Role of Fractional-Dose Intradermal Inactivated Poliovirus Vaccine in Halting Polio Transmission: Finding the Missing Piece for Global Polio Eradication

(See the Major Article by Gamage et al on pages 1876–82.) Global eradication of wild poliovirus (WPV) is almost complete, with the exception of few remaining endemic zones in Afghanistan and Pakistan. However, to achieve a poliovirus-free world, not only WPV but also polioviruses emanating from use of oral poliovirus vaccine (OPV), must be eliminated. This means that OPV use must be stopped and outbreaks of circulating vaccine-derived polioviruses (cVDPV) must be contained. Inactivated poliovirus vaccine (IPV) will eventually replace OPV; however, current shortages of IPV supply have resulted in the need to stretch the available doses, and use of intradermal IPV with fractional dose (fIPV; one-fifth of the full-dose IPV, ie, 0.1 mL as compared to 0.5 mL) has been extensively researched. Intradermal fIPV was demonstrated to be safe, and it induces good humoral immune responses. However, its impact on mucosal immunity was, until now, unknown. A study by Gamage et al published in this issue of the Journal of Infectious Diseases [1] reports an important finding to fill the data gap regarding boosting of mucosal immunity with intradermal fIPV. The investigators conducted a 3-arm, randomized controlled trial among children aged 10–12 years who had received their last tOPV dose at least 5 years earlier. They randomized the children to either receive a single dose of intramuscular IPV, intradermal fIPV, or no polio vaccine. After 1 month, the children were challenged with a trivalent oral poliovirus vaccine (tOPV; containing live attenuated poliovirus 1, 2, and 3) and their mucosal immunity was measured through the prevalence and duration of viral shedding. The authors concluded that a single intradermal fIPV boosts mucosal immunity in previously OPV-vaccinated children to the same extent as full-dose IPV. The finding is important to assure the national immunization technical advisory group of experts (NITAG), or their equivalent in other countries, to adopt the Strategic Advisory Group of Experts (SAGE) recommendation of 2016 regarding the introduction of fIPV rather than full-dose IPV [2]. This will help in stretching the existing limited supply of IPV to reach twice the population compared to when full-dose IPV is introduced. Besides cost and dose sparing, this finding also has implication for the 2-dose fIPV introduction at 6 and 14 weeks of age as compared to single IPV at 14 weeks. As the drop-out rate for diphtheria, pertussis, tetanus vaccination between age 6 and 14 weeks is substantial in developing countries [3], most of the children attending week 6 vaccination might not show up for the 14-week vaccination and, hence, will not get any IPV if a single full-dose IPV is implemented. Although the study by Gamage et al, with a methodologically robust design and excellent participants retention rate (>90%), provides compelling evidence to introduce intradermal fIPV in routine immunization, there are still a few remaining issues to address. First, intradermal injection is difficult to administer compared to intramuscular injection, and the success will depend on the correct technique of intradermal injection. The polio eradication program has already invested in this area and different intradermal devices and needle-free intradermal injectors have been evaluated for immunogenicity, acceptability, and programmatic feasibility in both routine and campaign setting. Among these devices, Helm West Pharma intradermal device and Tropis (PharmaJet) needle-free intradermal jet injector have been tested in different countries, including high-risk areas of Pakistan, and found to be easier to learn, user friendly, and efficient for correct administration of intradermal fIPV as compared to the traditional Bacillus Calmette-Guérin (BCG) needle syringe [4–6]. Helm West Pharma intradermal device and Tropis (PharmaJet) jet-injector are WHO prequalified for administering intradermal fIPV, and countries can easily obtain them through WHO for use in the program. Second, IPV is not licensed by the manufacturer for intradermal use and, hence, off-label use of intradermal dosing will require approval by the ministry of health and NITAG of the respective countries. It is not uncommon for countries to make decisions based on the latest available scientific evidence for vaccine administration that might be contrary to the labeled indications. Similarly, SAGE recommendation provides important support for the countries to start using fIPV in routine immunization. Third, IPV is mostly available in either 5 or 10-dose vials [7]. Switching to fIPV will increase the number of doses per vial by five fold (5 × 5 = 25 and 10 × 5 = 50 doses) and, hence, the number of piercings with a BCG needle through the vial stopper, which might compromise the integrity of the stopper. A study by PATH has successfully demonstrated that 50 piercings of the IPV vial with a 27-gauge needle met the target of <10% of particle formation, and 100 piercing did not result in any closure failure of the stopper [8]. While the 5-dose IPV vials will not create any problem, vials with more than 5 IPV doses might not be suitable for fIPV implementation. Lastly, introduction of intradermal fIPV with new intradermal injection devices, such as Helm West Pharma intradermal adapter or Tropis needle-free jet injectors might also require approval from the respective national regulatory authorities for biological/drug devices. While such types of approval (if needed) is a lot easier after WHO prequalification, the application process still consumes time and energy, possibly delaying the introduction of fIPV. Besides routine immunization, the findings of Gamage et al also have important implications for poliovirus outbreak response activities in situations where there is cocirculation of WP1 (wild poliovirus type 1) and cVDPV2 (circulating vaccine-derived poliovirus type 2). A single dose of fIPV, with excellent potential for boosting mucosal immunity among children whose primary response to OPV has waned, can be easily administered in campaigns to close the immunity gap and control the outbreak by halting poliovirus transmission. The SAGE recommendation in 2018 also endorses the use of intradermal fIPV, rather than full-dose IPV, in outbreak situations [9]. There are still a few questions that need to be answered after the implementation of intradermal fIPV in routine immunization programs: (1) the population level impact of fIPV on mucosal immunity among children has to be evaluated; (2) while studies have demonstrated humoral immunity and boosting of mucosal immunity after administration of intradermal fIPV among children primed with OPV, evidence is lacking about the duration of this immunity; and (3) unlike the study by Gamage et al, administration of intradermal fIPV at an earlier age (when the primary immune response to OPV has not waned) also should be studied for boosting of mucosal immunity. A systematic review in 2017 reported that the type 2 immunogenicity of 2 doses of fIPV was more immunogenic when started later in childhood and with a longer interval between the 2 doses [10]. Globally, demand for IPV is high and the supply is constrained. As the program is gradually eliminating OPV, eventually countries will rely solely on IPV, further increasing the demand for IPV. To counter the shortage of IPV, the best strategy is the introduction of 2 doses of fIPV into routine immunization. While fIPV can stretch the limited IPV supply, it provides similar humoral and mucosal protection when compared to full-dose IPV among children mucosally primed with OPV. In addition, it will play an important role in stopping poliovirus transmission and, hence, help in the eradication of WPV and cVDPV. Potential conflicts of interest. Author certifies no potential conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.