ORAL POLIO VACCINATION OF CHILDREN IN THE TROPICS

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1 AlIBHICAK JOUBNAL OF EPIDEJIIOLOQT Vol. W, No. Copyright O 1072 by The Johns Hoplrin* University Printed in U.S.A. ORAL POLIO VACCINATION OF CHILDREN IN THE TROPICS I. THE POOR SEROCONVERSION RATES A THE ABSENCE OF VIRAL INTERFERENCE 1 T. JACOB JOHN A P. JAYABAL (Received for publication April 10, 72) John, T. J. and P. Jayabal (Enterovirus Lab., Christian Medical College and Hospital, Vellore, Tamil Nadu, India). Oral poliovaccination of children in the tropics. I. The poor seroconversion rates and the absence of viral interference. Am J Epidemiol 9: 23-29, 72. A study of the efficacy of trivalent oral polio vaccine (OPV) was conducted in a group of children between the ages of 3 months and years, in Vellore, Tamil Nadu. Of the 1 children given the 1st dose of OPV, 72, 93 and 9 were found to be seronegative to poliovirus types 1, 2 and 3, respectively, prior to vaccination. The seroconversion rates in them were 35% to type 1, 7% to type 2 and 8% to type 3 following 2 doses 8 weeks apart. Among the triple seronegative children, the seroconversion rates after 2 doses were 28% to type 1, 77% to type 2 and % to type 3. These rates are very poor, especially when compared to seroconversion rates in children in temperate climates. Loss of potency of the vaccine, interference of enteric viruses prevalent at the time with vaccine viruses and interference among the 3 vaccine virus types have been excluded as the cause of the poor serologic response observed in these children. Results of this and other similar studies should be taken into account when formulating dosage schedules of OPV in the tropics. enteroviruses; poliovirus vaccine, oral; seroconversion; serology; viral interference INTRODUCTION conducted, it has been proven to be a highly In temperate climates where most studies effective prophylactic agent against poliowith oral polio vaccine (OPV) have been m y elitis W- A sin g le dose of bivalent OPV induces antibody response to all three sero- Abbreviations: MK, monkey kidney; OPV, oral types of polioviruses in a majority of seropolio vaccine. negative children (2). Studies in tropical 'From the Enterovirus Laboratory, Christian countries, though limited, have shown that Medical College and Hospital, Vellore, Tamil vaccination with Opv results in signifi- Nadu, India.. This investigation was supported in part by the lower rates of y seroconversion than in WHO and in part by grant No from the temperate areas (3-5). Despite the poor Center for Disease Control, Atlanta, Georgia. conversion rates in children, the use of OPV This study arose from discussions at an infor- in wen executed mass campaigns in tropical mal meeting of WHO on poliomyelitis vacc.nat.on countries hfld led to ft id and significant in the tropics held in Helsinki in 8, and at-.....,. tended by Drs. W. C. Cockbum, J. P. Fox, J. L. reduction in the incidence of the disease Melnick, D. Montefiore, A. B. Sabin, I. Tagaya, R. (-). With this background an investiga- Waldman and T. J. John. The authors thank Drs. A. J. Beale, W. C. Cockbum and R. Q. Robinson N. Jayakumar, Mr. P. Mukundan and Mrs. H. for material help, and Mrs. S. Christopher, Mr. Rajamaniekam for technical assistance. 23

2 2 JOHN A JAYABAL tion was set up in Vellore, Tamil Nadu, India to obtain further information on the response of children to OPV, a matter which is of obvious practical importance at this time to health authorities in warm-climate countries. MATERIALS A METHODS This study was conducted in children belonging to a group of families which were participating in a longitudinal morbidity survey program. The description of the area, the method of recruitment and the general plan of the program have been reported previously (7, 8). Twenty-two infants three to 12 months old and preschool children one to five years old were available for the administration of OPV. Trivalent OPV 2 was kindly supplied by Dr. A. J. Beale of the Wellcome Foundation, London. The vaccine was transported from the manufacturer to the laboratory in dry ice and stored in the laboratory at 20 C. It was thawed to C immediately before administration. If thawed vaccine was not fully used up, the remainder was left at C and used the next morning. Three drops of the vaccine were dropped on the back of the tongue or given on a lump of sugar. Each child war given two doses eight weeks apart starting in September 9. A sample of venous blood was collected from every child before each dose of the vaccine and eight weeks after the second dose. Samples of stools were collected from the vaccinees three weeks, two weeks and one week before, one week and two weeks after and on the day of feeding each dose of the vaccine. For this purpose pre-labelled plastic containers were delivered to the homes the previous evening and specimens collected the next morning. If a child defaulted, he was visited in the afternoon and if necessary again the next morning to collect the specimen. If a fecal sample was not "Wellcome Brand (Strains: type 1, L-Sc, 2 ab; type 2, p 712, Ch, 2ab; type 3, Leon 12 ab. Titer: type 1, 10"; type 2, 10*- 0 ; type 3, 10" TCID» per dose). available on the appointed day or the next day, a rectal swab was collected. These specimens were transported to the laboratory in crushed ice. The vaccine was administered only after a stool or rectal swab specimen was collected. The sera were separated and stored at 20 C. Poliovirus neutralizing antibody titers were determined in these sera according to standard procedures modified for use in microtiter system (9, 10). The sera were diluted 1:5, heated to 5 C for one-half hour and tested in eight steps of twofold dilutions starting at 1:10. If no antibody was detected at 1:10 dilution, the serum was considered negative and if antibody was detected at 1:10 it was considered positive. The test viruses (type 1, Mahoney; type 2, Mef and type 3 Saukett) and standard antisera were kindly supplied by the Center for Disease Control, Atlanta, Georgia. In the neutralization tests 100 TCID 80 of the test viruses were used and a known positive serum was included in every run. All serum samples from a child were tested together and each serum was tested in duplicate rows of wells. Samples of feces were prepared into 20 per cent (w/v) suspensions in Hank's basic salt solution containing penicillin, streptomycin, neomycin and amphotericin-b. These and rectal swab suspensions in similar diluent were inoculated in newborn mice, primary bonnet monkey kidney (MK) cells and HEp-2 cells as described previously (11, 12). RESULTS A DCUSSION The serologic response to OPV. Among the 1 children given the first dose of OPV, only were triple seronegative prior to vaccination. The seroresponse of these children to the first and second doses of the vaccine is summarized in table 1. There were 72, 93 and 9 children who were seronegative to poliovirus types 1, 2 and 3, respectively, prior to vaccination. The homologous seroresponse of these chil-

3 ORAL POLIO VACCINATION OF CHILDREN IN THE TROPICS 25 dren to the first and second doses of OPV is summarized in table 2. In the case of individual types of polioviruses, the seroconversion rate after the first dose of OPV was not significantly different from that following the second dose (table 2: type 1, p = 0.89; type 2, p = 0.07; type 3, p = 0.2). Therefore it would appear that the subsequent response of children who remained seronegative after the administration of one dose of OPV may be little different from that of children who are seronegative but have not previously been given OPV. On this basis we have added together the number of children who were seronegative before the first dose and those who remained seronegative at the time of second dose for further considerations of seroresponse. Thus 128 children seronegative to type 1, 129 children seronegative to type 2 and 7 children seronegative to type 3 were fed a dose of trivalent OPV. These seroconversion rates in triple seronegative as well as homologous seronegative children are very poor compared to those of previously reported studies from several nontropical countries (-1). However studies reported from Singapore and Nigeria, two tropical countries, have shown low rates of seroconversion especially for types 1 and 3 (3, ). An exception to this pattern was found in Toluca, Mexico (). A comparison of seroconversion rates in seronegative children fed trivalent OPV in different geographical areas is shown in table 3. The potency of the vaccine. Since OPV is a temperature sensitive live virus suspension, we checked whether it had lost its potency during transportation or storage. A sample of the OPV was titrated in MK cells using six tubes per dilution, after the last dose had been administered. The infectivity titer was found to be 10 - TCID 0 per 0.1 ml. The manufacturer's declaration was that the vaccine contained approximately 10-2 TCTDso per 0.1 ml. Thus no drop in potency had occurred during storage. Interference by enteric virus infection. TABLE 1 Seroresponse to two doses of OPV in triple seronegative children Seronegative before 1st dose Serooonverted after 1st dose Seroconversion rate (1st dose) Seronegative before 2nd do«after 2nd dose Serooonversion rate (2nd dose) Berooonverted after 1st 2nd doses Serooonversion rate (1st A 2nd doses) Actual number followed. 1 1% 33* % 11 28% 2 0% 7 % 31 77% J0% 27* % % TABLE 2 Seroresponse to two doses of OPV in homologous seronegalive children Seronegative before 1st dose Serooonverted after 1st dose 3eroconversion rate (1st dose) Seronegative before 2nd dose 3erooonverted after 2nd dose Serooonversion rate (2nd dose) Serooonverted after 1st & 2nd doses Serooonveraion rate (1st 2nd doses) Actual number followed % 5* 11»% 25 38% 93 0% 3* 2% 71 7% % S3* 25% 5 8% The fecal specimens collected from children on the day of the vaccine feeding were inoculated in newborn mice, MK cells and HEp 2 cells. The number of children discharging any viruses and the seroconversion rates among them are presented in table. The seroconversion rates in children whether or not found infected with viruses at the time of vaccine feeding were not significantly different. Since interference could possibly be due to the effects of recent infection, evidence for interference by infection present one week before the vaccine feeding was looked for. Table 5 presents the number of children found infected one week before vaccine feeding and the seroconversion rates among them in comparison with seroconversion rates in children not found infected. The

4 2 JOHN A JAYABAL TABLE 3 A comparison of seroconversion rales from several countries in seronegative children fed trivalenl OPV Country Seroconvenion rate (%) after one dose l 2 3 Seroconversion rate (%) after two doses l J 3 Reference No. USA USSR USSR Mexico South Africa Singapore Nigeria* Indiaf f Present study Present study 2 monovalent vaccine followed by types 1 and 3 together. t First line for triple seronegative children and second line for homologous seronegative children. J Not done. TABLE The effect of enteric virus infection at the lime of vaccination on seroconversion rates Total seronegative children* Positive for enterio viruses among them Bejooonversion rate Negative for enterio viruses among them Serooonversion rate l % 3 1% % % S3 30% 28% * The number of children who were seronegative before the first dose and those who remained seronegatlve before the 2nd dose were added together. TABLE 5 The effect of enteric virus infection one week before vaccine feeding on seroconversion rates Positive for viruses among sexonegntive children Serooonversion rate Negative for viruses among seronegative children Seroconversion rate l SO 20% a 8 18% % % 3 W 29 30% U seroconversion rates in uninfected and infected children were nearly identical. If the fecal specimens collected one week before and on the day of vaccine feeding were negative, the child was defined as un- TABLE Seroconversion rates according to the duration of enteric virus infections No. of children with no infeotlon' Serooonversion rate No. of children just recovered from infection t Serooonverted Serooonversion rate- No, of children with infection of short duration^ Seroconversion rmte No. of children with infection of long duration} Serooonverted Seroconversion rate l 22 18% 2 % 1 27% 1 21% % 1 7 7% % 0 3 0% J 23 17% % 2 7»% % * Fecal specimens collected on the day of vaccination and 1 week before were negative. t Fecal specimens collected 1 week before were positive, on the day of vaccination negative. t Fecal specimens collected 1 week before were negative, on the day of vaccination positive. I Fecal specimens collected 1 week before and on the day of vaccination were positive. infected and if the first specimen was negative but the second specimen was positive, the infection was defined as of short duration. If both specimens were positive the infection was defined as of long duration and if the first specimen was positive and the second was negative, the child was considered to have just recovered from an

5 OHAL POLIO VACCINATION OF CHILDREN IN THE THOPICS 27 TABLE 7 The effect of seroconversion to one type on the seroconversion to other types Seronegative to types 1 and 2 to type 2 Not seroconverted to type 2 No. of children R»te of Mroconverrion to type 1 9 (1%) (17%) 3 (10%) Seronegative to types 2 and 3 to type 2 Not seroconverted to type 2 Seronegative to types 1 and 3 to type 3 Not seroconverted to type 3 Seronegative to types 1 and 3 to type 1 Not seroconverted to type 1 Seronegative to types 1 and 2 to type 1 Not seroconverted to type 1 Seronegative to types 2 and 3 to type 3 Not seroconverted to type 3 infection. The seroconversion rates in these four groups are compared in table. The numbers in each group are small but the variations in the rates of seroconversion were not statistically significant. Thus there is no evidence to suggest that the duration of enteric infection by viruses influences the seroconversion rates. Interference among vaccine virus types. Interference among the three types of vaccine viruses have been previously reported (17). This phenomenon results in the failure of implantation of one or more vaccine virus types as a result of infection by one type, when trivalent OPV is administered. For the evaluation of such interference we have adopted the following method of analysis. In a group of children seronegative to to type 3 23 (29%) 18 (37%) 5 (%) to type 1 18 (20%) (29%) 12 (18%) to type 3 21 (2%) (33%) (21%) to type 2 35 (53%) (7%) 29 (51%) to type 2 8 (58%) 18 (78%) 30 (57%) polio types 1 and 2, a dose of trivalent vaccine may result in seroconversion to type 1 alone, type 2 alone, to both or to neither. If the group is divided into two subgroups on the basis of seroconversion to polio type 2, the seroconversion rates to polio type 1 in these two subgroups could be assessed. If type 2 interfered with type 1, one would expect a significantly lower seroconversion rate to type 1 in those who seroconverted to type 2 than in those who did not. The results are presented in table 7. The differences observed in the seroconversion rates in each group are not statistically significant except in one instance in which case seroconversion to type 2 appeared to enhance seroconversion to type 3. In no case did seroconversion to type 1, 2 or 3 ad-

6 28 JOHN A JAYABAL versely affect seroconversion to any other type. COMMENTS Drozdov and Cockburn (5) have reported that the seroconversion rates after feeding OPV are unsatisfactory in hot climates, based chiefly on results of investigations in Singapore, Nigeria and Brazil. Our studies add further support to this view. In a study from New Delhi, Ghosh et al. (18) reported very poor antibody response to three doses of trivalent OPV, but seroconversion rates were not presented. Arumanayagam and Mendis () have stated that three doses of trivalent OPV did not increase the immunity status of children to a significant extent in Ceylon. Thus it is becoming increasingly clear that the seroresponse of children in hot climates is much poorer than in temperate climates. In addition to the hot climate, the standards of hygiene and the nutritional levels are poor and the frequency of bacterial, viral and parasitic infections of the gastrointestinal tract and of diarrhea are high in children in many countries in the tropical belt. It is important to discover the factors that affect the seroconversion rates in order to ensure the use of the most effective means of vaccination in tropical areas. Several previous workers have demonstrated the phenomenon of interference between wild viruses and vaccine viruses (20-22). However our studies and some others (e.g. Poliomyelitis Commission, ) have failed to find any evidence for such interference. The results of the study of fecal specimens collected after OPV feeding will be reported later. We have not studied the role of breast milk in inhibiting infection by vaccine viruses. All vaccinees were over three months of age when the effect of breast milk is believed to be insignificant (23). However, further investigations are necessary to assess the effect of breast feeding on seroconversion rates. If the poor seroconversion rates are an indication that those who fail to respond are still susceptible, two or three doses would appear to be inadequate. However the question of susceptibility of the nonconverters is still unanswered. We have observed five paralytic cases in children three to 22 months after the third dose of vaccine was administered (2), but there is good epidemiologic evidence that vaccination significantly reduced the incidence of poliomyelitis in tropical climates at least when used in mass vaccination campaigns in which a large proportion of the susceptible age groups are covered in a very short time (3, ). REFERENCES 1. Sabin AB: Poliomyelitis: Accomplishments of live virus vaccine. In Proceedings of the 1st International Conference on Vaccines against Viral and Rickettsial Diseases of Man. Pan Am Health Organization, Washington, DC, 7, pp Chumakov MP, Voroshilova MK, Vasilieva KA, et al: Preliminary report on mass oral immunization of population against poliomyelitis with live virus vaccine from A. B. Sabin's attenuated strains. In Proceedings of the 1st International Conference on Live Poliovirus Vaccine. Pan Am Sanitary Bureau, Washington DC, 59, pp Lee LH, Wenner HA. Rosen L: Prevention of poliomyelitis in Singapore by live vaccine. Br Med J 1: ,. Poliomyelitis Commission, Western Region Ministry of Health, Nigeria. Poliomyelitis vaccination in Ibadon, Nigeria during with oral vaccine. Bull WHO 3: 85-87, 5. Drozdov SG, Cockburn WC: The state of poliomyelitis in the world. In Proceedings of the 1st International Conference on Vaccines against Viral and Rickettsial Diseases of Man. Pan Am Health Organization, Washington, DC 9, Sabin AB, Ramoz-Alvarez M, Alvareis-Amezquita J, et al. Live orally given poliovirus vaccine. Effects of rapid mass immunization on population under conditions of massive enteric infection with other viruses. JAMA 173: 21-2, 0 7. Feldman RA, Kamath KR, Sundar Rao PSS, et al: Infection and disease in a group of south Indian families. 1. Introduction, methods, definitions and general observations in a continuing study. Am J Epidemiol 89: 3-37, 9

7 ORAL POLIO VACCINATION OF CHILDREN IN THE TROPICS 29 S. John TJ, Kamath KR, Feldman RA, et al: Infection and disease in a group of south Indian families. IX. Poliovirus infection among preschool children. Indian J Med Res 58: , Melnick JL, Wenner HA, Rosen L: The enteroviruses. In Diagnostic Procedures for Viral and Rickettsial Diseases. (Edited by EH Lennette, NJ Schmidt.) New York, Am Public Health Assoc, 10. Lamb LH, Plexico K, Glezen WP, et al: Use of micro technique for serum neutralization and virus identification. Public Health Rep 80: 3-9, George S, Feldman RA: Susceptibilit3 - of bonnet monkey (M. radiata) kidney cell cultures to human enteroviruses. Indian J Med Res 57: , John TJ, Rathnam PV: Comparative sensitivity of two techniques of specimen inoculation for the isolation of viruses. Indian J Med Res 57: , 9. Dobrova IN, Yankevich OD, Voroshilova MK, et al: In Oral Live Poliovirus Vaccine. Moscow, 1. Quoted by Drozdov SG, Cockburn WC (reference 5) 1. Khozinski VI, Karoseva IA, Sueshinina JA: In Oral Live Poliovirus Vaccine. Moscow, 1. Quoted by Drozdov SG, Cockburn WC (reference 5). Winter PAD, Saayman LR, Spence RG, et al: Serological results of poliomyelitis vaccine. 8. Afr Med J 37: 510-, 3 1. Horstmann DM, Paul JR, Godenne-McCrea M, et al: Immunization of preschool children with oral polio vaccine (Sabin). JAMA 178: , Sabin AB: Recent studies and field tests with a live attenuated poliovirus vaccine. In Proceedings of the 1st International Conference on Live Poliovirus Vaccines, Pan Am Sanitary Bureau, Washington DC, 59, pp Ghosh S, Kumari S, Balaya S, et al: Antibody response to oral polio vaccine in infancy. Indian Pediatr 7: 78-81, 70. Arumanayagam P, Mendis NMP: Experiences in Ceylon of immunization against poliomyelitis using trivalent oral poliomyelitis virus vaccine (Sabin). Presented at the Fifth Malayasia- Singapore Congress of Medicine Benyesh-Melnick M, Melnick JL, Ramos-Alvarez M: Poliomyelitis infection rate among Mexican children fed attenuated poliovirus vaccines, a) Effect of pre-existing poliomyelitis antibody, b) Interfering rate of other enteroviruses. In Proceedings of the 1st International Conference on Live Poliovirus vaccines, Pan Am Sanitary Bureau, Washington DC, 59, pp Ramos-Alvarez M: Poliomyelitis: Discussion. In Proceedings of the 1st International Conference on Vaccines Against Viral and Rickettsial Disease of Man. Pan Am Health Organization, Washington DC, 7, pp Ramos-Alvarez M, Santos PG, Rivera LR, et al: Viral and serological studies in children immunized with live poliovirus vaccine preliminary report of a large trial conducted in Mexico. In Proceedings of the 1st International Conference on Live Poliovirus Vaccines. Pan Am Sanitary Bureau. Washington DC, 59, pp Warren RJ, Lepow ML, Bartsch GE, et al: The relationship of maternal antibody, breast feeding and age to the susceptibility of newborn infants to infection with attenuated polioviruses. Pediatrics 3: -, 2. John TJ, Ratnaswamy L, Mammen KC, et al: Paralytic poliomyelitis after 3 doses of oral poliovaccine. (Manuscript)