Controlled epidemiological study of live measles vaccines in Poland

Bull. Org. mond. Sante | 1971, 45, 331-335Bull. WldHlth Org. I~17,45 3-3 Controlled Epidemiological Study of Live Measles Vaccines in Poland POLISH MEASLES VACCINATION COMMITTEE ' Two types of live measles vaccine, the Schwarz and the L-16 vaccines, were tested in a controlled study. The control group consisted of children who were not vaccinated. Altogether 851 children were included in the trial. Observations ofclinical symptoms between the 5th and 15th days after vaccination showed that both vaccines were similar with regard to reactions, and no clinical evidence ofobjections to their use was discovered. The geometric mean antibody titres after vaccination with the Schwarz and L-16 vaccines were not significantly different (I :132 and 1: 100, respectively). Significant differences were found when the percentages of serological conversions were compared-Schwarz, 97 %; L-16, 82.9 %. The epidemiological observations were carried out for 24 months from the date of vaccination and showed that the immunogenic properties of both vaccines are similar, the Schwarz vaccine being slightly better. Both vaccines protected more than 91 % of children against measles for the period of observation. Comparative laboratory studies and controlled field trials of two live measles vaccines-Schwarz and L-16 -were carried out in Poland in 1967-69 to evaluate the post-vaccinal reactions and the efficacy of the vaccines. The latter was assayed on the basis of sero- logical response and on the results of epidemiological observation of the vaccinated children for 2 years. The results of the studies were to serve as the basis for the selection of a vaccine for a large-scale vacci- nation campaign. MATERIALS AND METHODS Vaccines The Schwarz-type vaccine prepared in chick fibro- blast culture, 32/6 D, was produced by Glaxo Labo- ratories, Greenford, Middlesex, England.2 One dose 1 General direction of the study: J. Kostrzewski and M. Kanitoch. Organization, supervision of vaccinations, and epidemiological observations: J. Berent, A. Dziok, B. Gabler, A. G6rska, D. Kozerska, M. Krajewska, M. Misiurewicz, D. Nowak-Lipiniska, H. Przestalska, A. Stoklosa, W. Szmu- ness, K. Wagner, R. Wentzel, T. Zalech, J. Zabicka. Sero- logical examination: I. Polna, D. Naruszewicz-Lesiuk, M. Wisniewski. The report was written by J. Kostrzewski, Chief, Depart- ment of Epidemiology, State Institute of Hygiene, Warsaw and D. Naruszewicz-Lesiuk, Senior Assistant, Department of Epidemiology, State Institute of Hygiene. 2 The vaccine was obtained from the World Health Organ- ization, Geneva, Switzerland. containing 103 TCD was administered subcutan- eously in a 1.0-ml amount. The L-16 vaccine3, lot No. 71, prepared in guinea- pig kidney tissue culture, was produced by the Mos- cow Research Institute of Viral Preparations. One dose containing 103 l TCD was applied subcutaneous- ly in a 0.5-ml amount. Controls The children used as controls were not vacci- nated against measles and did not receive placebo injections but they were given a simulated injection and were treated in the same way as those who were vaccinated. Organization of vaccination The studies were performed on children living in or attending day-nurseries or orphanages in Warsaw, Lodi, Bydgoszcz, and the provinces of Gdan'sk, Katowice, Lublin, Poznan', and Rzesz6w; 47.5% of the children under observation were from day nur- series and 52.5 % were from orphanages. The studies were carried out with children aged 9-36 months who had no history of measles and who showed no contraindications for vaccination. The ' The vaccine was obtained from Professor Andjaparidze, Moscow Institute for Research on Virus Preparations. 2731 - 331 - POLISH MEASLES VACCINATION COMMITTEE children were allocated at random to coded groups, the code being known only to persons performing the vaccination. The children under study were assigned numbers for identification and in order to link the results of subsequent clinical, epidemiolo- gical, and serological studies. To preserve the principle of a blind trial, vacci- nation was performed by a special team in the absence of the assistants and physicians who were to make the clinical and epidemiological observations. Observation ofpost-vaccinal reactions The children were observed for 28 days. Daily re- cords were made of the body temperature, measured in the rectum at about 16.00 hours, the presence of a skin rash (including details of type and intensity), cough, coryza, conjunctivitis, tonsillitis, and other symptoms. Serological investigations Blood for serological studies was taken twice, i.e., before and 28-30 days after vaccination. Sera were stored together at -20°C. The sera were coded so that the persons who performed the serological tests did not know from which group the children came. After all the sera had been collected, several pairs of sera were chosen at random each day for testing by the haemagglutination inhibition test. All the tests were made using the same pool of antigen. Epidemiological observations Physicians in charge of the children recorded the occurrence of measles, and contact with the disease, over a period of 24 months. If a child left the insti- tution he or she was visited and checked at home. If a child moved to another district, the observations were carried out by the appropriate Sanitary Epi- demiological Station. If, however, further obser- vations were impossible-e.g., if children were adop- ted or travelled outside the country-the actual date of the last observation was noted. Analysis of results The results were analysed statistically in three ways: (1) The comparability of the vaccinated and control groups, in terms of the age distribution and propor- tion of children with measles antibodies prior to vaccination, was tested using the x2 test. (2) The significance of the difference in reacto- genicity of the vaccines, in terms of the proportion of children with clinical symptoms, was checked using the x2 test. (3) To check the significance of the difference in efficacy of the vaccines, the antibody level after vacci- nation was tested using Student's t-test, while the significance of the difference in the percentage of children with seroconversion and in the number of children suffering from measles was tested using the x2 test. RESULTS Vaccination started on 14 September and was com- pleted on 9 November 1967; observations of the post- vaccinal reactions were completed on 8 December 1967, and the epidemiological observations were terminated on 10 November 1969. Although 851 children were tested, only 672 of them were included in the analysis, since blood sam- ples were not obtained from 38 children and measles antibodies were found in 141 of them (16 %). The distribution of the children by treatment group and by age group is shown in Table 1. The groups of children vaccinated with the Schwarz and L-16 vaccines and the controls did not differ significantly in their age and or in the percentage of children with measles antibodies before vaccination. Evaluation of serological response In the group of 235 children vaccinated with the Schwarz vaccine, no antibodies were found after vaccination in 7 children, seroconversion took place in 97 %, and the mean geometric antibody titre was 1: 132. In the group of 216 children vaccinated with L-16 vaccine, antibodies were not found after vacci- nation in 37 children, seroconversion occurred in 82.9 %, and the mean antibody titre was 1: 100. The tested groups of vaccinated children differed significantly in the percentage of seroconversion but the difference in the level of antibodies was not statis- tically significant. In the control group of 221 children, serocon- version was found in 4 children, their titres being 1: 8 (two children), 1: 16, and 1: 64. The children lived in different institutions where no contact with measles was observed. No symptoms of the disease were seen in the children during the clinical examinations. Evaluation ofpost-vaccinal reactions Children in whom no seroconversion was observed and controls with seroconversion were excluded from the analysis of the results of clinical observations. In addition, the data were not analysed if there had been a lack of continuity in the clinical observations (e.g., because of a move to another area), even if pre- 332 EPIDEMIOLOGICAL STUDY OF LIVE MEASLES VACCINES IN POLAND -U 6 z (1) cn > 1;.- o .C. CD -J 6 z 6 z Da C02 CDAC 0>a 0>- z XL -o ~0 -0 -0 cn :F CD CD 't X r CC (C 0 co N N CD 0 0 OD N _ N C) u a) 0(co 1- (6 (C)(DC)r' 't CV N '- (C) 0 Lo a) 5 CD CY) N -0 l (D (C O C o o t s c, a > 0 C z >D z 0s_ ( < 6 CY) z C:0) OC~~~~~~~~~C C 6 CU4 0 >ZN 'aDU a) 1 It (C C ~ ~ ~ ~ 0)< 7/ (C) lC) CD4 N1 0) r- D LO XC)N4 CY co N cise information was available, or if the children had contracted scarlet fever, purulent dermatitis, or other diseases during the observation period. The data on body temperature (measured in the rectum) are presented in Table 2. The highest tem- perature recorded between the 5th and 15th day after vaccination is shown. The majority of febrile reactions occurred between the 7th and the 9th day after vaccination. Temperatures between 37.8°C and 38.2°C occurred most frequently among the controls (difference statistically significant) and cannot be con- sidered as a post-vaccinal fever reaction. A rise in body temperature above 39.4°C may be regarded as a strong fever reaction and was recorded in 7.5 % of those who received Schwarz vaccine, 5.8 % of those who received L-16 vaccine, and 3.6% of the controls. No significant difference between the groups of child- ren vaccinated with different vaccines was found in the percentages having temperatures between 38.3°C and 40°C. There was, however, a significant diffe- rence between the vaccinated children and the control group in the percentages having temperatures be- tween 38.30C and 39.3°C. No difference was found in other clinical symp- toms between those who received the Schwarz vaccine and those who received the L-16 vaccine (Table 3). When the symptoms recorded in the vacci- nated and the control groups were compared, a signi- ficant difference was found in the occurrence of reddening of the throat. In addition, a significant difference was found between the L-16 vaccinated group and the controls in the occurrence of cough and conjuctivitis. In general, the percentage of chil- dren without clinical symptoms was only about 10% higher in the control group than in vaccinated chil- dren, but the difference was statistically significant. Evaluation of the efficacy based on epidemiological observations Of the 672 children included in the analysis, no information was available for 46 children and ob- servations on 73 children were terminated before the 24-month period had elapsed. To compare the re- sults of observations in vaccinated and control groups the period of observation per group was calculated in child-months. The incidence per 1 000 child- months was then calculated for the whole group and separately for children with and without serocon- version (Table 4). The incidence of measles among children who received Schwarz vaccine and those who received L-16 vaccine did not differ significantly. The proportion 333 c0a) CU c cnco Cn0) a C) .2 U) 0 CU a)0) 0 a)a) cU 0 0 0) E a) C 0 0) ._ CD V C co 0 E 0) z 0) Q) w - rn POLISH MEASLES VACCINATION COMMITTEE Table 2. Highest temperature recorded in children between the 5th and 1 5th days after vaccination Schwarz L - 1 6 No. % No. % 93 41.2 50 22.1 Control No. % 78 45.1 113 57.7 39 22.5 66 29.1 46 26.6 1 6 1 1 4.9 1 0 5.8 6 6 2.7 0 0 1 83 36.7 56 32.4 23 60 30.6 8.1 3.1 0.5 11.7 100 196 100 of protected children was slightly greater with the Schwarz vaccine (95.1 %) than with L-16 vaccine (91.4%) but the difference was not significant and should be ascribed to differences in the percentage of seroconversion found after vaccination. When only children with seroconversion are compared, the differences in the effectiveness of the two vaccines are even smaller-96.0 for Schwarz and 97.4% for L-1 6. The efficacy index indicates the number of measles cases among the controls for each case among the vaccinated children, and Table 4 shows it to be higher after administration of the Schwarz vaccine when all children are considered and higher after administration of the L-16 vaccine for those children with seroconversion. DISCUSSION AND CONCLUSIONS In spite of the rather rigid criteria of assessment, the results of the clinical observations on children vaccinated against measles show that the Schwarz and L-16 vaccines gave rise to similar post-vaccinal reactions and that there need be no reservations on clinical grounds to the use of either vaccine. The serological investigations (haemagglutination inhibition) showed that the Schwarz vaccine gave Table 3. Symptoms, except fever, most frequently found in children between the 5th and 1 5th days after measles vaccination Symptom rash cough coryza conjunctivitis sore throat Schwarz L- 16 Control No. % No. % No. % 37 56 96 41 87 no symptoms 74 no. of children included in analysis 226 16.4 24.8 42.5 18.1 38.5 32.7 29 16.8 22 47 27.2 36 85 49.1 78 39 22.5 24 66 38.2 46 11.2 18.4 39.8 12.2 23.5 57 32.9 83 42.3 173 196 Temperature ( C) 37.7 37.8-38.2 38.3-39.3 39.4-39.9 40 38.3-40.0 total 226 100 173 334 173 196 EPIDEMIOLOGICAL STUDY OF LIVE MEASLES VACCINES IN POLAND Table 4. Measles incidence in children vaccinated with Schwarz and with L-1 6 vaccines Schwarz L-1 6 Control Total Seropositive Seronegative Total Seropositive Seronegative total no. observed 207 221 216 5 198 162 36 no. observed for 24 months 191 190 185 5 172 138 34 no. contracting measles 98 (1 5 4 b 1 8 2 c 6 period of observation (no. of months x no. of children) 4785 4931 4811 120 4530 3689 841 incidence per 1000 child-months 20.48 1.01 0.83 8.33 1.76 0.54 7.13 percentage protected 95.1 96.0 59.3 91.4 97.4 65.2 index of efficacy 1 :20.3 1 :24.7 1:2.5 1 :11.6 1: 37.9 1 : 2.9 a One death from complications. b Two doubtful cases. c One doubtful case. a slightly higher rate of seroconversion than the L-16 vaccine. The epidemiological observations showed that the immunogenic properties of both vaccines were similar, the Schwarz vaccine having a slight advan- tage. Both vaccines protected more than 91% of children against measles for a period of 2 years. In view of the results of comparative studies it may be concluded that the Schwarz and L-16 vaccines both have moderate clinical reactivity and good immuno- genic properties and may be recommended for use for large-scale vaccination in this country. RESUME' ETUDE EPID1MIOLOGIQUE CONTROLtE DE VACCINS ANTIROUGEOLEUX VIVANTS, EN POLOGNE Deux vaccins antirougeoleux vivants, un vaccin de type Schwarz et le vaccin L-16, ont fait l'objet d'une etude comparative en Pologne, de 1967 a 1969. L'essai a porte sur 851 enfants ages de 9 a 36 mois, sans antecedents de rougeole, qui ont e repartis sur une base aleatoire en trois groupes: 289 ont e vaccines par le vaccin Schwarz, 284 par le vaccin L-16 et 278 (groupe temoin) n'ont pas e vaccines. Apres exclusion de 38 enfants chez lesquels les examens serologiques n'ont pu etre pratiques et de 141 enfants porteurs d'anticorps antirougeoleux avant la vaccination, l'analyse a porte sur 672 sujets. On n'a pas releve de difference significative entre les moyennes geometriques des titres d'anticorps, mesures par l'epreuve d'inhibition de l'hemagglutination, dans les groupes vaccines: 1: 132 (Schwarz) et 1: 100 (L-16). En revanche, les taux de seroconversion ont atteint 97 % avec le vaccin Schwarz et 82,9% avec le vaccin L-16. Les reactions postvaccinales, etudiees pendant 28 jours chez les sujets ayant presente une seroconversion, sont apparues avec une frequence et une intensite tres simi- laires dans les deux groupes; elles n'ont revetu aucun caractere de gravite susceptible de contre-indiquer l'em- ploi des vaccins. La proportion d'enfants sans sympt6mes cliniques durant la periode d'observation n'a e que de 10% environ plus elevee dans le groupe temoin que dans les groupes vaccines. Les observations epidemiologiques destinees a evaluer l'efficacite des vaccins ont e poursuivies pendant 24 mois. Aux fins de comparaison entre groupe temoin et groupes vaccines, l'incidence de la rougeole a e exprimee en nombre de cas par enfant-mois. Dans l'ensemble des deux groupes vaccines, on a constate des taux de protection tres voisins: 95,1 % pour le vaccin Schwarz et 91,4% pour le vaccin L-16, la difference devant ktre attribuee au taux de seroconversion plus e1eve dans le premier cas. Si l'analyse ne porte que sur les sujets ayant presente une seroconversion, le taux d'efficacit6 s'etablit a 96% pour le vaccin Schwarz et a 97,4% pour le vaccin L-16. 5 335