Polio Eradication: Status, Struggles and Strategies

Poliomyelitis is a potentially disabling, life-threatening and outbreak-prone disease caused by infection by 1 of 3 different serotypes of poliovirus (type-1, type-2, or type-3). Polioviruses can replicate in the pharyngeal and intestinal mucosa and are excreted in the feces and, to a lesser extent, in pharyngeal secretions. They can be transmitted through the fecal-oral route or to close contacts by the oral-oral route through respiratory droplets. Most infections are asymptomatic or self-limiting. In rare instances, the virus can infect the spinal cord, leading to limb paralysis or, in the most severe cases, respiratory paralysis and death. There is no cure for paralytic poliomyelitis, and treatment consists of physiotherapy for affected limbs or mechanical ventilation when breathing is affected.1 In the early 1950s, wild poliovirus (WPV) had become the most feared disease in the world, killing or paralyzing over half a million people each year and driving public support to finance the successful development of vaccines as an urgent medical need.2 Although the global incidence of poliovirus infections has decreased by 99.9%,3 primarily due to a concerted global eradication effort that has vaccinated over 2.5 billion children in the past three and a half decades, complexities remain in the final stretch to achieve eradication. With the risk of international spread, persistence of virus transmission in a few geographies and evolving challenges around vaccine-derived poliovirus transmission, polio remains the only disease currently designated as a public health emergency of international concern, highlighting its continued importance from a global health perspective.4 THE VACCINE CONUNDRUM The 2 primary types of polio vaccine currently available are the parenterally administered Salk inactivated polio vaccine (IPV) and the live, attenuated Sabin oral polio vaccine (OPV), introduced in 1955 and 1961, respectively. Both vaccines have contributed to the decline in poliomyelitis cases over the past 7 decades, but their characteristics also highlight some of the complexities in completing polio eradication. IPV is highly effective in preventing paralysis, eliciting seroconversion with poliovirus-neutralizing antibodies in over 95% of vaccines after 3 or more doses. OPV is also highly effective, typically eliciting protective humoral immunity after 3 doses in the primary series; however, geographic heterogeneity in the immune response to OPV has been observed, and some subpopulations may require more than 3 doses to induce a protective response.5,6 A critical difference between the 2 vaccines is that OPV is effective in inducing primary intestinal mucosal immunity, not only preventing polio infection in the vaccinee but also inhibiting fecal transmission of the virus.7 In contrast, IPV has a limited primary effect on intestinal immunity, with any meaningful impact reliant on previous receipt of OPV.8 Thus, multiple advantages—interruption of transmission, a relatively lower cost per dose, ease of delivery—have made OPV the preferred tool for outbreak response for low- and middle-income settings, but with a major disadvantage: the attenuated polioviruses in OPV can begin to lose their genetic attenuations following replication in the intestinal mucosa in as rapidly as 1–2 weeks following administration, potentially reacquiring neurovirulence.9,10 This propensity of loss of attenuating mutations is further aided through the recombination of OPV strains with other enteroviruses from concurrent infections prevalent in settings of poor sanitation and hygiene. In very rare instances (0.03–0.14/100,000 doses of trivalent OPV), reverted OPV strains can cause vaccine-associated paralytic poliomyelitis (VAPP), an aberrant neuroparalytic reaction in vaccinees or close contacts.11 Although the incidence of VAPP in close contacts can be modulated by increasing vaccination coverage to reduce the susceptible population, VAPP in vaccinees is an individual-level phenomenon that appears to be related to the level of preexisting polio antibodies upon receipt of OPV.12 Administering a dose of IPV before receipt of OPV has been demonstrated to decrease VAPP risk when compared with administering OPV to polio-naïve infants.1 Moreover, in settings of persistently poor immunization coverage, fecal excretion of reverted OPV strains as vaccine-derived polioviruses (VDPV) can cause paralytic outbreaks due to person-to-person transmission, giving rise to circulating VDPV (cVDPV).9 Finally, when given to individuals with primary immunodeficiencies, OPV can replicate for extended periods of time in the intestinal mucosa, resulting in prolonged shedding of immunodeficiency-associated vaccine-derived polioviruses (iVDPV) that can potentially spread among susceptible close contacts.13 Primary immunodeficiency patients are also at a higher risk of developing VAPP compared with immunocompetent individuals. GLOBAL ERADICATION EFFORTS In 1988, the World Health Organization (WHO) General Assembly passed a resolution to eradicate poliomyelitis by the year 2000.11 The resolution was accompanied by the launch of a public-private partnership, the Global Polio Eradication Initiative (GPEI), currently led by 6 partners—Rotary International, WHO, United States Centers for Disease Control and Prevention (US CDC), United Nations Children’s Fund (UNICEF), Bill & Melinda Gates Foundation (BMGF) and Gavi, the Vaccine Alliance. Since the launch of the GPEI, the global incidence of poliomyelitis has decreased markedly. Five of the 6 WHO regions—the African, American, European, South-East Asian and Western Pacific Regions—have been certified as free of wild poliovirus, and WPV2 and WPV3 have been certified as eradicated globally. The Eastern Mediterranean region has not yet been certified due to the persistence of WPV1 transmission in Afghanistan and Pakistan (Fig. 1). Although WPV1 transmission persists in these 2 countries, the number of paralytic cases is decreasing—84 cases were reported in Pakistan and 56 in Afghanistan in 2020, but only 6 in each country in 2023.14 Along with the decline in cases, the number of genetic lineages of WPV1 has also decreased considerably in recent years,15 indicating that the virus might be in the final phase of transmission, persisting in isolated pockets of geographic inaccessibility and political unrest.FIGURE 1.: Reported paralytic cases of wild poliovirus (WPV) and circulating vaccine-derived poliovirus (cVDPV) by country, globally. A: shows the decade of the last reported indigenous WPV case by country, with endemic countries (as of 2023) shown in yellow. Countries experiencing cases of WPV in the years following the last indigenous case are shaded with stripes. The following countries eliminated polio before 1950 but do not show up in shading due to resolution: Nauru (1910), Tuvalu (1936), Palau (1940). B: shows the year of the last reported paralytic case of cVDPV, by country, from 2000 to 2023. (Data were not routinely reported before 2000, and no countries reported the last paralytic case of cVDPV in 2000.) Countries in gray have not reported any paralytic cVDPV cases since 2000. WPV and cVDPV detections from environmental surveillance are not included in the figure. Data are current as of January 15, 2024. Data sources include the Global Polio Eradication Initiative surveillance database as housed in the Polio Information System (PolIS) (https://extranet.who.int/polis/), and other Global Polio Eradication Initiative data.12 , 14THE SWITCH AND CONSEQUENCES With the certification of global eradication of WPV2 in September 2015, the GPEI recommended cessation of use of OPV-containing poliovirus type-2 in essential immunization programs, which was achieved with a global switch from trivalent OPV to bivalent (poliovirus types 1 and 3) OPV in May 2016.16 Following an initial decline in cVDPV2 cases, the years following the switch saw cases due to cVDPV2 outbreaks outnumbering those due to WPV (Fig. 1). The majority of cVDPV2 cases have been reported from the African region, and international travel has resulted in the spread to countries that have long been free of poliovirus transmission: in 2022, a paralytic case was reported in New York state in an unimmunized adult,17 and cVDPV2 isolates were detected in wastewater in the United Kingdom, Canada and Israel,18,19 among other countries. These events illustrate the serious risk of the global spread of polioviruses. A MITIGATION TOOL: nOPV2 cVDPV outbreaks require the use of OPV to interrupt transmission, with the associated risk of further propagating cVDPVs if enough children are not reached with a timely vaccination response. In 2011, a consortium of researchers began the development of novel OPV type-2 (nOPV2), consisting of genetically engineered poliovirus designed at the molecular level to be more stable than Sabin OPV.20 Clinical development of nOPV2 required creativity and innovation, as the novel vaccine candidates became available only after the global switch21–23; however, close collaboration across partners enabled a successful development pathway. Based on supportive preclinical, clinical and manufacturing data, nOPV2 became the first vaccine to be authorized for use under the WHO Emergency Use Listing (EUL) pathway on November 13, 2020. By December 2023, over 1 billion doses had been administered for outbreak response campaigns in over 35 countries.24 Even with this massive usage, new cVDPV2 emergences derived from nOPV2 remain low, with risks estimated to be approximately 80% lower than the risks associated with Sabin OPV2 use, based on experience in the African region.25 nOPV2 received WHO prequalification on December 27, 2023, following the generation of data from phase III clinical study and field use.26 STRUGGLES IN THE FINAL STRETCH Despite the availability of effective vaccine tools such as IPV, bOPV and nOPV2, there are several remaining challenges to overcome before global eradication can be achieved. First is the inaccessibility in the pockets of persistent endemicity of WPV1 in Pakistan and Afghanistan, due primarily to the complicating effect of social and political unrest on the implementation of immunization campaigns. Further, the decline in immunization coverage across the world following the COVID-19 pandemic,27 along with the ease of international travel, make spread of polioviruses into polio-free areas a major risk as evidenced by WPV1 cases in Malawi and Mozambique (in 2021 and 2022, respectively)11 and cVDPV2 detection in the USA,14 UK, Canada and Israel15,16 in 2022. Polio vaccine coverage of at least 80%–90% is required to maintain herd immunity and protect against outbreaks, but needed coverage may be even higher in areas where vaccine effectiveness is lower and transmission rates are higher.28 Additionally, a shrinking global supplier base for polio vaccines, and more specifically recent disruptions in nOPV2 supply, have impacted the completeness of vaccination campaigns. Complexity in the choice of vaccines for outbreak response in areas with co-circulation of WPV1 and cVDPVs has led to suboptimal response and ongoing circulation. Finally, it takes several weeks for virologic confirmation of poliovirus transmission, a process complicated by the field logistics of sample shipment and reliance on culture-based methods, which can be labor- and time-intensive. Early detection through improved field operations and newer molecular methods could significantly improve the timeliness of outbreak response. STRATEGIES TO ACHIEVE AND SUSTAIN ERADICATION The GPEI recently updated its strategy for global eradication, targeting certification of WPV1 eradication and validation of the absence of cVDPVs by the end of 2026.12 To achieve eradication, key enabling activities, including political advocacy, sustained donor support, community engagement, integration with other services, expansion of surveillance network and adaptation of innovative tools for program use, will need to be strengthened, while the primary focus remains to improve vaccination efforts. Successfully meeting the goals of interrupting WPV1 and cVDPV transmission will require continued use of OPVs, especially for outbreak response or preventative mass vaccination campaigns. For cVDPV2, nOPV2 is an important tool that fundamentally changes the response-seeding cycle, bringing us closer to eradication. Building on this experience, nOPV1 and nOPV3 are in clinical development to provide more genetically stable options for response to type-1 and type-3 outbreaks.29,30 Such tools, if used in a timely and adequately scoped vaccination response, should help us close remaining outbreaks and phase out OPV usage. Timeliness of outbreak response could be improved by early detection of poliovirus transmission with promising new methods such as direct detection and nanopore sequencing. IPV will play an increasingly important role in the final phases of eradication, with the ongoing rollout of a second dose in essential immunization schedules in the near term and, subsequently, with the planned introduction of IPV-containing hexavalent vaccines. Moreover, targeted use of IPV following OPV use in outbreak response in areas with persistent transmission could increase the likelihood of virus interruption.31 In the mid- to long-term, once OPVs are phased out from essential immunization schedules, 2 primary sources of potential community reintroduction will remain: shedding of OPV-derived viruses from patients with primary immunodeficiencies (iVDPV) and accidental or intentional release of WPV used in the manufacturing of IPV.32 Research efforts for iVDPV risk mitigation focus on the development of safe and effective therapeutics to halt shedding in iVDPV excreters, the most advanced being the antiviral combination of pocapavir and imocitrelvir.33,34 Polio virus-like particles represent a promising approach toward the development of a vaccine that does not require the use of live virus during manufacture, with 1 candidate having entered phase I clinical trials in 2024.35 LONG-TERM VISION Achieving and maintaining a polio-free world will require successful implementation of current strategies with the existing tools and will also benefit from the availability of a suite of new innovations to overcome evolving challenges. Continued use of live attenuated polioviruses in vaccination is incompatible with completeness of eradication. However, successful replacement of OPV with IPV for essential immunization requires the mitigation of risk factors based on the lessons learned from the OPV type-2 cessation experience. Adequacy of nOPV stockpiles will be key to interrupting cVDPV outbreaks with a lower risk of generating new ones compared with Sabin OPV use. Environmental screening for polioviruses in wastewater is important for detecting silent spread. However, the efficiency of environmental surveillance is limited by the lack of infrastructure in low-income countries, and sustaining such a surveillance network beyond eradication will be challenging unless integrated with other disease surveillance systems. Further, the risk of cVDPV outbreaks will persist even after OPV cessation due to chronically infected immunodeficient individuals excreting iVDPVs; early availability of polio antiviral drugs would mitigate this risk. Finally, in the post- and peri-eradication context, there is an unmet need for a vaccine that elicits both humoral and intestinal immunity without the use of live poliovirus; this would both protect against spread and eliminate the risks of manufacturing release. Maintenance of a polio-free world will require the continuation of polio vaccination for some time following certification of eradication. Current guidelines from the Strategic Advisory Group of Experts on Immunization recommend that polio vaccination be included in essential immunization schedules for at least 10 years following bOPV cessation, and longer in countries with a continued risk of laboratory or manufacturing release.36 This recommendation took into consideration modeling inputs showing that type-2 VDPV emergence risk remains high up to 5 years after type-2 withdrawal,37 and the risk of prolonged excretion of iVDPV.13 Reducing the risks associated with the eventual cessation of all polio vaccination would be facilitated by the availability of safe and effective therapeutics for iVDPV and the lack of continued use of live poliovirus in manufacturing facilities (eg, via transition to virus-like particles-based vaccines). As scientific breakthroughs in polio vaccines, vaccine delivery and surveillance tools are made, enabling policies at global, national and local levels will need to evolve to promote community acceptance of safe and affordable vaccines and ensure all children have an opportunity to live and thrive in a polio-free world.

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