Abstract

The massive diphtheria epidemic in the former Soviet Union provides important lessons for all diphtheria immunization programs: It is important to achieve a high level of childhood immunization, maintain immunity against diphtheria in older age groups, and use anti-epidemic measures, including immunization, to control epidemics in the early phase. The immunization coverage among children should be at least 90%. Further studies are needed to elaborate the most effective strategy to maintain immunity against diphtheria in adults (periodic booster doses, immunization of selected age groups in health care settings, use of Td [tetanus-diphtheria toxoids with reduced diphtheria toxoid content] vaccine instead of monovalent tetanus toxoid whenever tetanus toxoid is indicated [e.g., in treatment of wounds or in school-based immunization programs]). Efforts should be undertaken to monitor diphtheria immunity in different groups by conducting age-specific serologic studies.

The epidemic of diphtheria in the Newly Independent States (NIS) of the former Soviet Union is the largest outbreak in the developed world in recent years and was considered by the World Health Organization (WHO) as an international public health emergency [1–4]. Since the epidemic began, >150,000 cases and 4500 deaths, representing >90% of all diphtheria cases reported worldwide during 1990–1995, have been reported to the WHO Regional Office for Europe [5].

The NIS epidemic provides three important lessons for diphtheria immunization programs. These lessons are related to childhood immunization, the need for maintaining immunity in older age groups, and the use of immunization in controlling epidemics. These three issues are discussed herein.

The Importance of Childhood Immunization

Analysis of the NIS diphtheria epidemic suggests that the potential for severe outbreaks of diphtheria is enhanced when a large proportion of susceptible adults and unimmunized children coexist in the same community. In the mid-1970s, the incidence of diphtheria among children in Russia was very low, with the lowest number of cases (52–57) registered in 1975–1976. Then, in the mid-1980s, the incidence began to increase, especially in preschool-aged children. The changes were clearly seen in Moscow, where the epidemic started (figure 1).

Figure 1

Incidence of diphtheria per 100,000 population, by age—Moscow, 1980, 1985, and 1990. Data from the Ministry of Health.

During the 1980s, changes in the immunization schedule in the former Soviet Union encouraged less intensive immunization of children [3]. By 1992, the epidemic was characterized by an increased incidence in all age groups, with the peak incidence in 5- to 10-year-old children and 30- to 50-year-old adults [2, 4]. This paralleled a country-wide drop in infant immunization coverage: During the late 1980s and the early 1990s, the reported coverage with a primary series of diphtheria toxoid–containing vaccine among 1-year-old children and with booster doses varied between 60% and 80% (table 1). However, in many urban areas, including Moscow and St. Petersburg, the diphtheria immunization coverage rates in infants were very low (range, 18%–59%) [7–10]. The drop in coverage was due to decreased public support for the childhood vaccination program, a vocal anti-immunization movement, and insufficiently motivated and improperly trained health care workers, especially at the primary health care level. An excessive list of contraindications named >50 specific diagnoses that precluded the administration of the diphtheria-tetanus toxoids-pertussis (DTP) vaccine [11], and a long list of permanent and temporary contraindications to immunization was used by specialists who are consultants for vaccination and who delayed immunization of children for long periods [6].

Table 1

Percentage of diphtheria vaccination coverage in various age groups, Russian Federation. 1989–1994.

% coverage

Age, years 1989 1990 1991 1992 1993 1994
1 82.7 68.5 69.1 72.6 79.2 88.1
3 77.2 77.3 74.6 81.3 83.0 97.5
10 86.0 87.5 88.1 88.3 92.4 98.9
14 84.8 68.6 81.7 86.0 92.4
16 83.4 80.1 86.5 97.1
% coverage

Age, years 1989 1990 1991 1992 1993 1994
1 82.7 68.5 69.1 72.6 79.2 88.1
3 77.2 77.3 74.6 81.3 83.0 97.5
10 86.0 87.5 88.1 88.3 92.4 98.9
14 84.8 68.6 81.7 86.0 92.4
16 83.4 80.1 86.5 97.1

NOTE. According to Narkevich and Tymchakovskaya [6].

Table 1

Percentage of diphtheria vaccination coverage in various age groups, Russian Federation. 1989–1994.

% coverage

Age, years 1989 1990 1991 1992 1993 1994
1 82.7 68.5 69.1 72.6 79.2 88.1
3 77.2 77.3 74.6 81.3 83.0 97.5
10 86.0 87.5 88.1 88.3 92.4 98.9
14 84.8 68.6 81.7 86.0 92.4
16 83.4 80.1 86.5 97.1
% coverage

Age, years 1989 1990 1991 1992 1993 1994
1 82.7 68.5 69.1 72.6 79.2 88.1
3 77.2 77.3 74.6 81.3 83.0 97.5
10 86.0 87.5 88.1 88.3 92.4 98.9
14 84.8 68.6 81.7 86.0 92.4
16 83.4 80.1 86.5 97.1

NOTE. According to Narkevich and Tymchakovskaya [6].

The general public lost confidence in immunization due to opinions of health care workers and to increasing and aggressive antivaccination propaganda in the mass media. In addition, large cohorts of children (up to 50%) were immunized with Td vaccine (tetanus-diphtheria toxoids vaccine with a reduced content of diphtheria compared with that in DTP) instead of DTP vaccine, due to unjustified overestimation of vaccine complications.

The diphtheria epidemic than began in Ukraine in 1992 has also been attributed to a significant decrease in immunization coverage in children [12]. The experiences of two of Russia's neighbors, Poland and Finland, provide another example of the importance of high immunization coverage among children. In these two countries, very high levels (>95%) of childhood immunization against diphtheria have been maintained for a long period. In Poland, despite a high influx of visitors from infected areas (Belarus, Ukraine, and Russia) and visits of Polish citizens to epidemic areas in the NIS, only 25 cases of diphtheria, mostly in young adults, with no secondary transmission were reported from 1992 to 1996 [13, 14]. In Finland, there was no secondary transmission of infection despite documented reports of disease importations [15].

Need for Maintenance of Immunity against Diphtheria among Older Age Groups

The gap in diphtheria immunization of adults is well documented in industrialized countries (table 2) [22–26], and it is important to close this gap with well-spaced booster doses of diphtheria toxoid. However, the routine use of such booster doses remains a controversial issue. Many countries recommend life-long immunization of adults with booster doses of diphtheria toxoid-containing vaccine at intervals of 10–20 years. A routine booster dose of Td vaccine is recommended every 10 years in many countries, including Australia [27], Canada [28], Germany [29], Italy [29], Austria [30], and the United States [31]. Td vaccine is recommended in adults in NIS countries and in Bulgaria (at 25 and 35 years of age) [32]. Several European countries have added extra doses of diphtheria toxoid-containing vaccines in their school-based immunization programs and for travelers [29]. A study in Denmark suggested that long-term protection may be assured by a booster dose of Td vaccine administered 20 years after primary immunization [33]. In 1989–1990, on the basis of sero-surveys indicating low antibody levels in persons >40 years of age [29], Finland initiated a mass vaccination campaign targeted at adults.

Table 2

Percentage of persons immune to diphtheria, by age, in various European countries, 1989–1997.

Age, years Belgiuma Denmarka Germanyb Italya Lithuaniaa Swedena United Kingdomc
<10 95.0 90 100
10–19 90.4 72.2 100 92.5 98 83 74
20–29 67.3 90 85.0 98 83 74
30–39 42.1 95 46.2 46 47 68
40–49 44.5 87 57.5 46 47 68
50–59 68.6 65 66.7 46 53 68
60–64 50 61.5 53 57
⩾65 57.4 53 57
Population studied General surgery, trauma, and emergency ward patients Military recruits Healthy blood donors and surgical patients Healthy persons Military personnel Medical staff Diagnostic samples, residuals
Reference Mathei et al., 1997 [16] Aggerbeck et al., 1995 [17] Klouche et al., 1995 [18] Wirz et al., 1995 [19] Rix et al., 1994 [20] Bjorkholm et al., 1989 [21] Miller et al., 1994 [22]
Age, years Belgiuma Denmarka Germanyb Italya Lithuaniaa Swedena United Kingdomc
<10 95.0 90 100
10–19 90.4 72.2 100 92.5 98 83 74
20–29 67.3 90 85.0 98 83 74
30–39 42.1 95 46.2 46 47 68
40–49 44.5 87 57.5 46 47 68
50–59 68.6 65 66.7 46 53 68
60–64 50 61.5 53 57
⩾65 57.4 53 57
Population studied General surgery, trauma, and emergency ward patients Military recruits Healthy blood donors and surgical patients Healthy persons Military personnel Medical staff Diagnostic samples, residuals
Reference Mathei et al., 1997 [16] Aggerbeck et al., 1995 [17] Klouche et al., 1995 [18] Wirz et al., 1995 [19] Rix et al., 1994 [20] Bjorkholm et al., 1989 [21] Miller et al., 1994 [22]
a

% ofpersons with titers >0.01IU/mL as determined bytissue culture neutralization test.

b

% of persons with titers >0.01 IU/mL as determinedby ELISA.

c

% of personswith titers >0.1 IU/mLas determined by ELISA.

Table 2

Percentage of persons immune to diphtheria, by age, in various European countries, 1989–1997.

Age, years Belgiuma Denmarka Germanyb Italya Lithuaniaa Swedena United Kingdomc
<10 95.0 90 100
10–19 90.4 72.2 100 92.5 98 83 74
20–29 67.3 90 85.0 98 83 74
30–39 42.1 95 46.2 46 47 68
40–49 44.5 87 57.5 46 47 68
50–59 68.6 65 66.7 46 53 68
60–64 50 61.5 53 57
⩾65 57.4 53 57
Population studied General surgery, trauma, and emergency ward patients Military recruits Healthy blood donors and surgical patients Healthy persons Military personnel Medical staff Diagnostic samples, residuals
Reference Mathei et al., 1997 [16] Aggerbeck et al., 1995 [17] Klouche et al., 1995 [18] Wirz et al., 1995 [19] Rix et al., 1994 [20] Bjorkholm et al., 1989 [21] Miller et al., 1994 [22]
Age, years Belgiuma Denmarka Germanyb Italya Lithuaniaa Swedena United Kingdomc
<10 95.0 90 100
10–19 90.4 72.2 100 92.5 98 83 74
20–29 67.3 90 85.0 98 83 74
30–39 42.1 95 46.2 46 47 68
40–49 44.5 87 57.5 46 47 68
50–59 68.6 65 66.7 46 53 68
60–64 50 61.5 53 57
⩾65 57.4 53 57
Population studied General surgery, trauma, and emergency ward patients Military recruits Healthy blood donors and surgical patients Healthy persons Military personnel Medical staff Diagnostic samples, residuals
Reference Mathei et al., 1997 [16] Aggerbeck et al., 1995 [17] Klouche et al., 1995 [18] Wirz et al., 1995 [19] Rix et al., 1994 [20] Bjorkholm et al., 1989 [21] Miller et al., 1994 [22]
a

% ofpersons with titers >0.01IU/mL as determined bytissue culture neutralization test.

b

% of persons with titers >0.01 IU/mL as determinedby ELISA.

c

% of personswith titers >0.1 IU/mLas determined by ELISA.

The strategy of spaced boosters has not been effectively implemented in any country. Routine decennial booster doses of Td vaccine for adults are difficult to monitor, and usually this strategy is only marginally effective. An alternative approach could be an immunization strategy that would be age-specific for ages at which people often contact health care providers (e.g., at 20 and 50 years of age). The choice of strategy depends on multiple local conditions and can be done only at the country level. In countries where the risk of diphtheria is considered high, periodic booster doses for adults will be indicated to prevent the resurgence of diphtheria in adults as immunity wanes. In other countries, adult diphtheria booster strategies need to be considered in the light of the perceived risk of diphtheria, the opportunities that exist for provision of booster vaccinations, and the sensitivity of surveillance so that rapid responses can be implemented should diphtheria be introduced.

In the United States, there was a debate on the appropriate frequency of tetanus immunization in adults [34–37]. It was argued that the current recommendation to give Td vaccine every 10 years throughout adulthood has failed and may not be cost effective [34, 35]. It was proposed to forsake decennial boosters in favor of a policy of including a single booster at age 65 along with other recommended health procedures reserved for that age group [34]. However, the analysis was limited to tetanus and did not include diphtheria toxoid policy. There are essential differences between these two models: Tetanus has now become a geriatric disease, while, as we learned from the diphtheria epidemic in the NIS, 30- to 50-year-old persons are at high risk for diphtheria. In 1993, the Advisory Committee on Immunization Practices (ACIP) reviewed the current status of tetanus and diphtheria in the United States and evaluated four options for vaccine use: (1) a single adult booster vaccine at age 65 years; (2) two adult booster vaccine doses, given at 15 and 55 years of age; (3) adult booster vaccine doses given every 20 years; and (4) no change from the current recommendations with decennial booster doses. The ACIP endorsed option 4 [37].

One strategy can be helpful in maintaining immunity against diphtheria in adults: Td vaccine can be used instead of monovalent tetanus toxoid whenever tetanus toxoid is indicated (e.g., in treating wounds or in school-based programs for administering booster doses of tetanus toxoid) [32, 38], and it can be used in high-risk groups likely to be exposed to diphtheria infection and identified by age, geographic distribution, or profession (e.g., health care, military, or school personnel and students, alcohol and drug abusers, and persons traveling to areas where diphtheria is endemic or epidemic).

On the basis of available data, at least 70% of adults who receive a booster dose of diphtheria toxoid (Td vaccine) respond with a protective level of diphtheria antibodies [39]. Similar results were obtained in studies done in adults in Odessa, Russia, and Kiev, Ukraine, with Td vaccine containing 2–5 limit of flocculation units of diphtheria toxoid [5].

The Use of Immunization to Control the Epidemic

The NIS epidemic was unexpected for local health authorities, who denied the existence of the epidemic during the first years, 1990–1992. The delay in undertaking rapid and adequate anti-epidemic measures during the early stages of the epidemic, when it was “localized,” was one of the factors influencing the extent and duration of the epidemic. The epidemic could have been stopped more easily and more quickly if control measures had been implemented earlier. The epidemic was declared such in 1993, when the number of cases exceeded 15,000 and the infection had spread over vast areas [6].

The importance of rapid anti-epidemic actions was shown in the epidemic of diphtheria among adults in Hubei Province, China [40]. A rapid immunization campaign with one dose of diphtheria toxoid was conducted during 2 months and covered 75% of persons >7 years of age (102,376/136,530 total population). After a vaccination campaign, diphtheria transmission declined rapidly.

During the last 4 years, intensified efforts were undertaken in the Russian Federation and other NIS to control the diphtheria epidemic. Countries adopted a strategy for one dose of vaccine to be administered in the shortest possible period of time to all children, adolescents, and adults, regardless of individual immunization histories. As a modification to this strategy, specific age cohorts with low levels of immunity (e.g., 30- to 50-year-old adults) received a full 3-dose primary series of Td vaccine. The list of medical contraindications to vaccination was reexamined and shortened, immunization schedules were revised, and the mass media were more widely used for spreading information about the epidemic and about the need for vaccination. Most NIS countries have made strenuous efforts to improve early diagnosis and treatment of cases. By the end of 1995 in the Russian Federation, 70%–80% of adults (⩾18 years of age) had had at least one dose of vaccine, compared with an estimated 20% coverage in 1990. The reported nationwide coverage with a primary series of diphtheria toxoid among 12- to 23-month-old children was 92.7% in 1995 [1]. The total number of vaccinated persons increased from 11.7 million in 1992 to 20.2 million (including 13.6 million adults) in 1993 and to 37.7 million (29.6 million adults) in 1994 [6].

Lessons Learned from the Diphtheria Epidemic

The return of epidemic diphtheria throughout the NIS after >30 years of successful control and the spread of infection to many European countries and Mongolia provides important lessons for diphtheria immunization programs:

  • The achievement of high immunization coverage (>90% of the population) with a primary series of three doses of DTP vaccine is of utmost importance. A primary course should start soon after birth, preferably at 2 months of age, and respect the minimal interval of 4 weeks between doses. The primary course should be completed before 6 months of age. For the primary immunization, only a full-strength pediatric-type of diphtheria vaccine (administered as DTP) should be used.

  • The use of a fourth dose of DTP vaccine in preschool-age children is recommended in countries that have achieved high coverage with the primary series. The age for a fourth dose should be selected after a careful analysis of the age distribution of cases of diphtheria, pertussis, and tetanus in a given area. Usually, it is given between 12 and 36 months of age. The immunization coverage with this dose should also exceed 90%. The need for an additional booster (fifth) dose of DTP vaccine should be assessed by individual national programs.

  • Immunization of school-aged children is recommended. For children immunized in infancy with DTP or DT (diphtheria-tetanus toxoids) vaccines, a booster dose is recommended when they enter and, preferably, when they leave school. In children <7 years of age, DT vaccine should be used, and in older children, Td vaccine is indicated.

  • Countries that have successfully controlled diphtheria through infant and childhood immunization programs should maintain immunity against diphtheria in adults by the use of Td vaccine (or d vaccine, an adult-type monovalent diphtheria toxoid for persons with a high immunity against tetanus). The choice of strategies depends on local conditions; Td vaccine can be given as periodic booster doses every 10–20 years, or the selected strategy can be age-specific for ages at which people are in contact with health care providers. Periodic booster doses are indicated in countries where the risk of introducing diphtheria is considered high. The maintenance of immunity against diphtheria in adults can be facilitated by using Td vaccine instead of monovalent tetanus toxoid vaccine when tetanus toxoid is indicated in the treatment of wounds and by wider use of Td vaccine in high-risk groups (e.g., military and health care personnel, kindergarten and school teachers, students, and drug and alcohol abusers).

  • In the face of the diphtheria epidemic, anti-epidemic measures should be undertaken rapidly and without delay, when transmission of Corynebacterium diphtheriae organisms is limited to specific organizational groups. The strategy that proved effective in the NIS epidemic was mass immunization of the entire population with at least one dose of diphtheria toxoid–containing vaccine, regardless of the previous immunization history, and two additional doses for specific age groups with low-level immunity (e.g., 30- to 50-year-old adults).

  • Special efforts should be undertaken to monitor diphtheria immunity in different groups by conducting age-specific serologic studies. In countries where diphtheria is successfully controlled and where there are no diphtheria cases, results of serologic testing are important for assessing the risk of diphtheria. In countries where diphtheria cases are still being reported, changes in age distribution of cases and trends in diphtheria incidence are useful factors for assessing the risk. In NIS countries, serologic testing was being excessively relied upon as a means of routine monitoring in each oblast (region). Given the cost and the staff time required, serologic testing should be reserved as a tool for specially designed and carefully executed studies aimed at identifying gaps in immunity in certain age groups.

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Immunization against diphtheria with special emphasis on immunization of adults
Vaccine
1996
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14
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845
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57
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40
Youwang
Y
Jioanming
D
Yong
X
Pong
Z
Epidemiological features of an outbreak of diphtheria and its control with diphtheria toxoid immunization
Int J Epidemiol
1992
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21
 (pg. 
807
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11
)

Author notes

a

Deceased.