A Phase 2 Study to Evaluate the Safety and Immunogenicity of Two Oral Poliovirus Vaccine Candidates
Condition: Poliomyelitis
MeSH terms: Poliomyelitis
Study type: Interventional
Phase: Phase 2

Summary: 
      This study is designed to evaluate the safety and immunogenicity of two novel type 2 oral
      poliovirus vaccine (nOPV2) candidates (nOPV2 candidate 1 and nOPV2 candidate 2) in adults.
      The primary objectives of the study include the general safety and immunogenicity of the two
      candidate vaccines in healthy volunteers previously vaccinated with Sabin monovalent OPV or
      inactivated polio vaccine (IPV) only.
    

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. The novel vaccine will
      eventually be licensed based on 3 criteria: a similar safety profile to the currently
      licensed monovalent OPV2 (mOPV2) of the Sabin strain, non-inferior immunogenicity, and
      reduced reversion to virulence.

      Due to the withdrawal of Sabin monovalent oral polio vaccine type 2 and prohibition of its
      use from April 2016 onward, well before the availability of nOPV2 for clinical testing, a
      head to head comparison of nOPV2 and mOPV2 is not possible. For these reasons, 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.

      This study is designed to evaluate the safety and immunogenicity of two novel type 2 OPV
      candidates in adults before testing in young children and then infants. The study will
      include both OPV-vaccinated and IPV-vaccinated adults to provide safety and immunogenicity
      data relevant to the decision to advance to future studies with testing in children who have
      not been exposed to OPV2. The primary objectives of the study include the general safety and
      immunogenicity of the two candidate vaccines, primarily based on comparison with historical
      data obtained in a Phase 4 study of Sabin mOPV2 for OPV-vaccinated subjects, in order to
      establish non-inferior immunogenicity and acceptable safety profile. Assessment of the
      general safety of the 2 candidate vaccines in IPV-only vaccinated participants will be based
      on comparison with data from a placebo group.

      The phase 4 control study (UAM1) used for the comparison in this study is registered with
      EudraCT (2015-003325-33). Participants were healthy adults aged 18-50 years with documented
      history of at least three polio vaccinations, including OPV, and were randomly assigned to
      either one dose or two doses of monovalent OPV2. Between January and March 2016, 100
      volunteers were enrolled and randomly assigned to receive one or two doses of monovalent OPV2
      (n=50 in each group).
    

Intervention name(s): Novel OPV2 candidate 1; Novel OPV2 candidate 2; Placebo
Intervention type(s): Biological; Biological; Biological
Intervention description(s): 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.; 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.; sugar syrup, propylene glycol (Sirupus simplex, Propylenglycolum, European Pharmacopoeia)
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: In this partial-blind study participants will be randomized into one of the following groups:
OPV-vaccinated adults:
1 dose of nOPV2 candidate 1 (Group 1);
2 doses of nOPV2 candidate 1 (Group 2);
1 dose of nOPV2 candidate 2 (Group 3);
2 doses of nOPV2 candidate 2 (Group 4);
IPV-only vaccinated adults:
2 doses of nOPV2 candidate 1 (Group 5);
2 doses of nOPV2 candidate 2 (Group 6);
2 doses of placebo (Group 7).
The first 100 OPV-vaccinated participants will be randomly assigned 1:1 to Groups 3 (1 dose) and 4 (2 doses) to receive nOPV2-c2. The second 100 OPV-vaccinated participants will be randomly assigned 1:1 to Groups 1 (1 dose) and 2 (2 doses) to receive nOPV2-c1. IPV-vaccinated adults will be enrolled in parallel and randomly assigned 2:1 to Group 6 (2 doses of nOPV2-c2) or Group 7 (2 doses of placebo), until Group 6 enrollment is complete, when 2:1 randomization will be continued for Group 5 (2 doses of nOPV2-c1) and Group 7 (2 doses of placebo).
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: IPV-primed; adults; vaccination; shedding; genetic stability; safety; neurovirulence; novel polio vaccine candidates