Study of Novel Types 1 and 3 Oral Poliomyelitis Vaccines

PATH226 enrolled

Overview

The purpose of this study is to assess the safety (primary objective), the ability to trigger the production of antibodies (immunogenicity; a secondary objective) and presence of vaccine virus in the stool (fecal shedding; a secondary objective) of two novel oral polio vaccines (nOPV), novel oral poliomyelitis vaccine type 1 (nOPV1) and novel oral poliomyelitis vaccine type 3 (nOPV3), as compared to Sabin strain monovalent oral poliomyelitis vaccine (mOPV) controls, in healthy adults.

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 a 4-cohort, 8-arm, randomized, observer-blind, controlled trial, with Sabin monovalent vaccines serving as the control for each type: Cohort 1: Healthy adults with an exclusive inactivated poliovirus vaccine (IPV) prior vaccination history will be randomized in a 1:1 ratio and allocated to receive nOPV1 (Group 1) or mOPV1 (Group 2). Cohort 2: Healthy adults with an OPV-containing prior vaccination history will be randomized in a 2:1 ratio and allocated to receive two doses of nOPV1 (Group 3) or mOPV1 (Group 4), respectively; Cohort 3: Healthy adults with an exclusive IPV prior vaccination history will be randomized in a 1:1 ratio and allocated to receive nOPV3 (Group 5) or mOPV3 (Group 6); Cohort 4: Healthy adults with an OPV-containing prior vaccination history will be randomized in a 2:1 ratio to study groups 3 and 4 and allocated to receive two doses of nOPV3 (Group 7) or mOPV3 (Group 8), respectively.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

TRIPLE

Enrollment

226

Conditions

Poliomyelitis

Interventions

Novel Oral Polio Vaccine Type 1 (nOPV1)BIOLOGICAL

Each 0.1 mL (2 drops) dose of vaccine contains approximately 10\^6.5 CCID50.

Novel Oral Polio Vaccine Type 3 (nOPV3)BIOLOGICAL

Each 0.1 mL (2 drops) dose of vaccine contains approximately 10\^6.5 CCID50.

Sabin Monovalent Oral Polio Vaccine Type 1 (mOPV1)BIOLOGICAL

The Sabin mOPV1 control vaccine contains ≥ 10\^6.0 CCID50 per 0.1 mL (2 drops) dose.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 45 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: 1. Males or females, from 18 to 45 years of age (inclusive) at the time of enrollment 2. 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 3. Willing and able to provide written informed consent prior to performance of any study-specific procedure 4. 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 5. 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) 6. 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 7. Able and willing to be contacted by telephone or text, and willing for study staff to leave telephone voice or electronic messages as needed 8. 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) 9. 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: 1. 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) 2. Receipt of polio vaccine within 12 months before the start of the study 3. Having Crohn's disease or ulcerative colitis or having had major surgery of the gastrointestinal tract involving significant loss or resection of the bowel 4. A known allergy, hypersensitivity, or intolerance to any components of the study vaccines, including all macrolide and aminoglycoside antibiotics (e.g., erythromycin and kanamycin) 5. 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 \[LLN\]) 6. 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) 7. 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) 8. Will have household direct or close professional contact during the study with pregnant women 9. 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) 10. Will have professional handling of food, catering, or food production activities during the study 11. Reside in homes with septic tanks 12. 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) 13. 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 14. 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 15. 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. 16. 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 17. Hepatitis B or C virus infection 18. 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. 19. 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/mm\^3 * Eosinophil count \> 650 cells/mm\^3 * Platelet count \< 125,000 cells/mm\^3 * Creatinine \> 1.4 mg/dL * ALT \> 1.1 X upper limit of normal (ULN) (per the site clinical laboratory's reference ranges)

Locations (4)

Pharmaron CPC, Inc.

Baltimore, Maryland, United States

Dartmouth Hitchcock Medical Center

Lebanon, New Hampshire, United States

University of North Carolina Institute for Global Health and Infectious Diseases (IGHID)

Chapel Hill, North Carolina, United States

University of Vermont Vaccine Testing Center

Burlington, Vermont, United States

Outcomes

Primary Outcomes

Number of Participants With Serious Adverse Events (SAEs)

A serious adverse event is any adverse 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 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

Time frame: From Day 1 to end of study, up to 169 days

Number of Participants With Solicited Adverse Events (AEs) 7 Days After First Dose of Study Vaccine

Solicited AEs are pre-specified 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 included: * Fever (oral temperature ≥ 38.0°C or 100.4°F) * Chills * Fatigue * Headache * Muscle aches/myalgias * Joint aches/arthralgias * Nausea * Vomiting * Abdominal pain * Diarrhea

Time frame: From vaccination to 7 days post vaccination (Days 1-7)

Number of Participants With Solicited Adverse Events 7 Days After Second Dose of Study Vaccine

Time frame: From Day 29 to Day 35

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 were reported as an AE.

Data from ClinicalTrials.gov

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Secondary Outcomes

Median Anti-poliovirus Type 1 Serum Neutralizing Antibody Titers at Baseline and Post-vaccination Among Participants With a Vaccine History of IPV

Blood samples collected from participants for type-specific poliovirus neutralizing antibodies were analyzed at the Polio and Picornavirus Laboratory Branch at the United States Centers for Disease Control and Prevention (CDC). For all immunogenicity endpoints, data are presented separately by: * Prior vaccination history (exclusively IPV vs OPV), and * Type-specific poliovirus vaccine received (type 1 vs type 3).

Time frame: Baseline and Day 29 (28 days post-vaccination)

Median Anti-poliovirus Type 1 Serum Neutralizing Antibody Titers at Baseline and Post-vaccination Among Participants With a Vaccine History of OPV

Time frame: Baseline, Day 29 (28 days post-vaccination) and Day 57 (28 days after 2nd vaccination)

Median Anti-poliovirus Type 3 Serum Neutralizing Antibody Titers at Baseline and Post-vaccination Among Participants With a Vaccine History of IPV

Time frame: Baseline and Day 29 (28 days post-vaccination)

Median Anti-poliovirus Type 3 Serum Neutralizing Antibody Titers at Baseline and Post-vaccination Among Participants With a Vaccine History of OPV

Time frame: Baseline, Day 29 (28 days after the 1st vaccination) and Day 57 (28 days after 2nd vaccination)

Geometric Mean Titer (GMT) of Anti-poliovirus Type 1 Serum Neutralizing Antibodies at Baseline and Post-vaccination Among Participants With a Vaccine History of IPV

GMT and 95% confidence intervals are maximum likelihood estimates incorporating left and right censoring at the lower limit of quantitation (LLOQ) and ULOQ, respectively.

Time frame: Baseline and Day 29 (28 days post-vaccination)

Geometric Mean Titer of Anti-poliovirus Type 1 Serum Neutralizing Antibodies at Baseline and Post-vaccination Among Participants With a Vaccine History of OPV

Time frame: Baseline, Day 29 (28 days after 1st vaccination) and Day 57 (28 days after 2nd vaccination)

Geometric Mean Titer of Anti-poliovirus Type 3 Serum Neutralizing Antibodies at Baseline and Post-vaccination Among Participants With a Vaccine History of IPV

Time frame: Baseline and Day 29 (28 days post-vaccination)

Geometric Mean Titer of Anti-poliovirus Type 3 Serum Neutralizing Antibodies at Baseline and Post-vaccination Among Participants With a Vaccine History of OPV

Time frame: Baseline, Day 29 (28 days after 1st vaccination) and Day 57 (28 days after 2nd vaccination)

Percentage of Participants With Any-Fold Rise, 2-fold Rise and 4-fold Rise in Anti-poliovirus Type 1 Serum Neutralizing Antibody Titers From Baseline to 28 Days After Vaccination Among Participants With a Vaccine History of IPV

* Seroconversion (SCR) is defined as a minimum 4-fold increase in titer from Baseline (pre-vaccination) to 28 days post-vaccination among those participants with a 4-fold increase possible to observe, i.e., with a Baseline titer not greater than 8.5 log₂. * Minimum 2-fold-rise from Baseline to 28 days post-vaccination among those participants with a 2-fold increase possible to observe, i.e., with a Baseline titer not greater than 9.5 log₂. * Any fold-rise is defined as any increase in titer from Baseline to 28 days post-vaccination (log₂ neutralizing antibody titer post-dose minus Baseline \> 0), among those with an increase possible to observe, i.e., with a Baseline titer less than 10.5 log₂.

Time frame: Baseline (pre-vaccination) and Day 29 (28 days post-vaccination)

Percentage of Participants With Any-Fold Rise, 2-fold Rise and 4-fold Rise in Anti-poliovirus Type 1 Serum Neutralizing Antibody Titers From Baseline to 28 Days After Each Vaccination Among Participants With a Vaccine History of OPV

Time frame: Baseline, Day 29 (28 days post-vaccination) and Day 57 (28 days after 2nd vaccination)

Percentage of Participants With Any-Fold Rise, 2-fold Rise and 4-fold Rise in Anti-poliovirus Type 3 Serum Neutralizing Antibody Titers From Baseline to 28 Days After Vaccination Among Participants With a Vaccine History of IPV

Time frame: Baseline and Day 29 (28 days post-vaccination)

Percentage of Participants With Any-Fold Rise, 2-fold Rise and 4-fold Rise in Anti-poliovirus Type 3 Serum Neutralizing Antibody Titers From Baseline to 28 Days After Each Vaccination Among Participants With a Vaccine History of OPV

Time frame: Baseline, Day 29 (28 days after 1st vaccination) and Day 57 (28 days after 2nd vaccination)

Time to Cessation of Fecal Shedding of Vaccine Virus in Participants With IPV Vaccination History

The presence of the vaccine virus in stool samples was 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). The time to cessation of fecal shedding of nOPV1 and nOPV3 in prior IPV recipients was estimated using Kaplan-Meier methodology with interval-censoring.

Time frame: Up to Day 57

Time to Cessation of Fecal Shedding of Vaccine Virus in Participants With OPV Vaccination History

The presence of the vaccine virus in stool samples was 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). The time to cessation of fecal shedding of nOPV1 and nOPV3 in prior OPV recipients was evaluated separately after each dose, estimated using Kaplan-Meier methodology with interval-censoring.

Time frame: From vaccination through 28 days after each vaccination

Percentage of Participants Shedding Type 1 Vaccine Virus at Each Post-vaccination Stool Collection in Participants With IPV Vaccination History

Presence of the vaccine virus in stool samples was assessed by polymerase chain reaction (PCR). This endpoint was pre-specified to be analyzed in participants with IPV vaccination history.

Time frame: Days 3, 5, 8, 10, 15, 22, 29, 36, 43, 50, and 57

Percentage of Participants Shedding Type 3 Vaccine Virus at Each Post-vaccination Stool Collection in Participants With IPV Vaccination History

Presence of the vaccine virus in stool samples was assessed by polymerase chain reaction (PCR). This endpoint was pre-specified to be analyzed in participants with IPV vaccination history.

Time frame: Days 3, 5, 8, 10, 15, 22, 29, 36, 43, 50, and 57

Amount of Type 1 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 were quantified using a cell culture infectious dose assay. Participants who were PCR-positive for type 1 viral shedding but with log₁₀ CCID50 per gram ≤ LLOQ contributed a value equal to the LLOQ. This endpoint was pre-specified to be analyzed in participants with IPV vaccination history.

Time frame: Days 3, 5, 8, 10, 15, 22, 29, 36, 43, 50, and 57

Amount of Type 3 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 were quantified using a cell culture infectious dose assay. Participants who were PCR-positive for type 3 viral shedding but with log₁₀ CCID50 per gram ≤ LLOQ contributed a value equal to the LLOQ. This endpoint was pre-specified to be analyzed in participants with IPV vaccination history.

Time frame: 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) was 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). Participants who were PCR-positive for type-specific viral shedding but with log₁₀ CCID50 per gram ≤ LLOQ contributed a value equal to the LLOQ. This endpoint was pre-specified to be analyzed in participants with IPV vaccination history.

Time frame: Days 8, 15, 22, and 29

Area Under the Curve From Vaccination to 28 Days After Vaccination (AUC₀-₂₈) of Vaccine Virus Shed in Stool in Participants With an IPV Vaccination History

Area under the curve (AUC) was computed for each participant using CCID50 per gram data collected through Day 29 using the linear trapezoidal rule. Participants were assumed to be not shedding at time of vaccination (i.e. there was no stool collection on Day 1). Participants who were PCR-positive for type-specific viral shedding but with log₁₀ CCID50 per gram ≤ LLOQ contributed a value equal to the LLOQ. This endpoint was pre-specified to be analyzed in participants with IPV vaccination history.

Time frame: Days 3, 5, 8, 10, 15, 22, and 29