The Topic of This Month Vol.19 No.10(No.224)

The incidence of diphtheria in Japan has markedly been reduced owing to the wide usage of vaccination, and it seldom occurs in recent years. However, large-scale epidemics occurred in the former USSR after 1990, substantiating the importance of diphtheria surveillance and immunization.

In Japan, in compliance with the National Epidemiological Surveillance of Vaccine-Preventable Diseases, the immune status of people against diphtheria is being monitored. About 10 prefectural and municipal public health institutes (PHIs) around the country measure diphtheria antibody levels in serum samples of healthy children at ages of 0-9 years (about 1,000 samples in all) once every two or three years. The Division of Immunization Program, Infectious Disease Surveillance Center (IDSC), National Institute of Infectious Diseases (NIID) collects this data from the PHIs. The antibodies are quantitatively determined by assaying for the diphtheria toxin-neutralizing antibody (antitoxin) with cultured Vero cells on microplates (Miyamura, K. et al.: J. Biol. Standard. 2, 203-209, 1974). These surveys have confirmed that the diphtheria antitoxin prevalence among children has been kept at a very high level owing to the vaccination policy in Japan as shown below. Such attention has no doubt helped to suppress incidence of diphtheria.

1. Incidence of diphtheria and history of vaccination
In Japan, about 86,000 patients of diphtheria (about 10% of them were fatal) were reported in 1945, whereas only 33 cases including one death were reported during 1988-1997 (Fig. 1). As an example of recent outbreaks, two patients with diphtheria were found in a home for the mentally handicapped in Akita Prefecture in 1992 and Corynebacterium diphtheriae var gravis was identified from five children. The two symptomatic cases had not received any diphtheria vaccination at that time (see IASR, Vol. 14, No. 7, 1993 and p. 225 of this issue). In 1993, other two patients were reported on the basis of clinical diagnosis in Oita Prefecture; both of them had not been vaccinated.

In Japan, monovalent diphtheria vaccine (D) was adopted in 1948 for routine vaccination, followed by diphtheria-pertussis combined vaccine (DP) in 1958 and DTP supplemented with tetanus toxoid (T) in 1968. Due to the postvaccination fatal accidents due to Bordetella pertussis cell components occurring in 1975 after DTP injection, routine DTP vaccination was interrupted for three months. In 1981, an adsorbed diphtheria-tetanus-acellular pertussis (DTaP) combined vaccine (purified B. pertussis protein antigens replaced the killed B. pertussis whole cells) was introduced. In April 1995, a new Preventive Vaccination Law came into effect, and the following standard vaccination schedule was proposed. For a primary vaccination series, three doses of DTaP are to be given at 3 to 8-week intervals to infants of the age between 3 and 12 months and a booster injection 12 to 18 months after the primary series. For an additional booster, DT is to be injected once at the age of 11 to 12 years.

2. Antitoxin prevalence in response to age
The diphtheria antitoxin prevalence in response to age determined in 1980, 1988, 1994, and 1995 are shown in Fig. 2. The ratio, of possession of antitoxin of potencies higher than 0.08 IU/ml by the age group of 0-9 years, increased linearly toward the age of 3 years in every year. In 1980, the antitoxin prevalence was low at any age, which was considered to have resulted from the decreased vaccination rate after suspending routine DTP vaccination in 1975. In 1988, the antitoxin prevalence among neonates to 1-year infants was low, which was due to the vaccination starting-age at 2 years in mass vaccination during 1975-1988. The low antitoxin prevalence of 7 to 9-year old children may have been due to the low vaccination rate in the first half of 1980s. The heightened antitoxin prevalence found in 1994 and 1995 reflects the increased vaccination rate owing to the introduction of DTaP combined vaccine in 1981. In December 1988, the Ministry of Health and Welfare issued a notification that vaccination with DTaP should conform basically individual inoculation at ages over 3 months and that, even in mass vaccination, inoculation can be started at the age of 3 months. Infants in the whole country, however, restarted to receive vaccination after the revision of the Preventive Vaccination Law in April 1995. Fig. 2 shows the increased antitoxin prevalence among infants aged 0-2 years during the period between 1988 and 1995, which may reflect the increased vaccination rate of infants during this transitional period.

3. Number of doses versus antitoxin potency
The antitoxin prevalence in response to the number of doses among 930 serum samples accompanied with the records of vaccination assayed in 1994 and 1995 are shown in Fig. 3. The antitoxin potencies of those not vaccinated and vaccinated only once were mostly below 0.01 IU/ml. On the other hand, the potencies of those vaccinated twice or three times distributed with a peak at 0.32 IU/ml. The peak potency of those completing the primary series of vaccination including three doses and a booster injection was 0.64 IU/ml, and the ratio of those possessing such a high antitoxin titer as >=2.56 IU/ml was high.

The antitoxin level necessary to prevent symptomatic diphtheria used to be estimated at 0.01 IU/ml, but a recent publication states that 0.1 IU/ml or a higher level may be required for satisfactory prevention (Hasselhorn, H. M. et al., Vaccine, 16, 70-75, 1998). In the present investigation, the ratios of those having potencies higher than 0.08 IU/ml were about 81% and 87% of those having received two and three doses, respectively, and about 90% of those having completed the primary series of vaccination, viz. three doses plus a booster.

4. Antitoxin prevalence among the elderly people
The antitoxin prevalence was investigated with all age groups by the Department of Bacterial and Blood Products, NIID. The serum specimens subjected to determination totaled 467. They included 258 samples, ages ranging from neonates to 57-year-old objects collected in 1994 and stored at the Serum Reference Bank, IDSC, NIID and other 209 from middle-aged and older persons of 50 to 99-year old (provided by St. Marianna University Hospital). As shown in Fig. 4, a majority of those aged 13 to 14 years possessed high titers due to the effects of booster injection with DT vaccine. The elderly people aged 50 years or more born before the start of routine diphtheria vaccination also showed high diphtheria antitoxin prevalence. In Japan, epidemics of diphtheria were reported during and shortly after World War II. Therefore, the possession of antitoxin by elderly people may reflect the past infection. The possession of antitoxin by those people over 50 years might have also been due to persistent exposure to the toxigenic organisms that might have been existed in the community. However, this hypothesis needs further investigation for validation.

Prevention is better than cure. In the former USSR, as many as 125,000 diphtheria patients were found with more than 4,000 deaths during the six-year period from 1990 to 1995. These cases accounted for about 90% of all diphtheria cases in the world during the same period (WHO, WER, 71, No. 33, 245, 1996). In the former USSR, the epidemics are coming to an end by strengthening vaccination. It is recommended that young people who are travelling abroad and have no history of diphtheria vaccination should be inoculated prior to departure.

If diphtheria is exterminated from Japan, physicians who are capable of diagnosing diphtheria and the laboratory techniques to isolate and identify C. diphtheriae will also be concluded. To establish adequate systems for clinical diagnosis, etiological diagnosis and therapeutic care for diphtheria, a manual for risk management of diphtheria is being edited in cooperation with NIID, PHIs and clinicians.

idsc-query@nih.go.jp

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