Diphtheria Toxoid Vaccine Effectiveness: a Case-Control Study in Russia

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Diphtheria Toxoid Vaccine Effectiveness: A Case-Control Study in Russia

Kristine M. Bisgard,1 Philip Rhodes,2,a 1Epidemiology and Surveillance Division and 2Data Management Iain R. B. Hardy,1,b Irina L. Litkina,3 Division, National Immunization Program, Centers for Disease 3 3 4 Control and Prevention, Atlanta, Georgia; Moscow City Center Nikolai N. Filatov, Anatoly A. Monisov, 4 1 for Sanitary-Epidemiologic Surveillance and Ministry of Health, and Melinda Wharton Moscow, Russian Federation Downloaded from https://academic.oup.com/jid/article/181/Supplement_1/S184/840264 by guest on 30 September 2021 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 months) and clinic registration. Vaccination history was 3ע) were matched to cases by age 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 out- Methods break of respiratory diphtheria began in Russia in 1990 [1]. The causes for the outbreak were unknown, but hypotheses A case-control study design was used to estimate effectiveness included increased susceptibility in the population due to low of a primary series and booster doses of diphtheria toxoid vaccine. vaccination coverage with diphtheria toxoid–containing vac- A case of diphtheria was defined as a physician-diagnosed illness cines among children, lack of routine boosters for adolescents with signs and symptoms compatible with respiratory diphtheria and adults, or low vaccine efficacy; other factors, such as crowd- (e.g., low-grade fever and sore throat) and laboratory isolation of ing and migration, that facilitated spread; or a combination of a toxigenic strain of Corynebacterium diphtheriae or as a physician- diagnosed illness with signs and symptoms compatible with res- host, agent, and environmental factors [2]. piratory diphtheria, including the presence of a pseudomembrane In 1993, a case-control study of vaccine effectiveness was in the upper respiratory tract that did not have another apparent done to address concerns about the potency of the Russian cause. Reported diphtheria cases in persons 6 months to 14 years diphtheria toxoid–containing vaccines. This study was per- old who lived in Moscow and who had illness onset in 1991 or formed in collaboration with the Moscow City Sanitary- 1992 were included in the study. Ten control subjects were matched months) and geographically by 3ע) Epidemiologic Service to examine the effectiveness of the to each case-patient by age Russian-manufactured diphtheria toxoid–containing vaccines the clinic where health care services had been sought (in Russia, in preventing diphtheria cases among children 6 months to 14 children were assigned to received health care at a given clinic on the basis of their residence location). Data were abstracted from a years of age. standardized form that was routinely used by the Russian public health case investigators to collect date of birth, culture results, Study results were based on national reportable surveillance data from outcome, and dates of vaccination on each case-patient. Date of diphtheria cases and review of nationally notifiable clinic vaccinationrecords birth and vaccination history for control children were obtained for matched control subjects; therefore, no informed consent was obtained from clinic immunization records. for the study. From 1980 to 1986, children were vaccinated according to one Financial support: CDC. a Current affiliation: Division of HIV/AIDS Prevention—Surveillance of two recommended vaccination schedules: (1) Children received and Epidemiology, National Center for HIV, STD, and TB Prevention, three doses of diphtheria and tetanus toxoids and whole cell per- CDC, Atlanta, Georgia. tussis vaccine (DTP) or the pediatric formulation of diphtheria and b Deceased. tetanus toxoids (DT) by age 12 months, a fourth dose by age 2 Reprints or correspondence: Dr. Kristine M. Bisgard, Centers for Disease Control and Prevention, Mailstop E-61, 1600 Clifton Road NE, Atlanta, years, and a booster dose at school entry (age 5–6 years), or (2) GA 30083 ([email protected]). they received an alternate schedule of two doses of reduced-content diphtheria vaccine (Td) by age 12 months, a third dose of Td by The Journal of Infectious Diseases 2000;181(Suppl 1):S184±7 ᭧ 2000 by the Infectious Diseases Society of America. All rights reserved. age 2 years, and a booster dose at school entry. In 1986, the rec- 0022-1899/2000/18102S-0029$02.00 ommended age for the booster was changed to 9 years because of JID 2000;181 (Suppl 1) Diphtheria Toxoid Vaccine Effectiveness in Russia S185

Table 1. Number (%) of case and control subjects, by age, who had not assigned to a polyclinic, and 85 (27%) were not included received one to six doses of diphtheria toxoid–containing vaccine by in our study because of staff limitations in identifying control the date of diphtheria onset in the case-patient—Russian Federation, 1991–1992. subjects and reviewing vaccination records. The age distribution and geographic distribution of study case-patients was similar Dose no. to that of case-patients not included in the study. Thus, 217 Age (years) 012 3 4 5 6 (68%) of the 319 cases and their 2169 matched controls were 0–2 included in the study. Among the 216 case-patients for whom

Case 14 (63) 1 (5) 0 (0) 7 (32) 0 (0) — — Downloaded from https://academic.oup.com/jid/article/181/Supplement_1/S184/840264 by guest on 30 September 2021 Control 20 (9) 16 (7) 45 (21) 120 (56) 15 (7) — — outcome and culture results were available, 6 (3%) died and 3–4 213 (99%) had positive culture results for C. diphtheriae. Of Case 18 (42) 2 (2) 5 (12) 10 (23) 8 (19) — — these 213 cases, 188 (88%) were biotype gravis and 25 (12%) Control 6 (1) 8 (5) 23 (5) 115 (27) 275 (64) — — 6–14 were biotype mitis. Case 16 (10) 3 (2) 2 (1) 39 (17) 64 (42) 25 (16) 3 (2) In general, control subjects had received more doses of diph- Control 14 (1) 10 (1) 29 (2) 257 (17) 747 (49) 388 (25) 80 (5) theria toxoid vaccine than had case subjects. Among subjects 0–2 years of age, 63% of controls had received three or more serologic evidence demonstrating persistence of protective levels of doses, compared with 32% of case-patients. Among subjects antibody [3]. 3–5 years of age, 91% of controls had received three or more In our analysis, we did not differentiate between DTP, DT, and doses, compared with 42% of case-patients, and among children Td doses but counted all doses of diphtheria toxoid that were 6–14 years of age, 96% of controls had received three or more recorded. For both case and control subjects, immunizations with doses, compared with 77% of case-patients (table 1). By 2 years diphtheria toxoid–containing vaccines were counted as valid if the first dose was given у42 days after birth, if у28 days had elapsed of age, 69% of control subjects had received three doses of between doses, and if the last dose was administered у14 days diphtheria toxoid, and by 6 years of age, 94% of controls had before the onset of disease. Conditional logistic regression was used received at least three doses (figure 1). to estimate the overall diphtheria toxoid vaccine effectiveness. Vac- The overall vaccine effectiveness of three or more doses of cine effectiveness was also calculated for each dose by age group diphtheria toxoid–containing vaccine compared with no doses and by incremental effectiveness of booster doses (i.e., four or more was 96.9% (95% confidence interval [CI]: 94.3–98.4). Vaccine doses). effectiveness increased with increasing number of doses, from 89% for one dose to 99% for five to six doses (table 2). Booster doses helped to protect children against diphtheria. Results Case-patients 3–5 years of age were 4.3 times more likely than During 1991 and 1992, 319 respiratory diphtheria cases controls to have received only three instead of four doses (95% among children aged 6 months to 14 years were identified from CI: 1.5–12.1;P=.006 ). Similarly, among subjects 6–14 years 106 clinics in Moscow and reported to local public health of- of age, the odds ratio for receipt of three doses compared with ficials. Of these, 17 (5%) occurred among children who were four doses was 2.0 (95% CI: 1.3–3.1;P=.002 ). Among subjects

Figure 1. Levels of diphtheria vaccine coverage among control subjects (n=2169 ) by dose and age, Russian Federation, 1991–1992 S186 Bisgard et al. JID 2000;181 (Suppl 1)

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 1 93.3 (31.8–99.4) 85.5 (Ϫ20.3–98.3) 79.7 (0.7–95.9) 89.0 (67.5–96.3) 2 100 91.3 (63.0–98.0) 95.6 (76.0–99.2) 95.9 (89.3–98.5)

3 97.2 (86.3– 99.4) 96.1 (87.4–98.8) 89.5 (73.0–95.9) 94.9 (90.2–97.4) Downloaded from https://academic.oup.com/jid/article/181/Supplement_1/S184/840264 by guest on 30 September 2021 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)

6–14 years of age, the odds ratio for receipt of four doses 1995 after high coverage levels were achieved among both chil- compared with five or more doses was 2.5 (95% CI: 1.4–4.6; dren and adults [2]. Increasing coverage and immunity levels P=.003). 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- Discussion patients, in contrast to carriers, may be more likely to transmit Our findings suggest that Russian-manufactured diphtheria the organism due to a higher bacterial load. Therefore, a decline toxoid–containing vaccines were highly effective in preventing in cases by increasing coverage and immunity is likely to ac- diphtheria and that low vaccine effectiveness was not a primary celerate the demise of an epidemic. In addition, among highly cause of the diphtheria epidemic in Russia. We found a vaccine vaccinated populations, toxigenic strains may lose their selec- effectiveness rate of 97% for the Russian-produced diphtheria tive advantage and decrease in frequency [9]. toxoid–containing vaccines for three or more doses, compared The high vaccine effectiveness of only one dose of diphtheria with zero doses, among children 6 months to 14 years of age toxoid suggests that reported vaccination histories may have in Moscow during 1991 and 1992. This estimate is consistent been incomplete for those children who were documented as with that of an earlier preliminary study in Ukraine [4]. Prior having received only one dose. These children may, in actuality, to this study, few studies had examined the vaccine effectiveness have received more doses. However, there was no evidence that of diphtheria toxoid since widespread use began in the 1950s cases and controls enrolled in the study differed from those not in developed countries, and no controlled clinical trials were in the study by the quality of their documentation of vacci- done to evaluate vaccine efficacy before licensure. During a nation. Although such misclassification may artificially inflate diphtheria outbreak in Texas in 1971, the vaccine effectiveness the vaccine effectiveness estimate for one dose, it was not likely for preventing a case of diphtheria was estimated to be 97% to affect the overall vaccine effectiveness estimate for receipt among fully vaccinated school-age children compared with of three or more doses. Due to limited resources, we could not nonvaccinated children [5]. After an outbreak in Canada in try to ascertain potential confounding factors, such as house- 1942, the vaccine effectiveness among persons of all age groups hold exposure to C. diphtheriae. In a study done in the Republic was estimated to be 85% [6]. Following a diphtheria outbreak of Georgia in 1995–1996, lack of vaccination was found to be in the Yemen Arab Republic, the vaccine effectiveness for re- the largest risk factor for diphtheria; exposure to an infected ceipt of three doses of DTP was estimated at 87% [7]. In 1945 person was the second largest risk factor [10]. in England and Wales, the vaccine effectiveness among children In this study, 17 cases were not included because the children !15 years of age was 96% against death and 71% against disease did not have an assigned polyclinic in Moscow (they were no- [8]. madic Gypsy children); these cases were excluded because An important finding of this study, which was subsequently control subjects had been chosen on the basis of their clinic confirmed by a later study, was that receipt of booster doses registration. The excluded case-children had lower coverage helps to prevent respiratory diphtheria among children of levels than enrolled cases (data not shown), suggesting that school age [3]. In Russia in 1996, Vitek et al. [3] documented coverage levels were lower among some populations in Russia. the beneficial effect of a booster dose administered at school However, the case fatality rate (3%) of enrolled case subjects entry; case-patients 6–8 years of age were 2.8 times more likely was similar to the rate for cases who were not enrolled (3%) than control subjects to have received only four doses, com- and to that reported nationally [2]. In general, surveillance data pared with five doses, of diphtheria toxoid. from Russia indicates that among children, diphtheria was rel- Inadequate population immunity due to low levels of vac- atively mild and death was infrequent, which is in contrast to cination among children and adults in Russia likely was an diphtheria among adults 40–49 years old, the age group that essential permissive factor in the Russian diphtheria epidemic. experienced the highest proportion of severe disease and death The number of diphtheria cases only began to decline late in [2, 8]. JID 2000;181 (Suppl 1) Diphtheria Toxoid Vaccine Effectiveness in Russia S187

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