Evolution of Inactivated Poliovirus Vaccine Use for the Endgame and Beyond Open Access

(See the Major Article by Resik et al, on pages 895–901.)

More than 6 decades after licensure of inactivated poliovirus vaccine (IPV) as the first polio vaccine, optimal use of IPV for polio prevention continues to be an area of interest. With the initiation of sequential, global withdrawal of oral polio vaccines (OPVs) from routine use, starting with type 2 OPV withdrawal, which was completed by May 2016, there is an increasing reliance on IPV during the interim phase of the eradication endgame. The major role of IPV in this phase is to induce immunity against types no longer in OPV so that, should polioviruses be reintroduced (eg, via a break in laboratory containment), the population is substantially protected from paralytic disease. Continuation of an all-IPV schedule with at least 2 doses has been recommended for at least 10 years after certification of eradication of wild polioviruses (WPVs) and withdrawal of all OPV use [1]. In recent years the number of countries using IPV in routine immunization schedules has increased dramatically, with most OPV-using countries introducing 1 dose of IPV, in accordance with the Polio Eradication and Endgame Strategic Plan of the Global Polio Eradication Initiative [2]. However, manufacturing challenges to provide enough full doses of IPV have led to shortages and delayed universal introduction in many countries. The report by Resik et al in this issue of The Journal of Infectious Diseases addresses a well-known but insufficiently studied strategy for overcoming supply constraints [3].

It is important to review the benefits of IPV in achieving and sustaining polio eradication. IPV is one of the safest and most well-tolerated vaccines ever developed, with no serious adverse event causally associated with its use found in clinical trials conducted over decades [4]. In addition, there is no risk of vaccine-associated paralytic poliomyelitis or emergence of vaccine-derived polioviruses (VDPVs) with IPV use—a significant advantage of IPV over OPVs during the final stages of eradication. Humoral immunogenicity from IPV is also consistent across geographies and populations, in contrast to OPV, for which immunogenicity has typically been low in developing countries [5]. High levels of maternally derived antibodies in early infancy are the biggest risk factors for the lack of vaccine take with IPV [6]. Therefore, a late administration of the last dose is expected to be key to close immunity gaps in IPV-only schedules, as reported by studies evaluating routine immunization schedules designed for the endgame, and the 4- and 8-month schedule evaluated by Resik et al is consistent with this [3, 7].

The role of IPV in inducing mucosal immunity remains less certain. IPV is considered comparable to OPV in reducing oropharyngeal excretion, as measured by OPV challenge studies, but it is inferior to OPV in inducing primary intestinal mucosal immunity [8–10]. This lack of a meaningful impact on primary intestinal mucosal immunity is considered a major shortcoming of IPV, since the principle of eradication hinges on successful interruption of virus transmission. There also appears to be no gain in primary intestinal immunogenicity of IPV with experimental formulations with several-fold higher D antigen content, although such formulations have a linear, favorable impact on humoral immunogenicity [11, 12]. Thus, IPV-only recipients, irrespective of primary schedule and doses, excrete the vaccine virus following an oral challenge in almost the same manner as those who are unvaccinated, with a marginal impact on reduction of duration and titer of virus shedding [9, 13, 14]. In contrast, in children previously exposed to OPV, a dose of IPV—either a full dose via the intramuscular route or fractional dose via the intradermal route—had a favorable impact in reducing the prevalence of shedding, and this effect was no less than an additional dose of OPV [15–17].

In studies done in the United States in the late 1950s, prior IPV vaccination reduced wild poliovirus (WPV) transmission in middle-class communities, perhaps because of reduction of oropharyngeal shedding [18]. In contrast, despite a national IPV3 coverage of 95% and 5 doses of IPV in its routine immunization schedule, Israel reported extensive circulation of WPV type 1 for more than a year in 2013, without any paralytic cases [19]. Compared with WPV transmission, there is less information on the transmission dynamics of Sabin-like (SL) polioviruses, which have a lower force of infection than WPVs or vaccine-derived polioviruses (VDPVs). Thus, it is not clear whether IPV receipt has a more meaningful impact on preventing emergence of VDPVs and transmission of Sabin-like viruses, compared with that of WPVs. In Yogyakarta, Indonesia, no VDPVs were detected following a switch to an IPV-only schedule, although this area is surrounded by provinces using OPV in routine immunization, and while Sabin-like viruses were detected in Yogyakarta, implying introduction from neighboring areas [20]. The issue of the impact of IPV on circulation of Sabin-like viruses is important since it is most likely that breaks in laboratory containment from clinical specimens would involve Sabin-like viruses and not WPVs. An analysis with case-based and environmental surveillance from Nigeria demonstrated that combined IPV and OPV supplementary immunization activities (SIAs) had a better impact on interrupting VDPV transmission, compared with OPV-only SIAs [21], presumably in part because of boosting of intestinal immunity in persons previously exposed to OPV. Similar trends were observed in Pakistan for interruption of WPV transmission [22]. In general, a differential impact of IPV on transmission of WPVs, compared with VDPVs and Sabin-like viruses, may become more significant in the postcertification era and during the phase of sequential OPV withdrawal.

Because IPV is more expensive to manufacture than OPV, several research and development initiatives are underway to mitigate the cost and supply constraints, with a focus on enhancing both humoral and intestinal immunogenicity of IPV by means of adjuvant use and antigen sparing, administering a fractional dose (one fifth of the normal dose) through the intradermal route as a dose-sparing strategy, and developing newer manufacturing platforms and cell lines to improve yield. Efforts are also underway to develop IPV from less infectious sources to mitigate posteradication risks of containment failure [4]. Several studies have reported on the safety and immunogenicity of fractional dose IPV when administered via the intradermal route with needle and syringe or delivery devices [23]. Given the constraints of cost and supply, fractional dose administration of IPV has shown promise, depending on the timing of administration, immunization schedule, and number of doses administered.

One of the widely accepted factors compromising the immunogenicity of fractional dose IPV has been the difficulties of intradermal administration [24]. The study by Resik et al reports a novel dose-sparing strategy that could alleviate the perceived difficulties of intradermal delivery [3]. In this randomized, controlled clinical trial conducted among infants in Cuba, they reported noninferior seroconversion rates for all 3 serotypes for fractional IPV administered via the intramuscular route, compared with fractional IPV administered via the intradermal route, after 2 doses, given at 4 and 8 months of age, to previously polio unvaccinated infants. These results are promising and open a new dimension in the spectrum of dose/antigen-sparing strategies, offering a possible solution to the challenges in IPV delivery. Use of the intramuscular route presumably will be substantially more acceptable to immunization programs throughout the world, especially in developing countries, and dose sparing can lead both to reduction in vaccine costs and a decrease in the burden on manufacturers to produce enough full doses of intramuscular IPV to ensure immunization of all children with 2 doses. While a minimum of 2 doses will be recommended after certification of WPV eradication and OPV withdrawal, the data also suggest that even a single intramuscular dose leads to high rates of immune priming.

As the global polio eradication effort gears up for complete OPV withdrawal and an era of IPV-only use, timely optimization of IPV cost, manufacturing, and delivery options will be critical for the long-term success of the program. The encouraging results reported by Resik et al may be extended to generate clinical evidence based on the immunogenicity of intramuscularly administered fractional dose IPV in younger age groups to inform policy formulation for the polio endgame and beyond.

Notes

Acknowledgment. We thank John F. Modlin (Bill and Melinda Gates Foundation) for his input on this article.

Potential conflicts of interest. Authors certify no potential conflicts of interest.

Both authors have 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.

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