Update on vaccine-derived polioviruses

In 1988, the World Health Assembly resolved to eradicate polio worldwide. The Global Polio Eradication Initiative (PEI) of the World Health Organization (WHO) has led to a decline in global polio incidence, from an estimated 350,000 cases in 1988 to fewer than 2,000 reported cases in 2005, and polio remains endemic to only four countries (Afghanistan, India, Nigeria, and Pakistan). However, two additional obstacles to global eradication involve vaccine-derived polioviruses (VDPVs). Polio outbreaks continue to be associated with circulating vaccine-derived polioviruses (cVDPVs) in areas with low oral poliovirus vaccine (OPV) coverage. In addition, long-term excretion of neurovirulent immunodeficiency-associated vaccine-derived polioviruses (iVDPVs) can lead to poliovirus spread to contacts. Overcoming these obstacles is challenging. High rates of OPV coverage will prevent all poliovirus spread, including spread of VDPVs, but will not prevent establishment of prolonged VDPV infections in certain persons with B-cell immunodeficiencies (i.e., having defects in antibody production). Inevitable gaps in vaccination coverage will give rise to cVDPVs as long as OPV use continues. This report updates a previous report on VDPVs and describes the potential implications of VDPVs in the final stages of global polio eradication. The findings underscore the critical need to strengthen strategies to prevent emergence of VDPVs and to stop all OPV use once wild polioviruses (WPVs) are eradicated.     

Laboratory surveillance for wild and vaccine-derived polioviruses--worldwide, January 2007-June 2008

The Global Polio Laboratory Network (GPLN), comprising 145 facilities in 100 countries and operating in all six World Health Organization (WHO) regions, was established in 1988 to support the Global Polio Eradication Initiative. GPLN isolates and characterizes polioviruses from stool specimens of patients with acute flaccid paralysis (AFP), from healthy contacts of AFP patients, and, in some laboratories, from sewage samples. Nucleotide sequences (viral capsid protein VP1 region; 900-906 nucleotides) are determined for wild poliovirus (WPV) isolates from each patient, contact, or sewage sample to target vaccination activities based on the patterns of virus transmission. This report updates previous reports describing GPLN activities and vaccine-derived poliovirus (VDPV) surveillance during January 2007-June 2008. GPLN routinely screens for and characterizes VDPVs, which have caused polio outbreaks in areas with low oral poliovirus vaccine (OPV) coverage and caused prolonged infections in persons with primary immunodeficiencies. Data from GPLN guide the global initiative to eliminate polio. GPLN data are used to confirm polio cases, identify reservoirs of endemicity, determine serotype distributions of circulating polioviruses, detect importations, identify VDPVs, and ultimately document the absence of WPV and VDPVs for certification of polio eradication.     

Update on vaccine-derived polioviruses--worldwide, July 2009-March 2011

In 1988, the World Health Assembly resolved to eradicate poliomyelitis worldwide. The live, attenuated oral poliovirus vaccine (OPV) has many advantages favoring its use in polio eradication: it is administered easily by mouth; confers intestinal immunity, making recent OPV recipients resistant to infection by wild polioviruses (WPVs); provides long-term protection against paralytic disease through durable humoral immunity; and is inexpensive. Despite its many advantages, OPV use carries the risk for occurrence of rare cases of vaccine-associated paralytic poliomyelitis among immunologically normal OPV recipients and their contacts and the additional risk for emergence of vaccine-derived polioviruses (VDPVs). Because of these risks, OPV use will be discontinued worldwide once the goal of eradicating all WPV transmission is achieved. VDPVs can cause polio outbreaks in areas with low OPV coverage and can replicate for years in immunodeficient persons; therefore, strategies to strengthen global polio immunization and surveillance are needed to limit emergence of VDPVs. This report updates previous surveillance summaries and describes VDPVs detected worldwide during July 2009--March 2011 and reported as of June 20, 2011. Three new outbreaks of circulating VDPVs (cVDPVs), ranging in size from six to 16 cases, were identified in Afghanistan, Ethiopia, and India; three previously identified outbreaks in Nigeria, Democratic Republic of Congo (DRC), and Somalia continued through late 2010 or into 2011 and resulted in 355, 37, and 13 total cases, respectively; two countries experienced importations of cVDPVs from Nigeria; nine newly identified paralyzed immunodeficient persons in seven middle-income and developing countries were found to excrete VDPVs; and VDPVs were found among persons and environmental samples in 15 countries. With the use of alternate OPV formulations since 2005 and with enhanced poliovirus surveillance sensitivity and laboratory screening, the number of identified cVDPV outbreaks per year has increased over time . To prevent VDPV emergence and spread, all countries should maintain high poliovirus vaccination coverage against all three poliovirus serotypes. Sensitive poliovirus surveillance to detect VDPVs will continue to increase in importance.     

Circulating vaccine-derived polioviruses: current state of knowledge

Within the past 4 years, poliomyelitis outbreaks associated with circulating vaccine-derived polioviruses (cVDPVs) have occurred in Hispaniola (2000-01), the Philippines (2001), and Madagascar (2001-02). Retrospective studies have also detected the circulation of endemic cVDPV in Egypt (1988-93) and the likely localized spread of oral poliovirus vaccine (OPV)-derived virus in Belarus (1965-66). Gaps in OPV coverage and the previous eradication of the corresponding serotype of indigenous wild poliovirus were the critical risk factors for all cVDPV outbreaks. The cVDPV outbreaks were stopped by mass immunization campaigns using OPV. To increase sensitivity for detecting vaccine-derived polioviruses (VDPVs), in 2001 the Global Polio Laboratory Network implemented additional testing requirements for all poliovirus isolates under investigation. This approach quickly led to the recognition of the Philippines and Madagascar cVDPV outbreaks, but of no other current outbreaks. The potential risk of cVDPV emergence has increased dramatically in recent years as wild poliovirus circulation has ceased in most of the world. The risk appears highest for the type 2 OPV strain because of its greater tendency to spread to contacts. The emergence of cVDPVs underscores the critical importance of eliminating the last pockets of wild poliovirus circulation, maintaining universally high levels of polio vaccine coverage, stopping OPV use as soon as it is safely possible to do so, and continuing sensitive poliovirus surveillance into the foreseeable future. Particular attention must be given to areas where the risks for wild poliovirus circulation have been highest, and where the highest rates of polio vaccine coverage must be maintained to suppress cVDPV emergence.     

World wide experience with inactivated poliovirus vaccine

As part of the global poliovirus eradication strategy, oral poliovirus vaccine (OPV) has successfully contributed to reduce polio incidence rates globally. However, because of the OPV-related risks of vaccine associated paralytic poliomyelitis (VAPP) and vaccine-derived polioviruses (VDPVs) OPV cessation is required in order to achieve complete eradication of polio. Inactivated poliovirus vaccine (IPV) is a viable option for incorporation into existing vaccination schedules so as to avoid these risks. Furthermore, the continuation of vaccination with IPV will protect populations in case of re-emergence of wild-type poliovirus from remote locations, laboratory samples, or through bioterrorism. The ability of IPV to prevent poliovirus outbreaks and provide herd protection has been demonstrated in several circumstances and in various settings. This paper reviews clinical experiences with IPV administration and outcomes in various countries in Europe, the Americas, Africa and Asia.     

Framework for evaluating the risks of paralytic poliomyelitis after global interruption of wild poliovirus transmission

With the interruption of wild poliovirus transmission globally, the need for new policies to deal with the post-certification era will rapidly arise. New policies will be required in four areas: detection and notification of circulating polioviruses; biocontainment of wild, vaccine-derived and attenuated strains of poliovirus; vaccine stockpiles and response mechanisms; and routine immunization against polioviruses. A common understanding of the potential risks of paralytic poliomyelitis in the post-certification period is essential to the development of these policies. Since 2000, there has been increasing international consensus that the risks of paralytic poliomyelitis in the post-certification era fall into two categories: those due to the continued use of the oral poliovirus vaccine (OPV) and those due to future improper handling of wild polioviruses. The specific risks within both categories have now been defined, and an understanding of the frequency and potential burden of disease associated with each is rapidly improving. This knowledge and clarity have provided a framework that is already proving valuable for identifying research priorities and discussing potential policy options with national authorities. However, this framework must be regarded as a dynamic tool, requiring regular updating as additional information on these risks becomes available through further scientific research, programmatic work, and policy decisions.     

End phase challenges of poliomyelitis eradication programme realization

The progress of poliomyelitis eradication programme realization, the implementation schedule and strategies for the future, are summarised based on publications of the World Health Organisation. During the following two years wild poliovirus strains should be globally eradicated. This means that potentially in 2010 the global eradication of wild polioviruses will be certified. To eradicate poliomyelitis, cessation of the oral polio vaccine (OPV) is necessary, since the vaccine strains produce cases of vaccine-associated paralytic poliomyelitis (VAPP) and cases of poliomyelitis caused by circulating vaccine-derived poliovirus (cVDPV). However, the WHO plan to stop immunization with OPV and the immunization with inactivated polio vaccine (IPV) shortly after, is alarming in the present situation. The article describes the measures undertaken to prevent or minimise the risk of reintroduction of wild poliovirus strains, which is potentially associated with WHO plan of action.     

Development and introduction of inactivated poliovirus vaccines derived from Sabin strains in Japan

During the endgame of global polio eradication, the universal introduction of inactivated poliovirus vaccines is urgently required to reduce the risk of vaccine-associated paralytic poliomyelitis and polio outbreaks due to wild and vaccine-derived polioviruses. In particular, the development of inactivated poliovirus vaccines (IPVs) derived from the attenuated Sabin strains is considered to be a highly favorable option for the production of novel IPV that reduce the risk of facility-acquired transmission of poliovirus to the communities. In Japan, Sabin-derived IPVs (sIPVs) have been developed and introduced for routine immunization in November 2012. They are the first licensed sIPVs in the world. Consequently, trivalent oral poliovirus vaccine was used for polio control in Japan for more than half a century but has now been removed from the list of vaccines licensed for routine immunization. This paper reviews the development, introduction, characterization, and global status of IPV derived from attenuated Sabin strains.     

Vaccine-Derived Polioviruses and Children with Primary Immunodeficiency,Iran, 1995–2014

Widespread use of oral poliovirus vaccine has led to an ≈99.9% decrease in global incidence of poliomyelitis (from ≈350,000 cases in 1988 to 74 cases in 2015) and eradication of wild-type poliovirus serotypes 2 and 3. However, patients with primary immunodeficiency might shed vaccine-derived polioviruses (VDPVs) for an extended period, which could pose a major threat to polio eradication programs. Since 1995, sixteen VDPV populations have been isolated from 14 patients with immunodeficiency in Iran. For these patients, vaccine-associated paralysis, mostly in >1 extremity, was the first manifestation of primary immunodeficiency. Seven patients with humoral immunodeficiency cleared VDPV infection more frequently than did 6 patients with combined immunodeficiencies. Our results raise questions about manifestations of VDPVs in immunodeficient patients and the role of cellular immunity against enterovirus infections. On the basis of an association between VDPVs and immunodeficiency, we advocate screening of patients with primary immunodeficiency for shedding of polioviruses.     

Update on vaccine-derived polioviruses--worldwide, January 2006-August 2007

In 1988, the World Health Assembly resolved to eradicate poliomyelitis worldwide. Subsequently, the Global Polio Eradication Initiative of the World Health Organization (WHO) reduced the global incidence of polio associated with wild polioviruses (WPVs) from an estimated 350,000 cases in 1988 to 1,998 reported cases in 2006 and reduced the number of countries that have never succeeded in interrupting WPV transmission to four (Afghanistan, India, Nigeria, and Pakistan). However, because vaccine-derived polioviruses (VDPVs) can produce polio outbreaks in areas with low rates of Sabin oral poliovirus vaccine (OPV) coverage and can replicate for years in immunodeficient persons, enhanced strategies are needed to limit emergence of VDPVs and stop all use of OPV once WPV transmission is eliminated. This report updates a summary of VDPV activity published in 2006 and describes VDPVs detected during January 2006-August 2007.     

The role of routine polio immunization in the post-certification era

The role of routine vaccination against poliomyelitis for the post-certification era remains an important area for policy decision-making. Two critical decisions need to be taken: first, to continue or discontinue vaccination with the live attenuated oral poliovirus vaccine (OPV); and second, if OPV is to be discontinued, whether vaccination with inactivated poliovirus vaccine (IPV) is needed. Four potential vaccination scenarios can be constructed: stop all polio vaccination; continue with current vaccination policies (OPV, IPV, or sequential schedule); discontinue OPV, but continue IPV universally; or discontinue OPV, but continue IPV in selected countries. All possible scenarios require continued investments in a surveillance and response strategy, including a stockpile of polio vaccine. Continuing vaccination would limit the savings that could be applied to the control of other health priorities. This report reviews the key issues associated with each scenario, highlights the advantages and disadvantages of each scenario, and outlines the major challenges for policy decision-making.     

Certification of polio eradication: process and lessons learned

Since the 1988 World Health Assembly resolution to eradicate poliomyelitis, considerable progress has been made towards interrupting the transmission of wild poliovirus globally. A formal process for the certification of polio eradication was established on the basis of experience gained during smallpox eradication. Independent groups of experts were designated at the global, regional, and country levels to conduct the process. The main requirements for the global certification of the eradication of wild poliovirus are the absence of wild poliovirus, isolated from suspect polio cases, healthy individuals, or environmental samples, in all WHO regions for a period of at least three years in the presence of high-quality, certification-standard surveillance and the containment of all wild poliovirus stocks in laboratories. Three WHO regions--the Region of the Americas (1994), Western Pacific Region (2000), and European Region (2002)--have already been certified free of indigenous wild poliovirus. Eradication and certification activities are progressing well in the three endemic regions (African, Eastern Mediterranean, and South-East Asia). Several challenges remain for the certification of polio eradication: the need for even closer coordination of certification activities between WHO regions, the verification of laboratory containment, the development of an appropriate mechanism to verify the absence of circulating vaccine-derived polioviruses in the future, and the maintenance of polio-free status in certified regions until global certification.     

Interrupting the transmission of wild polioviruses with vaccines: immunological considerations.

In 1988 the World Health Assembly set the goal of global poliomyelitis eradication by the year 2000. Substantial progress has been made, and 143 countries reported no poliomyelitis cases associated with the wild virus in 1993. This article reviews the immunological considerations relevant to interrupting the transmission of wild polioviruses with vaccines. Although serum immunity prevents poliomyelitis in the individual, it is local immunity that is important in preventing the transmission of polioviruses in the community. Natural infection and vaccination with oral polioviruses vaccine (OPV) produce local immunity in the intestine and the nasopharynx in about 70-80% of individuals. In contrast, inactivated poliovirus vaccine (IPV) produces local intestinal immunity in only 20-30% of the individuals. With either vaccine, however, a substantial proportion of the immunized population can transmit the wild virus. Moreover, although serum immunity is long-lasting, limited data suggest that local immunity may not be as persistent. To interrupt the transmission of wild polioviruses efforts should be made to achieve and sustain high levels of poliovirus vaccine coverage. Recent outbreaks show that wild poliovirus poses a risk for unimmunized individuals, even when overall coverage levels are high. Delivery of poliovirus vaccine to hard-to-reach populations will be of increasing importance as countries progress toward the final stages of poliomyelitis eradication. The immunization status of persons from poliomyelitis-free countries should be updated prior to travel to poliomyelitis-endemic areas.     

Global polio eradication: Where are we in Europe and what next?

The world was never so close to reach the polio eradication: only 37 cases notified in 2016 in only three countries, but the game is not yet at the end. The risk of polio outbreaks in the EU is smaller than it has ever been in the past, but it is not so small that we can ignore it. The EU MS must remain alert and plan and prepare for managing polio events or outbreaks because of the possible dire consequences. The IPV only vaccination schedule universally applied in EU has achieved satisfactory coverage, but constantly leaving small accumulating pockets of susceptible individuals. Moreover the IPV only schedule is not an absolute barrier against poliovirus silent transmission as demonstrated in the recent Israel outbreak. The availability of annually revised S.O.P. from WHO GPEI on the identification and response of a polio event, without local poliovirus transmission or a polio outbreak with sustained transmission, helps and challenge EU countries to update their polio national preparedness plans. The EU/EEA area, in fact, is a peculiar area regarding the polio risk both for its vaccination policy, the large polio vaccines manufactures and the constant immigration from areas at polio high risk, but also EU include cultural and financial potentials crucial to sustain the polio end game strategy and reach the benefit of a world without polio risk. Poliovirus eradication will continue to be challenged as long as there is the worldwide presence of polioviruses in laboratories and vaccine production plants. Most of the world’s OPV vaccines are produced in the EU and many laboratories and research centers store and handle polio viruses. EU Member States are engaged actively in implementing the poliovirus biocontainment plans that are part of the polio eradication strategy and to certify the destruction of poliovirus strains and potentially contaminated biological materials.     

Poliomyelitis: eradication in sight.

Eradication of poliomyelitis most likely will occur. In fact, it is almost gone from the Western Hemisphere. Health workers in Sweden, Finland, and the Netherlands routinely vaccinate almost all children with the inactivated poliovaccines (IPV). Despite good vaccination coverage, polio can still occur. For example, in 1978-1979, polio outbreaks occurred among people of closely knit interconnected religious groups in the Netherlands. The virulent type 1 poliovirus was imported from the Middle East and spread to related religious groups in Canada and U.S. Further, in 1984-1985, Finland experienced 10 polio cases. A wild type 3 variant was responsible. An outbreak in 1988 in Israel occurred among young adults who, although received the oral polio vaccine (OPV) as infants, did not receive booster doses. Thus they had an age related deficit in immunity against the wild virus. 6 countries in the Western Pacific Region were able to control polio by 1980, but wild type polioviruses were ubiquitous in 5 other countries in this region and infections were either asymptomatic or unrecognized. They could not control polio by 1980 and just recently able to exert some control. OPV induces serum antibodies, intestinal resistance, and rapid enduring immunity. Also it is easy to administer and inexpensive. Risk of paralytic polio with OPV is 1/1 million vaccinated infants. WHO advises that newborns should be immunized with OPV at the same time as BCG to protect them from polio and to reduce the transmission of wild polioviruses during infancy and childhood. Further many countries have incorporated OPV into routine immunization schedules, but can be difficult in developing countries with limited cold chain capabilities. While some developing countries host periodic mass OPV immunization campaigns. At proper doses, IPV imparts humoral immunity and can be incorporated into other injectable pediatric vaccines (e.g., DPT). Some countries use both IPV and OPV.     

Combined vaccination with live oral polio vaccine and the bovine rotavirus RIT 4237 strain

A clinical trial was carried out in 3-month-old infants to assess whether concomitant oral administration of live polio and rotavirus RIT 4237 vaccines would reduce their immunogenicities as a result of mutual interference. One hundred and sixty breast-fed male and female infants were randomly allocated to four study groups to receive in a blind fashion the poliovirus vaccine, the RIT 4237 vaccine, a combination of both vaccines or a placebo preparation. Antibody titres were measured in pre- and postvaccination serum samples by the ELISA test and the neutralizing antibody test (NT) for rotavirus and by the NT for polioviruses types 1 and 3. The percentage of subjects with immune responses to rotavirus in the placebo group was low, indicating the absence of wild rotavirus circulation in the population. Antibody responses against polio types 1 and 3 were found in about a quarter of the infants receiving a placebo because the study was performed during a polio vaccination campaign when vaccine viruses are known to circulate. The results showed that 73% of seroconversion was obtained when RIT 4237 was administered alone and that the responses to polioviruses types 1 and 3 were good. However, simultaneous administration of polio and RIT 4237 vaccines caused a significant reduction of the antibody response to rotavirus but not to polioviruses types 1 and 3.     

From emergence to eradication: the epidemiology of poliomyelitis deconstructed

Poliomyelitis has appeared in epidemic form, become endemic on a global scale, and been reduced to near-elimination, all within the span of documented medical history. Epidemics of the disease appeared in the late 19th century in many European countries and North America, following which polio became a global disease with annual epidemics. During the period of its epidemicity, 1900-1950, the age distribution of poliomyelitis cases increased gradually. Beginning in 1955, the creation of poliovirus vaccines led to a stepwise reduction in poliomyelitis, culminating in the unpredicted elimination of wild polioviruses in the United States by 1972. Global expansion of polio immunization resulted in a reduction of paralytic disease from an estimated annual prevaccine level of at least 600,000 cases to fewer than 1,000 cases in 2000. Indigenous wild type 2 poliovirus was eradicated in 1999, but unbroken localized circulation of poliovirus types 1 and 3 continues in 4 countries in Asia and Africa. Current challenges to the final eradication of paralytic poliomyelitis include the continued transmission of wild polioviruses in endemic reservoirs, reinfection of polio-free areas, outbreaks due to circulating vaccine-derived polioviruses, and persistent excretion of vaccine-derived poliovirus by a few vaccinees with B-cell immunodeficiencies. Beyond the current efforts to eradicate the last remaining wild polioviruses, global eradication efforts must safely navigate through an unprecedented series of endgame challenges to assure the permanent cessation of all human poliovirus infections.     

2007—2008年河北省急性迟缓性麻痹病例脊灰病毒核苷酸变异情况分析

目的及时发现河北省可能出现的脊灰疫苗衍生病例（VDPV）。方法对河北省2007—2008年急性弛缓性麻痹（AFP）病例的粪便标本进行病毒分离和血清定型。所有标本用L20B、RD细胞同时进行病毒分离,用PCR—RFLP法做型内鉴定。结果从报告的763例AFP病例粪便标本中分离到42株脊髓灰质炎病毒株（PV）,其中Ⅰ型4株,Ⅱ型11株,Ⅲ型11株,混合型13株,PV＋NEPV共3株;将混合株进行单型分离后,共得到58株,以Ⅲ型PV为主,均为疫苗变异株;发病年龄在1岁以内儿童占84．48％,男性发生变异39株,女性发生19株。结论河北省2007—2008年分离到的脊髓灰质炎疫苗病毒有部分变异,未发现疫苗衍生脊灰病毒。     

Inactivated poliovirus vaccine and the final stages of poliovirus eradication

The use of the inactivated poliovirus vaccine (IPV) will increase before and probably also after the global eradication of the wild type poliovirus. Before eradication, the switch from the use of oral poliovirus vaccine (OPV) to IPV has been due to the better safety record of IPV. Introduction of IPV in the regular immunisation schedules is made easier by the development of several combination vaccines, including IPV. Maternal antibodies and young age, often considered problematic for early initiation of IPV schedules, did not compromise optimal maintenance of seropositivity during infancy or long-term persisting antibody levels in our studies. OPV-derived, potentially pathogenic and transmissible poliovirus strains, excreted by some individuals for years, may present a problem for a blunt stopping of all polio immunisations after eradication. Our recent results suggest that locally excreted IgA might have a role in the elimination of poliovirus infection in the intestinal tissues.     

Cost analysis of post-polio certification immunization policies

OBJECTIVE: An analysis was conducted to estimate the costs of different potential post-polio certification immunization policies currently under consideration, with the objective of providing this information to policy-makers. METHODS: We analyzed three global policy options: continued use of oral poliovirus vaccine (OPV); OPV cessation with optional inactivated poliovirus vaccine (IPV); and OPV cessation with universal IPV. Assumptions were made on future immunization policy decisions taken by low-, middle-, and high-income countries. We estimated the financial costs of each immunization policy, the number of vaccine-associated paralytic poliomyelitis (VAPP) cases, and the global costs of maintaining an outbreak response capacity. The financial costs of each immunization policy were based on estimates of the cost of polio vaccine, its administration, and coverage projections. The costs of maintaining outbreak response capacity include those associated with developing and maintaining a vaccine stockpile in addition to laboratory and epidemiological surveillance. We used the period 2005-20 as the time frame for the analysis. FINDINGS: OPV cessation with optional IPV, at an estimated cost of US$ 20,412 million, was the least costly option. The global cost of outbreak response capacity was estimated to be US$ 1320 million during 2005-20. The policy option continued use of OPV resulted in the highest number of VAPP cases. OPV cessation with universal IPV had the highest financial costs, but it also had the least number of VAPP cases. Sensitivity analyses showed that global costs were sensitive to assumptions on the cost of the vaccine. Analysis also showed that if the price per dose of IPV was reduced to US$ 0.50 for low-income countries, the cost of OPV cessation with universal IPV would be the same as the costs of continued use of OPV. CONCLUSION: Projections on the vaccine price per dose and future coverage rates were major drivers of the global costs of post-certification polio immunization. The break-even price of switching to IPV compared with continuing with OPV immunizations is US$ 0.50 per dose of IPV. However, this doses not account for the cost of vaccine-derived poliovirus cases resulting from the continued use of OPV. In addition to financial costs, risk assessments related to the re-emergence of polio will be major determinants of policy decisions.