Vaccine for E. coli Infections

Recruiting at 1 trial location

Overseen By Robert W. Frenck

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must not be taking: Antibiotics, Corticosteroids, Antipsychotics, others

Disqualifiers: IBD, HIV, Neoplastic disease, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 8

72 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify that you must stop taking your current medications. However, any changes in medication should not be due to a worsening condition, and certain medications like systemic antibiotics and some over-the-counter drugs should not be taken close to the vaccination dates. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment CssBA+dmLT for E. coli infections?

The research on a multi-strain vaccine containing E. coli strains showed that it significantly reduced bladder infections in monkeys, suggesting potential effectiveness in preventing E. coli infections. Additionally, a study on a vaccine using the BamA protein in mice showed a high survival rate, indicating it could be a promising candidate for protecting against E. coli infections. ^{1 2 3 4 5}

How does the CssBA+dmLT treatment for E. coli infections differ from other treatments?

The CssBA+dmLT treatment is unique because it combines a vaccine component with an adjuvant (a substance that enhances the body's immune response) called double-mutant heat-labile toxin (dmLT), which boosts the immune response to the vaccine. This approach is different from traditional treatments as it aims to prevent infections by enhancing immunity rather than treating symptoms after infection occurs. ^{1 4 6 7 8}

What is the purpose of this trial?

The study is designed to evaluate the safety, immunogenicity, and efficacy of the intramuscular administration of a CS6 based vaccine (CssBA) against ETEC co-administered with double mutant labile toxin (dmLT) in preventing moderate-severe diarrhea (MSD) following challenge with ETEC strain B7A in healthy adults. Approximately 72 adult participants, divided into 4 cohorts of 18, will be randomized 1:1 to receive vaccine (45 micrograms CssBA with 0.5 micrograms dmLT) or placebo (normal saline) on an outpatient basis. All participants will receive 3 intramuscular (IM) doses of vaccine or placebo at 3-week intervals (days 1, 22 and 43). Following vaccination, participants will be followed as outpatients for safety using a memory aid from the time of each vaccination through 7 days post each vaccination. Approximately 28 days (plus or minus 1 day) after receipt of the 3rd dose of study agent, participants meeting challenge criteria will be admitted to an inpatient unit and be administered an oral dose of 1 x 10\^10 cfu (colony-forming unit) of ETEC strain B7A. Five days after challenge, participants will be treated with ciprofloxacin, except in cases of known allergy or intolerance. Participants will be discharged from the inpatient unit when they have completed their 3-day antibiotic course and are able to care for themselves. After discharge from the inpatient unit, participants will return for clinic visits and have a phone visit to provide any updates on medication, medical history and AE/SAEs. The primary objectives are: 1) Estimate CssBA+dmLT efficacy in preventing moderate-severe diarrhea (MSD) following challenge with ETEC strain B7A in healthy adults. 2) Evaluate the safety of intramuscular injection of CssBA+dmLT.

Eligibility Criteria

Healthy adults aged 18-49, not pregnant or breastfeeding, with a BMI of 19 to <40 kg/m^2. Participants must be willing to follow the study procedures and use effective contraception if applicable. They should have stable chronic health conditions and no acute illnesses that could affect the trial's outcomes.

Inclusion Criteria

My BMI is between 19 and 40.

My temperature is below 100.4°F (38°C) at enrollment.

I am willing and able to give my consent for the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Vaccination

Participants receive 3 intramuscular doses of vaccine or placebo at 3-week intervals

6 weeks

3 visits (in-person)

Challenge and Treatment

Participants meeting challenge criteria are admitted to an inpatient unit, receive an oral dose of ETEC, and are treated with antibiotics after 5 days

5-8 days

Inpatient stay

Follow-up

Participants are monitored for safety and immunologic parameters after discharge, with outpatient visits and a phone visit

4 weeks

5 visits (in-person), 1 visit (phone)

Treatment Details

Interventions

• CssBA+dmLT

Trial Overview The trial is testing a CS6 based vaccine (CssBA) combined with double mutant labile toxin (dmLT) against ETEC strain B7A-induced moderate-severe diarrhea in healthy adults. Participants will receive three IM doses of either the vaccine or placebo before being exposed to ETEC for efficacy evaluation.

Participant Groups

Group I: Cohort 2A Experimental Treatment 3 Interventions

Participants will receive 45 mcg CssBA with 0.5 mcg dmLT vaccine intramuscular injection on Days 1, 22 and 43, outpatient. Participants who meet the challenge criteria will orally receive 1x10\^10 cfu of ETEC strain B7A, inpatient, approximately 28 days after the third dose of study agent. N= 18.

Group II: Cohort 1A Experimental Treatment 3 Interventions

Participants will receive 45 mcg CssBA with 0.5 mcg dmLT vaccine intramuscular injection on Days 1, 22 and 43, outpatient. Participants who meet challenge criteria will orally receive 1x10\^10 cfu of ETEC strain B7A, inpatient, approximately 28 days after the third dose of study agent. N= 18.

Group III: Cohort 2B Placebo Group 2 Interventions

Participants will receive 0.6 mL of 0.9% normal saline intramuscular injection on Days 1, 22 and 43, outpatient. Participants who meet the challenge criteria will orally receive 1x10\^10 cfu of ETEC strain B7A, inpatient, approximately 28 days after the third dose of study agent. N= 18.

Group IV: Cohort 1B Placebo Group 2 Interventions

Participants will receive 0.6 mL of 0.9% normal saline intramuscular injection on Days 1, 22 and 43, outpatient. Participants who meet challenge criteria will orally receive 1x10\^10 cfu of ETEC strain B7A, inpatient, approximately 28 days after the third dose of study agent . N= 18.

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Findings from Research

The ∆aroA mutant strain of avian pathogenic E. coli was found to be safe for vaccination in chicks, as it did not cause mortality, lesions, or weight loss after administration.

However, the vaccine did not provide significant protection against colibacillosis challenges, likely due to factors like high maternal antibody levels and the vaccination method used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of immunity against avian colibacillosis induced by an aroA mutant containing increased serum survival gene in broilers. Salehi, TZ., Tabatabaei, S., Karimi, V., et al.[2021]

A multi-strain vaccine containing heat-killed uropathogenic bacteria significantly reduced bladder infections in cynomolgus monkeys after being administered either vaginally or intramuscularly following induced E. coli cystitis.

The vaccine demonstrated efficacy against cystitis in both nonhuman primates and humans, suggesting its potential as a viable treatment option for urinary tract infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vaginal immunization of monkeys against urinary tract infection with a multi-strain vaccine. Uehling, DT., Hopkins, WJ., James, LJ., et al.[2019]

The BamA protein from pathogenic E. coli shows high sequence conservation and low allergenicity, making it a promising candidate for a universal vaccine against colibacillosis and related infections from Salmonella and Shigella.

Immunization with the BamA protein significantly increased survival rates in mice (80% survival compared to 20% in the control group), and enhanced the phagocytic activity of neutrophils against E. coli, indicating its potential efficacy as a protective vaccine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In silico analysis and recombinant expression of BamA protein as a universal vaccine against Escherichia coli in mice. Guan, Q., Wang, X., Wang, X., et al.[2017]

The K88ac-3STa-LTB vaccine effectively neutralizes the STa toxin and stimulates strong immune responses, achieving an 85% protection rate in newborn piglets shortly after suckling, indicating its potential efficacy against E. coli diarrhea.

The vaccine was shown to be safe, as it lost the toxicity of the natural STa enterotoxin, and the minimum immunization doses were established at 0.2 mL for mice and 2.5 mL for pregnant sows, ensuring appropriate dosing for effective immunization.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preparation of novel trivalent vaccine against enterotoxigenic Escherichia coli for preventing newborn piglet diarrhea. Xu, C., Peng, K., She, Y., et al.[2023]

Hyperantigenic preparations of synthetic Escherichia coli heat-stable toxin (ST) can create more effective vaccines, showing nearly 10-fold less toxicity compared to traditional ST vaccines while maintaining similar immunogenicity.

Vaccines containing hyperantigenic ST preparations led to significant increases in protective mucosal immunoglobulin A antitoxin levels in rats, indicating enhanced immune response and protection against bacterial challenges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Properties of cross-linked toxoid vaccines made with hyperantigenic forms of synthetic Escherichia coli heat-stable toxin. Klipstein, FA., Engert, RF., Houghten, RA.[2021]

The double-mutant heat-labile toxin (dmLT) significantly enhances antibody responses to all seven antigens in the ETEC adhesin-based vaccine when administered subcutaneously, demonstrating its effectiveness as a parenteral adjuvant.

The optimal dose of dmLT for enhancing immune response was found to be 0.1 µg, indicating that even low doses can effectively boost the efficacy of vaccines, which could be beneficial for developing vaccines against ETEC and potentially other pathogens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant effect of enterotoxigenic Escherichia coli (ETEC) double-mutant heat-labile toxin (dmLT) on systemic immunogenicity induced by the CFA/I/II/IV MEFA ETEC vaccine: Dose-related enhancement of antibody responses to seven ETEC adhesins (CFA/I, CS1-CS6). Seo, H., Lu, T., Mani, S., et al.[2021]

Both live-attenuated and inactivated APEC vaccines provided significant protection against APEC infections in turkeys, indicating their efficacy in preventing acute colibacillosis.

The study found that Th2-biased immune responses were primarily induced by the vaccines, and using Th2-biasing adjuvants enhanced protection, suggesting that both antibody and cell-mediated responses are crucial for effective vaccination against APEC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune responses associated with homologous protection conferred by commercial vaccines for control of avian pathogenic Escherichia coli in turkeys. Sadeyen, JR., Wu, Z., Davies, H., et al.[2018]

Intramuscular vaccination with bacterial ghosts from Escherichia coli CE9 in mice generated a stronger immune response, including higher levels of IgG and IgA antibodies, compared to subcutaneous and oral routes, indicating its potential as an effective prophylactic strategy against colibacillosis.

The intramuscular route not only improved antibody production but also resulted in better survival rates and less tissue damage in vital organs compared to traditional inactivated vaccines and the oral route, highlighting its efficacy in preventing E. coli infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative study of subcutaneous, intramuscular, and oral administration of bovine pathogenic Escherichia coli bacterial ghost vaccine in mice. Mu, J., Lei, L., Zheng, Y., et al.[2022]

References

1. Brazil pubmed.ncbi.nlm.nih.gov

Assessment of immunity against avian colibacillosis induced by an aroA mutant containing increased serum survival gene in broilers. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Vaginal immunization of monkeys against urinary tract infection with a multi-strain vaccine. [2019]

3. Germany pubmed.ncbi.nlm.nih.gov

In silico analysis and recombinant expression of BamA protein as a universal vaccine against Escherichia coli in mice. [2017]

4. United States pubmed.ncbi.nlm.nih.gov

Preparation of novel trivalent vaccine against enterotoxigenic Escherichia coli for preventing newborn piglet diarrhea. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Properties of cross-linked toxoid vaccines made with hyperantigenic forms of synthetic Escherichia coli heat-stable toxin. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Adjuvant effect of enterotoxigenic Escherichia coli (ETEC) double-mutant heat-labile toxin (dmLT) on systemic immunogenicity induced by the CFA/I/II/IV MEFA ETEC vaccine: Dose-related enhancement of antibody responses to seven ETEC adhesins (CFA/I, CS1-CS6). [2021]

7. England pubmed.ncbi.nlm.nih.gov

Immune responses associated with homologous protection conferred by commercial vaccines for control of avian pathogenic Escherichia coli in turkeys. [2018]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Comparative study of subcutaneous, intramuscular, and oral administration of bovine pathogenic Escherichia coli bacterial ghost vaccine in mice. [2022]