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

Phase 1

Completed

Conditions: Polio

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

Registration Number: NCT04232943

Lead Sponsor: PATH

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 87

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Inactivated Poliomyelitis Vaccine (IPV)	Inactivated Poliomyelitis Vaccine (IPV)	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.
Bivalent Oral Polio Vaccine	Bivalent Oral Polio Vaccine (bOPV)	Participants will receive one dose (2 drops) of bOPV on Day 1 followed by a second dose of bOPV 28 days later.
Inactivated Poliomyelitis Vaccine + dmLT	E.coli Double Mutant Heat-Labile Toxin (dmLT) (adjuvant)	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.
Inactivated Poliomyelitis Vaccine + dmLT	Bivalent Oral Polio Vaccine (bOPV)	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.
Inactivated Poliomyelitis Vaccine (IPV)	Bivalent Oral Polio Vaccine (bOPV)	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.
Inactivated Poliomyelitis Vaccine + dmLT	Inactivated Poliomyelitis Vaccine (IPV)	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Unsolicited Adverse Events During the 28 Days Following Study Vaccination	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.
Number of Participants With Solicited Local Adverse Events	7 days following study vaccination	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.
Number of Participants With Solicited Systemic Adverse Events	7 days following study vaccination	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.
Number of Participants With Serious Adverse Events Over the Course of the Study	Up to 6 months	A serious adverse event (SAE) was any event that resulted in any of the following outcomes: 1. Death; 2. Was life-threatening; 3. Required inpatient hospitalization or prolongation of existing hospitalization; 4. Resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; 5. Congenital abnormality or birth defect; 6. 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.
Number of Participants With Severe Adverse Events During the 28 Days Following Study Vaccination	Up to 28 days after study vaccination (prior to bOPV challenge)	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.
Percentage of Participants Positive for bOPV Viral Shedding 7 Days Following bOPV Challenge	Day 36 (7 days after 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).

Secondary Outcome Measures

Name	Time	Method
Seroprotection Rate of Serum Poliovirus Neutralizing Antibodies at Baseline and 28 Days Following Vaccination	Baseline (before vaccination) and Day 29 (28 days after vaccination, prior to bOPV challenge)	Seroprotection rate of serum poliovirus neutralizing antibodies is defined as a type-specific poliovirus serum neutralizing antibody titer ≥ 1:8.
Level of Fecal Poliovirus Immunoglobulin A (IgA) Antibodies at Baseline, 28 Days After Vaccination and 14 Days After bOPV Challenge	Baseline (before vaccination), Day 29 (28 days after study vaccination, prior to bOPV challenge) and Day 43 (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.
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	Day 29 (28 days after study vaccination, prior to bOPV challenge)	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.
Percentage of Participants With a Circulating Poliovirus IgA Antibody-Secreting Cell Response	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)	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.
Percentage of Participants With a Positive Poliovirus Fecal Neutralization Response 28 Days After Vaccination and 14 Days After bOPV Challenge	Day 29 (28 days after study vaccination) and Day 43 (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.
Geometric Mean Fold-Rise in Serum Poliovirus Neutralizing Antibodies	Baseline (before vaccination) and Day 29 (28 days after 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)
Percentage of Participants With a Circulating Poliovirus Immunoglobulin G (IgG) Antibody-Secreting Cell Response	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)	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.
Area Under the Curve (AUC) of Viral Shedding in Stool for 28 Days After bOPV Challenge	Days 33, 36, 43, 50, and 57 (i.e., 4, 7, 14, 21, and 28 days, respectively, following bOPV challenge).	AUC was calculated using the linear trapezoidal rule with all samples collected from Day 33 to 57.
Time to Cessation of Viral Shedding in Stool After bOPV Challenge	Days 33, 36, 39, 43, 46, 50, and 57	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.
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)
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)