Phase 1 Novel Live Attenuated Serotype 2 Oral Polio Vaccine Study in Inactivated Polio Vaccine (IPV) Primed Adults

NCT03430349 | Completed Phase 1 Results DMC

• 2 other identifiers: UAM4a2017-000908-21
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

This first-in-human (FIH) phase 1 study is designed to evaluate in contained conditions the safety, immunogenicity, shedding, and genetic stability of two novel oral polio vaccine type 2 (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.

Conditions

Poliomyelitis

Keywords

IPV-primed; adults; vaccination; containment; shedding; genetic stability; safety; neurovirulence; novel polio vaccine candidates

Outcome Measures

Primary Outcomes (5)

• 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

  The time to cessation of shedding was defined as the time interval between administration of vaccine and the date of the first sample negative for type 2 poliovirus shedding (assessed by RT-PCR) after which the following two consecutive samples were also negative. Time to cessation of viral shedding was assessed using Kaplan-Meier methods; participants were right-censored if they had not met this endpoint with the last stool sample collected.

  Stool samples were collected from the day of vaccination to Day 28 or until shedding cessation; up to 89 days (novel OPV2 candidate 1) and 48 days (novel OPV candidate 2).

• Shedding Index

  A combined index of the prevalence, duration, and quantity of viral shedding in all participants. The viral shedding index was calculated for each participant as the mean of log₁₀(CCID₅₀/g) of samples collected 7, 14, 21, and 28 days after vaccine administration, with the lower limit of quantitation (2.75 log₁₀) as an observed value, and all titers in stool samples with negative shedding results (real-time RT-PCR-negative values) contributing 0 to the mean.

  Days 7, 14, 21, and 28

Secondary Outcomes (7)

• Number of Participants With Solicited Adverse Events

  Day 0 to Day 7

• Number of Participants With Unsolicited Adverse Events

  From Day 0 up to 42 days

• Number of Participants With Clinically Relevant Deviations From Normal Laboratory Evaluations

  Screening, Day 7, Day 14, and Day 28

• Anti-Poliovirus Type-2 Neutralizing Antibody Titers

  Day 0 and Day 28

• Seroprotection Rate

  Day 0 and Day 28

Study Arms (2)

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

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.

Novel OPV2 Candidate 1

Novel OPV2 candidate 2 BIOLOGICAL

Live-attenuated serotype-2 poliovirus derived from a modified Sabin type-2 infectious cDNA clone and propagated in Vero cells; candidate 2 (S2/S15domV/CpG40). 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. * silent non-coding modifications engineered within the capsid (VP1-4) designed to reduce replicative fitness and, potentially, to improve stability of the attenuated phenotype while also reducing transmission.

Novel OPV2 Candidate 2

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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;

You may not qualify if:

• 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.

Sponsors & Collaborators

• Pierre Van Damme: lead
• Bill and Melinda Gates Foundation: collaborator
• Centers for Disease Control and Prevention: collaborator
• PATH: collaborator
• Celerion: collaborator

Study Sites (1)

university of Antwerp - centre for the evaluation of vaccination

Wilrijk, Antwerp, 2610, Belgium

Location

Related Publications (1)

• 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.

  PMID: 31174831 DERIVED

MeSH Terms

Conditions

Poliomyelitis

Condition Hierarchy (Ancestors)

Myelitis; Central Nervous System Infections; Infections; Enterovirus Infections; Picornaviridae Infections; RNA Virus Infections; Virus Diseases; Central Nervous System Diseases; Nervous System Diseases; Spinal Cord Diseases; Neuroinflammatory Diseases; Neuromuscular Diseases

Results Point of Contact

• Title: Pierre Van Damme, MD, PhD
• Organization: University of Antwerp

pierre.vandamme@uantwerpen.be

+32 3 265 21 30

Study Officials

• pierre van damme, MD,PHD

  centre for the evaluation of vaccination

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: the study will be conducted with each candidate vaccine sequentially. After randomization of the first participant of Group 1 the next 14 participants will all be enrolled in the same Group and receive the same nOPV2 candidate and the next 15 participants will be enrolled in the other Group and receive the corresponding nOPV2 candidate. Prior to the start of the study the clinical research organization (CRO) will provide the site with 2 randomization envelopes for the first subject. By randomly choosing 1 of the envelopes first subject will be dedicated to a certain nOPV2 candidate and this will determine the allocation of the next 14 subjects to the same Group. Study staff will be blinded in the same way and will be blinded for individual shedding results of the participants of a Group until end of containment of this Group.
• Purpose: PREVENTION
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Full Professor

Study Record Dates

• First Submitted: January 21, 2018
• First Posted: February 12, 2018
• Study Start: May 16, 2017
• Primary Completion: September 30, 2017
• Study Completion: October 27, 2017
• Last Updated: February 4, 2021
• Results First Posted: February 4, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

BE (1)