Immunogenicity of oral poliomyelitis vaccine (OPV) against variants of wild poliovirus type 3.

Immunogenicity of oral poliomyelitis vaccine (OPV) against variants of wild poliovirus type 3 B. Bothig,' L. Danes,2 & S. Dittmann' Serological investigations of three groups of children from the German Democratic Republic (GDR) and from Czechoslovakia who had different immunization histories against poliomyelitis indicated that the immunity induced by oral poliovaccine (OPV) is effective against both the wild poliovirus Saukett strain and a new wild variant of poliovirus type 3 that was isolated during an outbreak of poliomyelitis in Finland in 1984. There is therefore no obvious risk that individuals in the GDR or Czechoslovakia, most of whom have been immunized with OPV, are threatened by new wild poliovirus variants. These findings are of importance, especially in connection with WHO's initiative for the global eradication of poliomyelitis by the year 2000. Introduction After 20 years' absence of poliomyelitis in Finland, an outbreak of the disease was reported in the country in 1984 (1,2). In view of the high vaccination coverage-more than 90% of children had been immunized with inactivated poliomyelitis vaccine (IPV)-this outbreak, which was caused by poliovirus type 3, was surprising (3). Additional proof of the wide distribution of wild poliovirus type 3 throughout the country was established by isolating the virus from the wastewater of several towns (3). Serological investigations showed that indi- viduals under 19 years of age had lower antibody titres against the epidemic poliovirus strain com- pared with those against the Saukett reference strain of the virus, which is a component of IPV (3). Similar results were found by Magrath et al. (4), who examined sera from Finns, Norwegians, and Swedes who had been administered IPV. The geometric mean antibody titre of the Finnish sera against the Saukett strain was 1:25, but only 1:4 against the Finnish wild virus isolate (P3/Finland/23127/84). Animal experiments revealed that the isolate of poliovirus type 3 from Finland exhibited strong antigenic variance; immune sera against the purified D antigen of this strain neutralized the homologous virus, but not the Saukett strain or the vaccine strain (Leon 12 a, b) of OPV. In contrast, an immune serum ' Central Institute for Hygiene, Microbiology and Epidemiology, Britzer Strasse 1-3, DDR-1190 Berlin (East), German Democratic Republic. Requests for reprints should be sent to Professor Dittmann at this address. 2 Institute for Hygiene and Epidemiology, Prague 100 42, Cze- choslovakia. Reprint No. 5113 of the Sabin strain neutralized both the homologous virus and the Saukett strain, but only to a limited extent the P3/Finland/23127/84 isolate (4). We therefore investigated whether the immunity induced by OPV provides adequate protection against the antigenically modified new Finnish wild poliovirus type 3 strain in the populations of the German Democratic Republic (GDR) and Czecho- slovakia. In both countries oral poliovaccine (Sabin) strains are used. This vaccine is produced in bulk in the Institute of Poliomyelitis and Viral Encephalitis, Moscow, USSR. No poliomyelitis cases caused by wild virus strains and no circulation of wild polio- viruses have been observed in the GDR or Czecho- slovakia for more than 20 years. Materials and methods Serum samples Group 1: sera from 155 children (GDR) aged 2-14 months who each received consecutively (at 4-week intervals) one dose of monovalent OPV (100 000 plaque-forming units (PFU) per dose) of type 1, type 2, and type 3. Group 2: sera from 102 children (GDR) aged 9 16 years, who received the same dose of monovalent OPV (type 1, type 2, and type 3) as the children in group 1 plus two additional trivalent (3 x 100 000 PFU per dose) booster doses in their second and eighth years of life. Group 3: sera from 76 Czechoslovakian child- ren aged 12-23 months, who received OPV type 1, as monovalent vaccine, and type 2 and 3, as bivalent vaccine. One year later about 30% of these children were revaccinated with the same vaccines. Children aged less than 6 months received 500000 PFU per dose of type 1 and type 2 vaccines and 1 million PFU per dose of type 3 vaccine; children aged greater than Bulletin of the World Health Organization, 66 (5): 597-600 (1990) © World Health Organization 1990 597 B. B6thig et al. 6 months received 100 000 PFU per dose of type 2 and type 3 and 200 000 PFU per dose of type 3 vaccine. Antibody determinations Antibody determinations were carried out in laboratories in Berlin (East) and Prague using the microneutralization test with 100 TCD50 of the Leon 12a,b (Sabin), Saukett, and P3/Finland/23127/84 strains of poliovirus type 3 in both laboratories. In Berlin (East), RD cell cultures were used, and read- ings were taken on the fifth day; while in Prague, BGM cell cultures were used and readings were made on the third day. Results Table 1 shows the proportion of children who had antibody titres > 1:4 against the Saukett, P3/Fin- land/23127/84, and Leon 12a,b strains of poliovirus type 3. The proportion of children who were antibody- positive against the Leon 12a1b strain, i.e., against the homologous virus strain after oral vaccination, was a little greater than the proportion of children who had antibodies against the two wild virus strains. In contrast, there was no significant difference between the proportion of children with antibodies against the Saukett and P3/Finland/23127/84 wild viruses in all three groups. Fig. 1 and 2 show the antibody titres against the Saukett and P3/Finland/23127/84 strains for groups 2 and 3, respectively. These plots indicate that the titres against these two wild virus variants were similar and that there was no tendency towards a lower immunity against one or other of these strains. For all three groups the geometric mean titres against the Leon 12a,b strain also were slightly higher, but the difference between the titres for the two wild virus strains was not significant (Table 2). Fig. 1. Plots showing antibody titres against the Saukett and P3/Finiand/23127/84 strains In children Immunized once with monovalent OPV type 3 and twice with trivaient OPV (group 2). Saukett 1.512 1:256 1 128 1 64 32 1 16 18 1 4 '1 4 i'1[ 0 II '7's I -------Ioi~~~~~~~~~~~~~~~~~~~~~~~~ -14 14 18 116 132 1,64 1128 1256 1,512 Titre P3 / Finland / 23127 / 84 Discussion Using monoclonal antibodies, Huovilainen et al. (5) established that the Finnish isolates of wild polio- virus type 3 exhibited clear antigenic differences com- pared with the strains used in IPV or OPV. The viruses isolated during the outbreak displayed con- siderable heterogeneity, indicating that antigenic evolution of type 3 had occurred under natural conditions. Through the use of oligonucleotide mapping procedures and monoclonal antibodies, Magrath et al. (4) confirmed that the Finnish wild virus isolates Table 1: Proportion of children with antibodies against the three strains of pollovirus type 3 tested In the study Poliovaccines % with antibody titres - 1:4 against: received Saukett P3/Finland/23127/84 Leon 12a,b Group 1 Monovalent type 3 69 70 73 (n= 155)' Group 2 Monovalent type 3+two doses trivalent 84 89 93 (n= 102)b Group 3 Bivalent type 2+type 3 87 83 92 (n= 76)' 2-14-month-olds from the German Democratic Republic. b 9-16-year-olds from the German Democratic Republic. c 12-23-month-olds from Czechoslovakia. WHO Bulletin OMS. Vol. 68 1990.IS98 Immunogenicity of OPV against wild pollovirus type 3 variants Fig. 2. Plots showing antibody titres against the Saukett and P3/F1niand/23127/84 strains In children Immunized once with bivalent type 2 and type 3 OPV (group 3). Saukett 1 512 1 256 1 128 1 l64 1:16 18 1:4 c1:4 < 1 4 1 4 // 1 8 1716 1:32 1,64 1 128 1:256 1512 Titre P3 / Finland / 23127/ 84 Table 2: Geometric mean titres against the three strains of pollovirus type 3 tested In the study Geometric mean titre against: Saukett P3/Finland/23127/ Leon 12a,b 84 Group 1 (n=155)' 1:8 1:7 1:11 Group 2 (n=102)b 1:9 1:9 1:13 Group 3 (n=76)c 1:8 1:6 1:15 2-14-month-olds from the German Democratic Republic. 9-16-year-olds from the German Democratic Republic. c 12-23-month-olds from Czechoslovakia. were not related to the vaccine virus strains and that they were antigenically unusual type-3 variants. Sequence analyses of the nucleotides of the region coding for the VP 1 and amino acid sequence analyses (4-6) revealed that 3 of the 12 amino acids of the VP 1 region are exchanged in the Finnish strain (4-6). Investigations with monoclonal antibodies also led Guo et al. (7) to conclude that the Finnish wild virus differs markedly from other strains of poliovirus type 3. These workers suggested that the protection effects of IPV and OPV also against such antigenic variants should be tested. The results of our study of three groups of children from two countries with different immuniza- tion schedules and histories were intended to deter- mine whether the immunity induced by OPV gives protection against antigenically modified wild type 3 polioviruses. The results obtained using the Saukett and P3/Finland/23127/84 wild poliovirus strains showed that the immunity induced by OPV is suf- ficient for effective prevention also of poliomyelitis caused by modified wild strains. Our investigation of immunity against variants of poliovirus wild strains in children who had received OPV suggests that there is little cause for concern. This is particularly reassuring, since in May 1988 the 41st World Health Assembly committed WHO to the global eradication of poliomyelitis by the year 2000. Acknowledgements We are grateful to Dr T. Hovi who kindly provided the poliovirus strain P3/Finland/23127/84 and to Mrs U. Kamolz and Mrs. K. Hebkci for skilful technical assis- tance. R6sum6 Immunogbniclt du vaccin antipollomyblltique buccal (VPO) A 1'6gard des virus sauvages de type 3 Grfice A I'analyse s6quentielle des nucleotides et aux anticorps monoclonaux, differents chercheurs ont etabli que la souche de poliovirus de type 3 isolee lors d'une epidemie de poliomyelite en Finlande en 1984 presentait des differences antig6niques avec les souches de type 3 utilisees pour preparer le vaccin inactive (VPI) et le vaccin buccal (VPO). Ils ont decrit la souche P3/Finland/ 23127/84 comme une variante du virus de type 3 presentant des caracteristiques antigeniques inhabituelles. Chez les enfants vaccines avec le VPI, les analyses serologiques ont montre que le titre des anticorps dirig6s contre la souche respon- sable de l'epidemie etait plus faible que celui des anticorps diriges contre la souche Saukett de reference utilisee pour preparer le vaccin. Nous avons donc entrepris en Republique democratique allemande et en Tch6coslovaquie une etude collective sur des enfants vaccin6s avec le VPO, afin de determiner leurs titres en anticorps diriges contre les souches de type 3 suivantes: la souche Leon 12 a,b, la souche Saukett et la nouvelle variante finlandaise. L'etude a porte sur trois groupes d'enfants WHO Bulletin OMS Vol. 68 1990. - s + + I f A/ ! § l}I I I A II II I i II 11 I i _/. II/ . .. .:: 599 B. B6thig et al. vaccines selon des modalites diff&rentes. Le premier groupe n'avait recu qu'une dose de vaccin monovalent de type 1, 2 ou 3; les deux autres groupes avaient en outre recu respectivement deux doses de rappel de vaccin trivalent et une dose de vaccin bivalent pr6pare a partir de souches de types 2 et 3. Le titre d'anticorps circulants diriges contre la souche virale utilisee pour la vaccination a ete plus eleve dans les trois groupes, mais aucune difference significative n'a et notee en ce qui concerne l'immunite a l'6gard des deux variantes sauvages. Les resultats de cette etude serologique montrent qu'il n'y a manifestement aucun risque de voir de nouvelles variantes de virus venir a bout de la defense immunitaire induite par le VPO. References 1. GDSC Report. Outbreak of poliomyelitis in Finland. British medical journal, 291: 41-42 (1985). 2. Lelnikkl, P.O. et al. Paralytic poliomyelitis in Finland. Lancet, 1: 507 (1985). 3. HovI, T. et al. Outbreak of paralytic poliomyelitis in Finland: widespread circulation of antigenically altered poliovirus type 3 in a vaccinated population. Lancet, 1: 1427-1432 (1986). 4. Magrath, D.l. et al. Antigenic and molecular properties of type 3 poliovirus responsible for an outbreak of poliomyelitis in a vaccinated population. Journal of general virology, 67: 899-905 (1986). 5. Huqvilalnen, A. et al. Evolution of poliovirus during an outbreak: sequential type 3 poliovirus isolates from several persons show shifts of neutralization determin- ants. Journal of general virology, 68: 1373-1378 (1987). 6. Minor, P.D. et al. Studies on the molecular aspects of antigenic structure and virulence of poliovirus. Annales de l'lnstitut Pasteur, Virologie, 137E: 107-125 (1986). 7. Guo, R. et al. Preliminary studies on antigenic varia- tion of poliovirus using neutralizing monoclonal antibodies. Journal of general virology, 68: 989-994 (1987). 600 WHO Bulletin OMS. Vol. 68 1990.