Pertussis vaccine in Japan

Transcription

1 J Infect Chemother (1999) 5: Japan Society of Chemotherapy 1999 REVIEW ARTICLE Tatsuo Kato Pertussis vaccine in Japan Received: June 23, 1999 / Accepted: July 7, 1999 Abstract Acellular pertussis vaccine has been developed and marketed in Japan since 1981, and has been used periodically, combined with diphtheria and tetanus toxoids in the form of an APDT vaccine. The acellular pertussis vaccines are manufactured, authorized, and used in Japan. The present report will briefly describe their clinical efficacy for immunization. Introduction In Japan, pertussis is legally designated as a communicable disease which must be reported to the authorities, and in fact it constitutes an extremely important infectious disease from the public health standpoint, in view of the fact that the incidence among infants and young children is relatively high. Severe cases develop with particularly high frequency during the early phase of infancy, and fatal cases still occur. Vaccines have for long been known to possess prophylactic efficacy with respect to this disease, and whole cell vaccines prepared from phase I Bordella pertussis organisms are widely employed for this purpose. Concomitantly with the widespread use of such vaccines, the number of pertussis cases in Japan has been decreasing yearly. As indicated in Fig. 1, in 1971, the vaccine immunization rate was 50%, and 270 cases were reported, representing 0.26 cases per population. This was the world s lowest pertussis morbidity. However, in 1975, accidents attributed to immunization with whole cell pertussis- Diphtheria-Tetanus conbined (WPDT) vaccine occurred, whereupon the Japanese government temporarily suspended periodic immunization with WPDT. Three months later, in view of the importance of pertussis, diphtheria, tetanus (PDT) vaccine, the government re- T. Kato ( ) Department of Pediatrics, St. Marianna University School of Medicine, Yokohama City Seibu Hospital, Yazashi-cho, Asahi-ku, Yokohama , Japan Tel sumed periodic immunization, with the prescribed age for primary inoculation raised from the previously designated 3 months to 2 years. However, owing to this raising of the statutory immunization age, as well as reports of immunization accidents, the PDT vaccine acceptance rate dropped sharply, to 13% in 1975, and to just 9% in Meanwhile, the development of partially purified PDT vaccines, characterized by decreased reactogenicity, was pursued in Japan, primarily by a group under the direction of Yuji Sato of the Japanese National Institute of Health. Figure 1 shows the incidence of pertussis among the total population of Japanese children up to 5 years of age for each year from 1947 to 1991, while Fig. 2 shows the corresponding data for the population up to 9 years of age from 1950 to The changes in Japanese legal and administrative provisions relating to pertussis immunization are indicated in Table 1. During 1981, acellular pertussis vaccines were developed by six Japanese companies or research institutes, were approved by the authorities, and were adopted for use in periodic APDT inoculations. Acellular pertussis vaccines developed in Japan As indicated in Table 2, acellular pertussis vaccines are produced by six Japanese manufacturers. The common feature of these six vaccines consists in the removal of endotoxins from B pertussis cells and the retention, as principal components, of PT (pertussis toxin) and FHA (filamentous hemagglutinin), now internationally regarded as the necessary antigens for pertussis vaccines. The vaccine manufactured by the Chiba Serological Institute (Chiba-Kessei) contains PT and FHA at a ratio of 1:1, as well as a small quantity of agglutinogen (AGG). The vaccines manufactured by Takeda Chemical Industries (Takeda) contain PT and FHA at a ratio of 1:9, as well as small quantities of AGG and Pertactin. The vaccine produced by the Osaka University Research Institute for Microbial Diseases (Biken) contain PT and FHA at a ratio of 1: 1 and no other antigens. The vaccine

2 186 manufactured by the Kitasato Institute (Kitasato) contains PT and FHA at an approximate ratio of 1: 4, as well as Pertactin and a small quantity of AGG. Finally, the Denka Seiken (Denka) vaccine contain PT and FHA at a ratio of 1:4, in addition to AGG and Pertactin. The vaccines produced by Chiba Kessei, Biken, Takeda, Kitasato, and Denka are manufactured by a similar process, and belong to the category of first-generation vaccines, so called by Professor C.D. Cherry of the United States. 2 On the other hand, in the vaccine produced by the Chemo- Sero-Therapeutic Research Institute, the PT and FHA are separated and their relative proportions can be varied arbitrarily. This product belongs to the category that Professor Cherry refers to as second-generation vaccines. The currently marketed products of this vaccine contain PT and FHA at a ratio of 1 :4, and no other antigens. Efficacy of the respective acellular pertussis vaccines Since physicians in Japan can arbitrarily select any of the vaccines produced by these six manufacturers, the market shares of the said vaccines range from 10% to 30%, and consequently the assessment of their respective efficacy is difficult. As shown by Fig. 1, pertussis morbidity in Japan has been progressively diminishing since immunization with APDT has commenced. Hence, the overall trend throughout Japan suggests that all six of these APDT vaccines are effective. For the purpose of ascertaining the individual efficacies of these vaccines, the present author has selected districts Table 1. Changes in Japanese legal provisions and administrative recommendations pertaining to pertussis immunization Year Legal provisions and administrative recommendations Fig. 1. Total annual number of pertussis cases in children up to 5 years of age reported to Japanese government, in relation to Japanese legal provisions and governmental recommendations. DP, Diphtheria pertussis vaccine; WPDT, whole cell pertussis-diphtheria-tetanus conbined vaccine; APDT, acellular pertussis, diphtheria, tetanus vaccine; M, age in months; Y, age in years Changes in Japanese legal and administrative provisions relating to pertussis immunization schedules 1958 Periodic immunization with combined diphtheria and pertussis (DP) was designated as mandatory from 3 months of age DP was replaced by a triple vaccine (combined with tetanus toxoid; DPT) for periodic immunization Owing to fatal post-inoculation accidents, the use of pertussis vaccine was suspended for approximately 3 months, and was susperseded by the use of a combined DT vaccine Periodic immunization using PDT vaccine was prescribed for children aged 2 years or above A pertussis vaccine with improved composition was approved, and was incorporated into an acellular pertussis vaccine combined with DT toxoids (APDT) for primary immunization of children from 3 months to 4 years of age. Immunization of children above 2 years of age was recommended Governmental authorities recommended immunization at the earliest feasible time, preferably prior to 2 years of age, as well as immunization at private clinics in place of mass immunization as far as possible. Table 2. Composition of acellular pertussis vaccines produced by various manufacturers in Japan PT µg PN/ml FHA µg PN/ml Pertactin µgpn/ml AGG µg PN/ml Total protein µgpn/ml Chiba Serological Institute The Chemo-Sero-Therapeutic Trace ( ) Research Institute Takeda Chemical Industries Osaka University Research Not detected Not detected 12.0 Institute for Microbial Diseases Kitasato Institute Not detected Denka Seiken Present Present PT, Pertussis toxin; FHA, filamentons hemagglutinin; AGG, agglutinogen; PN, pertactin

3 187 where one of the said vaccines has been used for at least 90% of the immunizations, and attempted to determine the efficacy on the basis of the vaccine immunization rate and the pertussis morbidity. Fig. 2. Incidence of pertussis among the total population of Japanese children up to 4 years of age (dots, continuous lines) and up to 9 years of age (dots, dashed lines) during each year from 1950 to 1990 Figure 3 shows the temporal changes in PDT vaccine immunization rate and pertussis morbidity in Osaka, where Biken s vaccine (manufactured by the Osaka University Research Institute for Microbial Diseases) which contains a 1:1 PT-to-FHA ratio, are used almost exclusively owing to its production in that locality. The corresponding data for Kumamoto prefecture refers to the second-generation vaccine manufactured by the Chemo-Sero Therapeutic Research Institute, which is located in that Prefecture. The corresponding data for Kawasaki city refer only to the vaccines manufactured by Takeda Chemical Industries (with a PT-to-FHA ratio of 1: 9). The vaccine is used for pertussis immunizations. Finally, the corresponding data for Chiba city refer only to the vaccine manufactured by Chiba Kessei. The subjects immunized were children less than 5 years of age, numbering approximately to in Osaka city, approximately to in Kumamoto prefecture, to in Kawasaki city, and in Chiba city. Figure 4, shows the number of reported pertussis cases and the PDT immunization rate in each district during the period 1971 through The PDT immunization schedule is indicated below the Fig. In each of the districts considered, the incidence of pertussis has increased concomitantly with decreased immunization rates. From 1981 onward, the prophylactic immunization rate has risen gradually, and this has been followed by a trend toward reduced numbers of pertussis cases; in particular, almost no cases of pertussis have been reported from Kawasaki city and Kumamoto prefecture, where the immunization rate has exceeded 80%. On the other hand, in Osaka city, although the number of pertussis cases reported has also diminished concomitantly with rising immunization rates, the immunization rate is somewhat low as compared with the other districts, and, accordingly, a comparatively greater number of pertussis cases have been reported from Osaka city. Fig. 3. Complete primary pertussis immunization rate in various districts in relation to Japanese legal provisions and governmental recommendations. Osaka city, closed circles, ; Kumamoto prefecture, crosses, ; Kawasaki city, open circles, ; Chiba city, open triangles,

4 188 Fig. 4. Number of reported pertussis cases and proportion of children having completed primary pertussis immunization in respective districts, in relation to Japanese legal provisions and governmental recommendations. Closed circles, Osaka city; crosses, Kumamoto prefecture; open circles, Kawasaki city; open triangles, Chiba city Similarly, Figure 4 shows the number of reported pertussis cases and the APDT vaccine immunization rates in Chiba city, where the APDT manufactured by the Chiba Serological Institute is almost exclusively used. The trend in Chiba city, where the immunization rate is comparatively high and yet a substantial rate of pertussis cases still occur, reflects on the practice of that city s inoculation of children only above the age of 2 years through mass immunization. Discussion As mentioned above, APDT was introduced in Japan in the year 1981, and the use of this vaccine has effectively curbed the prevalence of pertussis. Also, although this has not been mentioned in the above presentation, grave adverse reactions associated with the use of APDT have not been observed. However, local reactions, such as edema, erythema, and induration, have occurred more frequently than expected, and such reactions tend to become more pronounced with each successive re-inoculation. Local reactions following the third inoculation in the primary immunization schedule are observed in approximately 50% of cases, irrespective of the variety of APDT vaccine used for immunization. The reason for this phenomenon is still obscure. The number of pertussis cases has diminished since the introduction of APDT in Japan, and judging from the results of the above-described survey, there exist no great differences in efficacy among the individual varieties of vaccine. Furthermore, the fact that pertussis cases are still reported in districts where the immunization rate has not exceeded 80% suggests that inadequate immunization rates constitute a major cause of the persistent incidence of the disease. According to the data of Kimura, 3 the prevalence of pertussis among children immunized with APDT ranges from about 1.0% to 1.9%. In 1981, the Japanese Ministry of Public Welfare introduced a surveillance system for communicable diseases. The purpose of this system is to promptly identify seasonal outbreaks of contagious diseases and monitor them. Approximately 2000 physicians throughout the nation are designated as informants, and each week throughout the year these physicians report to the Ministry of Public Welfare on the number of cases of designated communicable diseases encountered in the course of their practice. According to the data obtained by this surveillance system, the total annual incidence of pertussis in Japan currently ranges from 1000 to 2000 cases, but since many actively practicing physicians are not designated under this system, the true current incidence of pertussis is probably even greater. Nevertheless, as shown by Fig. 5, the surveillance system data do indicate that the incidence of pertussis in Japan is steadily decreasing, and the surveillance data for each of the various individual regions in the nation also display the same trend. Thus, the results obtained by this system also appear to

5 189 Fig. 5. Pertussis incidence rate for respective years and seasons according to data of Japanese National Surveillance System Table 3. Status of APDT immunization Japan in 1992 Annually scheduled Annually implemented Rate of number of number of implementation immunizations immunizations 80.3% Comparison of ages of mass immunized and privately immunized groups Mass Immunization Private Immunization 2 Years 2 Years 2 Years 2 Years 35.6% 13.5% 0.7% 50.3% Data from Research group on Reactogenicity of prophylactic inoculations. Ministry of Public Health, and Welfare Japan 4 confirm that currently used APDT vaccines have effectively curbed the spread of pertussis. On the other hand, the period from 3 months to 4 years of age is recommended for primary APDT immunization in Japan. However, although these immunizations may be performed either through mass immunization or at private clinics, in 1988 the Ministry of Public Welfare re-recommended that private individual immunization be effected whenever possible and at the earliest feasible age. Table 3 shows the status of APDT immunization in Japan during the year 1992, according to data reported by Isomura 4 for the Research Group on Adverse Immunization Reactions, sponsored by the Ministry of Public Health and Welfare, Japan. According to these data, the overall APDT vaccine immunization rate for Japan during the year 1992 was 80.3%. Comparing the immunization ages for mass and for private immunization, one observes that immunization at ages 2 years or above was predominant in mass immunization, whereas almost all private immunization was performed at ages below 2 years. Therefore, the fact that pertussis during the first 2 years of life is associated with severe morbidity, as well as the fact that 98% of those immunized with APDT vaccine do not develop clinical pertussis, suggests that the Ministry of Public Welfare will hereafter recommend private immunization as far as possible to children under 1 year of age. Conclusions 1. The Japanese manufactured APDT used for immunization since the year 1981 has effectively curbed the incidence of pertussis in Japan. 2. Although the compositions of the said acellular vaccines differ according to the individual manufacturer, all are of nearly equal efficacy. 3. With a view to even more effective prevention of pertussis in Japan, immunization should preferably be performed before the age of 2 years, and if possible, at about 6 months of age. References 1. Sato Y, Kimura M, Hukumi H. Development of pertussis component in Japan. Lancet 1984;I: Cherry JD. Report of the task force on pertussis and pertussis immunization Pediatrics 1988;81(Suppl): Kimura M. Epidemiology of pertussis in Japan. Workshop on acellular pertussis vaccine. Bethesda, Maryland,1986: Isomura S. Report of the research group on prophylactic inoculation. 1992:1 15.