Immunodeficiency-related vaccine-derived poliovirus (iVDPV) cases: A systematic review and implications for polio eradication

Highlights

• 68 iVDPV cases reported from 25 countries were included in this analysis.

• 62%, 78%, 65% of case patients were male, presented with paralysis, and iVDPV2.

• 57% of case patients had antibody deficiencies, and the mortality rate was >60%.

• Poliovirus genome VP1 region mutation rate was calculated to be 0.72% per year.

• Economic and regional disparities were identified amongst the iVDPV cases.

Abstract

Background

Vaccine-derived polioviruses (VDPVs), strains of poliovirus mutated from the oral polio vaccine, pose a challenge to global polio eradication. Immunodeficiency-related vaccine-derived polioviruses (iVDPVs) are a type of VDPV which may serve as sources of poliovirus reintroduction after the eradication of wild-type poliovirus. This review is a comprehensive update of confirmed iVDPV cases published in the scientific literature from 1962 to 2012, and describes clinically relevant trends in reported iVDPV cases worldwide.

Methods

We conducted a systematic review of published iVDPV case reports from January 1960 to November 2012 from four databases. We included cases in which the patient had a primary immunodeficiency, and the vaccine virus isolated from the patient either met the sequencing definition of VDPV (>1% divergence for serotypes 1 and 3 and >0.6% for serotype 2) and/or was previously reported as an iVDPV by the World Health Organization.

Results

We identified 68 iVDPV cases in 49 manuscripts reported from 25 countries and the Palestinian territories. 62% of case patients were male, 78% presented clinically with acute flaccid paralysis, and 65% were iVDPV2. 57% of cases occurred in patients with predominantly antibody immunodeficiencies, and the overall all-cause mortality rate was greater than 60%. The median age at case detection was 1.4 years [IQR: 0.8, 4.5] and the median duration of shedding was 1.3 years [IQR: 0.7, 2.2]. We identified a poliovirus genome VP1 region mutation rate of 0.72% per year and a higher median percent divergence for iVDPV1 cases. More cases were reported from high income countries, which also had a larger age variation and different distribution of immunodeficiencies compared to upper and lower middle-income countries.

Conclusion

Our study describes the incidence and characteristics of global iVDPV cases reported in the literature in the past five decades. It also highlights the regional and economic disparities of reported iVDPV cases.

Introduction

The prevalence of poliomyelitis has decreased dramatically since the 1960s with the development and widespread use of the live attenuated Sabin oral poliovirus vaccine (OPV). OPV became the backbone of worldwide vaccine strategies launched by the Global Polio Eradication Initiative (GPEI) due to its low cost, ability to induce mucosal immunity, and ease of administration [1], [2]. However, the potential for OPV to mutate into neurovirulent strains through prolonged intestinal replication—which can result in vaccine-derived poliovirus (VDPV) outbreaks—poses a challenge to global polio eradication [3], [4], [5]. Given their relation to key polio endgame issues such as OPV cessation and vaccine stockpile design, VDPVs thus have implications for vaccination policies worldwide [6], [7]. Numerous studies have been conducted to assess the risks, costs, and benefits of different eradication options, including the evaluation of scenarios with VDPVs [8], [9], [10], [11].

VDPVs are identified based on their degree of genetic divergence from the parent OPV strain and can be comparable to wild-type poliovirus in their capacity to cause paralysis [12]. By definition, VDPVs of serotypes 1 and 3 have >1% genetic divergence, whereas VDPVs of serotype 2 have >0.6% divergence from parent OPV strains [12]. VDPVs are classified into 3 categories: cVDPVs, aVDPVs, and iVDPVs. Circulating vaccine-derived polioviruses (cVDPVs) occur when VDPVs establish and sustain circulation in under-immunized communities for an extended period of time [9], [13], [14], [15], [16]. Ambiguous vaccine-derived polioviruses (aVDPVs) are either isolated from people with no known immunodeficiency or from sewage whose ultimate source is unknown [16], [17], [18]. Immunodeficiency-related vaccine-derived polioviruses (iVDPVs) are a special case of VDPVs in which patients have a primary immunodeficiency (PID) [16], [19]. Unlike immunocompetent persons, who excrete the vaccine virus for a limited period of time, some immunodeficient persons are unable to clear intestinal replication of the vaccine virus after exposure to OPV [19], [20]. In this regard, iVDPVs pose a significant threat to the eradication campaign, as individuals that harbor the vaccine virus for prolonged periods of time could serve as sources of poliovirus reintroduction after polio eradication [16], [21], [22].

Several key efforts have been made to achieve better assessment of the risks posed by iVDPVs in recent years. The GPEI maintains a registry of iVDPV cases. Although this registry is not publicly available, a list of these cases is periodically published in the World Epidemiological Record (WER) and Morbidity and Mortality Weekly Report (MMWR) [12], [23], [24], [25], [26], [27], [28], [29], [30], [31]. Additional studies have been launched to search for potential iVDPV carriers. Although these studies either identified no or few cases, they are an important step toward understanding the true risk and prevalence of iVDPVs, as well as in confirming the feasibility and value of conducting polio surveillance programs [32], [33], [34], [35], [36].

A review by Kew et al. [19] providing a comprehensive overview of VDPVs included a brief chapter summarizing the main features of iVDPVs and a list of documented iVDPV excretors from 1962 to 2003. A review by Tebbens et al. [21] investigating the risks of continued vaccination with OPV modeled the occurrence of paralysis due to infection with the vaccine virus by type of VDPV. A list of iVDPV cases reported in 1962–2005 was presented, which the authors drew upon for inputs to their model. They also stratified their analysis by income level of the country in which a case was reported to assess regional differences. A review by Van de Ven et al. [37] explored the role of prolonged gastrointestinal infections in causing inflammatory enteropathy in patients with a PID. Poliovirus was among the enteroviruses examined, and the authors identified a select number of cases that were iVDPVs, with the most recent case reported in 2005.

In light of the initiatives launched by the GPEI and other researchers, as well as prior reviews regarding iVDPVs, we present the results of a systematic review of reported iVDPV cases in the literature from 1962 to 2012. The aims of this study are two-fold. The first is to present general characteristics and significant trends observed amongst iVDPV cases over five decades, elucidating key findings that have implications for polio eradication such as patterns in poliovirus genome evolution, regional differences in case prevalence, and information regarding case detection and transmission. Over 30 iVDPV cases have been reported since 2006, and given the increasing attention paid to iVDPVs as the world approaches polio eradication, our review provides an update on confirmed iVDPV cases published in the scientific literature.

Second, we aim to foster greater interest and further research regarding iVDPVs that will be useful in the development of appropriate vaccination strategies and policies to achieve and maintain polio eradication. To date, there are no licensed antiviral compounds for poliovirus. There are several antiviral agents such as pirodavir and pleconaril that are known to inhibit poliovirus replication and hence chronic excretion, but data have shown that pleconaril lacks efficacy against certain serotypes of poliovirus [38]. Thus far, the Polio Antivirals Initiative (PAI) has reported pocapavir as a promising agent [39], [40], [41].