Persistence of IPV Immunity
Condition: Poliomyelitis
MeSH terms: Poliomyelitis
Study type: Interventional
Phase: Phase 4

Summary: 
      In 2015, Strategic Advisory Group of Experts in Immunization (SAGE) recommended the global
      switch from trivalent to bivalent oral poliovirus vaccine (OPV) that does not contain type 2
      poliovirus and introduction of a single dose of inactivated poliovirus vaccine (IPV) to
      maintain population immunity to type 2 polio to reduce the risk of vaccine derived polio.
      Following SAGE recommendations, Nepal introduced one dose of IPV in routine immunization in
      2015 followed by withdrawal trivalent OPV in April 2016. However, Nepal, like many other
      countries had to stop vaccination by the end of 2016 because of a global shortage of IPV.

      Single dose of IPV induces detectable antibodies in 34% to 80% of infants, compared to >90%
      after three doses and most of seronegative children (84-98%) are "immunologically primed" by
      the first dose. Primed individuals produce protective antibody levels in serum within one
      week of exposure to a new dose of IPV or OPV. However, it is unknown whether seroconversion
      or priming responses persist, and for how long they persist after the single dose of IPV. IPV
      immunogenicity for vaccine delivered low-resource countries may also be inferior to that
      observed in clinical trials because of program factors that decrease vaccine efficacy.

      This cross sectional study aims to determine whether the immune response provided by a single
      dose of IPV delivered through routine immunization services persists for more than a year.

      The study will be implemented in three study sites in Kathmandu, Nepal during November 2018-
      July 2019.

      Information generated from this study is expected to allow better estimation of children
      partially protected (primed) or fully protected against type 2 poliovirus depending on
      coverage and time since last IPV vaccination. These estimates will help inform the Global
      Polio Eradication Initiative (GPEI) on vaccine choices for responding to type 2 vaccine
      derived poliovirus (VDPV) outbreaks and will help guide decisions on polio immunization
      schedules for Nepal and for other countries in future.
    

Detailed description: 
      Background and Rationale

      Importance of Poliomyelitis and Polioviruses and vaccine

      There are three polioviruses types, 1, 2 and 3, with minimal cross-immunity. About 1/200
      infections (depending on the type of poliovirus) produce paralytic poliomyelitis. An
      estimated 5-10% of individuals with paralytic poliomyelitis die and the remaining suffer from
      lifelong paralysis of one or more limbs without a cure. The presence of detectable antibodies
      in blood against each type protects against paralytic poliomyelitis, but intestinal immunity
      develops only after exposure to live poliovirus (vaccine or wild). Oral poliovirus vaccines
      that contain attenuated poliovirus strains and inactivated poliovirus vaccine both induce
      humoral immunity and protect against paralysis. OPV can also immunize or boost immunity of
      close contacts through secondary spread and trivalent OPV (tOPV) with poliovirus types 1, 2
      and 3, was the vaccine of choice for polio eradication.

      The immunological response to poliovirus vaccines is evaluated by measuring type-specific
      poliovirus antibodies using neutralization assays and can be detected as early as 1 to 3 days
      after infection with WPV or receipt of OPV or IPV. Antibody titers usually decline in the
      first two years (10- to 100-fold reduction) and then plateau, persisting for many years.
      However, administration of additional doses of vaccine or new exposures to wild poliovirus,
      induces a quick rise in antibody titers, with a peak reached within one week after the dose
      due to induction of "priming" or immunological memory.

      Changes in polio vaccine use with progress in global polio eradication

      Global Polio Eradication Initiative (GPEI) reduced polio cases enormously with the use of the
      tOPV in routine immunization and campaigns and WPV circulation is now limited to a few areas
      of the world. However, problems related to vaccines emerged. OPV strains may occasionally
      cause paralysis in vaccinated children and their close contacts (vaccine-associated paralytic
      poliomyelitis or VAPP). OPV strains can circulate among susceptible individuals for long time
      in areas with absence of wild poliovirus transmission and suboptimal coverage with routine
      immunization resulting in low population immunity. Prolonged person-to-person transmission
      can result in genetic changes and the emergence of circulating vaccine-derived polioviruses
      (cVDPV) with neurovirulence and transmissibility characteristics of WPV. Type 2 poliovirus
      was responsible for about 40% of annual VAPP cases reported, and 85% paralytic cases caused
      by cVDPVs during 2000-2015. Based on SAGE recommendation this led to removal of type 2 by
      switching from tOPV to bOPV in primary immunization and introduction of "at least one dose of
      IPV in routine immunization" in most of the countries of the world.

      Rationale for the study and expected outcomes and benefits for the GPEI

      Several recent studies have demonstrated that, although a single dose would result in
      seroconversion to type 2 for a limited number of infants (32% to 80% depending on the age of
      administration and study), a high proportion (>90%) of those infants who are seronegative,
      may actually "primed" by that single dose. Although it is not clear whether priming may
      protect directly against paralysis if a type 2 cVDPV 2 outbreak emerges, primed children
      should develop protective antibody levels quickly following a new OPV or IPV dose provided as
      a response to the outbreak.

      Studies assessing long-term immunity to IPV or OPV were conducted in individuals receiving
      three or more doses of poliovirus vaccines who could have been exposed to circulating wild or
      vaccine poliovirus. It is unknown whether the proportion of children who were seropositive or
      primed following a single dose of IPV will stay positive or primed, and for how long this
      immune response will persist. Additionally IPV delivered in clinics and outreach sites in
      low-resource countries may not produce the same response to those observed in clinical trials
      due to programmatic issues.

      Furthermore, global shortage of IPV resulting in IPV stock out in many countries including
      Nepal led many children to miss out their IPV dose in routine immunization. Reliable
      estimates of population immunity in a country or region based upon coverage and estimated
      immunogenicity of the type of vaccine and vaccination schedules received, are crucial to
      guide programmatic decisions and manage vaccine supply for outbreak responses to type 2
      poliovirus.

      Therefore, a cross-sectional study is being conducted to determine whether the immune
      response provided by a single dose of IPV persists for more than a year, by assessing the
      proportion of children born after the tOPV-bOPV switch and vaccinated with a single dose of
      IPV at about 14 weeks in routine immunization who are still seropositive or primed at around
      two years of age. These new estimates will inform the GPEI on vaccine choices for responding
      to type 2 VDPV outbreaks and guide decisions on polio immunization schedules after cessation
      of all OPV types.

      Objectives

      The study primarily will compare the proportion of infants vaccinated with one dose of IPV
      after 14 weeks of age who are seropositive or primed against type 2 poliovirus, either > 21
      months after vaccination (study group), or one month after vaccination (control group). Also
      we would determine the proportion of children seropositive to types 1 and 3 following a
      sequential bOPV-IPV or bOPV alone schedule, delivered through routine immunization services
      in a low resource country.

      Study Design/ Procedures

      This is an open-label phase IV clinical trial assessing immunogenicity to IPV. Study
      participants will be identified through screening of children who attend outpatient clinics
      at the study sites for well-child visits, immunization or minor illness. After screening,
      confirmation of eligibility and obtaining consent, children will be allocated to one of the
      two study arms, and given a dose of IPV after collecting clinical information and obtaining a
      blood sample. Children will be followed up according to the schedule for study arms to assess
      study objectives.

      Blood sample will be centrifuged within 24 hours of collection, serum aliquoted into two
      cryovials and stored at Institute of Medicine (IOM) laboratory at -20*C until final shipment
      to Centers for Disease Control and Prevention(CDC), Atlanta. Determination of poliovirus
      antibodies will be conducted using a microneutralization testing. Titers below 1:8 will be
      considered negative and the highest detectable titer will be 1:1448.

      Sample size and analytic plan:

      The sample size will be powered to address the primary objective based on previous trials
      that have shown 90 - 100% of children to develop detectable immunity to type 2 poliovirus
      after IPV dose. Using a one-sided test for differences between proportions with a continuity
      correction Z-test using pooled variance (PASS v14), 237 children will be required in each
      group to detect a one-sided difference of ≥10% with 90% power and 0.05 alpha. To account for
      potential 5% drop-outs, the sample will be rounded up to 250 per group or 500 children total.
    

Intervention name(s): Inactivated Polio Vaccine (IPV)
Intervention type(s): Biological
Intervention description(s): Children receive one or two doses of IPV based on study arm they fall in
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: IPV; Routine immunization; Single dose; Persistence of immunity