New England Journal of Medicine
October 16, 2014 Vol. 371 No. 16
Achieving and Maintaining Polio Eradication — New Strategies
John Modlin, M.D., and Jay Wenger, M.D.
N Engl J Med 2014; 371:1476-1479 October 16, 2014
It has been nearly 2 years since the last known case of type 3 poliomyelitis occurred in Nigeria, and although it’s still too early to celebrate, the disappearance of the second of the three poliovirus serotypes (type 2 transmission was eliminated in 1999) represents a major milestone and proof of principle that global eradication of paralytic poliomyelitis is achievable.
Poliovirus transmission has been identified in 10 countries this year, but more than 75% of the cases have occurred in Pakistan, where antigovernment militants have denied immunization to more than 300,000 children for more than 2 years. This summer, military activities opened some areas to vaccination teams and provided an opportunity to deliver oral polio vaccine (OPV) with other basic health services to displaced children and families, while also creating a risk of dispersal of poliovirus-infected persons more broadly in the region. Multiple supplemental immunization rounds are targeting the other countries with recent transmission of type 1 poliovirus and additional countries that are at risk for reinfection. Given the substantial progress in Nigeria and the small number of polio cases identified elsewhere in Africa in recent months, it is now possible that the continent will be free of polio by the end of the year.
The past decade has brought new partners to the Global Polio Eradication Initiative (GPEI) consortium, new tools for improving immunization and surveillance, a new sense of urgency about completing eradication, and confidence that such a feat is possible. Several factors are making a difference: improvements in planning for supplementary immunization activities, support for delivering other key health interventions through the polio program, innovations such as global-positioning-system mapping, and strategies including the establishment of immunization stations at transit points and the engagement of government, traditional, and religious leaders at all levels. To further reduce the risk of international exportation of polio from countries where it is endemic — exportation accounted for 60% of all polio cases in 2013 — the World Health Organization (WHO) recently designated polio as a public health emergency of international concern under the International Health Regulations and recommended that travelers leaving any country with active transmission receive additional immunization.
As the areas with sustained polio transmission shrink and the genetic diversity of the remaining type 1 polioviruses narrows, global public health authorities are preparing for a phased transition from the live, attenuated OPV to the inactivated polio vaccine (IPV) originally introduced in 1955. Although it may appear counterintuitive to replace OPV, a cheap vaccine easily administered in two oral drops, with IPV, which is at least 10 times as expensive to produce and is given by injection, discontinuation of OPV has always been a component of polio-eradication plans because of the occurrence of vaccine-associated paralytic poliomyelitis in a very small proportion of OPV recipients (<1 per 750,000 recipients in the United States, for example).
There are two additional challenges that make the switch from OPV to IPV necessary, neither of which was anticipated when the World Health Assembly launched the GPEI in 1988. The first is the magnitude of reduced effectiveness of OPV in locations with a high burden of enteric pathogens and diarrheal disease. This limitation can be striking, with seroconversion rates of less than 20% per dose of trivalent OPV (tOPV) in some locations, which leave many children who have received multiple doses still susceptible to polio. The elimination of naturally occurring type 2 polioviruses allowed for a partial solution to this problem: deployment in supplementary immunization activities of monovalent type 1 vaccine (mOPV1) and bivalent types 1 and 3 vaccine (bOPV), which induced improved immune responses to type 1 and type 3 polioviruses by removing the interfering type 2 OPV viruses from the formulation.
The second problem was uncovered with the development of viral genetic sequencing technology, which revealed that OPV viruses can regain fitness and neurovirulence with continuous person-to-person transmission in areas of low population immunity. Circulating vaccine-derived polioviruses (cVDPVs) were first recognized on Hispaniola in 2000 and have since caused outbreaks and isolated cases of paralytic disease from viruses of all three serotypes in multiple locations. The existence of cVDPVs dictates that all OPV use will need to cease in order to achieve full polio eradication.
A GPEI strategic plan for 2013 through 2018 envisions the complete cessation of circulation of wild-type poliovirus and VDPV followed by coordinated replacement of tOPV with bOPV for an interim period to prevent the generation of new type 2 cVDPVs, which have been responsible for virtually all emergences of VDPV during the past 5 years. The plan calls for the eventual discontinuation of OPV use once eradication of all types is achieved.
However, mathematical models suggest that the global risk of cVDPV reemergence from residual OPV type 2 circulation will be substantial in the first 1 to 3 years after OPV type 2 cessation.1 To mitigate this risk, the WHO Strategic Advisory Group of Experts on immunization has recommended that all countries that use OPV add at least one IPV dose to the routine immunization of infants in advance of the tOPV–bOPV switch, currently planned for 2016. The recommendation is based on affordability, the ability of a single vaccine dose to prime the immune system to respond to another dose administered during an outbreak, and the likelihood that one dose will moderately reduce the risk of disease among vaccinated children in the event of type 2 cVDPV exposure (one-dose seroconversion would be expected in 40 to 50% of recipients). This strategy enhances immunity to types 1 and 3 in two ways: by improving the immunogenicity of OPV with the removal of type 2 vaccine virus and by enhancing immunity in children who are given both bOPV and IPV during routine infant immunization.2
Two recent studies in India have shown that IPV administered to children previously given OPV boosts both humoral neutralizing-antibody levels and intestinal mucosal immunity.3,4 Attention to intestinal immunity has increased because of uncertainty about the extent to which polio may circulate in populations with only IPV-induced immunity. Unlike primary immunization with OPV, primary immunization with IPV provides only marginal intestinal immunity, as measured by poliovirus excretion after OPV challenge.5 Outbreaks of wild-type poliovirus have been adequately contained in the Netherlands and other developed countries that use only IPV for routine childhood immunization. However, recent experience in Israel with prolonged circulation of type 1 polioviruses in sewage effluents has generated substantial concern that IPV-induced intestinal immunity may not prevent silent transmission in developing countries despite high immunization rates and that infection could spread extensively before the first clinical case is detected.
In that event, the only realistic approach to control of the outbreak would be widespread immunization of the at-risk population with OPV or a combination of IPV and OPV. But either option requires creating a risk of downstream cVDPV, threatening final eradication. To better prepare for this possible threat, the Bill and Melinda Gates Foundation is supporting the development and clinical evaluation of new genetically stable OPV strains with reduced ability to genetically revert to cVDPVs.
Although our current optimism must be tempered by the tendency of polio to emerge in areas of armed conflict and humanitarian crisis where routine immunization systems have collapsed and it’s difficult to gain access to susceptible children, more of the world’s population than ever is living in certified polio-free regions, and we are inexorably approaching the end of polio. Key strategic components of the endgame plan, including the tOPV–bOPV switch and introduction of affordable IPV, are focused on the final obstacles to eradication. Development of improved vaccines will provide additional confidence that eradication can be sustained.