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

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.

Keywords: Immunodeficiency; Oral polio vaccine; Polio eradication; Poliomyelitis; iVDPV.

Fig. 1

Screening process for included manuscripts. This figure demonstrates the screening process for included and excluded citations from PubMed, Science Direct, Scopus, and Web of Science. Cases were included if (1) the patient had a PID reported by the authors, and (2) the vaccine virus isolated from the patient met the sequencing definition of VDPV (>1% divergence for serotypes 1 and 3 and >0.6% for serotype 2) and/or the case had been previously reported as an iVDPV by the World Health Organization.

Fig. 2

iVDPV incidence over time. This figure demonstrates the incidence of reported iVDPV cases included in our analysis.

Fig. 3

iVDPV incidence by income level of country of case origin overtime. This figure demonstrates iVDPV incidence by income status of the country of origin. Income level of the country is designated according to 2012 GNI per capita, calculated using the World Bank Atlas method. The groups are stratified as follows: low income: $1035 or less; lower middle income, $1036–$4085; upper middle income, $4086–$12,615; and high income, $12,616 or more.

Fig. 4

Reported iVDPV cases from 1960 to November 2012. This figure demonstrates the geographical representation of the iVPDV cases identified in our review, and the corresponding number of cases for each respective country. Twenty-five countries and the Palestinian territories (West Bank and Gaza Strip) reported iVDPV cases, although most countries reported only one case. Half (n = 34) of cases included in our analysis were from four countries: Iran, the United States, U.K., and China. Nine cases were reported in four African countries. More countries in Asia and the Middle East appear to have reported ≥1 case, but iVDPV case incidence was not isolated to a particular region.

Fig. 5

Correlation of duration of shedding and the genetic divergence of iVDPVs. This figure demonstrates the relationship of percent genetic divergence of OPV strains at the VP1 region with the duration of shedding (for both calculated and reported definitions) of the iVDPV cases included in our analysis. Single and multivariable regressions were performed. Shedding duration and age were statistically associated with divergence and age — each additional year of shedding and age corresponded to an increase in the percent divergence by 0.72% and 0.08%, even after controlling for gender, presence of AFP, serotype, and survival status (p<3e⁻¹⁵; p< 0.00013). However, it is important to note that there are limitations in this analysis given the high mortality rate among case patients if the patient was still shedding at the time of death and the inherent bias in that shedding is only reported starting at case detection. Both these factors may have artificially shortened the measure for duration of shedding.