A Bump in the Road Leading to Global Poliomyelitis Eradication
June 15, 2002 6 minutes read
Abstracts & Commentary
Editor’s Note: Although this event was recently discussed in Infectious Disease Alert by Dr. Kemper (Infectious Disease Alert. 2001;20[11]:83), the recent publication of the definitive report has prompted a second examination of the outbreak.
Synopsis: An outbreak of paralytic poliomyelitis in Haiti and the Dominican Republic was associated with circulation of a derivative of the Sabin oral poliovirus vaccine, which had reverted to a virulent phenotype.
Sources: Kew O, et al. Outbreak of poliomyelitis in Hispaniola associated with circulating type 1 vaccine-derived poliovirus. Science. 2002;296:356-359; Nathanson N, Fine P. Science. 2002;296:269-270.
In the summer of 2000, poliovirus type 1 was isolated from stool specimens of a number of cases of acute flaccid paralysis in Banao, Dominican Republic and Port-de-Paix, Haiti. Initial nucleic acid probe hybridization assays indicated that the isolated viruses were vaccine-derived and subsequent sequence characterization of the major capsid surface protein VP1 of 2 isolates demonstrated unrelatedness (< 82% VPI sequence identity) to wild type-1 poliovirus.
Consistent with the initial probe hybridization assays, the Dominican and Haitian isolates were closely related to each other and to the Sabin type 1 oral poliovirus vaccine (OPV) strain. The degree of relatedness to the OPV strain, however, which was in the range of 97.4-98.1%, was significantly less than the > 99.5% OPV relatedness usually detected in cases of acute flaccid paralysis or vaccine-associated paralytic poliomyelitis.
Furthermore, epidemiologic considerations also distinguished the Hispaniola cases, including the usual rarity (~ 1 case per 2 million distributed OPV doses) of vaccine-associated paralytic poliomyelitis as well as its sporadic occurrence, and the fact that such cases are usually associated with polioviruses types 2 and 3. Finally, the finding that the isolates shared 12 of the VP1 nucleic acid substitutions that distinguished them from Sabin 1 strongly suggested that they were derived, as is typical of wild outbreak-associated polioviruses, from a single ancestor.
Ultimately, 13 cases of acute flaccid paralysis in the Dominican Republic and 8 in Haiti (2 of which were fatal) were confirmed by isolation of poliovirus type 1 from either patients or their healthy contacts. The cases occurred in communities with low rates (7% to 40%) of vaccine coverage and all but one of the patients were either unvaccinated (11 patients), incompletely vaccinated (7), or had an unknown vaccination status (2). Analysis of 31 isolates (19 from polio patients and 12 from healthy contacts) found them to be closely related to each other and appeared to be the common progeny of a recent OPV infection. Through use of the VP1 sequence relationships among isolates, the dates of specimen collections, and an assumed rate of VP1 evolution of 0.030 substitutions per synonymous site per year, it was estimated that the initiating OPV dose occurred in late 1998 or early 1999, with further divergences occurring in Haiti and the common ancestral infection for the Dominican clade occurring in the spring of 2000.
All the outbreak isolates were recombinants, with the 5¢-untranslated and capsid region sequences derived from Sabin 1, but with most of the noncapsid sequences derived from other enteroviruses. The presence of a closely related block of recombinant sequences within each isolate confirmed derivation of the outbreak virus from a single-source infection, but with at least 4 different enteroviruses having recombined with the type 1 vaccine-derived poliovirus during its circulation in Hispaniola.
Reversion of the vaccine strain to a virulent phenotype was the consequence of at least 2 genetic changes. All isolates had a single nucleotide substitution resulting in restoration of a structural element that controls the efficiency of translation of poliovirus RNA. Other changes were associated with restoration of neurovirulence.
Comment by Stan Deresinski, MD, FACP
The fact that this publication reads like a detective novel is a tribute to the elegance of the science applied to detection of this outbreak of acute flaccid paralysis on the island of Hispaniola. Kew and associates identified the event and its victims, isolated the virus from victims and their healthy contacts, and performed extensive genetic analyses of the isolates—demonstrating their relatedness and the fact that they had arisen from a single ancestral Sabin vaccine infection with at least 4 subsequent recombination events with wild-type enteroviruses that resulted in reversion to virulence, leading to the outbreak. The evidence led Kew et al to believe that the outbreak began in Haiti with a dose of oral polio vaccine given to a child in a community with poor vaccine coverage.
As pointed out in an accompanying commentary, the Sabin OPV is comprised of the 3 major immunotypes of poliovirus, each of which was derived by tissue culture passage and clonal selection for the attenuated phenotype, a phenotype that is the consequence of a small number of critical point mutations. After administration, OPV infects and replicates in human intestinal mucosa and, as a consequence, generates mutants, some of which may result in restoration of neurovirulence. Such revertant viruses are estimated to be excreted by as many as one third of OPV recipients after which they may readily infect nonimmune contacts in whom further mutations may occur, some of which once again increase the virulence of the virus. In a setting of low vaccine coverage, this vaccine-derived poliovirus with restored virulence may sequentially spread, leading to an outbreak such as that described here, as well as to similar outbreaks such as small ones that recently occurred in the Philippines and in Egypt.
The outbreak, however, could not have occurred in the absence of the fertile ground provided by the circumstances in Hispaniola. Haiti has the lowest levels of polio vaccine coverage in the Americas and, while higher coverage is present in the Dominican Republic, this was not true of the communities in this country where cases occurred; coverage rates for 3 doses of oral polio vaccine in those communities was only 20-30%. Gaps in surveillance for cases of acute flaccid paralysis, particularly in Haiti, further contributed to the problem, as did prevalent poor hygiene.
Since the WHO resolved in 1988 to eradicate polio from the globe, the annual estimated incidence of this dreaded disease has decreased by 99%, with Nigeria, northern India, and Pakistan remaining as the 3 poliovirus reservoirs in which low routine OPV vaccination coverage and high population density favor transmission. As the world approaches the eradication of polio by use of an intensive vaccination program using the Sabin OPV, this outbreak in Hispaniola has important implications for the end game. The last case of poliomyelitis in the Americas was reported from Peru in 1991, while the last Caribbean cases had occurred in Haiti in 1989.
The Sabin OPV has a number of advantages over killed vaccines, including its route of administration, its provision of long-lasting mucosal immunity, and its ability to spread to contacts of vaccine recipients, thus immunizing individuals who do not directly receive the vaccine. Unfortunately, it is that last characteristic of OPV, together with its mutability, that leads to outbreaks due to infection with revertant strains of vaccine-derived poliovirus, as discussed here.
From this event, Kew et al conclude that the final eradication of wild poliovirus must be completed as rapidly as possible while, at the same time, immunity gaps in nonendemic countries are prevented. Once certification of wild poliovirus eradication is achieved, the orderly planned cessation of OPV use should be implemented throughout the world, while establishing stockpiles of vaccine for use in unforeseen emergencies that must be detected in a timely fashion by maintenance of sensitive global surveillance programs. One problem that may require attention in the future, when universal vaccination is no longer maintained, is the potential use of poliovirus as an agent of bioterrorism.
Dr. Deresinkski, Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor of Infectious Disease Alert.
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