Clinical Trial of Novel OPV2 Vaccine
Condition: Poliomyelitis
MeSH terms: Poliomyelitis
Study type: Interventional
Phase: Phase 2

Summary: 
      Though OPV is safe and effective, it can mutate and reacquire neurovirulence in rare
      circumstances. This can result in vaccine-associated paralytic polio and circulating
      vaccine-derived polioviruses. Use of tOPV had risk of generating VAPP and seeding new type 2
      circulating vaccine-derived polioviruses though wild type 2 virus was eradicated in September
      2015. For this reason tOPV vaccine was withdrawn globally in April 2016 and switched to bOPV.
      cVDPV2 outbreaks have occurred in sixteen countries after cassation of OPV2. Using stockpiled
      mOPV2 to respond to this situation risks propagating new cVDPVs. IPV induces only limited
      intestinal mucosal immunity not effective to interrupt fecal-oral route transmission in
      settings of poor hygiene and sanitation. Therefore, development of novel oral polio vaccine
      with enhanced genetic stability and lower risk of reversion to neurovirulence compared to
      current Sabin 2 strains is major priority of global polio eradication Program

      Current clinical development plan outlines studies through Phase II development with nOPV2
      candidate strains being tested in adult toddler and infant populations who received prior
      dose of OPV or IPV. No study has been conducted in truly naive newborns with no prior receipt
      of any polio vaccines

      Hypothesis: Vaccinating healthy newborns with novel type 2 polio virus candidate vaccines is
      safe and can induce putatively protective immune response

      Objectives

      Primary Objective

      Safety

      To evaluate the safety and tolerability after one and two doses of nOPV2 vaccine candidates 1
      given 4 weeks apart in poliovirus vaccine-naïve newborn Immunogenicity To evaluate the immune
      response to vaccination after one and two doses of nOPV2 vaccine candidate 1 given 4 weeks
      apart in poliovirus vaccine-naïve newborns

      Secondary objectives

      Immunogenicity

      To evaluate seroprotection rate geometric mean and median titers to vaccination after one
      dose of nOPV2 vaccine candidate 1 in poliovirus vaccine-naïve newborns To further evaluate
      seroprotection rate geometric mean and median titers to vaccination after two doses of nOPV2
      candidate 1 in poliovirus vaccine-naïve newborns

      Viral Shedding

      To assess trate of fecal viral shedding at fixed time points following one and two doses of
      nOPV2 vaccine candidate 1 in newborns To assess duration of fecal viral shedding at fixed
      time points following one and two doses of nOPV2 vaccine candidate 1 in newborns To assess
      extent of fecal viral at fixed time points following one and two doses of nOPV2 vaccine
      candidate 1 in newborns

      Exploratory objective

      To assess genetic stability through genetic deep sequencing assay and neurovirulence test
      through transgenic mice NV assays from a subset of participants stools samples
    

Detailed description: 
      Burden: Oral Polio Vaccine (OPV) contains attenuated (weakened) polioviruses. Though OPV is
      safe and effective, it can mutate and reacquire neurovirulence in rare circumstances. This
      can result in vaccine-associated paralytic polio (VAPP) and circulating vaccine-derived
      polioviruses (cVDPVs) on rare occasions. Use of tOPV, therefore, had the risk of generating
      VAPP and seeding new type 2 circulating vaccine-derived polioviruses (cVDPV2), even though
      the wild type 2 virus was eradicated in September 2015. For this reason tOPV vaccine was
      withdrawn globally in April 2016 and switched to the bivalent oral poliovirus vaccine (bOPV).
      Circulating vaccine-derived type-2 poliovirus (cVDPV2) outbreaks have occurred in sixteen
      countries after cassation of OPV2. Using stockpiled mOPV2 to respond to this situation risks
      propagating new cVDPVs and this phenomenon has already been observed in multiple geographies
      following the switch. Inactivated polio vaccine (IPV) induces only limited intestinal mucosal
      immunity and is not effective to interrupt fecal-oral route transmission in settings of poor
      hygiene and sanitation. Therefore, development of novel oral polio vaccine/s with enhanced
      genetic stability and lower risk of reversion to neurovirulence compared to current Sabin 2
      strains is a major priority of the global polio eradication Program.

      Knowledge gap: The current clinical development plan outlines studies through Phase II
      development with the nOPV2 candidate strains being tested in adult, toddler, and infant
      populations who have received prior dose/s of OPV and/or IPV. No study has been conducted in
      truly naive newborns with no prior receipt of any polio vaccines to strengthen the clinical
      evidence in favour of utilizing these novel OPV strains.

      Relevance: Existing Sabin type 2 polio virus vaccines can mutate in to pathogenic virus and
      become neurovirulent, causing VAPP and cVDVP. So novel type 2 polio virus candidate vaccines
      is an urgent need especially for outbreak situations. The nOPV2 strains are intended for use
      as safer alternatives to mOPV2 vaccines for outbreak response. Data from this proposed study
      result will further strengthen the clinical evidence base to deploy novel, genetically stable
      OPV strains to reduce the risk of generating cVDPV and VAPP. The study will generate data on
      novel OPV2 candidates for pre-licensure use in outbreak scenarios and for eventual full
      licensure and WHO Prequalification.

      Hypothesis : Vaccinating healthy newborns with novel type 2 polio virus candidate vaccines
      (nOPV2) is safe and can induce a putatively protective immune response.

      Objectives:

      Primary Objectives:

      Safety:

      • To evaluate the safety and tolerability after one and two doses of nOPV2 vaccine candidates
      1, given 4 weeks apart in poliovirus vaccine-naïve newborns.

      Immunogenicity:

      • To evaluate the immune response (measured by seroconversion rate) to vaccination after one
      and two doses of nOPV2 vaccine candidate 1, given 4 weeks apart in poliovirus vaccine-naïve
      newborns.

      Secondary objectives:

      Immunogenicity:

        -  To evaluate seroprotection rate, geometric mean and median titers to vaccination after
           one dose of nOPV2 vaccine candidate 1 in poliovirus vaccine-naïve newborns.

        -  To further evaluate seroprotection rate, geometric mean and median titers to vaccination
           after two doses of nOPV2 candidate 1 in poliovirus vaccine-naïve newborns.

      Viral Shedding:

        -  To assess the rate of fecal viral shedding (as determined by real-time RT-PCR) at fixed
           time points following one and two doses of nOPV2 vaccine candidate 1 in newborns.

        -  To assess the duration of fecal viral shedding (as determined by real-time RT-PCR) at
           fixed time points following one and two doses of nOPV2 vaccine candidate 1 in newborns.

        -  To assess the extent of fecal viral shedding ( the quantity of nOPV2 virus shedding,
           measured asCCID50 per g of stool) at fixed time points following one and two doses of
           nOPV2 vaccine candidate 1 in newborns.

      Exploratory objective:

      • To assess genetic stability through genetic deep sequencing assay and neurovirulence test
      through transgenic mice NV assays from a subset of participants stools samples.

      Methods:

      The study is a Phase II clinical trial which will be conducted in rural Bangladesh at Matlab.
      The total enrolment target for the clinical trial is 330 , with 220 in nOPV2 candidate 1 arm
      and 110 in placebo arm. All participants will be randomized (in block randomization of
      variable length) 2:1 ratio to nOPV2 vaccine candidate C1(2 drops) and placebo group (2
      drops). All eligible healthy newborn participants will be vaccinated orally at birth and at 4
      weeks of age with C1 (105.0± 0.5 CCID50, 2 drops) or placebo (2 drops) of age followed by
      fIPV + bOPV at week 8, bOPV at week 12 and fIPV + bOPV at week 16 and other vaccines
      according to EPI schedule in Bangladesh.

      In order to record any immediate reaction participants will be observed for 30 minutes
      following each dose of vaccination. Study staff will visit homes of the participants daily
      for 7 days to collect systemic solicited adverse events after study vaccination using
      electronic dairy cards. Unsolicited adverse events, adverse events of special interest and
      serious adverse events will be collected throughout the entire study period by weekly home
      visit. Mothers of the participant will be provided a telephone number to communicate with the
      investigator for any adverse or serious adverse events.

      Three blood samples each of 1 ml, will be collected to measure the immune response of nOPV
      vaccine candidate 1: the first pre-vaccine blood sample on the day of first dose nOPV2
      vaccine candidate 1 /placebo (at birth), second blood sample at 4 weeks before second dose
      nOPV2 vaccine candidate 1 /placebo and the third blood sample will be collected at 8 weeks
      before giving fIPV + bOPV vaccine.

      Mothers of enrolled participants will be requested to collect about 8 grams (about the size
      of one adult thumb) of stool from participants to assess viral sheddings. A total of seven
      stool samples will be collected: the first pre-vaccine sample will be collected on the day of
      first dose nOPV2 vaccine candidate 1 /placebo (at birth), second sample at week 2, third
      sample at week 4 before second dose nOPV2 vaccine candidate 1 /placebo, fourth stool sample
      at week 6, fifth stool at week 8 before giving fIPV + bOPV vaccine, sixth stool sample at
      week 10 and seventh sample at week 12 of age to assess viral shedding.

      Outcome measures/variables:

      Safety

        -  Incidence rate of solicited systemic AEs within 7 days after each dose of vaccine

        -  Incidence rate of unsolicited AEs during entire study period

        -  Incidence rate of serious AEs and AESIs during entire study period

      Immunogenicity

        -  Seroconversion rate as measured by microneutralization assay (MN) for OPV Type 2

        -  Seroprotection rate as measured as seropositivity by MN for OPV Type 2

        -  Geometric mean and median titers as measured by MN for OPV Type 2

      Viral Shedding

        -  Rate of fecal viral shedding by real-time RT-PCR

        -  Duration of fecal viral shedding by real-time RT-PCR

        -  Extent of fecal viral shedding ( the quantity of nOPV2 virus shedding, measured as
           CCID50 per g of stool) at fixed time points following different dose schedule.

      Genetic stability

      • Genetic deep sequencing assay and neurovirulence test through transgenic mice NV assays
      from a subset of participants stools samples.
    

Intervention name(s): novel oral polio type 2 vaccine (nOPV2); Placebo
Intervention type(s): Biological; Other
Intervention description(s): • nOPV2 (C1) is a live-attenuated serotype-2 poliovirus that was derived from a modified Sabin type-2 infectious cDNA clone and propagated in Vero cells (S2/cre5/S15domV/rec1/hifi3). Placebo contain sucrose in buffer.; Placebo contains no active ingradients, only sucrose in buffer
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Safety; Immunogenecity; nOPV2; Newborn; Bangladesh