IMMUNIZATION OF NEWBORN CHILDREN WITH LIVING ORAL TRIVALENT POLIOVIRUS VACCINE

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1 MMUNZATON OF NEWBORN CHLDREN WTH LVNG ORAL TRVALENT POLOVRUS VACCNE C. CAMPLLO-SANZ, A. ORNELAS HERNANDEZ, J. DE MUCHA MACAS, AND S. E. NAVA nstituto Naional de Virologia de la S.S.A., M4xio, D.F. Reeived for publiation April 9, 196 ABSTRACT CAMPLLO-SANZ, C. (nstituto Naional de Virologfa de la S.S.A., M6xio, D.F.), A. ORNELAS HERNANDEZ, J. DE MUCHA MACfAS, AND S. E. NAVA. mmunization of newborn hildren with living oral trivalent poliovirus vaine. J. Bateriol. 4: The serologial response to one dose of living oral trivalent poliovirus vaine was ompared in two groups of hildren, 49 vainated at birth and 44 vainated at the age of 4 months. Of those vainated at birth, 44 (90%) responded to the vaine strains of type 1 and type 3 and 30 (61 %) to the type strain. Of those vainated at 4 months of age; % responded to type 1, 5% to type, and % to type 3. The differene between the responses of the two groups, whih for type 1 is signifiant, may result from the interferene of other enteri viruses in the 4-month-old hildren. A seond dose of vaine, administered to the hildren vainated at birth when they reahed the age of 4 months, inreased the over-all immunologial response to 100% for types 1 and 3 and 96% for type, and showed that no immunologial tolerane had been developed. The vaine produed no undesirable effets in any of the hildren, and no paralyti poliomyelitis ourred among them. The observation of other investigators, that a high titer of maternal antibody inhibits immunologial response to vaination, was onfirmed, but breast feeding apparently had no unfavorable effet on response. n Mexio it is espeially desirable that any program of mass vaination against poliomyelitis inlude newborn hildren. Better protetion would be afforded, sine most ases of paralyti polio our during the first months of life. The effiay of the vaine would be more ertain, sine Mexian hildren are known to be infeted shortly after birth with other enteri viruses that an interfere with the vaine polioviruses (Campillo-Sainz et al., 1961). n addition, vaination in a maternity hospital is an easy and effiient way to immunize large numbers of hildren. For these three reasons, a study was planned with the following objetives: a omparative evaluation of the antigeniity of one dose of living trivalent vaine in healthy hildren at birth and at 4 months of age; and a determination of the effet of a seond dose of the vaine at 4 months of age on those hildren vainated at birth. MATERALS AND METHODS Vaination. The program was started in July 1960 and ompleted 4 months later. n the maternity pavilion of the General Hospital in Mexio City, 00 well, full-term infants were seleted and separated into two equal groups, one to reeive the vaine and the other a plaebo, both of whih were administered during the first 4 hr after birth. The vaine used in this study was obtained from Lederle Laboratories, Amerian Cyanamid Company, Pearl River, N.Y., and was prepared with the Lederle strains of attenuated poliovirus (Cabasso et al., 1960). Eah of the 100 hildren vainated reeived ml of living trivalent vaine (lot no Bi) ontaining approximately 600,000 TCD50 of eah type of poliovirus. Eah hild in the seond group reeived a dose of plaebo, of the same volume, whih looked and tasted like the vaine. Both vaine and plaebo were administered with a dropper, and are was taken to see that all of the dose was swallowed. mmediately afterward, the hildren were expeted to take breast feeding. During their 3-day hospital stay, the hildren were arefully observed; in most ases, surveillane was ontinued for 9 months by periodi home visits. At the age of 4 months, 49 of the 100 hildren vainated at birth and 44 of those who had reeived the plaebo at birth were fed a dose of vaine exatly like the first feeding. Colletion of samples. Blood samples were taken 446

2 VOL. 4, 196 MMUNZATON WTH LVNG ORAL POLOVRUS VACCNE 447 shortly before parturition from all the mothers of the hildren inluded in the study, and from all the hildren at the age of 4 months, prior to the first or seond vaination at that time, and again 1 month thereafter. Retal swabs also were taken from the hildren at the time of eah administration of vaine or plaebo. The swabs were plaed in 1.5 ml of Hank's solution ontaining 1,000 units of peniillin and 500,gg of streptomyin per ml, and were immediately frozen and held at -0 C until studied. solation of virus. Primary ultures of trypsinized rhesus-monkey kidney ells were used for both virus isolations and neutralization tests. To isolate virus, eah of four tissue-ulture tubes was inoulated with 0. ml of stool suspension from eah hild and examined daily for a period of 1 days for ytopathi effet. Fluid from any tube showing unertain ytopathi effet was subultured. Neutralization tests. Serum samples were assayed for antibodies by the following proedure. Sera were inativated at 56 C for 30 min. Then, twofold dilutions were made in isotoni saline, and 0.5 ml of eah dilution was mixed with the same volume of dilutions of eah of the three types of poliovirus ontaining approximately 100 TCD50 per 0.1 ml. These mixtures were inubated in a water bath at 37 C for 1 hr, after whih eah of four ulture tubes was inoulated with 0. ml of eah dilution. The tubes were maintained at 37 C and observed daiiy for 1 days. Essentially the same proedure was used to identify any poliovirus isolated from the retal swabs. RESULTS Effet of one dose of vaine on newborn hildren. The antibody titers of the newborn hildren were assumed to be essentially the same as their mothers', and the titers of the mothers were used to alulate the residual onentration of passive antibodies in eah hild when the seond blood sample was obtained. These alulations took into aount the half-life of maternal antibodies in a hild, aording to Martins da Silva et al. (195), whih was estimated at 37 days. All of the maternal serum samples ontained neutralizing antibodies against all three types of poliovirus, with titers ranging from 1: to 1:51 and averaging approximately 1:1. Beause passive antibody, partiularly when of high titer, onfuses.=s :rv 0 L 51,+56-4.) O 4 F <4. Type 1 4 ' 41 5:, L i 4 i 4 _ < :,154S or < Calulated Titers of Residual 4 Type a 1 16 A,% ^ &A J-0013MCCA*,4 4! 16 b' 5Z <4 ~, A A Aers.m- SE s tsaa0 f i5e 156 z Anti 4YzA44 body at 4=t CJO~~~~~~~~~~~~~~~~~~~~~~~ 4 months of Age, ; ;15651 or <16,^<16 4 5! 4 --' _ Titers of Maternal Antibody Passed at Birth 4 16 ' or FG. 1. Poliovirus antibody onversions determined 4 months after administration of living oral trivalent vaine (600,000 TCD5o) to 49 newborn hildren. a l 1, ', Type, 3

3 44 CAMPLLO-SANZ ET AL. J. BACTEROL. the determination of antigeni response, the responses of the hildren vainated at birth were not determined until they reahed the age of 4 months. A hild was onsidered to have responded to antigeni stimulation after birth if the neutralizing antibodies in his serum sample taken 4 months after vaination represented a fourfold or greater inrease over the titer alulated from his maternal antibody. The antibody responses during the first 4 months of life, by this riterion, were very muh greater in the hildren vainated at birth than in those who reeived only a plaebo. Of -the 49 vainated hildren, 44 responded to types 1 and 3, and 30 to type, whih amounted to a response of 9.% for types 1 and 3 and 61.% for type (Fig. 1). Of the 44 hildren who reeived the plaebo, only 4 (9%) aquired antibodies for types 1 and 3 and only (4.5%) for type (Fig. ). t is Jear that most of the immunologial response in the vainated hildren is attributable to the vaine, and very little to spontaneous infetion with poliovirus. ndeed, the real serologial response due to the vaine, obtained by subtrating the response of the plaebo group from that of the vainated group, omes, in round figures, to 1 % for types 1 and 3 and 57% for type. Effet of maternal antibody titer on the immunologial response of newborn hildren. The antibody responses of those hildren whose mothers had titers between 1: and 1: and of those whose mothers had titersbetween 1:1 and 1:51 were ompared. The over-all onversion of the first group (low antibody titer) was 90% and that of the high antibody titer group was 47% (Table 1). Effet of one dose of vaine at 4 months of age. For those hildren who reeived a plaebo at birth and one dose of vaine at the age of 4 months, the riterion of response was an antibody level, at 1 month after vaination, eight times the level in the prevaination blood sample. The over-all response for all three types of poliovirus was,66%: 63% to type 1, 5% to type, and % to type 3. The data for the hildren vainated at birth and those vainated at CL Type Type Type 3 &o ; ' e 1 6-4' LJ L a 3 -F <4 3 P- 5 i < < t 1- t l _ - a t, -AO% AMA AO%a eale MA-6., A A ab All!!. 9bot OA - -NEO-- -.A#% if < Z Z5654 < E5651 < a,, Calulated Titers of Residual Antibody at 4 months of Age FG.. Poliovirus antibody onversions determined 4 months after administration of plaebo to 44 newborn hildren. TABLE 1. Effet of maternal antibody titer on immunologial response of 49 newborn hildren to living oral trivalent poliovirus vaine ontaining 600,000 TCD50 of eah virus type Children responding to vaine Maternal antibody at birth Type 1 Type Type 3 Total (range) No. % No. % No. % No. % 1:-1: 3/ / / / :1-1:51 6/9 67 4/14 9 6/ /34 47

4 VOL. 4, 196 MMUNZATON WTH LVNG ORAL POLOVRUS VACCNE 449 TABLE. mmunologial responses of hildren to one dose of living trivalent polioviruis vaine ontaining 600,000 TCD5o of eah virus type fed at birth or at 4 months of age Children responding to vaine Age at Type 1 Type Type 3 Total No. N No. % No. % No. % Newborn 44/ / / / Months /44 3/ /44 7/1 66 TABLE 3. mmunologial responses of hildren vainated at birth to a seond dose of living trivalent poliovirus vaine ontaining 600,000 TCD5o of eah virus type, fed at 4 months of age Children responding to nd dose mmunologial response to Type 1 Type Type 3 Total first dose No. % No. % No. % No. % None 5/ /19 9 5/ /9 93 Responded 1/44 7 /30 7 1/44 7 6/11 4 months of age are ompared in Table. The antibody response for all three virus types was greater in the hildren vainated at birth, and signifiantly greater for type 1. Effet of a seond dose of vaine at 4 months of age on hildren vainated at birth. The riterion for evaluating responses to the seond dose was the same as that for the hildren vainated only at 4 months of age. For types 1 and 3, all of the hildren who failed to respond to the first dose responded to the seond, so that the over-all response for these two types was 100% (Table 3). For type, 17 of the 19 hildren (9%) who failed to respond to one dose responded to the seond. Retal swabs. No ytopathi agents were found in any of the retal swabs from newborn hildren, and no poliovirus was found in the swabs taken at the age of 4 months. However, 1 of the 93 hildren (3%) at that age were exreting some other ytopathi agent. Those 1 hildren inluded 10 vainated for the first time at 4 months of age, 6 of whom failed to respond to any of the three types of poliovirus vaine. Clinial findings. No reations attributable to the vaine were observed, and no ases of paralyti polio ourred among the hildren during the observation period. Breast feeding apparently had no unfavorable effet on antibody responses. DSCUSSON Administration of the living trivalent vaine to newborn hildren proved to be an effetive means of immunization against poliomyelitis, and the onveniene of this kind of vaination should be onsidered in the fight against polio in Mexio. Children vainated at birth responded better to all three types of poliovirus than hildren vainated at the age of 4 months, and signifiantly better to type 1, the ause of most paralyti polio. n the older hildren, enteri viruses may have interfered with the ation of the vaine, but the number of ases studied is too small to affirm this. All the hildren vainated at birth who failed to respond to poliovirus types 1 and 3 did respond to a seond dose of vaine, and 9% of the hildren who originally failed to respond to type responded to a seond dose. A small perentage of the hildren who responded to the first dose also responded to the seond. Thus, the first dose apparently did not result in immunologial tolerane, and, in some of the hildren infeted by the first dose, there was no loal resistane to multipliation of the vaine virus in the gut. The results obtained in this study relating to passive antibody in infants are in general agreement with the findings of other investigators (Koprowski et al., 1956; Prem, MKelvey, and

5 450 CAMPLLO-SANZ ET AL. J. BACTEROL. Fergus, 1959; Prem et al., 1960; Plotkin, Pagano, and Koprowski, 1960), inluding those who used an early antibody response, rather than the delayed one used here. Maternal antibody titers higher than 1:1, whih 3% of the mothers in this study had, definitely inhibited the responses of the hildren studied; similar observations have been made by other investigators (Plotkin et al., 1960). Therefore, the influene of high maternal antibody ertainly should be taken into aount in evaluating the results of any vaination program. n this study, it was more onvenient to obtain the maternal blood samples required to establish the passive antibody titer of the hildren by bleeding the mothers just before parturition, instead of taking samples diretly from the umbilial ord. Although previous studies have shown that the antibody titer of a newborn hild may be slightlv lower than the mother's titer (Martins da Silva et al., 195), no suh allowane was made here, and the titers of mother and infant were assumed to be the same. ACKNOWLEDGMENTS The authors express their gratitude to Salvador Beltrin for his ollaboration in the administration of the vaine and in the surveillane of the ases, as well as to Franiso Salido for his help in the writing of the manusript. LTERATURE CTED CABASSO, V. J., G. A. JERVs, A. W. MOYER, M. ROCA-GARCA, E. V. ORS, AND H. R. Cox Cumulative testing experiene with onseutive lots of oral poliomyelitis vaine. Brit. Med. J. 1: CAMPLLO-SANZ, C., J. DE MUCHA MACfAS, F. LOPEZ PNTADO, R. ZAMUDO BENDERAS,. SANCHEZ SPNDOLA, AND S. E. NAVA Estudios sobre la vauna antipoliomielitia trivalente administrada por via oral en una o dos dosis a nifios de M6xio. Bol. ofi. sanit. panam. 5: KoPROWSK, H., W. T. NORTON, K. HUMMELER, J. STOKES, D. A. HUNT, AND A. FLACK mmunization of infants with living attenuated poliomyelitis virus. J. Am. Med. Asso. 16:11-1. MARTNS DA SLVA, M., K. A. PREM, A. E. JOHN- SON, J. L. MCKELVEY, AND J. T. SYVERTON Response of pregnant women and their infants to poliomyelitis vaine. J. Am. Med. Asso. 16:1-5. PLOTKN, A. S., S. J. PAGANO, AND H. KoPROWSK Vaination of full-term infants with attenuated polioviruses. nd ntern. Conf. on live Poliomyelitis Vaines, Pan Am. Health Org., Washington, D. C., p PREM, K. A., J. L. MCKELVEY, AND J. FERGUS mmunologi response of infants under six months of age to oral trivalent poliomyelitis vaine. 1st ntern. Conf. on Live Poliomyelitis Vaines, Pan Am. Sanit. Bur., Washington, D. C., p PREM, K. A., J. W. FERGUS, J. E. MATHERS, AND J. L. MCKELVEY Vaination of pregnant women and young infants with trivalent oral attenuated live poliomyelitis vaine. nd ntern. Conf. on Live Poliomyelitis Vaines, Pan Am. Health Org., Washington, D. C., p