Safety and immunogenicity of an improved oral inactivated multivalent enterotoxigenic Escherichia coli (ETEC) vaccine administered alone and together with dmLT adjuvant in a double-blind, randomized, placebo-controlled Phase I study

Lundgren, Anna; Bourgeois, Louis; Carlin, Nils; Clements, John D.; Gustafsson, Björn; Hartford, Marianne; Holmgren, Jan; Petzold, Max; Walker, Richard I.; Svennerholm, Ann Mari

doi:10.1016/j.vaccine.2014.10.069

Cited by 117 publications

(145 citation statements)

References 27 publications

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“…Vaccines currently under study attempt to confront this challenge by using multiple live attenuated strains (32) or whole-cell killed strains that each present different CF antigens and are combined with mutant forms or subunits of heat-labile toxin (28). Interestingly, recent studies of more than 800 isolates from ETEC diarrhea cases in Bangladesh demonstrated that only approximately half of the strains expressed colonization factors (CFs) that could be identified by immunoassays (33), and new CF antigens continue to be identified by genomic sequencing (34).…”

Section: Discussionmentioning

confidence: 99%

Immunogenicity and Protective Efficacy against Enterotoxigenic Escherichia coli Colonization following Intradermal, Sublingual, or Oral Vaccination with EtpA Adhesin

Luo

Vickers

Fleckenstein

2016

Clin Vaccine Immunol

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c Enterotoxigenic Escherichia coli (ETEC) strains are a common cause of diarrhea. Extraordinary antigenic diversity has prompted a search for conserved antigens to complement canonical approaches to ETEC vaccine development. EtpA, an immunogenic extracellular ETEC adhesin relatively conserved in the ETEC pathovar, has previously been shown to be a protective antigen following intranasal immunization. These studies were undertaken to explore alternative routes of EtpA vaccination that would permit use of a double mutant (R192G L211A) heat-labile toxin (dmLT) adjuvant. Here, oral vaccination with EtpA adjuvanted with dmLT afforded significant protection against small intestinal colonization, and the degree of protection correlated with fecal IgG, IgA, or total fecal antibody responses to EtpA. Sublingual vaccination yielded compartmentalized mucosal immune responses with significant increases in anti-EtpA fecal IgG and IgA, and mice vaccinated via this route were also protected against colonization. In contrast, while intradermal (i.d.) vaccination achieved high levels of both serum and fecal antibodies against both EtpA and dmLT, mice vaccinated via the i.d. route were not protected against subsequent colonization and the avidity of serum IgG and IgA EtpA-specific antibodies was significantly lower after i.d. immunization compared to other routes. Finally, we demonstrate that antiserum from vaccinated mice significantly impairs binding of LT to cognate GM1 receptors and shows near complete neutralization of toxin delivery by ETEC in vitro. Collectively, these data provide further evidence that EtpA could complement future vaccine strategies but also suggest that additional effort will be required to optimize its use as a protective immunogen. Enterotoxigenic Escherichia coli (ETEC) strains are among the most common causes of diarrheal illness in developing countries, where young children are most susceptible (1, 2). In addition, these pathogens are also a common cause of diarrhea in immunologically naive travelers (3) who venture to areas of endemicity where sanitation and clean water remain limited.Given the significant impact of ETEC on global health, a vaccine to prevent these infections is a significant priority (4). However, despite decades of investigative efforts following the discovery of toxin-producing E. coli in patients with clinical illnesses indistinguishable from cholera (5), a vaccine that affords broadbased protection has yet to be developed.All of the ETEC-specific virulence genes described to date are encoded on plasmids. These include the heat-labile and/or heatstable enterotoxins that define this pathovar and the colonization factors (CFs). Most vaccines to date have primarily targeted these colonization factors, which include a broad array of fimbrial as well as afimbrial surface antigens thought to be essential for intestinal colonization and/or heat-labile toxin.Unfortunately, the heterogeneity of CF antigenic structures presents a challenge to development of a broadly protective vaccine. ...

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Section: Discussionmentioning

confidence: 99%

Immunogenicity and Protective Efficacy against Enterotoxigenic Escherichia coli Colonization following Intradermal, Sublingual, or Oral Vaccination with EtpA Adhesin

Luo

Vickers

Fleckenstein

2016

Clin Vaccine Immunol

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“…There is convincing evidence indicating that CFA/I fimbriae can serve as a protective antigen (9)(10)(11), and further proof-of-principle is awaited from clinical studies of CFA/I-containing live and inactivated wholecell ETEC vaccines currently in development (17)(18)(19). In vitro studies indicate that CfaE plays an essential role in binding of CFA/I-ETEC to intestinal cells (6,51).…”

Section: Discussionmentioning

confidence: 99%

“…LT and LT-like vaccines have been shown to confer protection but are hampered by limited coverage and durability (12)(13)(14). New whole-cell live and inactivated vaccines containing both fimbriae and LT-based components are currently in clinical evaluation (17)(18)(19). Elucidation of the structure and function of CFA/I fimbriae suggests an alternative approach that targets the tip-localized adhesin to more specifically elicit antiadhesive immunity to abrogate the initial step of ETEC colonization.…”

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confidence: 99%

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

et al. 2015

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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.

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“…This led to regulatory authorities cautioning against the intranasal use of GM1 binding adjuvants [127] although these molecules may still hold significant promise as oral adjuvants where they can exhibit unique potency. Recently a double mutant LT (dmLT) was developed [128], having greater stability in the presence of trypsin, strong oral adjuvant properties [129] and an acceptable enterotoxicity profile, even at high doses, and is currently being assessed as part of a prototype oral ETEC vaccine in clinical trials [130].…”

Section: Mucosal Adjuvantsmentioning

confidence: 99%

Delivery strategies to enhance oral vaccination against enteric infections

Davitt

Lavelle

2015

Advanced Drug Delivery Reviews

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102

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Safety and immunogenicity of an improved oral inactivated multivalent enterotoxigenic Escherichia coli (ETEC) vaccine administered alone and together with dmLT adjuvant in a double-blind, randomized, placebo-controlled Phase I study

Cited by 117 publications

References 27 publications

Immunogenicity and Protective Efficacy against Enterotoxigenic Escherichia coli Colonization following Intradermal, Sublingual, or Oral Vaccination with EtpA Adhesin

Immunogenicity and Protective Efficacy against Enterotoxigenic Escherichia coli Colonization following Intradermal, Sublingual, or Oral Vaccination with EtpA Adhesin

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

Delivery strategies to enhance oral vaccination against enteric infections

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