Inactivated Poliovirus Vaccine (IPV) With or Without E.Coli Double Mutant Heat-Labile Toxin (dmLT) Challenge Study in Healthy Adults

Study Overview
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Brief Summary
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In this study, the safety and tolerability of inactivated polio vaccine (IPV) co-administered with dmLT will be assessed, as well as whether co-administration of dmLT with IPV enhances mucosal responses compared to those with IPV alone.

Detailed Description
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A major component of the strategy aimed at worldwide eradication of polio advanced by the World Health Organization (WHO) is based on the replacement of oral polio vaccine (OPV) with IPV; however, IPV is not efficient in preventing person-to-person poliovirus transmission, particularly in settings of poor hygiene, due to limited impact on intestinal mucosal immunity compared to OPV. The addition of an adjuvant, in particular one that may direct the response towards mucosal homing may offset that deficiency. In this study, the safety and tolerability of IPV co-administered with dmLT will be assessed, as well as whether co-administration of dmLT with IPV enhances mucosal responses to polioviruses types 1, 2, and 3 in comparison with administration of IPV alone and provides greater mucosal immunity, assessed following oral bOPV challenge. The positive control arm (bOPV) is included in order to confirm the level of shedding observable following a dose of an oral vaccine known to develop intestinal immunity.

Official Title
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A Phase 1 Randomized Study to Examine the Safety, Tolerability, and Immunogenicity of Inactivated Poliovirus Vaccine (IPV) With or Without E.Coli Double Mutant Heat Labile Toxin (dmLT) and Impact on Poliovirus Shedding Post-bOPV Challenge in Healthy IPV-Primed Adult Subjects

Conditions
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Polio

Intervention / Treatment
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* Biological: Inactivated Poliomyelitis Vaccine (IPV)
* Biological: E.coli Double Mutant Heat-Labile Toxin (dmLT) (adjuvant)
* Biological: Bivalent Oral Polio Vaccine (bOPV)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult male or female, ages 18-45, inclusive Healthy as defined by absence of clinically significant medical condition, either acute or chronic, as determined by medical history and clinical assessment History of prior receipt of at least 3 doses of IPV Willing and able to provide written informed consent and willing to comply with study requirements Intention to remain in the area during the study period If female and of childbearing potential, not breastfeeding and not pregnant (based on a negative serum pregnancy test at screening and negative urine pregnancy tests prior to vaccine administration and bOPV challenge), planning to avoid pregnancy until at least three months after bOPV challenge, and willing to use an adequate method of contraception consistently. Effective methods include intrauterine device or hormonal contraceptives (oral, injectable, patch, implant, vaginal ring). Women with credible history of abstinence or in monogamous relationship with a vasectomized partner are also eligible. Exclusion Criteria: History of receiving any OPV at any time Receipt of IPV in the last five years History of or planned household contact with an individual receiving OPV in prior 4 weeks, or at any point during the study Regular contact with children younger than six months (and thus not yet fully vaccinated against polio) and immunocompromised individuals Presence of fever on the day of vaccination (oral temperature ≥ 38°C) Received an investigational product within 30 days prior to randomization or planning to participate in another research study involving investigational product during the conduct of this study Presence of any systemic disorder (cardiovascular, pulmonary, hepatic, renal, gastrointestinal, hematological, endocrine, immunological, dermatological, neurological, cancer or autoimmune diseases) as determined by medical history and/or physical examination that would compromise the participant's health or is likely to result in nonconformance to the protocol or would interfere with the evaluation of responses according to the opinion of the investigator History of allergic disease or known hypersensitivity to any component of the study vaccine History of anaphylactic reaction Receipt of any immunoglobulin therapy and/or blood products in the last 6 months or planned administration during the study period History of chronic administration (defined as more than 14 days) of immunosuppressant medications, including oral steroids, parenteral steroids, or high-dose inhaled steroids (> 800 μg/day of beclomethasone dipropionate or equivalent), in the last 6 months to either the study subject or their close household contacts (those on nasal or topical steroids may be permitted to participate in the study) Symptoms of an acute self-limited illness, such as an upper respiratory infection or gastroenteritis, including a temperature ≥ 38.0°C, within the 7 days prior to study vaccines administration Positive test for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody Clinically significant screening laboratory value History of receipt of experimental E. coli, enterotoxigenic E. coli (ETEC) labile toxin (LT), or cholera vaccines or live E. coli or Vibrio cholerae challenges. Receipt of any licensed vaccine within 28 days before enrollment in this study or plans to receive any licensed vaccine between enrollment and 28 days after the bOPV challenge History of alcohol or drug abuse in the last 5 years Any condition that in the opinion of the investigator would pose a health risk to the subject if enrolled, or could interfere with the evaluation of the study vaccine

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will receive a single dose of licensed trivalent IPV, administered intramuscularly (IM), with or without dmLT, or bOPV, administered orally (PO). IPV or IPV + dmLT will be administered to groups of 30 participants each. Both participants and clinical staff will be blinded to group assignment (IPV alone vs IPV + dmLT). A positive unblinded control group will be included, composed of 20 participants receiving bOPV. One month (28 days) after receiving study vaccine, all participants will receive a standard oral dose of bOPV to assess relative impact of study vaccine on shedding of that challenge virus.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Inactivated Poliomyelitis Vaccine (IPV)<br>Participants will receive a single intramuscular injection of 0.5 mL inactivated poliomyelitis vaccine (IPV) on Day 1 followed by a single dose (2 drops) of bivalent oral polio vaccine (bOPV) 28 days later. | Biological: Inactivated Poliomyelitis Vaccine (IPV)<br>* IMOVAX® Polio is a highly purified, inactivated poliovirus vaccine. Each 0.5 mL dose contains: Type 1 (Mahoney) 40 D-antigen units Type 2 (MEF1) 8 D-antigen units Type 3 (Saukett) 32 D-antigen units<br>* Other names: IMOVAX® Polio Vaccine;Biological: Bivalent Oral Polio Vaccine (bOPV)<br>* Polio Sabin™ One and Three (oral) is a bivalent, live attenuated poliomyelitis virus vaccine of the Sabin strains Type 1 (LSc, 2ab) and Type 3 (Leon 12a, 1b), propagated in MRC5 human diploid cells. Each dose (0.1 mL) contains not less than 10⁶ 50% cell culture infectious dose (CCID₅₀) of Type 1 and 10⁵·⁸ CCID₅₀ of Type 3.<br>* Other names: Polio Sabin™ One and Three (Oral);|
| Experimental: Inactivated Poliomyelitis Vaccine + dmLT<br>Participants will receive a single intramuscular injection of 0.5 mL IPV co-administered with 0.5 μg of dmLT on Day 1 followed by a single dose (2 drops) of bOPV 28 days later. | Biological: Inactivated Poliomyelitis Vaccine (IPV)<br>* IMOVAX® Polio is a highly purified, inactivated poliovirus vaccine. Each 0.5 mL dose contains: Type 1 (Mahoney) 40 D-antigen units Type 2 (MEF1) 8 D-antigen units Type 3 (Saukett) 32 D-antigen units<br>* Other names: IMOVAX® Polio Vaccine;Biological: E.coli Double Mutant Heat-Labile Toxin (dmLT) (adjuvant)<br>* LT (R192G/L211A), or dmLT, is a protein toxoid derived from wild-type enterotoxigenic Escherichia coli (ETEC) labile toxin (LT). The LT toxin has been shown to have inherent mucosal adjuvant properties for co-administered antigens and thus has potential as a mucosal adjuvant for different co-administered vaccines. LT has been genetically modified by replacing the arginine at amino acid position 192 with glycine and the leucine at amino acid position 211 with alanine. These two amino acid substitutions take place in proteolytic cleavage sites, which are critical for activation of the secreted toxin molecules.<br>* Other names: LT (R192G/L211A);Biological: Bivalent Oral Polio Vaccine (bOPV)<br>* Polio Sabin™ One and Three (oral) is a bivalent, live attenuated poliomyelitis virus vaccine of the Sabin strains Type 1 (LSc, 2ab) and Type 3 (Leon 12a, 1b), propagated in MRC5 human diploid cells. Each dose (0.1 mL) contains not less than 10⁶ 50% cell culture infectious dose (CCID₅₀) of Type 1 and 10⁵·⁸ CCID₅₀ of Type 3.<br>* Other names: Polio Sabin™ One and Three (Oral);|
| Active Comparator: Bivalent Oral Polio Vaccine<br>Participants will receive one dose (2 drops) of bOPV on Day 1 followed by a second dose of bOPV 28 days later. | Biological: Bivalent Oral Polio Vaccine (bOPV)<br>* Polio Sabin™ One and Three (oral) is a bivalent, live attenuated poliomyelitis virus vaccine of the Sabin strains Type 1 (LSc, 2ab) and Type 3 (Leon 12a, 1b), propagated in MRC5 human diploid cells. Each dose (0.1 mL) contains not less than 10⁶ 50% cell culture infectious dose (CCID₅₀) of Type 1 and 10⁵·⁸ CCID₅₀ of Type 3.<br>* Other names: Polio Sabin™ One and Three (Oral);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serious Adverse Events Over the Course of the Study | A serious adverse event (SAE) was any event that resulted in any of the following outcomes: Death; Was life-threatening; Required inpatient hospitalization or prolongation of existing hospitalization; Resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; Congenital abnormality or birth defect; Important medical event that did not result in one of the above outcomes but jeopardized the health of the study participant or required medical or surgical intervention to prevent one of the outcomes listed in the above definition of SAE. | Up to 6 months | 
| Number of Participants With Severe Adverse Events During the 28 Days Following Study Vaccination | Severe adverse events are events that interrupted a participant's usual daily activity and may have required systemic drug therapy or other treatment. Severe events are usually potentially life-threatening or incapacitating. | Up to 28 days after study vaccination (prior to bOPV challenge) | 
| Number of Participants With Solicited Local Adverse Events | Solicited adverse events (AEs) are pre-specified local and systemic adverse events that are common or known to be associated with vaccination and that are actively monitored as indicators of vaccine reactogenicity. Local/injection site reactions included pain, erythema/redness, swelling, induration, and hyperpigmentation, applicable to participants in the IPV and IPV + dmLT arms who received study injections. Severity was graded according to the following: Mild: Transient or mild discomfort; does not interfere with activities, erythema or swelling 2.5 - 5 cm, hyperpigmentation 1- 4 cm. Moderate: Mild to moderate limitation in activity; no or minimal medical intervention/therapy required, erythema or swelling 5.1 - 10 cm, hyperpigmentation 4.1 - 8 cm, or repeated use of nonnarcotic pain reliever > 24 hours. Severe: All normal activity is prevented for 24 hours or more, erythema or swelling > 10 cm, hyperpigmentation > 8 cm, or any use of narcotic pain reliever. | 7 days following study vaccination | 
| Number of Participants With Solicited Systemic Adverse Events | Systemic reactions included fever (oral temperature ≥ 38.0°C), chills, fatigue, headache, muscle aches/myalgia, joint ache/arthralgia, rash, nausea, vomiting, and diarrhea. Severity was graded according to the following: Mild: Transient or mild discomfort; does not interfere with activities, 2-3 vomiting episodes in 24 hours, 3-5 loose stools/day or diarrhea volume <1000 mL/day, or temperature 38.0 - 38.9˚C. Moderate: Mild to moderate limitation in activity; no or minimal medical intervention/therapy required, 4-5 vomiting episodes in 24 hours, 6-9 loose stools/day or 1000-1999 mL output per 24 hours, or temperature 39.0 - 39.9˚C. Severe: All normal activity is prevented for 24 hours or more, > 6 vomiting episodes in 24 hours, > 10 loose stools/day or orthostatic hypotension, or temperature > 40.0˚C. | 7 days following study vaccination | 
| Number of Participants With Unsolicited Adverse Events During the 28 Days Following Study Vaccination | An adverse event is any untoward medical occurrence in a participant after administration of the investigational vaccine and that does not necessarily have a causal relationship with the investigational vaccine. AEs were graded for severity on the following scale: Grade 1 - Mild: Transient or mild discomfort; does not interfere with activities; Grade 2 - Moderate: Mild to moderate limitation in activity; no or minimal medical intervention/therapy required; Grade 3 - Severe: All normal activity is prevented for 24 hours or more. | 28 days following study vaccination | 
| Percentage of Participants Positive for bOPV Viral Shedding 7 Days Following bOPV Challenge | The presence of the bOPV virus (Sabin strains Type 1 and Type 3) in stool samples was determined using polymerase chain reaction (PCR). | Day 36 (7 days after bOPV challenge) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Positive Poliovirus Fecal Neutralization Response 28 Days After Vaccination and 14 Days After bOPV Challenge | Positive response is defined as a minimum 4-fold increase from the pre-vaccination (Baseline) value in fecal anti-poliovirus neutralization antibodies. Serotype-specific poliovirus neutralizing antibody quantitation was conducted using standardized assays at the Wright Laboratory at Dartmouth University. | Day 29 (28 days after study vaccination) and Day 43 (14 days after bOPV challenge) | 
| Level of Fecal Poliovirus Immunoglobulin A (IgA) Antibodies at Baseline, 28 Days After Vaccination and 14 Days After bOPV Challenge | Fecal IgA were quantified using a Luminex assay in which monovalent IPVs are covalently conjugated to fluorescently coated beads in order to quantify total and polio-type specific concentrations of IgA in stool specimens. | Baseline (before vaccination), Day 29 (28 days after study vaccination, prior to bOPV challenge) and Day 43 (14 days after bOPV challenge) | 
| Change From Baseline in Fecal Poliovirus IgA Antibodies 28 Days After Study Vaccination and 14 Days After bOPV Challenge |  | Baseline, Day 29 (28 days after study vaccination, prior to bOPV challenge) and Day 43 (14 days after bOPV challenge) | 
| Serum Neutralizing Antibody Seroconversion Rate 28 Days After Study Vaccination | Serum neutralizing antibody seroconversion rate is defined as the percentage of participants demonstrating a minimum four-fold increase in type-specific poliovirus serum neutralizing antibody titers between baseline and 28 days post vaccination, or post-vaccination titer > 1:8 if seronegative at baseline. | Day 29 (28 days after study vaccination, prior to bOPV challenge) | 
| Geometric Mean Titer of Serum Poliovirus Neutralizing Antibodies at Baseline and 28 Days After Study Vaccination |  | Baseline (pre-vaccination) and Day 29 (28 days after study vaccination, prior to bOPV challenge) | 
| Seroprotection Rate of Serum Poliovirus Neutralizing Antibodies at Baseline and 28 Days Following Vaccination | Seroprotection rate of serum poliovirus neutralizing antibodies is defined as a type-specific poliovirus serum neutralizing antibody titer ≥ 1:8. | Baseline (before vaccination) and Day 29 (28 days after vaccination, prior to bOPV challenge) | 
| Geometric Mean Fold-Rise in Serum Poliovirus Neutralizing Antibodies |  | Baseline (before vaccination) and Day 29 (28 days after vaccination, prior to bOPV challenge) | 
| Percentage of Participants With a Circulating Poliovirus IgA Antibody-Secreting Cell Response | Poliovirus antibody secreting cell (ASC) response is defined as ≥ 8 ASC/10⁶ peripheral blood mononuclear cells (PBMC) at any time point following both study vaccination and bOPV challenge. | Baseline (pre-vaccination), Day 8 (7 days after study vaccination), Day 29 (28 days after study vaccination prior to bOPV challenge), and Day 36 (7 days after bOPV challenge) | 
| Number of Circulating Poliovirus IgA Antibody Secreting Cells at Baseline and After Study Vaccination |  | Baseline (pre-vaccination), Day 8 (7 days after study vaccination), Day 29 (28 days after study vaccination prior to bOPV challenge), and Day 36 (7 days after bOPV challenge) | 
| Percentage of Participants With a Circulating Poliovirus Immunoglobulin G (IgG) Antibody-Secreting Cell Response | Poliovirus antibody secreting cell (ASC) response is defined as ≥ 8 ASC/10⁶ peripheral blood mononuclear cells (PBMC) at any time point following both study vaccination and bOPV challenge. | Baseline (pre-vaccination), Day 8 (7 days after study vaccination), Day 29 (28 days after study vaccination prior to bOPV challenge), and Day 36 (7 days after bOPV challenge) | 
| Number of Circulating Poliovirus IgG Antibody Secreting Cells at Baseline and After Study Vaccination |  | Baseline (pre-vaccination), Day 8 (7 days after study vaccination), Day 29 (28 days after study vaccination prior to bOPV challenge), and Day 36 (7 days after bOPV challenge) | 
| Area Under the Curve (AUC) of Viral Shedding in Stool for 28 Days After bOPV Challenge | AUC was calculated using the linear trapezoidal rule with all samples collected from Day 33 to 57. | Days 33, 36, 43, 50, and 57 (i.e., 4, 7, 14, 21, and 28 days, respectively, following bOPV challenge). | 
| Time to Cessation of Viral Shedding in Stool After bOPV Challenge | Time to cessation of viral shedding in stool is defined as the study day of the first instance of 3 consecutive samples PCR-negative for virus, with samples taken on separate days. | Days 33, 36, 39, 43, 46, 50, and 57 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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inactivated polio vaccine (IPV), double mutant [LT(R192G/L211A)] Enterotoxigenic E coli heat toxin (dmLT)