Skip directly to site content Skip directly to page options Skip directly to A-Z link Skip directly to A-Z link Skip directly to A-Z link
Volume 27, Number 2—February 2021
Dispatch

Vaccine-Derived Polioviruses, Central African Republic, 2019

Marie-Line Joffret1, Joël Wilfried Doté1, Nicksy Gumede, Marco Vignuzzi, Maël Bessaud2Comments to Author , and Ionela Gouandjika-Vasilache2
Author affiliations: Institut Pasteur, Paris, France (M.-L. Joffret, M. Vignuzzi, M. Bessaud); Institut Pasteur, Bangui, Central African Republic (J.W. Doté, I. Gouandjika-Vasilache); World Health Organization African Region Office, Brazzaville, Congo (N. Gumede)

Cite This Article

Abstract

Since May 2019, the Central African Republic has experienced a poliomyelitis outbreak caused by type 2 vaccine-derived polioviruses (VDPV-2s). The outbreak affected Bangui, the capital city, and 10 districts across the country. The outbreak resulted from several independent emergence events of VDPV-2s featuring recombinant genomes with complex mosaic genomes. The low number of mutations (<20) in the viral capsid protein 1–encoding region compared with the vaccine strain suggests that VDPV-2 had been circulating for a relatively short time (probably <3 years) before being isolated. Environmental surveillance, which relies on a limited number of sampling sites in the Central African Republic and does not cover the whole country, failed to detect the circulation of VDPV-2s before some had induced poliomyelitis in children.

Poliomyelitis results from infection of the central nervous system by poliovirus, a picornavirus of the species Enterovirus C (1). The Global Polio Eradication Initiative (https://polioeradication.org) managed to eradicate wild poliovirus of 2 of the 3 serotypes and to contain virus of the third serotype in Pakistan and Afghanistan. The Initiative relies on 2 pillars: surveillance of poliovirus circulation and vaccination. Contrary to the inactivated polio vaccine, the oral polio vaccine (OPV) induces strong intestinal immunity that blocks transmission of poliovirus in subsequent infections (2). Consequently, OPV is currently the only tool capable of stopping poliovirus transmission. However, because attenuated strains of OPV replicate in the gut and are excreted in feces, low vaccine coverage enables circulation of these strains and loss of their attenuated phenotype through genetic drift (3,4). Since May 2019, the Central African Republic (CAR) has experienced a poliomyelitis outbreak caused by serotype 2 vaccine-derived polioviruses (VDPV-2s). To ascertain the origin of these VDPV-2s, we determined and analyzed their full-length genomic sequences.

The Study

Figure 1

Central African Republic. Shading indicates districts where VDPV-2s were detected May–December 2019: triangles indicate districts where environmental surveillance has been implemented; numbers indicate total numbers of VDPVs; numbers in parentheses indicate number of confirmed poliomyelitis cases, letters A–L indicate VDPV lineages (based on the viral capsid protein 1–encoding region [Figure 2, panel A]). VDPV-2, type 2 vaccine-derived polioviruses.

Figure 1. Central African Republic. Shading indicates districts where VDPV-2s were detected May–December 2019: triangles indicate districts where environmental surveillance has been implemented; numbers indicate total numbers of VDPVs; numbers in parentheses...

During May–December 2019, using standardized procedures of the Global Polio Laboratory Network (https://polioeradication.org), we detected VDPV-2s in fecal samples of 19 children with acute flaccid paralysis (AFP). Positive samples came from 10 districts across the country, including Bangui, the capital city (Figure 1). In addition, we detected 49 VDPV-2s in fecal samples from healthy children living in the vicinity of the children with poliomyelitis; 17 were detected in environmental samples. In December 2017, routine environmental surveillance was implemented in CAR, restricted to 4 sampling sites in Bangui; 6 additional sites were gradually opened in 2019 (Figure 1). Compared with the vaccine Sabin-2 strain (reference strain), CAR VDPV-2s had 6–20 nt differences in the viral capsid protein 1 (VP1)–encoding region (903 nt), above the threshold used to discriminate VDPV-2s from Sabin-2 (>6 mutations within the VP1-encoding sequence). Given the evolutionary rate of this genomic region (≈10−2 nucleotide changes/site/year [5]), this range suggests that VDPVs had been circulating in CAR from a few months to a couple of years before detection.

Figure 2

Molecular characterization of VDPV-2s isolated in the Central African Republic in 2019. A) Phylogram of the VP1-encoding sequence drawn by using the maximum-likelihood method based on the data-specific model. Alternating blue and red indicate evolutionary branches (A–L); open circles indicate sequences of VDPVs from patients with acute flaccid paralysis circles; closed circles indicate sequences of VDPVs from healthy children; black triangles indicate sequences of VDPVs from environmental samples. The district where the isolate was sampled and the recombinant pattern the isolate belongs to (patterns 1–12 or nonrecombinant [Figure 2, panel B]) are indicated; asterisks indicate isolates that have not been fully sequenced. Scale bar indicates nucleotide substitutions per site. B) Schematic representation of the genomic patterns of the VDPVs. Top row shows poliovirus genetic organization, with the main open reading frame flanked by the 5′ and 3′ untranslated regions (UTRs). Approximate locations of the recombination sites (1–12 on left) are shown. Sequences with different colors differ by <3%. Letters in parentheses on the right indicate the VP1 branches where each recombinant pattern can be found. NR, no recombination. C) Similarity plot drawn by comparing the sole genome of pattern 5 with genomes of patterns 3 (green), 4 (red), and 6 (blue) in the 3′ half of the genome. Sliding window width, 200 nt; step distance, 20 nt. VDPV-2s, type 2 vaccine-derived polioviruses; VP1, viral capsid protein 1.

Figure 2. Molecular characterization of VDPV-2s isolated in the Central African Republic in 2019. A) Phylogram of the VP1-encoding sequence drawn by using the maximum-likelihood method based on the data-specific model. Alternating...

Phylogenetic analysis based on VP1-encoding regions showed that the CAR VDPV-2s fell into different lineages (Figure 2, panel A; Appendix Figure). Although the low number of nucleotide differences in young VDPVs makes precise marking of the boundaries of phylogenetic clusters challenging, we identified >12 main branches in this phylogram (Figure 2, panel A, branches A–L), indicating the concomitant emergence of multiple VDPV lineages. Branches A and J gathered sequences of VDPVs sampled from districts located hundreds of kilometers apart (Figure 1), which suggests active circulation of these lineages in the country; by contrast, some lineages (F, I, K, L) were detected only 1 time. No isolates from patients with AFP were of lineages D, F, G, I, K, L; however, determining whether some AFP cases were missed or, alternately, whether surveillance managed to uncover VDPV lineages before they caused poliomyelitis, is not possible. Environmental surveillance is expected to detect poliovirus circulation before it causes the first poliomyelitis case, but the alert system is efficient only if the surveillance is dense enough to cover the entire country, a goal that is difficult to reach in CAR because of the political troubles.

Among the 70 CAR VDPV-2s for which genomes have been fully sequenced through gene walking and Sanger sequencing, only 4 (branches G and L, from healthy children) were free of recombination events and feature a global nucleotide divergence <1% compared with Sabin-2. The 66 other CAR VDPV-2 genomes comprised sequences derived from Sabin-2 and from other nonpolio enteroviruses in 12 recombinant patterns; polio/nonpolio breakpoints were within the 2A, 2B, 2C, 3A, 3C, and 3D-encoding regions (Figure 2, panel B; Appendix Figure). In the nonpolio region, the unique representative of recombinant pattern 5 (member of VP1 branch B) shared recent common ancestors through recombination with the genomes of patterns 3 and 6: it was closely related to genomes of pattern 6 from the 2A through the 3C genomic regions and to the genomes of pattern 3 downstream (Figure 2, panel C). Pattern 4 also shared a recent common ancestor with pattern 3, from which it diverged only near the 3′ extremity of the genome (Figure 2, panel B). Similarly, the genomes of patterns 7 and 8 were closely related from the 2B region through the middle of the 3C region and substantially diverged downstream. Genomic mosaicism is a common trait found in enterovirus ecosystems because of frequent recombination exchanges between cocirculating enteroviruses, including the poliovirus vaccine strains. Thus, VDPVs generally feature genomes resulting from multiple recombination events (6). Three VP1 branches (A, B, and D) contained various recombinant patterns (Figure 2, panel A); reciprocally, 2 recombinant patterns (3 and 11) were each found in several VP1 branches (Figure 2, panel B), thereby illustrating how recombination can make different segments of the enterovirus genome evolve independently (7).

Although VDPV-2s commonly harbor a recombinant nonpolio 5′ untranslated region (UTR), all CAR VDPVs had a 5′ UTR from the vaccine Sabin-2 strain. Nonetheless, an A→G reversion was found in all genomes at nt position 481, which harbors one of the major determinants of attenuation of the Sabin-2 strain (8). A second major determinant of Sabin-2, located within the VP1-encoding region (nt position 2909), had also reverted (U→C, isoleucine-to-threonine) in all CAR VDPVs.

Conclusions

The origin of the CAR VDPV-2s remains unknown. In April 2016, a switch from use of the trivalent OPV to the bivalent OPV, which contains the Sabin-1 and Sabin-3 attenuated strains (but not Sabin-2), was synchronized globally (9). The low nucleotide divergence observed within the VP1-encoding sequence between the CAR VDPV-2s and Sabin-2 makes the hypothesis of silent circulation of Sabin-2–derived strains originating from the trivalent OPV over >3 years unlikely. More likely, the CAR VDPV-2s may derive from the Sabin-2 strain contained in the monovalent OPV that was used to control a 2017–2018 VDPV-2 outbreak in the Democratic Republic of the Congo, which borders CAR (10). Population movements across the border between the 2 countries could have allowed introduction of Sabin-2–derived viruses into CAR, a country in which most children born after the global vaccine switch have no immunity against serotype 2. The silent circulation of these viruses for several months was probably rendered possible by the difficulties of implementing efficient surveillance in some regions of CAR because of the civil war that has been ongoing in the country since 2012.

We show that the CAR VDPV-2 outbreak resulted from several independent emergence events, involving recombinant genomes with no recombination in the 5′ UTR. Beyond the situation in CAR, 2019 was a dark year for the Global Polio Eradication Initiative; VDPV-2 outbreaks surged in many countries in Africa (11). OPV of serotype 2 remains the best tool to stop VDPV-2 outbreaks, but it also constitutes the seed for emergence of VDPVs. The pending release of a novel OPV that contains a genetically stabilized serotype 2 strain less prone to reversion is expected to put an end to this vicious cycle (12).

Dr. Joffret is a scientist with the Institut Pasteur in Paris, France. Her main research interest is surveillance of poliovirus and other nonpolio enteroviruses in Africa.

Top

Acknowledgment

We are indebted to Charlotte Balière and Aurelia Kwasiborski for Sanger sequencing.

Top

References

  1. Zell  R, Delwart  E, Gorbalenya  AE, Hovi  T, King  AMQ, Knowles  NJ, et al.; Ictv Report Consortium. ICTV virus taxonomy profile: Picornaviridae. J Gen Virol. 2017;98:24212. DOIPubMed
  2. Bandyopadhyay  AS, Garon  J, Seib  K, Orenstein  WA. Polio vaccination: past, present and future. Future Microbiol. 2015;10:791808. DOIPubMed
  3. Combelas  N, Holmblat  B, Joffret  ML, Colbère-Garapin  F, Delpeyroux  F. Recombination between poliovirus and coxsackie A viruses of species C: a model of viral genetic plasticity and emergence. Viruses. 2011;3:146084. DOIPubMed
  4. Burns  CC, Diop  OM, Sutter  RW, Kew  OM. Vaccine-derived polioviruses. J Infect Dis. 2014;210(Suppl 1):S28393. DOIPubMed
  5. Jorba  J, Campagnoli  R, De  L, Kew  O. Calibration of multiple poliovirus molecular clocks covering an extended evolutionary range. J Virol. 2008;82:442940. DOIPubMed
  6. Bessaud  M, Joffret  ML, Blondel  B, Delpeyroux  F. Exchanges of genomic domains between poliovirus and other cocirculating species C enteroviruses reveal a high degree of plasticity. Sci Rep. 2016;6:38831. DOIPubMed
  7. Muslin  C, Mac Kain  A, Bessaud  M, Blondel  B, Delpeyroux  F. Recombination in enteroviruses, a multi-step modular evolutionary process. Viruses. 2019;11:859. DOIPubMed
  8. Minor  PD, Macadam  AJ, Stone  DM, Almond  JW. Genetic basis of attenuation of the Sabin oral poliovirus vaccines. Biologicals. 1993;21:35763. DOIPubMed
  9. Garon  J, Seib  K, Orenstein  WA, Ramirez Gonzalez  A, Chang Blanc  D, Zaffran  M, et al. Polio endgame: the global switch from tOPV to bOPV. Expert Rev Vaccines. 2016;15:693708. DOIPubMed
  10. Mbaeyi  C, Alleman  MM, Ehrhardt  D, Wiesen  E, Burns  CC, Liu  H, et al. Update on vaccine-derived poliovirus outbreaks—Democratic Republic of the Congo and Horn of Africa, 2017–2018. MMWR Morb Mortal Wkly Rep. 2019;68:22530. DOIPubMed
  11. Jorba  J, Diop  OM, Iber  J, Henderson  E, Zhao  K, Quddus  A, et al. Update on vaccine-derived poliovirus outbreaks—worldwide, January 2018–June 2019. MMWR Morb Mortal Wkly Rep. 2019;68:10248. DOIPubMed
  12. Van Damme  P, De Coster  I, Bandyopadhyay  AS, Revets  H, Withanage  K, De Smedt  P, et al. The safety and immunogenicity of two novel live attenuated monovalent (serotype 2) oral poliovirus vaccines in healthy adults: a double-blind, single-centre phase 1 study. Lancet. 2019;394:14858. DOIPubMed

Top

Figures

Top

Cite This Article

DOI: 10.3201/eid2702.203173

Original Publication Date: January 18, 2021

1These first authors contributed equally to this article.

2These senior authors contributed equally to this article.

Table of Contents – Volume 27, Number 2—February 2021

Comments

Please use the form below to submit correspondence to the authors or contact them at the following address:

Address for correspondence Maël Bessaud, Institut Pasteur 25-28, rue du Dr Roux, 75 015 Paris, France

Send To

10000 character(s) remaining.

Top

Page created: December 07, 2020
Page updated: January 24, 2021
Page reviewed: January 24, 2021
The conclusions, findings, and opinions expressed by authors contributing to this journal do not necessarily reflect the official position of the U.S. Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention, or the authors' affiliated institutions. Use of trade names is for identification only and does not imply endorsement by any of the groups named above.
file_external