The maintaining of the active laboratory-based surveillance of the acute flaccid paralysis (AFP) cases in Romania in the framework of the strategic plan of the global polio eradication initiative

Until 2008 poliomyelitis was controlled in Romania by predominantly using Oral Poliovirus Vaccine Sabin (OPV); the alternative vaccination schedule (IPV formalin Inactivated Poliovirus Vaccine/OPV) will be implemented starting September 2008. The vaccination coverage with 4 doses of TOPV (trivalent oral polio vaccine) in the first 14 months of life has been > 90% since 1980. In Romania, the risk of the Vaccine-Associated Paralytic Poliomyelitis cases (VAPP) decreased from less than 2 VAPP cases/year in the 1995-2006 interval to 0 VAPP cases in 2007. The serological study was performed in 2006-2007 only in cases with pair serum samples from 28 acute flaccid paralysis (AFP) cases (age = 3 months - 14 years) and from 45 facial paralysis (FP) cases (age -6 months - 4 years 9 months). A high level of vaccinal coverage was shown for all poliovirus serotypes: >95% in AFP serum samples investigated; and for FP serum samples investigated the levels of antibodies against poliovirus (PV) serotypes were 98% for PV type 1; 87% for PV type 2: and 89% for PV type 3. If the European region is polio free since 2002, the risk of wild PV importation from endemic region remains present. The laboratory capacity for the fast detection and molecular investigations of the emergence of the new epidemic strains and a high level of population immunity must be maintained. A national seroprevalence study concerning all three PV serotypes must be performed.     

Paralytic poliomyelitis in Russian Federation in 1998-2005

From 1998 through 2005 3,294 cases of acute flaccid paralysis (AFP) including 93 cases with clinical picture of poliomyelitis were registered in Russian Federation. From the latter cases 91 were classified as vaccine-associated paralytic poliomyelitis (VAPP): 66 were VAPP cases in oral poliomyelitis vaccine (OPV) recipients and 25--VAPP cases in contacts. VAPP rate was 1 case per 1.6 million of distributed OPV doses, 1 case per 2.2 million doses for OPV recipients, and 1 case per 186,000 doses for recipients of 1st OPV dose in children aged < 1 year. Majority of VAPP cases in recipients occurred after 1st dose (89.4%) and in contacts--in non-vaccinated children (76%). Mean interval between OPV administration and onset of VAPP in recipients was 21 days. Children aged < 1 year were predominant among VAPP cases (92.4% among recipient VAPP cases, and 80% among contact VAPP cases). Majority of the patients had unfavorable health status including defects of immunity. Most of poliovirus strains isolated from VAPP cases belonged to type 3 (52.9%) whereas to type 2 and 1--29.8% and 17.4% of strains respectively. All VAPP cases were associated with vaccine-derived polioviruses. A highly diverged poliovirus type 1 (2.65% of nucleotide substitutions in VP1 region) was isolated from patient with contact VAPP. Formation of poliovirus-neutralizing serum antibodies in children with VAPP including persons with immunodeficiency reflects the ability of the organism to produce specific antiviral immune response.     

深圳市2005—2012年脊髓灰质炎疫苗相关病例流行病学分析

目的了解深圳市脊髓灰质炎疫苗相关病例(VAPP)发生情况及流行病学特征,为消灭脊髓灰质炎后期脊灰疫苗免疫策略的研究提供基础数据。方法采用流行病学方法对深圳市2005—2012年残留麻痹急性弛缓性麻痹AFP病例个案资料、病原学检测结果、VAPP病例进行分析。结果 2005—2012年共报告残留麻痹病例55例,其中VAPP病例8例,占15.54%;深圳市VAPP病例均为小年龄组小于6月龄的儿童,总发生率0.20/10万,无接触者VAPP病例,其中首次服苗的VAPP发生率为0.51/10万;无明显的地区和时间分布聚集性。结论 VAPP的发生是接种脊髓灰质炎减毒活疫苗难以克服的弱点,为减少VAPP病例及防止脊灰疫苗衍生病毒的发生,应在消灭脊髓灰质炎后期科学、合理地调整消灭脊髓灰质炎的免疫策略。     

Outbreaks of paralytic poliomyelitis and polio surveillance in Shandong province of China.

Widespread outbreaks of paralytic poliomyelitis occurred in Shandong province, China, starting from 1988. In 1989, 484 cases were recorded, which was the peak during the past 4 years. Although emergency immunization with trivalent oral poliovirus vaccine (OPV) was carried out in selected counties in 1989 and 1990, control of the outbreak was not satisfactory. OPV mass immunization campaigns were introduced to cover the whole province in early 1991, and the number of patients with paralytic poliomyelitis decreased to 95. In addition to this new immunization strategy, we began to construct new polio surveillance systems. These were a network for case-negative reporting and an immediate reporting system of acute flaccid paralysis (AFP). As for the case-negative reporting, presently more than 90% of counties have been reporting presence or absence of new AFP cases. Monitoring of AFP immediate reporting has also shown a gradual improvement in several aspects. These polio surveillance activities are crucial to polio eradication programme management.     

西安市1995-2008年检出脊髓灰质炎疫苗病毒的急性弛缓性麻痹病例流行病学分析

分析脊髓灰质炎(脊灰)病毒(PV)的急性弛缓性麻痹(AFP)病例流行病学特征,提高对疫苗衍生脊灰病毒(VDPVs)和循环的疫苗衍生脊灰病毒(cVDPVs)的认识,增加AFP病例监测系统敏感性。对西安市1995-2008年检出的PV阳性AFP病例进行流行病学分析。对疫苗变异PV采用VP1基因核苷酸序列测定方法进行分子生物性状分析。西安市1995-2008年共检出PV13株,检出率4.29%。分离到的PV以II、III型为主,AFP病例散在发生,无聚集性。未全程免疫儿童(全程免疫儿童,年龄以≤1岁儿童为主(84.62%)。麻痹残留率高达84.62%。脊灰相关病例(VAPP)的发生危险性为0.24/100万。型内特征鉴定有1株为疫苗变异PV,经VP1基因核苷酸序列测定未达到VDPV的分类标准。维持无脊灰阶段,存在着VDPV和发生cVDPVs的可能,在保持高水平脊髓灰质炎疫苗(OPV)免疫覆盖率的同时,高质量的AFP病例流行病学监测和病毒学监测工作,具有重要的现实意义。     

The final stages of the global eradication of poliomyelitis

The global incidence of poliomyelitis has dropped by more than 99 per cent since the governments of the world committed to eradication in 1988. One of the three serotypes of wild poliovirus has been eradicated and the remaining two serotypes are limited to just a small number of endemic regions. However, the Global Polio Eradication Initiative (GPEI) has faced a number of challenges in eradicating the last 1 per cent of wild-virus transmission. The polio endgame has also been complicated by the recognition that vaccination with the oral poliovirus vaccine (OPV) must eventually cease because of the risk of outbreaks of vaccine-derived polioviruses. I describe the major challenges to wild poliovirus eradication, focusing on the poor immunogenicity of OPV in lower-income countries, the inherent limitations to the sensitivity and specificity of surveillance, the international spread of poliovirus and resulting outbreaks, and the potential significance of waning intestinal immunity induced by OPV. I then focus on the challenges to eradicating all polioviruses, the problem of vaccine-derived polioviruses and the risk of wild-type or vaccine-derived poliovirus re-emergence after the cessation of oral vaccination. I document the role of research in the GPEI''s response to these challenges and ultimately the feasibility of achieving a world without poliomyelitis.     

Characterization of the immune status of patients with vaccine-associated poliomyelitis

Specific humoral immunity, total immune status and typing of HLA antigens, class 1, in loci A and B were studied in children with vaccine-associated paralytic poliomyelitis (VAPP). The immune status investigation revealed that changes in the content of serum immunoglobulins were most frequent. Out of 8 examined children, 5 children had IgA deficiency and 1 child had total variable immunodeficiency. In one case disturbances in cell-mediated immunity prevailed. Tissue typing revealed the presence of HLA A2 and B44 in 5 out of 6 examined children, which considerably exceeded their average occurrence among the Belorussian population. In spite of frequent detection of immunological disturbances in VAPP patients, out of 38 serologically examined children 36 (95%) were found to have virus-neutralizing serum antibodies to poliovirus, which was indicative of the capacity of their immune system for response to the administration of vaccine virus. To minimize the risk of VAPP in children and to achieve the goal of poliomyelitis eradication the combined immunization scheme consisting of 1-3 vaccinations with inactivated poliovaccine with subsequent administration of oral vaccine prepared from attenuated Sabin viruses is regarded as most promising.     

The control of viral diseases in the developing countries with the use of existing vaccines]

In developing countries, every year about 70 million measles cases occur with 1.5 million deaths, over 200,000 children contract paralytic poliomyelitis, 50 million people get infected with viral B hepatitis causing over 1 million deaths, and several thousand people perish because of yellow fever according to WHO data. At the present time, there are 12 vaccines against viruses: vaccines against German measles and mumps in addition to the above. The universal immunization program (UIP) of WHO targets measles and polio. In 1989, a WHO resolution envisioned a 90% immunization coverage by the year 2000. Measles vaccination is recommended for children aged 9-23 months, since most children have maternal antibodies during the first 3-13 months of age. The Edmonston-Zagreb vaccine provided seroconversion of 92, 96, and 98% for 18 months vs. the 66, 76, and 91% rate of the Schwarz vaccine. In the US, measles incidence increased from 1497 cases in 1983 to 6382 cases in 1988 to over 14,000 cases in 1989, prompting second vaccination in children of school age. The highest incidence of polio was registered in Southeast Asia, although it declined from 1 case/100,000 population in 1975 to .5/100,000 in 1988. Oral poliomyelitis vaccine (OPV) provides protection: there is only 1 case/2.5 million vaccinations. Hepatitis B has infected over 2 billion people. About 300 million are carriers, with a prevalence of 20% in African, Asian, and Pacific region populations. Plasmatic and bioengineered recombinant vaccine type have been used in 30 million people. The first dose is given postnatally, the second at 1-2 months of age, and the 3rd at 1 year of age. Yellow fever vaccine was 50 years old in 1988, yet during 1986-1988 there were 5395 cases with 3172 deaths in Africa and South America. Vaccination provides 90-95% seroconversion, and periodic follow-up vaccinations under UIP could eradicate these infections and their etiologic agents.     

Enteroviruses in the XX and XXI centuries

The modern view of the role of enteroviruses in the eradication of poliomyelitis is presented. Enteroviruses were discovered in the XX century. In the 1950s they caused great epidemics of poliomyelitis and serous meningitis in many countries of the world. The introduction of oral poliomyelitis vaccine (OPV) into medical practice made it possible to eliminate the epidemics of poliomyelitis in a short time. Poliomyelitis morbidity was reduced to sporadic cases and in a number of regions disappeared. OPV produced non-specific influence also on the epidemics of serous meningitis, as well as on a case incidence. The eradication of poliomyelitis viruses and the cessation of immunization with OPV will not result in eradication of paralytic diseases. Paralytogenic viruses of 20 serotypes circulate in nature, and some of these viruses are capable of causing the outbreaks of severe paralytic diseases. The authors propose either to retain immunization with OVP as tour immunizations with monovaccine of type 2, or to create new live enterovirus vaccines on the basis of avirulent enterovirus strains.     

消灭脊髓灰质炎行动现状分析及免疫策略建议

脊髓灰质炎曾在全球广泛流行和传播,严重危害儿童健康。自1988年世界卫生大会发起全球消灭脊髓灰质炎行动倡议以来,全球脊髓灰质炎防控工作取得显著进展,但消灭脊髓灰质炎工作仍面临重重挑战。在目前维持无脊髓灰质炎状态下,我国面临的主要问题是疫苗相关麻痹型脊髓灰质炎(vaccine associated paralytic poliomyelitis, VAPP)病例和脊髓灰质炎疫苗衍生病毒(vaccine-derived poliovirus,VDPV)病例的发生。为此,通过回顾消灭脊髓灰质炎工作取得的进展,总结不同国家或地区在消灭脊髓灰质炎过程中所采用的防控策略,尤其是不同国家或地区的脊髓灰质炎疫苗使用经验,分析消灭脊髓灰质炎最后阶段面临的挑战,进而提出应对策略和建议,即科学评价防控措施、适时调整脊髓灰质炎免疫策略、努力消除接种犹豫并提高疫苗接种率,这对早日实现根除脊髓灰质炎的目标是非常有必要的。     

A statistical model of the international spread of wild poliovirus in Africa used to predict and prevent outbreaks

Background

Outbreaks of poliomyelitis in African countries that were previously free of wild-type poliovirus cost the Global Polio Eradication Initiative US$850 million during 2003–2009, and have limited the ability of the program to focus on endemic countries. A quantitative understanding of the factors that predict the distribution and timing of outbreaks will enable their prevention and facilitate the completion of global eradication.

Methods and Findings

Children with poliomyelitis in Africa from 1 January 2003 to 31 December 2010 were identified through routine surveillance of cases of acute flaccid paralysis, and separate outbreaks associated with importation of wild-type poliovirus were defined using the genetic relatedness of these viruses in the VP1/2A region. Potential explanatory variables were examined for their association with the number, size, and duration of poliomyelitis outbreaks in 6-mo periods using multivariable regression analysis. The predictive ability of 6-mo-ahead forecasts of poliomyelitis outbreaks in each country based on the regression model was assessed. A total of 142 genetically distinct outbreaks of poliomyelitis were recorded in 25 African countries, resulting in 1–228 cases (median of two cases). The estimated number of people arriving from infected countries and <5-y childhood mortality were independently associated with the number of outbreaks. Immunisation coverage based on the reported vaccination history of children with non-polio acute flaccid paralysis was associated with the duration and size of each outbreak, as well as the number of outbreaks. Six-month-ahead forecasts of the number of outbreaks in a country or region changed over time and had a predictive ability of 82%.

Conclusions

Outbreaks of poliomyelitis resulted primarily from continued transmission in Nigeria and the poor immunisation status of populations in neighbouring countries. From 1 January 2010 to 30 June 2011, reduced transmission in Nigeria and increased incidence in reinfected countries in west and central Africa have changed the geographical risk of polio outbreaks, and will require careful immunisation planning to limit onward spread. Please see later in the article for the Editors'' Summary     

A vision of a world without polio: the OPV cessation strategy.

Once the eradication of wild poliovirus has been confirmed, the public health benefits of routine immunization with OPV will no longer outweigh the burden of disease either due to paralysis caused by OPV (vaccine associated paralytic polio), or by outbreaks caused by circulating vaccine-derived polioviruses. The eventual cessation of OPV use in routine immunization programmes worldwide will become necessary to assure a lasting eradication of polio. As the world moves towards polio eradication and its certification, preparations are therefore being intensified for OPV cessation, and the risk management framework for safe OPV cessation is being put in place. The framework includes bio-containment of all known poliovirus and potentially infected substances, development of an international stockpile of oral polio vaccine, ensuring a mechanism for continued global surveillance and response for polio after eradication has been certified, and national policies if countries decide to continue vaccinating with inactivated polio vaccine (IPV). It is ironic that the vaccine on which the world has depended for polio eradication will itself become a risk to eradication once the transmission of wild poliovirus has been interrupted. Final preparations for the eventual global and simultaneous cessation of OPV will require the same level of international cooperation and coordination that has brought the world to the verge of polio eradication.     

Co-circulation and evolution of polioviruses and species C enteroviruses in a district of Madagascar

Between October 2001 and April 2002, five cases of acute flaccid paralysis (AFP) associated with type 2 vaccine-derived polioviruses (VDPVs) were reported in the southern province of the Republic of Madagascar. To determine viral factors that favor the emergence of these pathogenic VDPVs, we analyzed in detail their genomic and phenotypic characteristics and compared them with co-circulating enteroviruses. These VDPVs appeared to belong to two independent recombinant lineages with sequences from the type 2 strain of the oral poliovaccine (OPV) in the 5'-half of the genome and sequences derived from unidentified species C enteroviruses (HEV-C) in the 3'-half. VDPV strains showed characteristics similar to those of wild neurovirulent viruses including neurovirulence in poliovirus-receptor transgenic mice. We looked for other VDPVs and for circulating enteroviruses in 316 stools collected from healthy children living in the small area where most of the AFP cases occurred. We found vaccine PVs, two VDPVs similar to those found in AFP cases, some echoviruses, and above all, many serotypes of coxsackie A viruses belonging to HEV-C, with substantial genetic diversity. Several coxsackie viruses A17 and A13 carried nucleotide sequences closely related to the 2C and the 3D(pol) coding regions of the VDPVs, respectively. There was also evidence of multiple genetic recombination events among the HEV-C resulting in numerous recombinant genotypes. This indicates that co-circulation of HEV-C and OPV strains is associated with evolution by recombination, resulting in unexpectedly extensive viral diversity in small human populations in some tropical regions. This probably contributed to the emergence of recombinant VDPVs. These findings give further insight into viral ecosystems and the evolutionary processes that shape viral biodiversity.     

Cross reactivity among human enterovirus serotypes as revealed by microneutralization assay technique

Paired or tripled serum specimens examined for cross reactions between poliomyelitis viruses and other non-polio enteroviruses were obtained from 356 patients (217 males and 139 females) with various clinical diagnoses (aseptic meningitis, meningoencephalitis, paretic neuro-infections, upper respiratory tract infections, bronchopneumonia) who were sampled in 1984 and 1985. The sera were examined by the microneutralization assay technique in flat-bottomed 96-well polyvinyl chloride plates against 100-300 TCD50 of these enterovirus serotypes: CA9, CB1-CB5, E1, E2, E4-E9, E17, E20, E24, E30, EV71 and polioviruses P1-P3. The tests were carried out on BGM or RD cells. Confirmed significant seroconversions to at least one enterovirus serotype were observed in 87 (24.2%) patients. Of these, 27 (31%) reacted by parallel significant or insignificant increases in the heterotypic antibody titre to poliovirus, which accounted for 7.6% of all patients examined. Heterotypic antibody responses may become source of errors in individuals examined for poliovaccine efficacy or the state of specific immunity response to polio, but are unlikely to discredit the overall outcomes of the seroepidemiological surveys conducted in the general population.     

中山市2011年健康儿童脊髓灰质炎、麻疹和乙型肝炎抗体水平监测

目的了解中山市1~14岁健康儿童脊髓灰质炎(脊灰)病毒、麻疹病毒和乙型肝炎(乙肝)病毒抗体水平状况,为维持无脊灰、消除麻疹和控制乙肝提供依据。方法采用多阶段整群抽样方法,随机选择220名1~14岁健康儿童抽取静脉血,采用ELISA法检测麻疹病毒抗体Ig G、乙肝病毒表面抗原和抗体;用中和试验检测脊灰(Ⅰ、Ⅱ、Ⅲ)型病毒中和抗体。结果脊灰、麻疹和乙肝病毒抗体阳性率分别为91.36%、93.18%和66.36%,脊灰病毒Ⅰ、Ⅱ、Ⅲ型和麻疹病毒抗体几何平均滴度(GMT)分别为1∶215.90、1∶119.05、1∶31.40和1∶1 254.45;乙肝病毒表面抗原阳性率为1.36%。结论中山市1~14岁健康儿童对脊灰病毒具有较高的免疫水平,已形成对脊灰病毒有效的免疫屏障;乙肝得到有效控制;但麻疹未能形成有效的免疫屏障。     

Circulating Vaccine Derived Polio Viruses and their Impact on Global Polio Eradication

Poliomyelitis vaccination via live Oral Polio Vaccine (OPV) suffers from the inherent problem of reversion: the vaccine may, upon replication in the human gut, mutate back to virulence and transmissibility resulting in circulating vaccine derived polio viruses (cVDPVs). We formulate a general mathematical model to assess the impact of cVDPVs on prospects for polio eradication. We find that for OPV coverage levels below a certain threshold, cVDPVs have a small impact in comparison to the expected endemic level of the disease in the absence of reversion. Above this threshold, the model predicts a small but significant endemic level of the disease, even where standard models predict eradication. In light of this, we consider and analyze three alternative eradication strategies involving a transition from continuous OPV vaccination to either continuous Inactivated Polio Vaccine (IPV), pulsed OPV vaccination, or a one-time IPV pulse vaccination. Stochastic modeling shows continuous IPV vaccination is effective at achieving eradication for moderate coverage levels, while pulsed OPV is effective if higher coverage levels are maintained. The one-time pulse IPV method may also be a viable strategy, especially in terms of the number of vaccinations required and time to eradication, provided that a sufficiently large pulse is practically feasible. More investigation is needed regarding the frequency of revertant virus infection resulting directly from vaccination, the ability of IPV to induce gut immunity, and the potential role of spatial transmission dynamics in eradication efforts. B.G. Wagner’s research is supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) Doctoral Scholarship. D.J.D. Earn’s research is supported by the Canadian Institutes of Health Research (CIHR), Natural Sciences and Engineering Research Council of Canada (NSERC) and the J.S. McDonnell Foundation.     

Estimating the extent of vaccine-derived poliovirus infection

Background

Eight outbreaks of paralytic polio attributable to circulating vaccine-derived poliovirus (cVDPV) have highlighted the risks associated with oral poliovirus vaccine (OPV) use in areas of low vaccination coverage and poor hygiene. As the Polio Eradication Initiative enters its final stages, it is important to consider the extent to which these viruses spread under different conditions, so that appropriate strategies can be devised to prevent or respond to future cVDPV outbreaks.

Methods and Findings

This paper examines epidemiological (temporal, geographic, age, vaccine history, social group, ascertainment), and virological (type, genetic diversity, virulence) parameters in order to infer the numbers of individuals likely to have been infected in each of these cVDPV outbreaks, and in association with single acute flaccid paralysis (AFP) cases attributable to VDPVs. Although only 114 virologically-confirmed paralytic cases were identified in the eight cVDPV outbreaks, it is likely that a minimum of hundreds of thousands, and more likely several million individuals were infected during these events, and that many thousands more have been infected by VDPV lineages within outbreaks which have escaped detection.

Conclusions

Our estimates of the extent of cVDPV circulation suggest widespread transmission in some countries, as might be expected from endemic wild poliovirus transmission in these same settings. These methods for inferring extent of infection will be useful in the context of identifying future surveillance needs, planning for OPV cessation and preparing outbreak response plans.     

A RT-PCR method for selective amplification and phenotypic characterization of all three serotypes of Sabin-related polioviruses from viral mixtures

Outbreaks caused by vaccine-derived polioviruses are challenging the final eradication of paralytic poliomyelitis. Therefore, the surveillance of the acute flaccid paralysis cases based on poliovirus isolation and characterization remains an essential activity. Due to the use of trivalent oral poliovirus vaccine (OPV), mixtures containing more than one serotype of Sabin-related polioviruses are frequently isolated from clinical samples. Because each poliovirus isolate needs to be individually analyzed, we designed polymerase chain reaction primers that can selectively distinguish and amplify a genomic segment of the three Sabin-related poliovirus serotypes present in mixtures, thus, optimizing the diagnosis and providing prompt information to support epidemiologic actions.