A Campaign-based ID fIPV Administration Trial
Condition: Poliomyelitis
MeSH terms: Poliomyelitis
Study type: Interventional

Summary: 
      The introduction of one dose of the inactivated poliovirus vaccine (IPV) into routine
      immunization schedules in OPV-only using countries as part of the Global Polio Eradication
      Initiative (GPEI) was planned for completion in 2016. However, due to recent developments in
      the global IPV supply landscape, the GPEI polio eradication program is facing a critical
      shortage of the vaccine which is forecast to continue until at least the end of 2017. The
      shortage means that some countries that have already introduced the vaccine, but which are
      considered to be relatively low risk (The Gambia included), will be left without adequate
      supplies and in other countries IPV introduction is being unavoidably delayed.

      Exacerbating the shortage is the need to reserve IPV for future outbreak responses (OBR). The
      current OBR protocol recommends that, if a circulating vaccine-derived poliovirus type 2
      (cVDPV2) outbreak occurs (after the recent global switch from trivalent to bivalent OPV), a
      large scale IPV campaign will be implemented to increase population immunity to the type 2
      poliovirus in an large area surrounding the outbreak as high risk of extending transmission.

      Due to above, dose-sparing through the administration of intra-dermal (ID) fractional (one
      fifth - 0.1mL) doses of IPV (fIPV) has become a very important focus and, for planning
      purposes, there is an urgent need to assess the practical and logistic challenges a country
      such as The Gambia would face in rapidly undertaking an ID fIPV campaign.
    

Detailed description: 
      Background information and rationale

      Background information

      Polio eradication requires the removal of all polioviruses from the human population, whether
      wild-type poliovirus (WPV) or those vaccine-derived polioviruses (VDPV) emanating from the
      oral poliovirus vaccine (OPV). The Polio Eradication & Endgame Strategic Plan 2013-2018
      provides a framework for interruption of WPV transmission in remaining endemic foci and lays
      out plan for the new polio endgame. This will include the withdrawal of Sabin strains,
      starting with the type 2 strain, and the introduction of the inactivated poliovirus vaccine
      (IPV), for risk mitigation purposes.

      The introduction of one dose of IPV into routine immunization schedules in OPV-only using
      countries was planned for completion in 2016. However, due to recent developments in the
      global IPV supply landscape, the polio eradication program is facing a critical shortage of
      the vaccine which is currently forecast to continue until at least the end of 2017. The
      shortage is not only preventing the universal introduction of one dose of IPV into some
      routine immunization schedule but may also mean that some countries who have already
      introduced the vaccine, but are considered to be relatively low risk, will be left without
      adequate supplies.

      Exacerbating the shortage is the demand to reserve IPV for future outbreak responses (OBR).
      The current OBR protocol recommends that, in the event of a circulating vaccine-derived
      poliovirus type 2 (cVDPV2) outbreak after the switch, a large scale IPV response is
      implemented - a preventive campaign in the zone surrounding the outbreak (rather than the
      core area of the outbreak itself) to increase population immunity to the type 2 poliovirus in
      an area at high risk of driving further transmission considering the ongoing VDPV2 outbreak
      nearby.

      In light of the number of individuals to be vaccinated under such circumstances, dose-sparing
      through the administration of intradermal (ID) fractional (one fifth - 0.1mL) doses of IPV
      (fIPV) has become a very important focus. The approach is not new, having been assessed in
      trials undertaken in vaccine-naive infants, in OPV-primed infants and children, as well as in
      adults. In addition, given the practical and logistical challenges of needle and syringe
      (N&S)-based ID vaccine administration, the use of needle-free administration devices has also
      been explored previously.

      In these trials, the administration of one fifth of a full dose by the ID route has
      consistently demonstrated a good safety profile. The rates of local reactions related to the
      administration of the vaccine by the ID route compared to the intramuscular (IM) route are
      higher in some although not in other trials. However, those reactions reported are generally
      mild and self-limiting irrespective of the method of administration employed. No significant
      systemic reactions or serious adverse events (SAE) related to ID fIPV administration have
      been reported. Furthermore, although when comparisons have been undertaken, the
      seroconversion rates and neutralizing antibody titres generated by the ID fIPV are
      consistently lower than those generated by a full IM dose of the same vaccine, the
      immunogenicity is such that the approach is viewed as a viable alternative in the context of
      the current Global Polio Eradication Initiative (GPEI) strategy.

      Of particular importance, in studies undertaken in Cuba and Bangladesh, the administration of
      a single ID fIPV dose to poliovirus-vaccine naive infants has been shown to effectively prime
      the immune system for a subsequent rapid anamnestic response to an ID fIPV booster. In Cuba,
      priming with ID fIPV at four months of age resulted in a response within seven days of a
      subsequent ID fIPV booster dose at eight months - resulting in a cumulative seroconversion
      rate of 98% for poliovirus serotype 2 over the two dose course . The equivalent figure was
      81% following a six and 14 week prime-boost schedule in Bangladesh. In both cases, the
      cumulative seroconversion rate following two ID fIPV doses was significantly higher for all
      serotypes than the seroconversion rate recorded following a single full-dose of IPV
      administered by the IM route (98% versus 62% in Cuba; 80% versus 39% in Bangladesh for
      serotype 2). The demonstrated anamnestic responses described, provide an effective strategy
      for rapidly inducing seroprotection in a primed population through the campaign-based
      provision of a second dose of ID fIPV - initiated as part of an OBR. In addition, if coverage
      can be assured, the use of a two dose ID fIPV routine schedule provides higher levels of
      seroprotection than a single IM IPV dose while still remaining dose sparing (0.2mL versus
      0.5mL).

      Based on the data available and their assessment of the current global landscape, the latest
      WHO position paper on polio vaccines, published in March 2016, suggests that '...countries
      could consider instituting a 2-dose fractional dose schedule, which could ensure that all
      eligible infants receive IPV...'. The same paper indicates that 'One fractional-dose IPV may
      be particularly appropriate for outbreak response if supplies are limited'. Based on this
      recommendation, and their own assessment, several states in India have subsequently decided
      to introduce two ID fIPV doses into their routine immunization schedule.

      Rationale

      While the safety and immunogenicity of ID fIPV is established in a clinic setting, there are
      little data examining the feasibility of rapid ID fIPV delivery in community-based campaign.

      Many countries across sub-Saharan Africa, and other parts of the world where OPV
      supplementary immunization activities (SIA) are ongoing, have an established and highly
      effective framework for the campaign-based delivery of oral vaccines and other orally
      administered interventions (e.g. vitamin A and medendazole). However, such SIA commonly rely
      on the use of non-clinically trained individuals for frontline delivery (for example,
      volunteers from youth groups and other community organizations play a key role in such
      campaigns in The Gambia).

      National campaigns involving the delivery of IM vaccines (e.g. MenAfriVac™ and most recently
      the measles and rubella combined vaccine [90-95% coverage of 802 425 target nine-month to 15
      year olds in The Gambia in April 2016]) have also been undertaken very successfully - in this
      case relying on nurses and public health officers (or other health professionals involved in
      the routine provision Expanded Programme on Immunization (EPI) schedule) to administer the
      vaccines. However, the delivery of IM injections is part of the routine day-to-day practice
      of such professionals and can be completed with almost 100% success following limited
      training.

      In contrast, the reliable delivery of ID injections, as is required to ensure the consistent
      immunogenicity of fIPV, is notoriously difficult with a N&S, particularly in active infants
      and children, and requires not only training but also significant practical experience.
      Indeed, data from both Cuba and The Gambia highlight that the immunogenicity of ID fIPV is
      directly determined by injection quality, as assessed by both ID bleb size and fluid loss at
      the injection site ([14] and The Gambia - unpublished data). Furthermore, given the nature of
      the injection, the approach is more time consuming than an IM vaccination (The Gambia -
      Figure 1 [unpublished data]) and markedly more time consuming than the delivery of a dose of
      OPV. This has important manpower implications even assuming personnel with the requisite
      skills are available.

      Given these challenges, this pragmatic trial will specifically compare the feasibility of ID
      fIPV delivery using three different methods of administration in a campaign setting in rural
      part of The Gambia:

        -  Needle and syringe [N&S] (auto-disable, fixed needle)

        -  Intradermal Adapter [IDA] - West Pharmaceutical Services Inc

        -  Tropis™ Disposable Syringe Jet Injector [DSJI] - Pharmajet

      Gaining an understanding of the utility of different methods of ID fIPV delivery in a
      campaign represents an important final step before key decisions regarding the approaches
      taken to fIPV delivery, particularly in an OBR, are finalized. A number of qualitative and
      quantitative endpoints will be assessed related to the practicalities of implementation.
      Information on solicited local and systemic reactogenicity will also be collected to
      strengthen the existing data set with this regard particularly related to campaign-based
      administration. Immunogenicity data will also be generated in a subset of 24 to 59 month old
      vaccine recipients to ensure that any factors enhancing the speed and ease of ID fIPV
      administration do not significantly compromise the ID fIPV immunogenicity - for example as a
      result of poor injection quality. This age group is chosen to limit the potential confounding
      effects of having received a different number of OPV and/or IPV doses present in younger age
      groups.

      The data will also expand what is currently a very limited data-set regarding ID fIPV
      administration in sub-Saharan Africa - a setting where the risks of future cVDPV2 outbreaks
      is not inconsiderable despite recent sustained progress.
    

Intervention name(s): ID adaptor; ID Jet Injector (Tropis, Pharmajet); Needle and syringe
Intervention type(s): Device; Device; Device
Intervention description(s): ID adaptor fixed to the end of a standard ID needle and syringe to facilitate ID administration of the inactivated poliovirus vaccine; ID disposable syringe (needle free) jet injector to facilitate ID administration of the inactivated poliovirus vaccine; Standard ID needle and syringe for ID administration of the inactivated poliovirus vaccine
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Device Feasibility