beneficial . An unexpected finding was that infection with LT-ETEC after primary oral cholera immunization appears to augment the antitoxin response to WC/rBS vaccine . ( J Travel Med 2:22 - 27 , 1995 ABSTRACT A vaccine against enterotoxigenic Escherichia coli ( ETEC ) is needed to prevent diarrheal illness among children in developing countries and at-risk travelers . Two live attenuated ETEC strains , PTL002 and PTL003 , which express the ETEC colonization factor CFA/II , were evaluated for safety and immunogenicity . In a r and omized , double-blind , placebo-controlled trial , 19 subjects ingested one dose , and 21 subjects ingested two doses ( days 0 and 10 ) of  PTL-002 or PTL-003  at 2 × 109 CFU/dose . Anti-CFA/II mucosal immune responses were determined from the number of antibody-secreting cells ( ASC ) in blood measured by enzyme-linked immunospot assay , the antibody in lymphocyte supernatants ( ALS ) measured by enzyme-linked immunosorbent assay ( ELISA ) , and fecal immunoglobulin A ( IgA ) levels determined by ELISA . Time-resolved fluorescence ( TRF ) ELISA was more sensitive than st and ard colorimetric ELISA for measuring serum antibody responses to CFA/II and its components , CS1 and CS3 . Both constructs were well tolerated . Mild diarrhea occurred after 2 of 31 doses ( 6 % ) of PTL-003 . PTL-003 produced more sustained intestinal colonization than PTL-002 and better IgA response rates : 90 % versus 55 % ( P = 0.01 ) for anti-CFA/II IgA-ASCs , 55 % versus 30 % ( P = 0.11 ) for serum anti-CS1 IgA by TRF , and 65 % versus 25 % ( P = 0.03 ) for serum anti-CS3 IgA by TRF . Serum IgG response rates to CS1 or CS3 were 55 % in PTL-003 recipients and 15 % in PTL-002 recipients ( P = 0.02 ) . Two doses of either strain were not significantly more immunogenic than one . Based on its superior immunogenicity , which was comparable to that of a virulent ETEC strain and other ETEC vaccine c and i date s , PTL-003 will be developed further as a component of a live , oral attenuated ETEC vaccine Enterotoxigenic Escherichia coli ( ETEC ) is the most commonly isolated pathogen responsible for travelers ' diarrhea and the cause of up to 650 million cases of pediatric diarrhea per year in the developing world . As a safe alternative to the prophylactic use of antibiotics , a hyperimmune bovine milk antibody product with specific activity against purified colonization factor antigens ( CFAs ) was developed and evaluated in a human challenge study . Twenty-five healthy adult volunteers were challenged orally with 10(9 ) cfu of a virulent CFA/I-bearing ETEC . In the r and omized double-blind trial , 7 of 10 volunteers receiving a lactose-free placebo developed clinical diarrhea after challenge , compared with only 1 of 15 cases in volunteers receiving active product ( Fisher 's exact test , P < .0017 ) . It is concluded that antibodies against CFAs alone are sufficient for protection and that prophylaxis with milk-derived immunoglobulin is a feasible alternative to existing drug interventions The safety and immunogenicity of a ' new ' oral B subunit-whole cell ( B-WC ) cholera vaccine based on recombinantly produced B subunit was evaluated in Swedish volunteers . The recombinant B-WC vaccine was comparable to the ' old ' type of B-WC vaccine in inducing IgA and IgG antitoxin antibody responses as well as vibriocidal antibody responses in serum , which are known to be good serological correlates of the gut mucosal IgA antitoxic and antibacterial immune responses after oral immunization with B-WC vaccine . Neither of the two B-WC vaccines was associated with any significant side-effects . The results indicate that the more easily and cheaply produced recombinant B subunit can replace the ' old ' type of B subunit isolated from cholera toxin for use in the oral B-WC cholera vaccine As a step in the development of an oral vaccine against ETEC , we evaluated the safety and immunogenicity of CS6 , a polymeric protein commonly found on the surface of ETEC . Formulations included 1 and 5 mg doses of CS6 , either encapsulated in biodegradable polymer poly(D , L)-lactide-co-glycolide ( PLG ) , or as free protein , administered orally in a solution of either normal saline or a rice-based buffer . Three doses of CS6 were given at 2-week intervals . Blood was collected immediately before and 7 days after each dose . All formulations were well tolerated . Four of five volunteers who received 1 mg CS6 in PLG microspheres with buffer had significant IgA ASC responses ( median=30 ASC per 10(6 ) P BMC ) and significant serum IgG responses ( median=3.5-fold increase ) . Oral administration of these prototype ETEC vaccine formulations are safe and can elicit immune responses . The ASC , serum IgA , and serum IgG responses to CS6 are similar in magnitude to the responses after challenge with wild-type ETEC [ Coster et al. , unpublished data ] . Further studies are underway to determine whether these immune responses are sufficient for protection We tested the efficacy of a killed oral vaccine for enterotoxigenic Escherichia coli ( ETEC ) diarrhoea to determine if two doses of vaccine with colonization factor antigens ( CF ) and cholera B subunit would protect against ETEC diarrhoea of travellers . Six hundred seventy-two healthy travellers going to Mexico or Guatemala were studied in a prospect i ve , r and omised , placebo-controlled trial . The primary outcome was a vaccine preventable outcome ( VPO ) , defined as an episode of ETEC diarrhoea with an ETEC organism producing heat labile toxin ( LT ) or CF homologous with the vaccine , without other known causes . The vaccine was safe and stimulated anti-heat labile toxin antibodies . There was a significant decrease in more severe VPO episodes ( PE=77 % , p=0.039 ) as defined by symptoms that interfered with daily activities or more than five loose stools in a day , although the total number of VPO events did not differ significantly in the vaccine and placebo groups . We conclude that the new oral ETEC vaccine reduces the rate of more severe episodes of traveller 's diarrhoea ( TD ) due to VPO-ETEC , but it did not reduce the overall rate of ETEC diarrhoea or of travellers ' diarrhoea due to other causes BACKGROUND Enterotoxigenic Escherichia coli ( ETEC ) is a major cause of travellers ' diarrhoea . We investigated the rate of diarrhoea attacks , safety , and feasibility of a vaccine containing heat-labile enterotoxin ( LT ) from ETEC delivered to the skin by patch in travellers to Mexico and Guatemala . METHODS In this phase II study , healthy adults ( aged 18 - 64 years ) who planned to travel to Mexico or Guatemala and had access to a US regional vaccination centre were eligible . A central ised r and omisation code was used for allocation , which was masked to participants and site staff . Primary endpoints were to investigate the field rate of ETEC diarrhoea , and to assess the safety of heat-labile toxins from E coli ( LT ) delivered via patch . Secondary endpoints included vaccine efficacy against travellers ' diarrhoea and ETEC . Participants were vaccinated before travel , with two patches given 2 - 3 weeks apart . Patches contained either 37.5 mug of LT or placebo . Participants tracked stool output on diary cards in country and provided sample s for pathogen identification if diarrhoea occurred . Diarrhoea was grade d by the number of loose stools in 24 h : mild ( three ) , moderate ( four or five ) , and severe ( at least six ) . Analysis was per protocol . The trial is registered with Clinical Trials.gov , number NCT00516659 . FINDINGS Recruitment closed after 201 participants were assigned patches . 178 individuals received two vaccinations and travelled and 170 were analysed . 24 ( 22 % ) of 111 placebo recipients had diarrhoea , of whom 11 ( 10 % ) had ETEC diarrhoea . The vaccine was safe and immunogenic . The 59 LT-patch recipients were protected against moderate-to-severe diarrhoea ( protective efficacy [ PE ] 75 % , p=0.0070 ) and severe diarrhoea ( PE 84 % , p=0.0332 ) . LT-patch recipients who became ill had shorter episodes of diarrhoea ( 0.5 days vs 2.1 days , p=0.0006 ) with fewer loose stools ( 3.7 vs 10.5 , p<0.0001 ) than placebo . INTERPRETATION Travellers ' diarrhoea is a common ailment , with ETEC diarrhoea illness occurring in 10 % of cases . The vaccine patch is safe and feasible , with benefits to the rate and severity of travellers ' diarrhoea The B subunit ( BS ) of cholera toxin and that of the heat-labile enterotoxin ( LT ) of enterotoxigenic Escherichia coli ( ETEC ) are antigenically similar . We therefore assessed whether a combined cholera toxin BS/whole-cell ( BS-WC ) oral vaccine against cholera conferred cross-protection against LT-producing ETEC ( LT-ETEC ) diarrhea in a r and omized , double-blind field trial among rural Bangladeshi children and women . The 24,770 persons who ingested two or more doses of BS-WC vaccine  were compared with 24,842 controls who took two or more doses of killed whole-cell ( WC ) oral cholera vaccine .  Sixty-seven percent fewer episodes of LT-ETEC diarrhea were noted in the BS-WC group than in the WC group during short-term ( three-month ) follow-up ( P less than .01 ) , but no reduction was evident during the ensuing nine months . Short-term protection was particularly notable against LT-ETEC diarrhea causing life-threatening dehydration ( protective efficacy , 86 % ; P less than .05 ) A completely synthetically produced peptide vaccine , consisting of the 18-aminoacid Escherichia coli heat-stable toxin and the 26-aminoacid epitope of the heat-labile toxin B subunit , was given orally to thirteen volunteers . It raised antitoxin titres to both toxin components four-fold in serum sample s and seven-fold in jejunal aspirates over preimmunisation control titres . Jejunal aspirates taken after immunisation from vaccinees , but not controls , neutralised the secretory activity of both toxins in appropriate biological assays . These findings show that synthetically produced vaccines are immunogenic in human beings . The peptide used is a promising vaccine for diarrhoeal disease caused by enterotoxigenic strains of E coli Diarrhea caused by enterotoxigenic E.coli ( ETEC ) is an important health problem in developing countries and in travelers to these areas . In previous trials formulations of ETEC vaccines containing the B-subunit of cholera toxin , which is antigenically similar to the heat labile enterotoxin of ETEC , and the most prevalent colonization factor antigens of ETEC , were shown to stimulate relevant mucosal immune responses in volunteers from Sweden and Egypt ABSTRACT Oral delivery of toxin-negative derivatives of enterotoxigenic Escherichia coli ( ETEC ) that express colonization factor antigens ( CFA ) with deletions of the aroC , ompC , ompF , and toxin genes may be an effective approach to vaccination against ETEC-associated diarrhea . We describe the creation and characterization of an attenuated CFA/I-expressing ETEC vaccine c and i date , ACAM2010 , from a virulent isolate in which the heat-stable enterotoxin ( ST ) and CFA/I genes were closely linked and on the same virulence plasmid as the enteroaggregative E. coli heat-stable toxin ( EAST1 ) gene . A new suicide vector ( pJCB12 ) was constructed and used to delete the ST and EAST1 genes and to introduce defined deletion mutations into the aroC , ompC , and ompF chromosomal genes . A phase I trial , consisting of an open-label dose escalation phase in 18 adult outpatient volunteers followed by a  placebo-controlled double-blind phase in an additional 31 volunteers , was conducted . The vaccine was administered in two formulations , fresh culture and frozen suspension . These were both well tolerated , with no evidence of significant adverse events related to vaccination . Immunoglobulin A ( IgA ) and IgG antibody-secreting cells specific for CFA/I were assayed by ELISPOT . Positive responses ( greater than twofold increase ) were seen in 27 of 37 ( 73 % ) subjects who received the highest dose level of vaccine ( nominally 5 × 109 CFU ) . Twenty-nine of these volunteers were secreting culturable vaccine organisms at day 3 following vaccination ; five were still positive on day 7 , with a single isolation on day 13 . This live attenuated bacterial vaccine is safe and immunogenic in healthy adult volunteers Background . We conducted the first trial to assess the safety and immunogenicity of an oral , killed enterotoxigenic Escherichia coli plus cholera toxin B-subunit vaccine in children < 2 years old . Methods . Three doses of vaccine or killed E. coli K-12 control were given at 2-week intervals to 64 Egyptian infants , 6 to 18 months old , in a r and omized , double blind manner . Adverse events were monitored for 3 days after each dose . Blood was collected before immunization and 7 to 10 days after each dose to assess vaccine-specific serologic responses . Results . There was no statistically significant intergroup difference in the percentage of subjects reporting the primary safety endpoint ( diarrhea or vomiting ) after the first ( 31 % , vaccine ; 30 % , control ) or third ( 14 % , vaccine ; 18 % , control ) dose , whereas there was a trend toward greater reporting in the vaccine group after Dose 2 ( 36 % , vaccine ; 18 % , control;P = 0.052 ) . The percentage of children showing IgA seroconversion after any dose was higher in the vaccine than the control group for recombinant cholera toxin B-subunit ( 97%vs . 46 % ) , colonization factor antigen I ( 61%vs . 18 % ) and coli surface antigen 4 ( 39%vs . 4 % ) ( P < 0.001 for each comparison ) . IgG seroconversion rates in the vaccine and control groups were 97 and 21 % to recombinant cholera toxin B-subunit ( P < 0.001 ) , 64 and 29 % for colonization factor antigen I ( P < 0.01 ) , 53 and 21 % for coli surface antigen 2 ( P < 0.05 ) and 58 and 4 % for coli surface antigen 4 ( P < 0.001 ) , respectively . The third vaccine dose was followed by augmented IgG antitoxin titers . Conclusion . The oral enterotoxigenic E. coli vaccine was safe and immunogenic in this setting in Egyptian infants During the last decade there has been a rapid progress in the development of new , much improved vaccines against cholera . These vaccines , which are given orally to stimulate the gut mucosal immune system , are based on either a combination of purified cholera toxin B ( binding ) subunit and killed cholera vibrios of Inaba and Ogawa serotypes and El Tor and classical biotypes ( B subunit-whole cell vaccine , B-WC ) or on a live attenuated mutant strain of Vibrio cholerae producing the B subunit ( CVD 103-HgR ) . The safety of the oral B-WC cholera vaccine and the immunogenicity and protective efficacy of this vaccine against both cholera and diarrhoea caused by enterotoxigenic Escherichia coli have been extensively documented , e.g. in a large r and omized , placebo-controlled field trial in 90,000 persons living in a cholera endemic area . The potential for inexpensive large-scale manufacturing of the B-WC vaccine has recently been much facilitated by the introduction of recombinant DNA technology for production of the B subunit component . This now gives promise that this vaccine could become a useful , cost-effective tool in future strategies to control cholera both in endemic situations and in relation to acute epidemic outbreaks Enterotoxigenic Escherichia coli ( ETEC ) is the leading cause of bacterial diarrhea in young children in developing countries . The safety and immunogenicity of a killed , oral ETEC vaccine consisting of whole cells plus recombinantly produced cholera toxin B subunit ( rCT B ) was evaluated in Egypt , which is endemic for ETEC diarrhea . Seventy-four healthy Egyptian adults ( 21 - 45 years old ) were r and omized and received two doses of the ETEC/ rCT B vaccine ( E003 ) or placebo 2 weeks apart . The frequency of adverse events after either dose did not differ by treatment group , and no severe adverse events were reported . After vaccination , peripheral blood IgA B cell responses to CTB ( 100 % ) and to vaccine colonization factor antigens CFA/I ( 94 % ) , CS4 ( 100 % ) , CS2 ( 81 % ) , and CS1 ( 69 % ) were significantly higher than response rates for the placebo group . These favorable results in Egyptian adults indicate that the ETEC/ rCT B vaccine is a promising c and i date for evaluation in younger age groups in this setting B-subunit/whole-cell cholera vaccine ( BS-WC ) has been shown to give Bangladeshi mothers and children only 3 months ' protection against severe diarrhoea due to enterotoxigenic Escherichia coli ( ETEC ) . Since a long-lasting effect is not necessary for protection against travellers ' diarrhoea , a prospect i ve double-blind study was conducted among tourists who went to Morocco from Finl and . 307 tourists received two oral doses of BS-WC , whereas 308 controls received a placebo before departure . A research team went out with tourists and a laboratory for enteric pathogens was set up on location . A faecal specimen was taken from 100 r and omly selected subjects before departure , from all travellers with diarrhoea , and routinely after return . Enteropathogenic bacteria were not isolated from any of the pre-departure specimens but were present during or after the holiday in 47 % of tourists with travellers ' diarrhoea , and in 14 % of those without diarrhoea . BS-WC induced a 52 % protection ( p = 0.013 ) against diarrhoea caused by ETEC . The protection was better for mixed infections ( 65 % , p = 0.016 ) . The protective efficacy against a combination of ETEC and any other pathogen was 71 % ( p = 0.02 ) , and that against ETEC plus Salmonella enterica even better at 82 % ( p = 0.01 ) . Partial protection against travellers ' diarrhoea is thus obtainable by active immunisation with BS-WC We have evaluated an oral vaccine based on an Salmonella enteric serovar typhi ( S. typhi ) Ty2 derivative TSB7 harboring deletion mutations in ssaV ( SPI-2 ) and aroC together with a chromosomally integrated copy of eltB encoding the B subunit of enterotoxigenic Escherichia coli heat labile toxin ( LT-B ) in volunteers . Two oral doses of 108 or 109 CFU were administered to two groups of volunteers and both doses were well tolerated , with no vaccinemia , and only transient stool shedding . Immune responses to LT-B and S. typhi lipopolysaccharide were demonstrated in 67 and 97 % of subjects , respectively , without evidence of anti-carrier immunity preventing boosting of LT-B responses in many cases . Further development of this salmonella-based ( spi-VEC ) system for oral delivery of heterologous antigens appears warranted ABSTRACT An oral , microencapsulated anti-colonization factor 6 antigen ( meCS6 ) vaccine , with or without heat-labile enterotoxin with mutation R192 G ( LTR192 G ) ( mucosal adjuvant ) , against enterotoxigenic Escherichia coli ( ETEC ) was evaluated for regimen and adjuvant effects on safety and immunogenicity . Sixty subjects were enrolled into a three-dose , 2-week interval or four-dose , 2-day interval regimen . Each regimen was r and omized into two equal groups of meCS6 alone ( 1 mg ) or meCS6 with adjuvant ( 2 μg of LTR192 G ) . The vaccine was well tolerated and no serious adverse events were reported . Serologic response to CS6 was low in all regimens ( 0 to 27 % ) . CS6-immunogloublin A ( IgA ) antibody-secreting cell ( ASC ) responses ranged from 36 to 86 % , with the highest level in the three-dose adjuvanted regimen ; however , the magnitude was low . As expected , serologic and ASC LT responses were limited to adjuvanted regimens , with the exception of fecal IgA , which appeared to be nonspecific to LT administration . Further modifications to the delivery strategy and CS6 and adjuvant dose optimization will be needed before conducting further clinical trials with this epidemiologically important class of ETEC
BACKGROUND Infection with enterotoxigenic Escherichia coli ( ETEC ) bacteria is a common cause of diarrhoea in adults and children in developing countries and is a major cause of ' travellers ' diarrhoea ' in people visiting or returning from endemic regions .
A killed whole cell vaccine ( Dukoral ® ) , primarily design ed and licensed to prevent cholera , has been recommended by some groups to prevent travellers ' diarrhoea in people visiting endemic regions .
This vaccine contains a recombinant B subunit of the cholera toxin that is antigenically similar to the heat labile toxin of ETEC .
This review aims to evaluate the clinical efficacy of this vaccine and other vaccines design ed specifically to protect people against diarrhoea caused by ETEC infection .
OBJECTIVES To evaluate the efficacy , safety , and immunogenicity of vaccines for preventing ETEC diarrhoea .