Phase 1 Novel Live Attenuated Serotype 2 Oral Polio Vacci... | NCT03430349

NCT03430349

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

ID	Type	Description	Link
2017-000908-21	EudraCT Number

Status Module

Name	Class
Bill and Melinda Gates Foundation	OTHER
Centers for Disease Control and Prevention	FED
PATH	OTHER
Celerion

Description Module

Detailed Description

Two nOPV2 vaccine candidates have been developed as attenuated serotype 2 polioviruses derived from a modified Sabin 2 infectious complementary deoxyribonucleic acid (cDNA) clone. nOPV2 Candidate 1 (S2/cre5/S15domV/rec1/hifi3) and nOPV2 Candidate 2 (S2/S15domV/CpG40) were generated by modifying the Sabin-2 ribonucleic acid (RNA) sequence to improve phenotypic stability and make the strains less prone to reversion to virulence.

Due to the withdrawal of Sabin monovalent oral polio vaccine type 2 (mOPV2) and prohibition of its use from April 2016 onwards, well before the availability of nOPV2 for clinical testing, Phase 4 trials have been conducted with Sabin mOPV2 to provide control data on safety, immunogenicity, against which data for nOPV2 in subsequent Phase I and II studies will be evaluated and compared. The Phase 4 trials of Sabin mOPV2 were designed to parallel the expected design of the Phase 1 and 2 nOPV2 studies with respect to overall design, inclusion of similar study cohorts. As for these reasons head to head comparison of nOPV2 and mOPV2 is not possible, the overall clinical development plan with the Phase I and II studies was designed taking into consideration the unique situation of OPV2 cessation in April 2016, and the global public health need of a vaccine with lower risk of vaccine-associated paralytic poliomyelitis (VAPP) and vaccine-derived type-2 poliovirus (cVDPV2) (VDPV2) for outbreak response in the post-cessation era.

This first-in-human phase 1 study is designed to evaluate in contained conditions the safety, immunogenicity, shedding and genetic stability of both nOPV2 vaccine candidates in IPV-primed adults before testing in a larger adult and adolescent (> 15 y of age) population, and then in young children and infants.

This Phase 1 study will include 30 IPV-only vaccinated adults to be vaccinated with the study vaccines (15 subjects per candidate vaccine) and followed in contained conditions (28 days) to obtain safety, immunogenicity, shedding and genetic stability data relevant to the decision to advance to future studies with testing in un-contained conditions.

Participants were isolated in a purpose-built containment facility named Poliopolis at the University of Antwerp Hospital (Antwerp, Belgium), to minimize the risk of environmental release of the novel OPV2 candidates. Volunteers were enrolled sequentially in two groups, with each group receiving one of the two vaccine candidates, to avoid cross-contamination, after which they were confined to Poliopolis for 28 days, with further monitoring until end of shedding. A final safety follow-up call (for those no longer shedding) or visit (for those still shedding) was made 42 days after vaccine administration.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Novel OPV2 Candidate 1	Experimental	Participants received one vaccination with novel OPV2 candidate 1 on study Day 0, administered orally as six drops (0.3 mL total; approximately 10⁶ 50% cell culture infectious dose units [CCID50]).	Biological: Novel OPV2 candidate 1
Novel OPV2 Candidate 2	Experimental	Participants received one vaccination with novel OPV2 candidate 2 on study Day 0, administered orally as six drops (0.3 mL total; approximately 10⁶ CCID50).	Biological: Novel OPV2 candidate 2

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Novel OPV2 candidate 1	Biological	Live-attenuated serotype-2 poliovirus derived from a modified Sabin type-2 infectious cDNA clone and propagated in Vero cells; candidate 1 (S2/cre5/S15domV/rec1/hifi3). Modifications included the following: Changes to the viral nucleotide sequence in part of the 5'-untranslated region to improve the genetic stability of this major attenuating determinant of Sabin type-2 to avoid reversion by single nucleotide changes. Two modifications in the polymerase 3D to further improve stability of the attenuation and reduce frequency of recombination events Relocation of a key replication element from the 2C coding region to the 5'-untranslated region, to inhibit recombination.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Participants With Serious Adverse Events and Severe Adverse Events Throughout the Study	Serious adverse events are medical events that resulted in death, were life-threatening, required admission to hospital, or resulted in notable incapacity of the individual. Adverse events were also graded from mild to severe; Severe adverse events are medical events that prevent normal everyday activities or fever > 39°C; this category does not include serious adverse events. Serious adverse events and severe adverse events include both solicited and unsolicited events. Solicited events comprised signs and symptoms that were reported by the participant using a predefined checklist in a diary card, or a fever, as determined by the participant's measurement of their body temperature, for up to 7 days after vaccination. Unsolicited events comprised other signs and symptoms recorded through the end of the study. Adverse events were assessed by the investigator for causality as unrelated, unlikely, possibly, or probably related to the vaccination.	From Day 0 up to 42 days
Percentage of Participants With Viral Shedding	Participants provided stool samples for assessment of viral shedding, defined as the presence of type 2-specific poliovirus ribonucleic acid (RNA) in stools. Samples were analyzed by the US Centers for Disease Control and Prevention (CDC; Atlanta, GA, USA) for the presence of type-2 poliovirus genome using a Sabin multiplex real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay of total nucleic acid extracted from stool suspensions (50% weight to volume in cell culture medium).	Days 0, 1, 2, 3, 4, 5, 6, 7, 14, 21, and 28
Cell Culture Infective Dose of Shed Virus in Virus-positive Stool Samples	In stool samples that were positive for type-2 poliovirus detected by RT-PCR, infectious virus was measured as 50% cell culture infective dose (CCID₅₀) per gram of stool by use of a modification of the World Health Organization (WHO) cell sensitivity assay.	Days 1, 2, 3, 4, 5, 6, 7, 14, 21, and 28
Time to Shedding Cessation

Secondary Outcomes

Measure	Description	Time Frame
Number of Participants With Solicited Adverse Events	Adverse events were solicited from the participants by the medical team during the 7 days after vaccination. Solicited events comprised signs and symptoms that were reported with a predefined checklist in a diary card, including headache, fatigue, myalgia, arthralgia, paresthesia, anesthesia, paralysis, nausea, vomiting, diarrhea and abdominal pain, or fever defined as a temperature of 37.5°C or higher. Adverse events were graded as mild (easily tolerated), moderate (sufficiently discomforting to interfere with normal everyday activities), or severe (preventing normal everyday activities, or temperatures higher than 39.0°C). Adverse events were assessed by the investigator for causality as unrelated, unlikely, possibly, or probably related to the vaccination.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Healthy male or female, between 18 and 50 years old, extremes included, having received at least 3 doses of IPV in the past (more than 12 months before the start of the study);
In good physical and mental health as determined on the basis of medical history, laboratory screening tests and general physical and psychological examination;
Female subjects of childbearing potential must agree to the use of an effective method of birth control throughout the study and up to 3 months after vaccine administration;
Willing to adhere to the prohibitions and restrictions specified in this protocol;
Willing to adhere to the restrictions of containment for duration as specified in the protocol;
Informed Consent Form (ICF) signed voluntarily by the subject before any study-related procedure is performed, indicating that the subject understands the purpose of and procedures required for the study and is willing to participate in the study.

Furthermore, willing to adhere to following restrictions as long as shedding will be observed at the end of the containment period:
No intention to travel to the Netherlands and to polio endemic countries (updated list will be made available at the start of the study);
No professional handling of food, catering or food production activities;
Not having household or professional contact with known immunosuppressed people or people without full polio vaccination (i.e. complete primary infant immunization series), e.g. babysitting;
No neonatal nursing activities or other professional contact with children under 6 months old;

Exclusion Criteria:

A condition that, in the opinion of the Investigator, could compromise the well being of the subject or course of the study, or prevent the subject from meeting or performing any study requirements;
Ever having received any OPV in the past;
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 the study vaccine, or to any of its components or to any antibiotics;
Any confirmed or suspected immunosuppressive or immunodeficiency condition (including human immunodeficiency virus [HIV] infection, hepatitis B and C infections or negative for total serum IgA);
Chronic administration (i.e., longer than 14 days) of immunosuppressant drugs or other immune-modifying drugs within 6 months prior to the administration of study vaccine or planned use during the study. For instance, for corticosteroids, this means prednisone, or equivalent, ≥ 0.5 mg/kg/day (inhaled and topical steroids are allowed whereas intra-articular and epidural injection/administration of steroids are not allowed);
Presence of contraindications to administration of the study vaccine on Day 0: acute severe febrile illness deemed by the Investigator to be a contraindication for vaccination or persistent diarrhea or vomiting;
Indications of drug abuse or excessive use of alcohol at Day 0;
Being pregnant or breastfeeding. Women of childbearing potential will undergo a pregnancy test at Screening (serum) and at Day 0 (urine). Subjects with a positive pregnancy test will be excluded;
Participation in another clinical study within 28 days prior to entry in this study or receipt of any investigational product (drug or vaccine) other than the study vaccine within 28 days prior to the administration of study vaccine, or planned use during the study period;
Administration of any vaccine other than the study vaccine within 28 days prior to the administration of study vaccine and during the entire study period;
Administration of polio vaccine within 12 months before the start of the study;
Having had a transfusion of any blood product or application of immunoglobulins within the 4 weeks prior to the administration of study vaccine or during the study;
Subject is an employee of the Investigator or study site, with direct involvement in the proposed study or other studies under the direction of that Investigator or study site, or is a family member of an employee or the Investigator.

Name	Affiliation	Role
pierre van damme, MD,PHD	centre for the evaluation of vaccination	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
university of Antwerp - centre for the evaluation of vaccination		Wilrijk	Antwerp	2610	Belgium

PubMed Identifier	Type	Citation	Retractions
31174831	Derived	Van Damme P, De Coster I, Bandyopadhyay AS, Revets H, Withanage K, De Smedt P, Suykens L, Oberste MS, Weldon WC, Costa-Clemens SA, Clemens R, Modlin J, Weiner AJ, Macadam AJ, Andino R, Kew OM, Konopka-Anstadt JL, Burns CC, Konz J, Wahid R, Gast C. The safety and immunogenicity of two novel live attenuated monovalent (serotype 2) oral poliovirus vaccines in healthy adults: a double-blind, single-centre phase 1 study. Lancet. 2019 Jul 13;394(10193):148-158. doi: 10.1016/S0140-6736(19)31279-6. Epub 2019 Jun 4.

ID	Title	Description
FG000	Novel OPV2 Candidate 1	Participants received one vaccination with novel OPV2 candidate 1 on study Day 0, administered orally as six drops (0.3 mL total; approximately 10⁶ 50% cell culture infectious dose units [CCID50]).
FG001	Novel OPV2 Candidate 2	Participants received one vaccination with novel OPV2 candidate 2 on study Day 0, administered orally as six drops (0.3 mL total; approximately 10⁶ CCID50).

ID	Title	Description
BG000	Novel OPV2 Candidate 1	Participants received one vaccination with novel OPV2 candidate 1 on study Day 0, administered orally as six drops (0.3 mL total; approximately 10⁶ 50% cell culture infectious dose units [CCID50]).
BG001	Novel OPV2 Candidate 2

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Participants With Serious Adverse Events and Severe Adverse Events Throughout the Study

Serious adverse events are medical events that resulted in death, were life-threatening, required admission to hospital, or resulted in notable incapacity of the individual. Adverse events were also graded from mild to severe; Severe adverse events are medical events that prevent normal everyday activities or fever > 39°C; this category does not include serious adverse events.

Serious adverse events and severe adverse events include both solicited and unsolicited events. Solicited events comprised signs and symptoms that were reported by the participant using a predefined checklist in a diary card, or a fever, as determined by the participant's measurement of their body temperature, for up to 7 days after vaccination. Unsolicited events comprised other signs and symptoms recorded through the end of the study.

Adverse events were assessed by the investigator for causality as unrelated, unlikely, possibly, or probably related to the vaccination.

All randomized participants who received a dose of study vaccine.

Posted

Count of Participants

Participants

From Day 0 up to 42 days

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Mar 21, 2017	Jan 14, 2021	Prot_000.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Jun 7, 2017	Jan 14, 2021	SAP_001.pdf

ID	Term
D009187	Myelitis
D002494	Central Nervous System Infections
D007239	Infections
D004769	Enterovirus Infections

OG000	Novel OPV2 Candidate 1	Participants received one vaccination with novel OPV2 candidate 1 on study Day 0, administered orally as six drops (0.3 mL total; approximately 10⁶ CCID50).
OG001	Novel OPV2 Candidate 2	Participants received one vaccination with novel OPV2 candidate 2 on study Day 0, administered orally as six drops (0.3 mL total; approximately 10⁶ CCID50).