Study of Novel Types 1 and 3 Oral Poliomyelitis Vaccines

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the safety (primary objective) and immunogenicity (secondary objective) and fecal shedding of vaccine viruses (secondary objective) of two novel oral polio vaccines, nOPV1 and nOPV3, as compared to Sabin monovalent vaccine controls, in 150-230 healthy adults.

Detailed Description
-----------------
This multicenter trial is the first-in-human assessment of two novel oral polio vaccines for poliovirus type 1 and type 3. It will be an 8-arm, randomized, observer-blind, controlled trial, with Sabin monovalent vaccines serving as the control for each type. One hundred and fifty to 230 healthy, adult participants will be recruited, 70-80 participants with an exclusive inactivated poliovirus vaccine (IPV) prior vaccination history and 120-150 participants with an oral poliomyelitis vaccine (OPV)-containing prior vaccination history.

Official Title
-----------------
A First-in-human, Phase 1, Randomized, Observer-blind, Controlled Study to Assess the Safety and Immunogenicity of Novel Live Attenuated Type 1 and Type 3 Oral Poliomyelitis Vaccines in Healthy Adults

Conditions
-----------------
Poliomyelitis

Intervention / Treatment
-----------------
* Biological: Novel Oral Polio Vaccine Type 1 (nOPV1)
* Biological: Novel Oral Polio Vaccine Type 3 (nOPV3)
* Biological: Sabin Monovalent Oral Polio Vaccine Type 1 (mOPV1)
* Biological: Sabin Monovalent Oral Polio Vaccine Type 3 (mOPV3)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males or females, from 18 to 45 years of age (inclusive) at the time of enrollment Healthy, as defined by the absence of any clinically significant medical conditions, either acute or chronic, as determined by medical history, physical examination, screening laboratory test results, and clinical assessment of the investigator Willing and able to provide written informed consent prior to performance of any study-specific procedure If female and of childbearing potential*, be not breastfeeding and not pregnant (based on a negative serum pregnancy test at screening and a negative urine pregnancy test during the 24 hours prior to any study vaccination), agreeing to have repeated pregnancy tests prior to any study vaccination, and having practiced adequate contraception** for 30 days prior to first study vaccination and willing to continue using adequate contraception consistently for at least 90 days after the last study vaccination and until cessation of vaccine virus shedding is confirmed * Females can be considered not of childbearing potential if they are with current bilateral tubal ligation, occlusion or removal, or post-total hysterectomy, or post-bilateral ovariectomy ** Adequate contraception is defined as a contraceptive method with failure rate of less than 1% per year when used consistently and correctly and when applicable, in accordance with the product label, for example: • Abstinence from penile-vaginal intercourse • Combined estrogen and progesterone oral contraceptives Hormonal (e.g., progestogen) injections Hormonal (e.g., etonogestrel or levonorgestrel) implants Contraceptive vaginal ring Percutaneous contraceptive patches Intrauterine device Intrauterine hormonal system Male condom combined with a vaginal spermicide (foam, gel, film, cream, or suppository), and/or progesterone alone oral contraceptive Monogamous relationship with vasectomized (≥ 180 days prior to enrollment) partner Resides in study area and is able and willing to adhere to all study restrictions and to all study visits and procedures (as evidenced by a signed informed consent form [ICF] and assessment by the investigator) Agrees not to and has no plans to travel outside the United States (US) until confirmation of cessation of vaccine virus shedding in stool at or after the study Day 57 stool collection Able and willing to be contacted by telephone or text, and willing for study staff to leave telephone voice or electronic messages as needed Neutralizing antibody titer ≥ 1:8 for poliovirus type 1 (for participants in cohorts 1 and 2) and ≥ 1:8 for poliovirus type 3 (for participants in cohorts 3 and 4) For Cohorts 1 and 3 only: previously received at least 3 doses of IPV and with no history of receipt of OPV. For Cohorts 2 and 4 only: previously received a primary polio immunization series containing OPV Exclusion Criteria: Have any condition (medical, psychiatric or behavioral) that, in the opinion of the investigator, would increase the participant's health risks in study participation or would increase the risk of not achieving the study's objectives (e.g., would compromise adherence to protocol requirements or interfere with planned safety and immunogenicity assessments) Receipt of polio vaccine within 12 months before the start of the study Having Crohn's disease or ulcerative colitis or having had major surgery of the gastrointestinal tract involving significant loss or resection of the bowel A known allergy, hypersensitivity, or intolerance to any components of the study vaccines, including all macrolide and aminoglycoside antibiotics (e.g., erythromycin and kanamycin) Any confirmed or suspected immunosuppressive or immunodeficiency condition (human immunodeficiency virus [HIV] infection, or total serum immunoglobulin A (IgA) or immunoglobulin G (IgG) level below the testing laboratory's lower limit of normal [LLN]) Administration of any long-acting immune-modifying drugs (e.g., infliximab or rituximab) or the chronic administration (i.e., longer than 14 days) of immunosuppressant drugs (e.g., oral or systemic steroids) or other immune-modifying drugs within 6 months prior to the first vaccine dose or planned use during the study (inhaled and topical steroids are allowed whereas intraarticular and epidural injection/administration of steroids are not allowed) Will have household direct or close professional contact during the study with individuals expected to be immunosuppressed (due to underlying condition or treatments) or individuals who have not yet completed their primary infant polio immunization series (i.e., three doses) Will have household direct or close professional contact during the study with pregnant women Will have household direct or close professional (e.g., neonatal nurses) contact during the study with children less than 2 years of age or with individuals who are encopretic (i.e., infants/toddlers who are not yet toilet trained or other individuals, including adults, with fecal incontinence) Will have professional handling of food, catering, or food production activities during the study Reside in homes with septic tanks Acute illness or fever (body temperature measured orally ≥ 38°C or 100.4°F) at the time of study vaccine administration (once acute illness/fever is resolved, if appropriate, as per investigator assessment, participant may complete screening) Indications of drug abuse or excessive use of alcohol as deemed by the investigator to confound safety assessments or render the participant unable or unlikely to adhere to protocol requirements or provide accurate safety reports Participation in another investigational product (drug or vaccine) clinical trial within 30 days prior to entry in this study or receipt of any such investigational product other than the study vaccine within 30 days prior to the first administration of study vaccine, or planned use during the study period Administration of any vaccine (except seasonal inactivated influenza and COVID-19 vaccines which are prohibited for only 14 days prior to or following each study vaccination) other than the study vaccine or any intramuscular injection within 30 days prior to the first dose of study vaccine or planned administration within 30 days prior to or after any study vaccination. Receipt of transfusion of any blood product or application of immunoglobulins within the 12 weeks prior to the first administration of study vaccine or planned use during the study period Hepatitis B or C virus infection Any hematological# or chemistry** parameter that is out of range of normal†† and is considered clinically significant by the investigator #Complete blood count (CBC), includes hemoglobin, hematocrit, white blood cell (WBC) count, neutrophil count, lymphocyte count, eosinophil count, and platelet count **Creatinine, alanine transaminase (ALT), total bilirubin ††Per the site clinical laboratory's reference ranges. All tests with out of range results that are regarded as clinically significant by the clinician must be repeated and determined to be not clinically significant before any participant can be enrolled. The following hematological or chemistry laboratory results will be considered exclusionary, irrespective of assessment of clinical significance: Hemoglobin (Male) < 12.5 g/dL Hemoglobin (Female) < 11.0 g/dL Neutrophil count < 1,000 cells/mm3 Eosinophil count > 650 cells/mm3 Platelet count < 125,000 cells/mm3 Creatinine > 1.4 mg/dL ALT > 1.1 X Upper limit of normal (ULN) †† ††Per the site clinical laboratory's reference ranges

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: It will be an 8-arm, randomized, observer-blind, controlled trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group1: nOPV1 (IPV History)<br>15-20 healthy adults fully vaccinated against polio exclusively by IPV will be administered 1 vaccination of novel OPV type 1 (nOPV1) containing 10^6.5 CCID50/dose. | Biological: Novel Oral Polio Vaccine Type 1 (nOPV1)<br>* Each 0.1 mL (2 drops) dose of vaccine contains approximately 10^6.5 CCID50.<br>|
| Active Comparator: Group 2: mOPV1 (IPV History)<br>15-20 healthy adults fully vaccinated against polio exclusively by IPV will be administered 1 vaccination of mOPV1 containing 10^6.0 CCID50/dose. | Biological: Sabin Monovalent Oral Polio Vaccine Type 1 (mOPV1)<br>* The Sabin mOPV1 control vaccine contains ≥ 10^6.0 CCID50 per 0.1 mL (2 drops) dose.<br>|
| Experimental: Group 3: nOPV1 (OPV History)<br>30-50 healthy adults fully vaccinated against polio by OPV will be administered 2 vaccinations of nOPV1 containing 10^6.5 CCID50/dose, given 28 days apart. | Biological: Novel Oral Polio Vaccine Type 1 (nOPV1)<br>* Each 0.1 mL (2 drops) dose of vaccine contains approximately 10^6.5 CCID50.<br>|
| Active Comparator: Group 4: mOPV1 (OPV History)<br>15-25 healthy adults fully vaccinated against polio by OPV will be administered 2 doses of mOPV1containing ≥ 10^6.0 CCID50/dose, given 28 days apart | Biological: Sabin Monovalent Oral Polio Vaccine Type 1 (mOPV1)<br>* The Sabin mOPV1 control vaccine contains ≥ 10^6.0 CCID50 per 0.1 mL (2 drops) dose.<br>|
| Experimental: Group 5: nOPV3 (IPV History)<br>15-20 healthy adults fully vaccinated against polio exclusively by IPV will be administered 1 vaccination of nOPV3 containing 10^6.5 CCID50/dose. | Biological: Novel Oral Polio Vaccine Type 3 (nOPV3)<br>* Each 0.1 mL (2 drops) dose of vaccine contains approximately 10^6.5 CCID50.<br>|
| Active Comparator: Group 6: mOPV3 (IPV History)<br>15-20 healthy adults fully vaccination against polio by exclusively IPV will be administered 1 vaccination of mOPV3 containing ≥ 10^5.8 CCID50/dose. | Biological: Sabin Monovalent Oral Polio Vaccine Type 3 (mOPV3)<br>* the Sabin mOPV3 control vaccine contains ≥ 10^5.8 CCID50 per 0.1 mL (2 drops) dose.<br>* Other names: Sabin monovalent oral polio vaccine type 3;|
| Experimental: Group 7: nOPV3 (OPV History)<br>30-50 healthy adults fully vaccinated against polio by OPV will be administered 2 vaccinations of nOPV3 in a dose of 10^6.5 CCID50/dose, given 28 days apart. | Biological: Novel Oral Polio Vaccine Type 3 (nOPV3)<br>* Each 0.1 mL (2 drops) dose of vaccine contains approximately 10^6.5 CCID50.<br>|
| Active Comparator: Group 8: mOPV3 (OPV History)<br>15-25 healthy adults fully vaccinated against polio by OPV will be administered 2 vaccinations of mOPV3 containing ≥ 10^5.8 CCID50/dose, given 28 days apart. | Biological: Sabin Monovalent Oral Polio Vaccine Type 3 (mOPV3)<br>* the Sabin mOPV3 control vaccine contains ≥ 10^5.8 CCID50 per 0.1 mL (2 drops) dose.<br>* Other names: Sabin monovalent oral polio vaccine type 3;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Serious Adverse Events (SAEs) | A serious adverse event is any adverse event that results in any of the following outcomes: Death Is life-threatening Requires inpatient hospitalization or prolongation of existing hospitalization Results in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions Congenital anomaly or birth defect Important medical event that may not result in one of the above outcomes but may jeopardize the health of the study participant and/or require medical or surgical intervention to prevent one of the outcomes listed above | From Day 1 to end of study, up to 169 days | 
| Number of Participants with Solicited Adverse Events (AEs) 7 Days after Each Dose of Study Vaccine | Solicited AEs are pre-specific AEs that are common or known to be associated with vaccination that are actively monitored as potential indicators of vaccine reactogenicity. Solicited AEs for this study are: Fever (oral temperature ≥ 38.0°C or 100.4°F) Chills Fatigue Headache Muscle aches/myalgias Joint aches/arthralgias Nausea Vomiting Abdominal pain Diarrhea | From vaccination to 7 days post vaccination (Day 8 and Day 36) | 
| Number of Participants with Unsolicited Adverse Events (AEs) up to 28 days Post Vaccination | Unsolicited AEs are any AEs reported spontaneously by the participant, observed by the study personnel during study visits or those identified during review of medical records or source documents. In the absence of a diagnosis, abnormal physical examination findings or abnormal clinical safety laboratory test results that are assessed by the investigator to be clinically significant will be reported as an AE. | From vaccination to 28 days post vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Anti-polio Serum Neutralizing Antibody Titers for Poliomyelitis Type 1 at Baseline and Post-vaccination among Participants with a Vaccine History of IPV |  | Baseline and 28 days post-vaccination | 
| Median Anti-polio Serum Neutralizing Antibody Titers for Poliomyelitis Type 1 at Baseline and Post-vaccination among Participants with a Vaccine History of OPV |  | Baseline and 28 days post-vaccination | 
| Median Anti-polio Serum Neutralizing Antibody Titers for Poliomyelitis Type 3 at Baseline and Post-vaccination among Participants with a Vaccine History of IPV |  | Baseline and 28 days post-vaccination | 
| Median Anti-polio Serum Neutralizing Antibody Titers for Poliomyelitis Type 3 at Baseline and Post-vaccination among Participants with a Vaccine History of OPV |  | Baseline and 28 days post-vaccination | 
| Geometric Mean Titer of Anti-polio Serum Neutralizing Antibody Titer for Poliomyelitis Type 1 at Baseline and Post-vaccination among Participants with a Vaccine History of IPV |  | Baseline and 28 days post-vaccination | 
| Geometric Mean Titer of Anti-polio Serum Neutralizing Antibody Titer for Poliomyelitis Type 1 at Baseline and Post-vaccination among Participants with a Vaccine History of OPV |  | Baseline and 28 days post-vaccination | 
| Geometric Mean Titer of Anti-polio Serum Neutralizing Antibody Titer for Poliomyelitis Type 3 at Baseline and Post-vaccination among Participants with a Vaccine History of IPV |  | Baseline and 28 days post-vaccination | 
| Geometric Mean Titer of Anti-polio Serum Neutralizing Antibody Titer for Poliomyelitis Type 3 at Baseline and Post-vaccination among Participants with a Vaccine History of OPV |  | Baseline and 28 days post-vaccination | 
| Geometric Mean Titer Ratio of Anti-polio Serum Neutralizing Antibody Titer for Poliomyelitis Type 1 among Participants with a Vaccine History of IPV |  | 28 days post-vaccination | 
| Geometric Mean Titer Ratio of Anti-polio Serum Neutralizing Antibody Titer for Poliomyelitis Type 1 among Participants with a Vaccine History of OPV |  | 28 days post-vaccination | 
| Geometric Mean Titer Ratio of Anti-polio Serum Neutralizing Antibody Titer for Poliomyelitis Type 3 among Participants with a Vaccine History of IPV |  | 28 days post-vaccination | 
| Geometric Mean Titer Ratio of Anti-polio Serum Neutralizing Antibody Titer for Poliomyelitis Type 3 among Participants with a Vaccine History of OPV |  | 28 days post-vaccination | 
| Percentage of Participants with Any-Fold Rise, 2-fold rise and 4-fold rise in Anti-polio Serum Neutralizing Antibody Titers for Poliomyelitis Type 1 among Participants with a Vaccine History of IPV |  | Baseline and 28 days post-vaccination | 
| Percentage of Participants with Any-Fold Rise, 2-fold rise and 4-fold rise in Anti-polio Serum Neutralizing Antibody Titers for Poliomyelitis Type 1 among Participants with a Vaccine History of OPV |  | Baseline and 28 days post-vaccination | 
| Percentage of Participants with Any-Fold Rise, 2-fold rise and 4-fold rise in Anti-polio Serum Neutralizing Antibody Titers for Poliomyelitis Type 3 among Participants with a Vaccine History of IPV |  | Baseline and 28 days post-vaccination | 
| Percentage of Participants with Any-Fold Rise, 2-fold rise and 4-fold rise in Anti-polio Serum Neutralizing Antibody Titers for Poliomyelitis Type 3 among Participants with a Vaccine History of OPV |  | Baseline and 28 days post-vaccination | 
| Time to Cessation of Fecal Shedding of the Vaccine Virus | The presence of the vaccine virus in stool samples will be assessed using polymerase chain reaction (PCR). Time to cessation of shedding is defined as the time between vaccination and the last PCR-positive stool prior to 2 consecutive PCR-negative stools (with a minimum 24-hour interval between the 2 negative stools). | Up to 169 days | 
| Percentage of Participants Shedding Vaccine Virus at each Post-vaccination Stool Collection in Participants with IPV Vaccination History | Presence of the vaccine virus in stool samples will be assessed by polymerase chain reaction (PCR). | Days 3, 5, 8, 10, 15, 22, 29, 36, 43, 50, and 57 | 
| Amount of Vaccine Virus in each Stool Sample Positive for Virus in Participants with IPV Vaccination History | Samples positive for vaccine virus in stool as detected by PCR will be quantified using a cell culture infectious dose assay. | Days 3, 5, 8, 10, 15, 22, 29, 36, 43, 50, and 57 | 
| Shedding Index of Vaccine Virus Shedding in Stool in Participants with IPV Vaccination History | The Shedding Index Endpoint (SIE) will be computed as the mean of the log10 cell culture infectious dose 50% (CCID50) per gram from nominal collection days 7, 14, 21, and 28 post-dose (i.e., study days 8, 15, 22, and 29 following the first dose). | Days 8, 15, 22, and 29 | 
| Area Under the Curve (AUC) of Vaccine Virus Shed in Stool in Participants with an IPV Vaccination History |  | Day 3, 5, 8, 10, 15, 22, 29, 36, 43, 50, and 57 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Vaccine tolerability, Vaccine reactogenicity, Vaccine viral shedding, Vaccine immunogenicity