administration of trivalent oral poliovirus vaccine and seroprevalence of poliovirus neutralizing antibodies

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1 Lessons from Cub: mss cmpign dministrtion of trivlent orl poliovirus vccine nd seroprevlence of poliovirus neutrlizing ntibodies P. Ms Lgo,1 J. Rmon Brvo,1 J.K. Andrus,2 M.M. Comells,1 M.A. Glindo,3 C.A. de Qudros,4 & E. Bell5 The immunogenicity of trivlent orl poliovirus vccine (TOPV), which is less effective in tropicl thn in temperte res, my potentilly be improved in severl wys, including incresing the number of doses. Little informtion is vilble on TOPV when more thn 6 doses re given. The sitution in Cub provides unique opportunity to relte the seroprevlence of neutrlizing ntibodies to the dose of TOPV becuse Cub hs not reported culture-confirmed poliomyelitis since 1973 nd TOPV is only dministered in twice yerly 1-week mss immuniztion cmpigns. Ser from 2000 children ntionwide were studied for neutrlizing ntibody mong children who received 0, 2, 4, 6 nd 8 doses of TOPV. These doses were dministered in the period , when TOPV (from the USSR) ws being used with , , nd medin tissue-culture-infecting doses (TCID50) for types 1, 2 nd 3, respectively-the 5:2:3 formultion. Seroprevlence of neutrlizing ntibody fter two TOPV doses ws 91.5% for type 1, 90.8% for type 2, nd 45.9% for type 3. Seroprevlence of type-3 neutrlizing ntibody fter 6 doses remined low (73.4%), but incresed to 83.5% fter 8 doses (P<0.05). Although 16.5% of the children remined unprotected for type-3 infection even fter 8 doses, mss cmpign immuniztion strtegies were sufficient to erdicte the trnsmission of wild poliovirus in Cub. Becuse the seroprevlence of type-1 neutrlizing ntibody ws high (91.5%) fter two cmpign doses, dditionl studies using different formultions re needed to determine whether simultneous improvement in the type-3 response to two cmpign doses cn be chieved. Introduction Although seroprevlence following the dministrtion of trivlent orl poliovirusvccine (TOPV) pproches 100% in most industrilized countries, only 73% (rnge, 36-99%) nd 70% (rnge 40-99%) of children in developing countries hve detectble ntibody to poliovirus types 1 nd 3, respectively, fter the three-dose stndrd schedule (1). Vrious fctors ccounting for these differences re recogni- Institute of Tropicl Medicine "Pedro Kouri", Ministry of Helth, Hvn, Cub. 2 Expnded Progrm on Immuniztion, Pn Americn Helth Orgniztion (PAHO), Wshington, DC, USA (on ssignment from Centers for Disese Control nd Prevention to PAHO). 3Expnded Progrm on Immuniztion, Ministry of Helth, Cub. 4Expnded Progrm on Immuniztion, PAHO. Requests for reprints should be sent to Dr C. de Qudros, Pn Americn Helth Orgniztion, 525, 23rd Street N.W., Wshington, DC 20037, USA. 5Expnded Progrmme on Immuniztion, World Helth Orgniztion, Genev, Switzerlnd. Decesed 24 November Reprint No zed but hve not yet been fully elucidted. Approches such s incresing the number of doses of TOPV, ltering the reltive components of the trivlent vccine, using supplementl mss TOPV cmpigns, nd the combined use of orl nd inctivted poliovirus vccines re currently under review nd/or evlution in field trils by the WHO Expnded Progrmme on Immuniztion (EPI). In Cub, TOPV is distributed only during two one-week periods ech yer (Februry nd April), with two-month intervl between them. During these periods, TOPV is given twice to ll children ged 0-3 yers nd once to children t 9 yers of ge, irrespective of their immuniztion sttus (2). For the remining 50 weeks of the yer TOPV is not vilble in the locl helth units for dministrtion. Between 1970 nd 1991, the TOPV tht ws distributed cme from the sme source in the USSR. This vccine hd , nd medin tissue-culture-infecting doses (TCID50) for poliovirus types 1, 2 nd 3, respectively. Between 1963 nd 1973, only 7 virologiclly confirmed cses of prlytic poliomyelitis were reported. Since 1973 nd until the present (August Bulletin of the World Helth Orgniztion, 1994, 72 (2): World Helth Orgniztion

2 P. Ms Lgo et l. 1993) there hs been no evidence of trnsmission of wild poliovirus in Cub. Given these conditions, we conducted study to evlute the seroprevlence of poliovirus neutrlizing ntibodies for types 1, 2 nd 3 when TOPV ws dministered by mss cmpigns nd when >6 doses of TOPV were given. Methods Acute flccid prlysis is reportble condition in Cub. All such cses re reported to nd investigted by the Ministry of Helth. Of the totl popultion of 10 million people, 2 million live in the cpitl Hvn. Using ntionl census dt, subset of ll Cubn children 0-3 yers of ge ws selected by pplying strtified rndom smpling, proportionte to size, by geogrphic distribution. Children were grouped ccording to hving received 0, 2, 4, 6 or 8 doses of TOPV. The trget number to be included in ech dose group ws 400. Any child bom between Februry nd April of ny yer of the study period ws excluded, nd only cohorts of children with even numbers of doses were evluted for seroprevlence. Also excluded were those children whose dte of birth ws not obtined. Stndrd methods were used to mesure the serum neutrlizing ntibody titres. Briefly, this involved testing ech serum in the dilution rnge from 1/8 to 1/1024, using two wells per dilution. The Stndrd procedure for determining immunity to poliovirus using the microneutrliztion test (unpublished WHO document WHO/EPI/GEN/93.9, 1993). serum/virus mixtures were held t 36 C for 3 hours before ddition of HEp-2 (Cincinnti) cell suspension; tests were red t 5 dys. Seroprevlence ws expressed s the percentge of children tested who hd ny detectble ntibody. Increses in seroprevlence of type-specific ntibodies were consecutively evluted for sttisticl significnce from one dose group to the next, beginning with the zero dose group. Results Between December 1991 nd Jnury 1992 (before the next scheduled TOPV mss immuniztion cmpign in Februry 1992) 2087 children 0-3 yers of ge ntionwide were bled for ser. After exclusion of children who were bom between Februry nd April, or whose birth dte ws not known, serum smples from 2000 children were tested for neutrlizing ntibody to poliovirus types 1, 2 nd 3. Demogrphic chrcteristics nd immuniztion sttus of these children re listed in Tble 1. The totl number of children enrolled by ge group ws similr. The seroprevlence of neutrlizing ntibodies to poliovirus type 1 ws 91.5% following 2 doses nd 96.5% fter 4 doses, the percentge increse between these two ws sttisticlly significnt (P = 0.05), but not fter 6 or 8 doses where the increse ws only smll (Tble 2). The response to poliovirus type 2 ws lso significnt fter 2 nd 4 doses, therefter smll (not significnt) increse ws observed (Tble 2). The seroprevlence of neutrlizing ntibodies to poliovirus type 3 fter 2 doses ws low (45.9%), compred with 91.5% nd 90.8% to poliovirus 1 nd Tble 1: TOPV immuniztion sttus nd demogrphic chrcteristics of the surveyed children ged 0-3 yers, Cub, 1992 No. of Sex Rceb Domicilec Totl doses Mle Femle White Mixed Blck Urbn Rurl tested Subtotl Totl In Cub there is slight excess of mles over femles nd the dominnt rce is white, followed by mixed nd blck rces. This demogrphic distribution is represented in the group of children tested in this serosurvey. b The rce of 7 children ws not given (1 ech in the 0-, 2- nd 8-dose groups; 2 ech in the 4- nd 6- dose groups). c Domicile ws not given for 4 children (2 in the 0-dose group nd 1 ech in the 4- nd 8-dose groups.) 222 WHO Bulletin OMS. Vol

3 Seroprevlence of pollovirus ntibodies In Cub Tble 2: Percentge of children with ntibody to poliovirus types 1, 2 nd 3, by the number of TOPV doses dministered, Cub, 1992 No. of No. of children Percentge with ntibody doses tested Type 1 Type 2 Type (19.6, 28.2)b 25.2 (20.8, 29.6) 11.9 (8.6, 15.2) c (88.7, 94.3) 90.8C (87.9, 93.7) 45.9C (40.9, 50.9) C (94.6, 98.3) 97.2C (95.6, 98.8) 71.2C (66.8, 75.6) (96.4, 99.4) 98.4 (97.1, 99.7) 73.4 (66.9, 77.9) (97.0, 99.6) 98.8 (97.7, 99.9) 83.5c (79.8, 87.2) Totl (80.4, 83.8) 82.7 (81.0, 84.4) 57.6 (55.4, 59.8) A titre equl to or greter thn 8. b Figures in prentheses indicte the 95% confidence intervls. c Figures in itlics indicte sttisticlly significnt increse from the previous dose group. 2, respectively (Tble 2). After 4 doses the bsolute level for seroprevlence of type-3 neutrlizing ntibodies remined low (71.2%); however, the increse from 2 doses of TOPV ws significnt. A 6th dose of TOPV showed smll nd insignificnt increse in seroprevlence of type-3 neutrlizing ntibodies, but following 8 doses the increse to 83.5% ws sttisticlly significnt (P = 0.01). In the zero TOPV dose group there were 385 children who hd not yet received ny TOPV becuse they were born fter the preceding April immuniztion cmpign. As there hs been no detectble circultion of wild poliovirus in Cub since 1973 nd only 7 cses of prlytic poliomyelitis were recorded between 1963 nd 1973, it cn resonbly be ssumed tht most of these 385 children cquired their poliovirus immunity from mternl ntibodies rther thn from wild poliovirus exposure. Exct ge, by month, ws vilble for 381 of the 385 children in the zero dose group. Of the 20 children ged 1 month the percentge with ntibody to poliovirus types 1 nd 3 ws low (55.0% nd 30.0%, respectively) (Tble 3). By 7 months of ge none of the 53 children tested hd detectble ntibody t titre of 1/8 to poliovirus types 1 nd 3 nd only 1.9% hd titres.1/8 to poliovirus type 2. By 9 months of ge the percentge of children with ntibodies to the three poliovirus serotypes incresed to 46% for types 1 nd 2, nd to 17.9% for type 3 (Tble 3). Although ll these children were born fter the lst TOPV cmpign (in April), the reson for the presence of detectble ntibodies my be tht they were old enough to hve been exposed to vccinted children who were excreting vccinerelted polioviruses. Seroprevlence of neutrlizing ntibodies by the number of TOPV doses ws not influenced by sex, rce, nd urbn or rurl plce of domicile. The only exception to this ws tht fter 2 doses of TOPV, children in rurl res showed greter response to poliovirus types 1 nd 3 (P <0.05). Discussion The observed low seroprevlence of type-3 neutrlizing ntibody my hve been due in prt to the low titre of the polio-3 component of the USSR-produced TOPV, which ws hlf tht recommended by PAHO ( TCID50 insted of the EPI/PAHO-recommended titre of TCID50).b However, low seroprevlence of type-3 neutrlizing ntibody hs been observed in severl studies in developing countries using routine delivery services, regrdless of the dose or formultion used (1). To our knowledge, the sttisticlly significnt increse in seroprevlence of type-3 neutrlizing ntibodies from the sixth to the eighth cmpign dose hs not been observed previously. Cub, unlike other countries in the Westem Hemisphere, relied solely on twice-yerly mss TOPV immuniztion cmpigns to erdicte the trnsmission of indigenous wild poliovirus. Despite inherent difficulties with response to the type-3 component by the individuls in this nd other studies, the use of mss immuniztion cmpigns in the bsence of routine vccine delivery ws sufficient to erdicte poliomyelitis in Cub (2, 3). Minlnd countries in Ltin Americ pper to hve erdicted poliomyelitis by supplementing routine immuniztion services with nnul ntionl mss immuniztion cmpigns (4). Control of poliob Pn Americn Helth Orgniztion. Finl report: 5th Meeting of the Technicl Advisory Group on Polio Erdiction in the Americs. Lim, PAHO, WHO Bulletin OMS. Vol

4 P. Ms Lgo et l. Tble 3: Results of testing for ntibody to pollovirus types 1, 2 nd 3 mong 381 unvcclnted children ged 1-9 months, Cub, 1992 Age No. of children Percentge with ntibody (months) testedb Type 1 Type 2 Type (32.8, 77.2)C 65.0 (42.6, 87.4) 30.0 (9.5, 50.5) (35.6, 64.4) 47.9 (33.5, 62.3) 22.9 (10.8, 35.0) (15.0, 41.6) 39.1 (24.7, 53.5) 15.2 (4.6, 25.8) (13.1, 39.1) 21.7 (9.5, 33.9) 8.7 (0.4, 17.0) (9.6, 31.8) 24.5 (12.7, 36.3) 13.2 (3.9, 22.5) (2.8, 21.2) 6.0 (0.0, 12.7) 2.0 (0.0, 6.0) (0.0, 0.0) 1.9 (0.0, 5.7) 0.0 (0.0, 0.0) (0.0, 12.8) 13.5 (2.3, 24.7) 8.1 (0.0, 17.1) (27.6, 65.2) 46.4 (27.6, 65.2) 17.9 (3.4, 32.4) A titre equl to or greter thn 8. b Not included re 4 children whose ge in months is not known. c Figures in prentheses indicte the 95% confidence intervls. myelitis ws chieved in tropicl res of the Americs using TOPV with the ntigeniclly poor type-3 component. The use of mss immuniztion cmpigns tkes dvntge of the community response, not the individul's response, to the rpid exposure of lrge numbers of children to TOPV (5, 6). Flooding communities bruptly with vccine-relted polioviruses by mss immuniztion of children my quickly induce sufficient proportion of children to develop the necessry gut immunity to prevent the spred of wild poliovirus. Children ged 1-9 months who hd not yet received TOPV showed rpid decline in mteml ntibody to undetectble levels by 6-7 months of ge. The gp in poliomyelitis immunity observed in children ged 6-7 months in Cub should not be s evident in other countries becuse of ongoing dministrtion of TOPV through the routine helth services. Overll, the seroprevlence of type-i neutrlizing ntibody fter three doses of TOPV hs been reported in developing countries to be only 73% (rnge 36-99%) (1). In the present study the seroprevlence of type-i neutrlizing ntibody fter two cmpign doses ws 91.5%. Perhps cmpign dministrtion of TOPV improves the immunogenicity of specific types of poliovirus. If so, to minimize the "mrgin of error" ttributble to the low ntigenicity of the type-3 component of TOPV, it would be highly useful for globl erdiction efforts to determine, using other vccine formultions, whether it is possible to improve the immunogenicity of the type-3 component of TOPV simultneously with the fvourble type-i response to two cmpign doses. 224 Acknowledgements We thnk the stff of ll the Cubn helth clinics visited for their help in smpling the children enrolled in this study. We cknowledge the finncil support given by the Expnded Progrm on Immuniztion of the Pn Americn Helth Orgniztion, which is WHO's Regionl Office for the Americs in Wshington, DC, nd by the Expnded Progrmme on Immuniztion of WHO, Genev. In ddition, we re grteful to Ros Plmer for her excellent technicl ssistnce. Resume Les leqons de Cub: cmpgne d'dministrtion de msse du vccin ntipoliomy6litique orl trivlent et s6ropr6vlence des nticorps neutrlisnt les poliovirus L'immunog6nicite du vccin ntipoliomyelitique orl trivlent (PVOT), moins efficce en zone tropicle que sous les climts temper6s, peut etre m6lior6e de plusieurs fqons, pr exemple en ugmentnt le nombre de doses. On dispose de peu d'informtions sur l'efficcite du PVOT lorsque le nombre de doses est superieur six. L sitution Cub offre une occsion unique d'evluer l s6roprevlence des nticorps neutrlisnts (AN) en fonction des doses de PVOT, cr Cub n' ps signle de cs de poliomy6lite confirmes pr culture depuis 1973 et le PVOT n'y est dministr6 qu'u cours de cmpgnes de vccintion de WHO Bulletin OMS. Vol

5 Seroprevlence of pollovirus ntibodies In Cub msse d'une semine qui ont lieu deux fois pr n. L recherche des AN e fite sur le s6rum de 2000 enfnts de toutes les regions du pys qui vient requ 0, 2, 4, 6 et 8 doses de PVOT u cours de l periode Le vccin utilise provenit d'urss et contenit , et DICT (doses infectntes medines pour les cultures tissulires) pour les types 1, 2 et 3 respectivement (formule 5:2:3). L seroprevlence des AN pres deux doses de PVOT etit de 91,5% pour le type 1, 90,8% pour le type 2 et 45,9% pour le type 3. L seroprevlence des AN type 3 6tit encore fible pres 6 doses (73,4%), mis elle tteignit 83,5% pres 8 doses (P <0,05). Bien que 16,5% des enfnts soient restes sns protection contre l'infection de type 3 pres 8 doses, les cmpgnes de vccintion de msse ont suffi pour mettre fin l trnsmission du poliovirus suvge Cub. Etnt donne l seroprevlence 6levee des AN type 1 (91,5%) pres deux doses dministr6es dns le cdre d'une cmpgne, il fudrit proceder des 6tudes compl6- mentires portnt sur des formultions differentes fin de determiner s'il est possible d'meliorer de l meme fgon l r6ponse en AN de type 3 deux doses dministr6es dns les memes conditions. References 1. Ptrirc PA, Wright PF, John TJ. Fctors ffecting the immunogenicity of orl poliovirus vccine in developing countries: review. Rev. infect. dis., 1991, 13: Ocho EG, Lgo PM. Epidemiologicl surveillnce nd control of poliomyelitis in the Republic of Cub. J. hyg. epidemiol. microbiol. immunol., 1987, 31(4): Cruz R.R. Cub: mss polio vccintion progrm, Rev. infect. dis., 1984, 6(Suppl.2): S408-S de Qudros CA et l. Polio erdiction from the Western Hemisphere. Ann. rev. publ. helth, 1992, 13: de Qudros CA et l. Erdiction of poliomyelitis: progress in the Americs. Peditr. infect. dis. j., 1991, 10: Sbin AB et l. Live, orlly given poliovirus vccine: effects of rpid mss immuniztion on popultion under conditions of mssive enteric infection with other viruses. J. Am. Med. Assoc., 1960, 173: WHO Bulletin OMS. Vol