New England Journal of Medicine
June 16, 2011 Vol. 364 No. 24
The Polio Endgame
Bruce Aylward, M.D., and Tadataka Yamada, M.D.
N Engl J Med 2011; 364:2273-2275June 16, 2011
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Infection with poliovirus can have devastating consequences, including paralysis and death. In 1988, a year when an estimated 350,000 or more children were paralyzed by polio, the World Health Assembly initiated a global effort to eradicate the infection once and for all. It was an audacious undertaking, given that the virus circulates largely undetected, requires laborious cell-culture techniques to confirm infection, and is tackled with vaccines that provide imperfect protection in the gut.
Initially, the number of polio cases and countries with infections fell rapidly, particularly as financing and political support increased in the mid-1990s. The last case of paralytic poliomyelitis caused by the serotype 2 wild poliovirus was detected in 1999. The number of new polio cases caused by the two remaining wild serotypes had decreased by 99% between 1988 and 2005, but progress had stalled and there was a danger of failure when wild polio viruses were reintroduced into large areas of Africa and Asia. By the end of 2009, sustained investments in innovation had produced a new bivalent oral poliovirus vaccine (OPV)1 and novel tactics for reaching children who had been missed consistently by vaccination campaigns. A new independent monitoring process was established for overseeing the program and guiding course corrections. Since January 2010, new polio cases have decreased by 95% in the world’s largest remaining reservoirs of indigenous virus in northern India and northern Nigeria; the number of cases caused by serotype 3 has fallen by 92% globally; and most countries where poliovirus had been reintroduced have again become polio-free
Declines in the intensity of poliovirus transmission in India and Nigeria are key to interrupting wild poliovirus globally, since viruses originating in these countries have been responsible for all the recent importation-associated outbreaks in previously polio-free countries. Besides India and Nigeria, indigenous polioviruses now survive only in Pakistan and one part of Afghanistan, with just eight other countries currently responding to outbreaks caused by imported viruses. However, in three of these countries — Angola, Chad, and the Democratic Republic of Congo — transmission was reestablished (i.e., at least one imported virus continued to circulate for more than 12 months). All three countries then became secondary wild-poliovirus reservoirs, with onward spread to other previously polio-free countries. The logistic challenges of reaching more than 90% of young children in mass OPV immunization campaigns in countries with reestablished transmission are similar in scale to those faced in the remaining countries with endemic disease, where conflict, insecurity, and weak public services complicate eradication operations.
Although there is still much distance to cover to eradicate the remaining wild polioviruses, recent progress has generated new confidence in the eradication effort, and talk of the polio “endgame” has intensified. However, preventing new polio outbreaks in a “post-eradication era” will require more than biocontainment measures to prevent the reintroduction of wild virus from laboratory stocks or sites where inactivated (Salk) polio vaccine (IPV) is produced. Achieving a polio-free world will eventually require stopping routine immunization with OPV and eliminating vaccine-derived polioviruses (VDPVs), particularly circulating VDPVs, which are Sabin-strain viruses that have acquired both neurovirulence and the capacity to circulate.2
Of the three risks associated with OPV, the most frequently realized one is vaccine-associated paralytic poliomyelitis (VAPP). This risk will disappear with the cessation of use of OPV. Outbreaks caused by circulating VDPVs are rarer than VAPP cases, but new diagnostic tests have confirmed their regular emergence, particularly that of serotype 2 circulating VDPVs, which were found in eight of the nine countries reporting VDPV outbreaks between 2008 and 2010. The persistence of such an outbreak for more than 4 years in Nigeria highlights the importance of reducing the risk of VDPV outbreaks when OPV use ceases and of actively managing any persisting outbreaks.
The rarest risk associated with OPV use is chronic VDPV excretion by people with severe primary B-cell immune disorders. All but one of these chronic immunodeficiency-associated VDPVs to date have occurred in industrialized countries that no longer use OPV. However, people with such infections may excrete virulent virus for years and are themselves at risk for fatal disease (see Brief Report by DeVries et al. in this issue of the Journal, pages 2316–2323). Although industrialized countries now use IPV and will therefore no longer generate new immunodeficiency-associated VDPVs, additional strategies and tools are required to mitigate the associated risk. Ongoing studies in nine low- and low-middle-income countries should help to inform more robust surveillance and, if necessary, case-management strategies for chronic immunodeficiency-associated VDPVs in such settings.
Stopping routine immunization with OPV globally after wild poliovirus is eradicated will eliminate VAPP immediately and halt the generation of new circulating and immunodeficiency-associated VDPVs. The challenge will be to synchronize global cessation of OPV immunization and then manage the transition, potentially lasting several years, to the point where residual VDPVs have been eliminated. Five years ago, the tools for executing this endgame didn’t exist. Today, 12 monovalent OPVs, at least 1 for each serotype, are licensed, and a global stockpile is being built to facilitate a rapid response to any circulating VDPVs that persist after OPV immunization ceases.
It is important to decrease the risk of emergence and transmission of circulating VDPVs in low-income countries, as well as the transmission of any wild viruses introduced through breaks in laboratory containment. Low-cost solutions have been sought to facilitate routine immunization with IPV in such settings and thereby maintain some immunity to polio through at least the first 5 to 10 years after cessation of OPV administration, when risk would probably be highest. It now appears increasingly feasible to create an IPV administration schedule that costs no more than existing OPV schedules, through some combination of reducing the number of doses, delivering one fifth the amount of antigen per dose by intradermal administration, using adjuvants, and introducing seed strains (e.g., Sabin strains) that can be produced safely by low-cost manufacturers in developing countries.3,4 To help address the problem of chronic shedding of immunodeficiency-associated VDPV and reduce the potential for emergence of resistance, there are at least two antiviral candidates in early stages of development. Given the potentially fatal outcome of chronic infection, the availability of such treatments should also facilitate screening of at-risk but asymptomatic people.
Of course, none of these tools is perfect. Using monovalent OPVs to combat residual circulating VDPVs incurs the small risk of generating a new circulating VDPV — a risk that could increase with time after OPV use ceases. Since IPV does not induce the same level of intestinal mucosal immunity as OPV, we don’t yet know how effective IPV would be in terminating transmission of a circulating VDPV in tropical settings. Even if an antiviral drug is successfully developed, viral resistance may be encountered in the treatment of chronic shedders of immunodeficiency-associated VDPVs. Further research is providing additional tools and strategies that may be necessary for managing the risks in the posteradication era. Already the availability of these new tools has allowed serious discussions to begin regarding replacing trivalent OPV with bivalent OPV in routine vaccination programs, to take advantage of the apparent eradication of wild poliovirus type 2 and eliminate the VDPV risks associated with continued routine use of live vaccines with a type 2 component.
Uncertainties about the risks associated with cessation of OPV use have contributed to arguments that continued OPV immunization might be a more prudent approach to the polio endgame. However, there is accumulating evidence that intelligent application of innovative tools and strategies has shifted the balance of risk so that sustaining routine OPV immunization after the eradication of wild-type virus would present a greater risk to society and cost much more5 than eventual cessation of OPV immunization as a critical step in eradicating all polio disease.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
From the World Health Organization, Geneva (B.A.); and the Bill and Melinda Gates Foundation, Seattle (T.Y.).