Failure to clear persistent vaccine-derived neurovirulent poliovirus infection in an immunodeficient man.
BACKGROUND
Individuals who chronically excrete neurovirulent poliovirus of vaccine-origin are of considerable concern to the Global Polio Eradication programme. Chronic infection with such polioviruses is a recognised complication of hypogammaglobulinaemia.


METHODS
We did a series of in-vitro and in-vivo therapeutic studies, with a view to clearing persistent neurovirulent poliovirus infection in an individual with common variable immunodeficiency, using oral immunoglobulin, breast milk (as a source of secretory IgA), ribavirin, and the anti-picornaviral agent pleconaril. We undertook viral quantitation, antibody neutralisation and drug susceptibility assays, and viral gene sequencing.


RESULTS
Long-term asymptomatic excretion of vaccine-derived neurovirulent poliovirus 2 was identified in this hypogammaglobulinaemic man, and was estimated to have persisted for up to 22 years. Despite demonstrable in-vitro neutralising activity of immunoglobulin and breast milk, and in-vitro antiviral activity of ribavirin, no treatment was successful at clearing the virus, although in one trial breast milk significantly reduced excretion levels temporarily. During the course of study, the virus developed reduced susceptibility to pleconaril, precluding the in-vivo use of this drug. Sequence analysis revealed the emergence of a methionine to leucine mutation adjacent to the likely binding site of pleconaril in these isolates.


CONCLUSIONS
Chronic vaccine-associated poliovirus infection in hypogammaglobulinaemia is a difficult condition to treat. It represents a risk to the strategy to discontinue polio vaccination once global eradication has been achieved.
MacLennan
Calman
C
MRC Centre for Immune Regulation, Division of Immunity and Infection, University of Birmingham, Birmingham, UK. cmaclennan@mlw.medcol.mw
Dunn
Glynis
G
Huissoon
Aarnoud P
AP
Kumararatne
Dinakantha S
DS
Martin
Javier
J
O'Leary
Paula
P
Thompson
Ronald A
RA
Osman
Husam
H
Wood
Philip
P
Minor
Philip
P
Wood
David J
DJ
Pillay
Deenan
D
D000328:Adult; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D036022:Capsid Proteins / Q000235:genetics; D002353:Carrier State / Q000276:immunology / Q000628:therapy* / Q000821:virology; D017074:Common Variable Immunodeficiency / Q000276:immunology / Q000821:virology*; D005243:Feces / Q000821:virology; D000882:Haplorhini; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D008297:Male; D008826:Microbial Sensitivity Tests; D008895:Milk, Human / Q000276:immunology; D009154:Mutation; D011051:Poliomyelitis / Q000209:etiology / Q000276:immunology / Q000628:therapy / Q000821:virology*; D017955:Poliovirus / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification* / Q000472:pathogenicity; D011055:Poliovirus Vaccine, Oral / Q000009:adverse effects*; D017211:Treatment Failure; D014774:Virulence
D000998:Antiviral Agents; D036022:Capsid Proteins; D016756:Immunoglobulins, Intravenous; D011055:Poliovirus Vaccine, Oral; C062481:VP1 protein, polyomavirus