Abstract

Prior to the completion of this and other studies, low effectiveness of diphtheria toxoid-containing vaccine was suspected to be a major contributing factor to the diphtheria epidemic that began in the Russian Federation in 1990. A vaccine effectiveness study was done in Moscow by enrolling physician-diagnosed cases and 10 control subjects per case. Controls were matched to cases by age (±3 months) and clinic registration. Vaccination history was abstracted from a standardized form for case-patients and from clinic vaccination records for control subjects. Two hundred seventeen case-patients and 2169 matched controls were included in the study. Most controls (92%) had received three or more doses of a diphtheria toxoid vaccine, compared with 72% of case-patients. The vaccine effectiveness for three or more doses was 97% (95% confidence interval: 94.3–98.4). Low vaccine effectiveness was not a contributing factor to the diphtheria epidemic in the Russian Federation. To control and prevent diphtheria epidemics, it is necessary to achieve and maintain high vaccination coverage with three or more doses of diphtheria toxoid among adults and children.

Following decades of good diphtheria control, a major outbreak of respiratory diphtheria began in Russia in 1990 [1]. The causes for the outbreak were unknown, but hypotheses included increased susceptibility in the population due to low vaccination coverage with diphtheria toxoid-containing vaccines among children, lack of routine boosters for adolescents and adults, or low vaccine efficacy; other factors, such as crowding and migration, that facilitated spread; or a combination of host, agent, and environmental factors [2].

In 1993, a case-control study of vaccine effectiveness was done to address concerns about the potency of the Russian diphtheria toxoid-containing vaccines. This study was performed in collaboration with the Moscow City Sanitary-Epidemiologic Service to examine the effectiveness of the Russian-manufactured diphtheria toxoid-containing vaccines in preventing diphtheria cases among children 6 months to 14 years of age.

Methods

A case-control study design was used to estimate effectiveness of a primary series and booster doses of diphtheria toxoid vaccine. A case of diphtheria was defined as a physician-diagnosed illness with signs and symptoms compatible with respiratory diphtheria (e.g., low-grade fever and sore throat) and laboratory isolation of a toxigenic strain of Corynebacterium diphtheriae or as a physician-diagnosed illness with signs and symptoms compatible with respiratory diphtheria, including the presence of a pseudomembrane in the upper respiratory tract that did not have another apparent cause. Reported diphtheria cases in persons 6 months to 14 years old who lived in Moscow and who had illness onset in 1991 or 1992 were included in the study. Ten control subjects were matched to each case-patient by age (±3 months) and geographically by the clinic where health care services had been sought (in Russia, children were assigned to received health care at a given clinic on the basis of their residence location). Data were abstracted from a standardized form that was routinely used by the Russian public health case investigators to collect date of birth, culture results, outcome, and dates of vaccination on each case-patient. Date of birth and vaccination history for control children were obtained from clinic immunization records.

From 1980 to 1986, children were vaccinated according to one of two recommended vaccination schedules: (1) Children received three doses of diphtheria and tetanus toxoids and whole cell pertussis vaccine (DTP) or the pediatric formulation of diphtheria and tetanus toxoids (DT) by age 12 months, a fourth dose by age 2 years, and a booster dose at school entry (age 5–6 years), or (2) they received an alternate schedule of two doses of reduced-content diphtheria vaccine (Td) by age 12 months, a third dose of Td by age 2 years, and a booster dose at school entry. In 1986, the recommended age for the booster was changed to 9 years because of serologic evidence demonstrating persistence of protective levels of antibody [3].

In our analysis, we did not differentiate between DTP, DT, and Td doses but counted all doses of diphtheria toxoid that were recorded. For both case and control subjects, immunizations with diphtheria toxoid-containing vaccines were counted as valid if the first dose was given ⩾42 days after birth, if ⩾28 days had elapsed between doses, and if the last dose was administered ⩾14 days before the onset of disease. Conditional logistic regression was used to estimate the overall diphtheria toxoid vaccine effectiveness. Vaccine effectiveness was also calculated for each dose by age group and by incremental effectiveness of booster doses (i.e., four or more doses).

Results

During 1991 and 1992, 319 respiratory diphtheria cases among children aged 6 months to 14 years were identified from 106 clinics in Moscow and reported to local public health officials. Of these, 17 (5%) occurred among children who were not assigned to a polyclinic, and 85 (27%) were not included in our study because of staff limitations in identifying control subjects and reviewing vaccination records. The age distribution and geographic distribution of study case-patients was similar to that of case-patients not included in the study. Thus, 217 (68%) of the 319 cases and their 2169 matched controls were included in the study. Among the 216 case-patients for whom outcome and culture results were available, 6 (3%) died and 213 (99%) had positive culture results for C. diphtheriae. Of these 213 cases, 188 (88%) were biotype gravis and 25 (12%) were biotype mitis.

In general, control subjects had received more doses of diphtheria toxoid vaccine than had case subjects. Among subjects 0–2 years of age, 63% of controls had received three or more doses, compared with 32% of case-patients. Among subjects 3–5 years of age, 91% of controls had received three or more doses, compared with 42% of case-patients, and among children 6–14 years of age, 96% of controls had received three or more doses, compared with 77% of case-patients (table 1). By 2 years of age, 69% of control subjects had received three doses of diphtheria toxoid, and by 6 years of age, 94% of controls had received at least three doses (figure 1).

Table 1

Number (%) of case and control subjects, by age, who had received one to six doses of diphtheria toxoid-containing vaccine by the date of diphtheria onset in the case-patient—Russian Federation, 1991–1992.

 Dose no. 
 
 
Age (years) 
0–2        
Case 14 (63) 1 (5) 0 (0) 7 (32) 0 (0) — — 
Control 20 (9) 16 (7) 45 (21) 120 (56) 15 (7) — — 
3–4        
Case 18 (42) 2 (2) 5 (12) 10 (23) 8 (19) — — 
Control 6 (1) 8 (5) 23 (5) 115 (27) 275 (64) — — 
6–14        
Case 16 (10) 3 (2) 2 (1) 39 (17) 64 (42) 25 (16) 3 (2) 
Control 14 (1) 10 (1) 29 (2) 257 (17) 747 (49) 388 (25) 80 (5) 
 Dose no. 
 
 
Age (years) 
0–2        
Case 14 (63) 1 (5) 0 (0) 7 (32) 0 (0) — — 
Control 20 (9) 16 (7) 45 (21) 120 (56) 15 (7) — — 
3–4        
Case 18 (42) 2 (2) 5 (12) 10 (23) 8 (19) — — 
Control 6 (1) 8 (5) 23 (5) 115 (27) 275 (64) — — 
6–14        
Case 16 (10) 3 (2) 2 (1) 39 (17) 64 (42) 25 (16) 3 (2) 
Control 14 (1) 10 (1) 29 (2) 257 (17) 747 (49) 388 (25) 80 (5) 
Figure 1

Levels of diphtheria vaccine coverage among control subjects (n = 2169) by dose and age, Russian Federation, 1991–1992

Figure 1

Levels of diphtheria vaccine coverage among control subjects (n = 2169) by dose and age, Russian Federation, 1991–1992

The overall vaccine effectiveness of three or more doses of diphtheria toxoid-containing vaccine compared with no doses was 96.9% (95% confidence interval [CI]: 94.3–98.4). Vaccine effectiveness increased with increasing number of doses, from 89% for one dose to 99% for five to six doses (table 2).

Table 2

Effectiveness of diphtheria toxoid-containing vaccine by number of doses received and age group, compared with zero doses received—Russian Federation, 1991–1992.

 Vaccine effectiveness (%) (95% confidence interval) by age group 
 
 
Dose 0–2 years 3–5 years 6–14 years Overall 
93.3 (31.8–99.4) 85.5 (-20.3–98.3) 79.7 (0.7–95.9) 89.0 (67.5–96.3) 
100 91.3 (63.0–98.0) 95.6 (76.0–99.2) 95.9 (89.3–98.5) 
97.2 (86.3– 99.4) 96.1 (87.4–98.8) 89.5 (73.0–95.9) 94.9 (90.2–97.4) 
100 99.1 (96.6–99.8) 94.7 (86.5–97.8) 97.8 (95.7–98.9) 
5–6 — — 97.9 (94.1–99.2) 99.0 (97.7–99.6) 
 Vaccine effectiveness (%) (95% confidence interval) by age group 
 
 
Dose 0–2 years 3–5 years 6–14 years Overall 
93.3 (31.8–99.4) 85.5 (-20.3–98.3) 79.7 (0.7–95.9) 89.0 (67.5–96.3) 
100 91.3 (63.0–98.0) 95.6 (76.0–99.2) 95.9 (89.3–98.5) 
97.2 (86.3– 99.4) 96.1 (87.4–98.8) 89.5 (73.0–95.9) 94.9 (90.2–97.4) 
100 99.1 (96.6–99.8) 94.7 (86.5–97.8) 97.8 (95.7–98.9) 
5–6 — — 97.9 (94.1–99.2) 99.0 (97.7–99.6) 

Booster doses helped to protect children against diphtheria. Case-patients 3–5 years of age were 4.3 times more likely than controls to have received only three instead of four doses (95% CI: 1.5–12.1; P = .006). Similarly, among subjects 6–14 years of age, the odds ratio for receipt of three doses compared with four doses was 2.0 (95% CI: 1.3–3.1; P = .002). Among subjects 6–14 years of age, the odds ratio for receipt of four doses compared with five or more doses was 2.5 (95% CI: 1.4–4.6; P = .003).

Discussion

Our findings suggest that Russian-manufactured diphtheria toxoid-containing vaccines were highly effective in preventing diphtheria and that low vaccine effectiveness was not a primary cause of the diphtheria epidemic in Russia. We found a vaccine effectiveness rate of 97% for the Russian-produced diphtheria toxoid-containing vaccines for three or more doses, compared with zero doses, among children 6 months to 14 years of age in Moscow during 1991 and 1992. This estimate is consistent with that of an earlier preliminary study in Ukraine [4]. Prior to this study, few studies had examined the vaccine effectiveness of diphtheria toxoid since widespread use began in the 1950s in developed countries, and no controlled clinical trials were done to evaluate vaccine efficacy before licensure. During a diphtheria outbreak in Texas in 1971, the vaccine effectiveness for preventing a case of diphtheria was estimated to be 97% among fully vaccinated school-age children compared with nonvaccinated children [5]. After an outbreak in Canada in 1942, the vaccine effectiveness among persons of all age groups was estimated to be 85% [6]. Following a diphtheria outbreak in the Yemen Arab Republic, the vaccine effectiveness for receipt of three doses of DTP was estimated at 87% [7]. In 1945 in England and Wales, the vaccine effectiveness among children <15 years of age was 96% against death and 71% against disease [8].

An important finding of this study, which was subsequently confirmed by a later study, was that receipt of booster doses helps to prevent respiratory diphtheria among children of school age [3]. In Russia in 1996, Vitek et al. [3] documented the beneficial effect of a booster dose administered at school entry; case-patients 6–8 years of age were 2.8 times more likely than control subjects to have received only four doses, compared with five doses, of diphtheria toxoid.

Inadequate population immunity due to low levels of vaccination among children and adults in Russia likely was an essential permissive factor in the Russian diphtheria epidemic. The number of diphtheria cases only began to decline late in 1995 after high coverage levels were achieved among both children and adults [2]. Increasing coverage and immunity levels in the population help to stop an epidemic by both protecting the individual and by decreasing transmission of C. diphtheriae [5]. This decrease in transmissibility likely occurs because case-patients, in contrast to carriers, may be more likely to transmit the organism due to a higher bacterial load. Therefore, a decline in cases by increasing coverage and immunity is likely to accelerate the demise of an epidemic. In addition, among highly vaccinated populations, toxigenic strains may lose their selective advantage and decrease in frequency [9].

The high vaccine effectiveness of only one dose of diphtheria toxoid suggests that reported vaccination histories may have been incomplete for those children who were documented as having received only one dose. These children may, in actuality, have received more doses. However, there was no evidence that cases and controls enrolled in the study differed from those not in the study by the quality of their documentation of vaccination. Although such misclassification may artificially inflate the vaccine effectiveness estimate for one dose, it was not likely to affect the overall vaccine effectiveness estimate for receipt of three or more doses. Due to limited resources, we could not try to ascertain potential confounding factors, such as household exposure to C. diphtheriae. In a study done in the Republic of Georgia in 1995–1996, lack of vaccination was found to be the largest risk factor for diphtheria; exposure to an infected person was the second largest risk factor [10].

In this study, 17 cases were not included because the children did not have an assigned polyclinic in Moscow (they were nomadic Gypsy children); these cases were excluded because control subjects had been chosen on the basis of their clinic registration. The excluded case-children had lower coverage levels than enrolled cases (data not shown), suggesting that coverage levels were lower among some populations in Russia. However, the case fatality rate (3%) of enrolled case subjects was similar to the rate for cases who were not enrolled (3%) and to that reported nationally [2]. In general, surveillance data from Russia indicates that among children, diphtheria was relatively mild and death was infrequent, which is in contrast to diphtheria among adults 40–49 years old, the age group that experienced the highest proportion of severe disease and death [2, 8].

The diphtheria epidemic in the Russian Federation and other Newly Independent States (NIS) of the former Soviet Union where control of diphtheria had been achieved prior to the epidemic underscores the importance of age-appropriate vaccination for receipt of the primary series as well as for booster doses for prevention of diphtheria among both children and adults. Vaccine coverage rose with institution of aggressive outbreak-control measures by Russian public health authorities, and the outbreak has come under control. Although the factors that allowed the occurrence of this outbreak and others in the NIS are not completely understood, it is likely that high population immunity achieved by vaccination coverage with three or more doses among both children and adults would have prevented the epidemic. With inadequate population immunity, diphtheria can again emerge as an epidemic disease.

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Author notes

Study results were based on national reportable surveillance data from diphtheria cases and review of nationally notifiable clinic vaccination records for matched control subjects; therefore, no informed consent was obtained for the study.
Financial support: CDC.
a
Current affiliation: Division of HIV/AIDS Prevention—Surveillance and Epidemiology, National Center for HIV, STD, and TB Prevention, CDC, Atlanta, Georgia.
b
Deceased.