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Edited by Eckard Wimmer, Stony Brook University, Stony Brook, NY, and approved July 23, 2014 (received for review December 17, 2013)
Significance
In 2010, a large outbreak of poliomyelitis involving 445 laboratory-confirmed cases occurred in the Republic of Congo. The 47% case-fatality rate was unusually high. Outbreak severity was attributed to low immunization coverage but vaccine-mediated immunity against the outbreak virus was never investigated. We isolated the poliovirus type 1 responsible for the outbreak and located its evolutionary origins to Southeast Asia. Fatal cases showed evidence for previous vaccination against polioviruses and the outbreak virus was refractive against neutralization by monoclonal and vaccine-derived antibodies. This pointed to immune escape contributing to the severity of the outbreak. Sustained vaccination regimens in polio-free regions, together with clinical and environmental poliovirus surveillance will be necessary to combat antigenetically variant polioviruses in the poliomyelitis eradication endgame.
Abstract
In 2010, a large outbreak of poliomyelitis with unusual 47% lethality occurred in Pointe Noire, Republic of Congo. Vaccine-mediated immunity against the outbreak virus was never investigated. A wild poliovirus 1 (WPV1) isolated from a fatal case (termed PV1-RC2010) showed a previously unknown combination of amino acid exchanges in critical antigenic site 2 (AgS2, VP1 capsid protein positions 221SAAL→221PADL). These exchanges were also detected in an additional 11 WPV1 strains from fatal cases. PV1-RC2010 escaped neutralization by three different mAbs relevant for AgS2. Virus neutralization was tested in sera from fatal cases, who died before supplementary immunization (n = 24), Gabonese recipients of recent oral polio vaccination (n = 12), routinely vaccinated German medical students (n = 34), and German outpatients tested for antipoliovirus immunity (n = 17) on Vero, human rhabdomyosarcoma, and human epidermoid carcinoma 2 cells. Fatal poliomyelitis cases gave laboratory evidence of previous trivalent vaccination. Neutralizing antibody titers against PV1-RC2010 were significantly lower than those against the vaccine strain Sabin-1, two genetically distinct WPV1s isolated in 1965 and 2010 and two genetically distinct vaccine-derived PV strains. Of German vaccinees tested according to World Health Organization protocols, 15–29% were unprotected according to their neutralization titers (<1:8 serum dilution), even though all were protected against Sabin-1. Phylogenetic analysis of the WPV1 outbreak strains suggested a recent introduction of virus progenitors from Asia with formation of separate Angolan and Congolese lineages. Only the latter carried both critical AgS2 mutations. Antigenetically variant PVs may become relevant during the final phase of poliomyelitis eradication in populations with predominantly vaccine-derived immunity. Sustained vaccination coverage and clinical and environmental surveillance will be necessary.
Footnotes
↵1J.F.D., G.G., E.M.L., and C.D. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: drosten{at}virology-bonn.de or eric.leroy{at}ird.fr.
Author contributions: J.F.D., E.M.L., and C.D. designed research; J.F.D., G.G., A.N.L., L.I.K., S.B., G.U., J.R., S.E.L.-D., and S.D. performed research; G.G., A.P.G., R.T.-T., D.N., and M.K. contributed new reagents/analytic tools; J.F.D., A.N.L., A.M.E.-H., S.D., M.K., E.M.L., and C.D. analyzed data; and J.F.D., E.M.L., and C.D. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The nucleotide sequences reported in this paper have been deposited in the GenBank database (accession nos. JF838278–JF838290).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1323502111/-/DCSupplemental.
- Jan Felix Drexlera,1,
- Gilda Grardb,1,
- Alexander N. Lukashevc,
- Liubov I. Kozlovskayac,
- Sindy Böttcherd,
- Gökhan Uslue,
- Johan Reimerinke,
- Anatoly P. Gmylc,f,
- Raphaël Taty-Tatyg,
- Sonia Etenna Lekana-Doukib,
- Dieudonné Nkogheb,
- Anna M. Eis-Hübingera,
- Sabine Diedrichd,
- Marion Koopmanse,
- Eric M. Leroyb,h,1,2, and
- Christian Drostena,1,2
- aInstitute of Virology, University of Bonn Medical Centre, 53127 Bonn, Germany;
- bCentre International de Recherches Médicales de Franceville, BP 769 Franceville, Gabon;
- cChumakov Institute of Poliomyelitis and Viral Encephalitides, Moscow 142782, Russia;
- dRobert Koch Institute, National Reference Laboratory for Poliomyelitis and Enteroviruses, 13302 Berlin, Germany;
- eNetherlands Center for Infectious Disease Control, 3720, Bilthoven, The Netherlands;
- fLomonosov Moscow State University, Moscow 119991, Russia;
- gMinistry of Health, Pointe Noire, Republic of Congo; and
- hInstitut de Recherche pour le Développement, Unité Mixte de Recherche 224 (Maladies Infectieuses et Vecteurs: Écologie, Génétique, Évolution et Contrôle), Institut de Recherche pour le Développement/Centre National de la Recherche Scientifique/Unité Mixte 1, 34032 Montpellier, France
Edited by Eckard Wimmer, Stony Brook University, Stony Brook, NY, and approved July 23, 2014 (received for review December 17, 2013)
Significance
In 2010, a large outbreak of poliomyelitis involving 445 laboratory-confirmed cases occurred in the Republic of Congo. The 47% case-fatality rate was unusually high. Outbreak severity was attributed to low immunization coverage but vaccine-mediated immunity against the outbreak virus was never investigated. We isolated the poliovirus type 1 responsible for the outbreak and located its evolutionary origins to Southeast Asia. Fatal cases showed evidence for previous vaccination against polioviruses and the outbreak virus was refractive against neutralization by monoclonal and vaccine-derived antibodies. This pointed to immune escape contributing to the severity of the outbreak. Sustained vaccination regimens in polio-free regions, together with clinical and environmental poliovirus surveillance will be necessary to combat antigenetically variant polioviruses in the poliomyelitis eradication endgame.
Abstract
In 2010, a large outbreak of poliomyelitis with unusual 47% lethality occurred in Pointe Noire, Republic of Congo. Vaccine-mediated immunity against the outbreak virus was never investigated. A wild poliovirus 1 (WPV1) isolated from a fatal case (termed PV1-RC2010) showed a previously unknown combination of amino acid exchanges in critical antigenic site 2 (AgS2, VP1 capsid protein positions 221SAAL→221PADL). These exchanges were also detected in an additional 11 WPV1 strains from fatal cases. PV1-RC2010 escaped neutralization by three different mAbs relevant for AgS2. Virus neutralization was tested in sera from fatal cases, who died before supplementary immunization (n = 24), Gabonese recipients of recent oral polio vaccination (n = 12), routinely vaccinated German medical students (n = 34), and German outpatients tested for antipoliovirus immunity (n = 17) on Vero, human rhabdomyosarcoma, and human epidermoid carcinoma 2 cells. Fatal poliomyelitis cases gave laboratory evidence of previous trivalent vaccination. Neutralizing antibody titers against PV1-RC2010 were significantly lower than those against the vaccine strain Sabin-1, two genetically distinct WPV1s isolated in 1965 and 2010 and two genetically distinct vaccine-derived PV strains. Of German vaccinees tested according to World Health Organization protocols, 15–29% were unprotected according to their neutralization titers (<1:8 serum dilution), even though all were protected against Sabin-1. Phylogenetic analysis of the WPV1 outbreak strains suggested a recent introduction of virus progenitors from Asia with formation of separate Angolan and Congolese lineages. Only the latter carried both critical AgS2 mutations. Antigenetically variant PVs may become relevant during the final phase of poliomyelitis eradication in populations with predominantly vaccine-derived immunity. Sustained vaccination coverage and clinical and environmental surveillance will be necessary.
Footnotes
↵1J.F.D., G.G., E.M.L., and C.D. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: drosten{at}virology-bonn.de or eric.leroy{at}ird.fr.
Author contributions: J.F.D., E.M.L., and C.D. designed research; J.F.D., G.G., A.N.L., L.I.K., S.B., G.U., J.R., S.E.L.-D., and S.D. performed research; G.G., A.P.G., R.T.-T., D.N., and M.K. contributed new reagents/analytic tools; J.F.D., A.N.L., A.M.E.-H., S.D., M.K., E.M.L., and C.D. analyzed data; and J.F.D., E.M.L., and C.D. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The nucleotide sequences reported in this paper have been deposited in the GenBank database (accession nos. JF838278–JF838290).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1323502111/-/DCSupplemental.
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