A first in human clinical trial assessing the safety and immunogenicity of transcutaneously delivered enterotoxigenic Escherichia coli fimbrial tip adhesin with heat-labile enterotoxin with mutation R192G

Riddle, Mark S.; Maciel, Milton; Porter, Chad K.; Poole, S.; Gutiérrez, Ramiro L.; Gormley, Robert; Laird, Renée M.; Sebeny, Peter J.; Dori, Kathleen E.; Greenleaf, Melissa E.; Hoq, Fahmida; Turiansky, George W.; Jarell, Abel; Hawk, Douglas; Tribble, David R.; Savarino, Stephen J.

doi:10.1016/j.vaccine.2020.09.025

Cited by 19 publications

(13 citation statements)

References 28 publications

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“…Parenteral immunization is suggested to enable a vaccine to protect against mucosal diseases ( 35 ). Indeed, early studies on cholera vaccine candidates ( 36 , 37 ) and more recently on other ETEC vaccine candidates ( 15 , 38 ) showed that parenteral immunization of a protein- or lipopolysaccharide (LPS)-based vaccine candidate induces IgG and/or IgA antibodies to protect against cholera or ETEC diarrhea. While local mucosal immunity, especially that provided by seIgA antibodies, is believed to play a more important role against enteric infections, the current study indicated that rabbits intramuscularly immunized with CFA/I/II/IV MEFA protein or MecVax were protected from ETEC colonization at small intestines, even when no apparent anti-adhesin IgA antibodies were detected.…”

Section: Discussionmentioning

confidence: 99%

“…It was reported that low levels of IgA responses were detected in Aotus nancymaae or human volunteers after parenteral administration of ETEC antigens and that a high dose of adjuvant dmLT attributed to elicitation of IgA response ( 15 , 38 , 39 ). Future rabbit immunization studies with MecVax adjuvanted with a higher dose of dmLT should help us to decipher the role played by dmLT in mounting vaccine antigen-specific IgA responses and whether an elevation of IgA response protects rabbits better from ETEC intestinal colonization.…”

Section: Discussionmentioning

confidence: 99%

“…A vaccine providing broad protection against enterotoxicity of ETEC enterotoxins LT and, especially, STa and also against adhesin-mediated bacterial adherence to host receptors and colonization at small intestines would be effective against ETEC children’s diarrhea and travelers’ diarrhea ( 9 , 10 ). ETEC vaccine candidates currently under clinical investigation primarily target ETEC adhesin antigens and LT toxin ( 11 – 15 ), but they do not carry STa toxin antigens to induce protective antibodies against this key ETEC toxin, which plays a more important role in causing children’s diarrhea and travelers’ diarrhea ( 1 , 2 , 16 ). Different from those candidates, MecVax, an injectable multivalent vaccine candidate composed of two polyvalent protein immunogens, ETEC toxoid fusion 3xSTa N12S -mnLT R192G/L211A and adhesin multiepitope fusion antigen (MEFA) CFA/I/II/IV, induces functional antibodies against adherence of the seven most important ETEC adhesins (CFA/I, CS1 to CS6) and enterotoxicity of LT but also STa toxins ( 17 – 19 ).…”

Section: Introductionmentioning

confidence: 99%

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Intramuscularly Administered Enterotoxigenic Escherichia coli (ETEC) Vaccine Candidate MecVax Prevented H10407 Intestinal Colonization in an Adult Rabbit Colonization Model

Upadhyay

Lauder

et al. 2022

Microbiol Spectr

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An effective ETEC vaccine would prevent hundreds of millions of diarrhea clinical cases and save nearly 100,000 lives annually. MecVax, a protein-based injectable multivalent ETEC vaccine candidate, has been shown for the first time to induce functional antibodies against both ETEC enterotoxins (STa, LT) produced by all ETEC strains and seven ETEC adhesins (CFA/I, CS1 to CS6) expressed by ETEC strains causing a majority of ETEC diarrhea clinical cases and the moderate-to-severe cases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Intramuscularly Administered Enterotoxigenic Escherichia coli (ETEC) Vaccine Candidate MecVax Prevented H10407 Intestinal Colonization in an Adult Rabbit Colonization Model

Upadhyay

Lauder

et al. 2022

Microbiol Spectr

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“…In addition to CssBA, the currently envisioned final vaccine formulation includes CfaEB, CsbDA-CooA, and CotDA. CfaEB, a fusion of the adhesin (CfaE) and pilin (CfaB) subunits of CFA/I, is anticipated to provide coverage against ETEC strains expressing class 5a fimbriae (CFA/I, CS4, and CS14) and is a second generation form of the CfaE antigen that has demonstrated efficacy in Aotus nancymaae and safety and immunogenicity in humans (NCT01382095; NCT01644565; NCT01922856) [41] , [42] . CsbDA-CooA, a pilin-adhesin fusion containing the adhesin (CsbD) and the pilin (CsbA) of CS17 and the pilin of CS1, is anticipated to cover all class 5b fimbriae ETEC strains (CS1, CS17, CS19, and PCFO71).…”

Section: Discussionmentioning

confidence: 99%

Safety and immunogenicity of intramuscularly administered CS6 subunit vaccine with a modified heat-labile enterotoxin from enterotoxigenic Escherichia coli

Lee

Gutiérrez

Maciel

et al. 2021

Vaccine

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Introduction Enterotoxigenic Escherichia coli (ETEC) is a common cause of infectious diarrhoea and a leading cause of morbidity and mortality in children living in resource-limited settings. It is also the leading cause of travellers’ diarrhoea among civilian and military travellers. Its dual importance in global public health and travel medicine highlights the need for an effective vaccine. ETEC express colonization factors (CFs) that mediate adherence to the small intestine. An epidemiologically prevalent CF is coli surface antigen 6 (CS6). We assessed the safety and immunogenicity of a CS6-targeted candidate vaccine, CssBA, co-administered intramuscularly with the double-mutant heat-labile enterotoxin, dmLT [LT(R192G/L211A)]. Methods This was an open-label trial. Fifty subjects received three intramuscular injections (Days 1, 22 and 43) of CssBA alone (5 µg), dmLT alone (0.1 µg) or CssBA (5, 15, 45 µg) + dmLT (0.1 and 0.5 µg). Subjects were actively monitored for adverse events for 28 days following the third vaccination. Antibody responses (IgG and IgA) were characterized in the serum and from lymphocyte supernatants (ALS) to CS6 and the native ETEC heat labile enterotoxin, LT. Results Across all dose cohorts, the vaccine was safe and well-tolerated with no vaccine-related severe or serious adverse events. Among vaccine-related adverse events, a majority (98%) were mild with 79% being short-lived vaccine site reactions. Robust antibody responses were induced in a dose-dependent manner with a clear dmLT adjuvant effect. Response rates in subjects receiving 45 µg CssBA and 0.5 µg dmLT ranged from 50 to 100% across assays. Conclusion This is the first study to demonstrate the safety and immunogenicity of CssBA and/or dmLT administered intramuscularly. Co-administration of the two components induced robust immune responses to CS6 and LT, paving the way for future studies to evaluate the efficacy of this vaccine target and development of a multivalent, subunit ETEC vaccine.

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“…The most advanced of these, based on the donor strand complemented (dsc) tip adhesin structure of CFA/I, dscCfaE, was used previously to generate bovine immune colostral IgG antibodies that afforded robust passive protection against subsequent challenge with H10407 (120). This tip adhesin complex was subsequently tested for immunogenicity when delivered transcutaneously with mutant LT (R192G) via patch in human volunteers (87). Although these studies indicate that additional effort will be required for optimal delivery of the fimbrial tip adhesin complex (121), recent studies of dscCfaE genetically fused in a chimeric complex with the A2 subunit of cholera toxin and the B subunit of LT (dscCfaE-sCTA2/LTB) resulted in substantial protection in an Aotus nancymaae model of infection, following intradermal vaccination with mLT(R192G) (89).…”

Section: Development Of Cf and Cs Subunit Vaccinesmentioning

confidence: 99%

Confronting Challenges to Enterotoxigenic Escherichia coli Vaccine Development

Fleckenstein

2021

Front. Trop. Dis

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The enterotoxigenic Escherichia coli (ETEC) are a diverse and genetically plastic pathologic variant (pathovar) of E. coli defined by their production of heat-labile (LT) and heat-stable (ST) enterotoxins. These pathogens, which came to recognition more than four decades ago in patients presenting with severe cholera-like diarrhea, are now known to cause hundreds of millions of cases of symptomatic infection annually. Children in low-middle income regions of the world lacking access to clean water and basic sanitation are disproportionately affected by ETEC. In addition to acute diarrheal morbidity, these pathogens remain a significant cause of mortality in children under the age of five years and have also been linked repeatedly to sequelae of childhood malnutrition and growth stunting. Vaccines that could prevent ETEC infections therefore remain a high priority. Despite several decades of effort, a licensed vaccine that protects against the breadth of these pathogens remains an aspirational goal, and the underlying genetic plasticity of E. coli has posed a fundamental challenge to development of a vaccine that can encompass the complete antigenic spectrum of ETEC. Nevertheless, novel strategies that include toxoids, a more complete understanding of ETEC molecular pathogenesis, structural details of target immunogens, and the discovery of more highly conserved antigens essential for virulence should accelerate progress and make a broadly protective vaccine feasible.

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A first in human clinical trial assessing the safety and immunogenicity of transcutaneously delivered enterotoxigenic Escherichia coli fimbrial tip adhesin with heat-labile enterotoxin with mutation R192G

Cited by 19 publications

References 28 publications

Intramuscularly Administered Enterotoxigenic Escherichia coli (ETEC) Vaccine Candidate MecVax Prevented H10407 Intestinal Colonization in an Adult Rabbit Colonization Model

Intramuscularly Administered Enterotoxigenic Escherichia coli (ETEC) Vaccine Candidate MecVax Prevented H10407 Intestinal Colonization in an Adult Rabbit Colonization Model

Safety and immunogenicity of intramuscularly administered CS6 subunit vaccine with a modified heat-labile enterotoxin from enterotoxigenic Escherichia coli

Confronting Challenges to Enterotoxigenic Escherichia coli Vaccine Development

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