Immunogenicity and Reactogenicity of the Adult Tetanus–Diphtheria Vaccine. How Many Doses Are Necessary?

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Epidemiol. Infect. (2001), 127, 451–460. # 2001 Cambridge University Press DOI: 10.1017\S095026880100629X Printed in the United Kingdom

Immunogenicity and reactogenicity of the adult tetanus–diphtheria vaccine. How many doses are necessary?

" " " # $ J.M. BAYAS *, A. VILELLA , M.J. BERTRAN , J. VIDAL , J. BATALLA , % $ M.A. ASENJO  L.L. SALLERAS

" Adult Vaccination Center, Preentie Medicine Department, UASP IDIBAPS, ClıTnic Hospital, Barcelona, Spain # Microbiology Department, ClıTnic Hospital, Barcelona, Spain $ Directorate of Public Health, Department of Public Health and Social Security, Generalitat of Catalonia % Technical and Quality Management, ClıTnic Hospital, Barcelona, Spain

(Accepted 25 July 2001)

SUMMARY The immunogenicity and reactogenicity of the tetanus–diphtheria adult type vaccine was compared in two groups: group I (n l 201, 18–30 years old, presumably vaccinated with the DTP vaccine) and group II (n l 147, & 45 years old, without vaccination antecedents). Before vaccination, the seroprotection levels for tetanus were 90n5% (group I) and 30n6% (group II). These rose to 99n5% and 81n7%, respectively, after administration of one vaccine dose. For diphtheria, prevaccination seroprotection levels were 38n3% (group I) and 19n0% (group II). These rose to 85n8% and 65n7%, respectively, after vaccination. The logistic regression analysis showed an association between antibody titre and age. In group II, 3 doses of Td vaccine were needed to reach titres similar to those achieved in group I with a single dose. Stated reactogenicity was greater in: young subjects, women, those with higher titres of tetanus antibodies and those receiving other vaccines simultaneously. These results conﬁrm the need for vaccination schedules adapted to the characteristics of each population age-group.

made mandatory in 1964 (DTP at age 3, 5, 7 and 18 INTRODUCTION months and 4–6 years). In 1967, tetanus vaccination Throughout history, there have been various secular of servicemen was introduced, and in 1998, adult cycles of diphtheria, from the so-called ‘‘garrotillo’’ in tetanus–diphtheria (Td) vaccination. The last two Spain at the end of the 16th century to the outbreaks indigenous cases of diphtheria in Spain were recorded during 1990–8 in Russia, the Ukraine and other in 1986 [4]. countries of the former USSR [1, 2] in which 157000 The reduction in the circulation of toxigenic strains cases and 4000 deaths were oﬃcially reported, mainly of Corynebacterium diphtheriae, the result of child- in adults and adolescents. In developed countries, the hood vaccination [5], makes exposure to natural disease was almost eliminated at the end of the 1970s boosters diﬃcult, thus contributing to an increase in thanks to systematic paediatric vaccination. In Spain, susceptibility to diphtheria. At the same time, better severe outbreaks were registered during the Civil War conditions of hygiene help to slow down the cir- (4000 deaths in 1939) and the immediate post-war culation of the strains responsible for the cutaneous period [3]. Systematic paediatric vaccination was forms of the disease, favouring the appearance of population groups, basically young adults, where the * Author for correspondence: Mandri 62, At 2a 08022 Barcelona, Spain. majority do not possess protective antibodies [6–8].

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This has been shown by various recent studies in Italy vaccines administered annually) of a university hos- [8–11], France [12], Spain [13–16], Germany [17, 18] pital over a period of almost 3 years (May 1995 to and the United Kingdom [19]. Although the major March 1998). The study protocol was approved by the epidemic in East European countries has been in Clinical Research Ethics Committee of the Hospital remission since 1996 [20], more than 7000 cases were Clinic, Barcelona, Spain. After written informed reported in 1997 and more than 2500 in 1998 [2]. consent was obtained, subjects in whom the Td Various neighbouring countries have reported vaccination was indicated (subjects not vaccinated in imported cases [21]. the 10 preceding years with the Td vaccination or the With respect to tetanus, vaccination programmes, monovalent anti-tetanus vaccination) and who agreed together with aseptic measures, have reduced the to participate in the study, were included. The vaccine notified incidence of the disease to less than 0n2 cases used was the combined adult tetanus–diphtheria per 100000 inhabitants\year in developed countries. vaccine with a 0n5 ml dose containing 40 IU of tetanus In this group of countries, one of the highest rates of toxoid and 4 IU of diphtheria antitoxin, adsorbed incidence is in Spain, where in recent years, around 50 in 1n5 mg of aluminium hydroxide (0n5mg of cases are reported annually, most of them in people AIjjj) and 0n01% of thiomersal as preservative over 60 years and in males. Sixty-six percent of those (Smith Kline Beecham Biologicals, Risenxart, affected have never been vaccinated, and 30% are Belgium). The vaccination was administered by deep ignorant of their vaccination history [22, 23]. The intramuscular injection in the deltoid muscle. situation in Spain with respect to tetanus is far from Two groups were established. Group I included satisfactory. Although there have been few subjects between 18 and 30 years of age, corre- population-based seroepidemiological studies on the sponding to the birth cohorts of 1965–80, that is, prevalence of tetanus antibodies, the available in- subjects presumed to be previously vaccinated with formation shows a low level of protection [24]. the DTP vaccine (paediatric vaccination became The high levels of susceptibility to tetanus and mandatory in Spain in 1964). This group was given a diphtheria have two main causes. Firstly, the de- single dose of Td vaccine as a booster dose. In velopment of immunity against these diseases, es- addition, levels of tetanus and diphtheria antibodies pecially in the case of tetanus is fundamentally were measured immediately after and 1 month after vaccine-based, as the natural infection does not confer the dose was given. Group II included subjects of 45 immunity [25]. Secondly, even in many developed years and over corresponding to birth cohorts anterior countries where levels of vaccination coverage with to 1953 who stated they had not received previous the DTP vaccine in the infant population are high diphtheria or tetanus vaccinations. This group [26], the absence of periodic revaccination during received 3 doses of Td vaccine at 0, 1 and 6 months, adulthood means that many people become sus- which was considered as primovaccination. In ad- ceptible to tetanus and diphtheria again, emphasizing dition blood samples were taken at 0, 1, 6 and 7 the need for vaccination strategies against both months in order to determine levels of tetanus and diseases in accordance with WHO recommendations diphtheria antibodies. In both groups and for each [27]. dose, the possible simultaneous administration of The Td vaccine is indicated in subjects over 7 years, other vaccinations and their type was investigated. both for primovaccination and revaccination. In Other inclusion criteria were good health according Spain this vaccine has been available since 1995 [13]. to the clinical history and the physical examination The aim of this study was to determine the immuno- given at inclusion and, in the case of fertile women, genicity (how many doses are necessary) and the the expressed intention of not becoming pregnant reactogenicity of the Td vaccine, both in subjects during the study period. Exclusion criteria were: (1) A assumed to have been vaccinated and in those not history of significant and persistent problems in- previously vaccinated against these diseases. volving the haematologic, hepatic, renal, cardiovascu- lar or respiratory systems. (2) Acute illness at entry into the study. (3) Chronic pharmacological treat- METHODS ment, including any immunosuppressive drug which A prospective non-randomized study was carried out might interfere with the response to the vaccine and in subjects who attended, for whatever reason, the (4) A history of hypersensitivity which could be Adult Vaccination Centre (23000 doses of different stimulated by any component of the vaccine.

Antibodylevelsweredeterminedbyenzymoimmuno- RESULTS analysis (BINDAZYME, Binding-Site for tetanus and VIROTECH, System-Diagnostika for diphtheria), Three hundred and forty-eight subjects were included Seroprotection was defined as antibody titres equal or in the study: 201 in group I (age 24n3p3n3 years, range greater than 0n1IU\ml. When using neutralization 18–30 years, 30n7% males) and 147 in group II (age techniques, these levels correspond to absolute sero- 55n4p7n7 years, range 45–79 years, 44n4% males). A protection [28]. The correlation between the results complete follow-up was possible in 91% (183\201) obtained with these techniques and those obtained subjects in group I and in 69n4% (102\147) subjects in with ELISA would be low for titres ! 0n1IU\ml, as group II. the ELISA technique could overestimate the result In group I, at the time of administration of the Td [29, 30]. dose, a total of 609 doses of other vaccines were The reactogenicity of each dose of vaccine (clinical administered simultaneously: 152 hepatitis B, 105 signs and symptoms) was measured by information hepatitis A, 89 typhoid (87 oral and 2 parenteral), 47 registered by vaccinated subjects on cards supplied by IPV, 12 rabies and 2 meningococcal A–C, resulting in the researcher. During days 0–3 general symptoms an average of 2n0p1n0 doses for each dose of Td. Only were noted: axillary temperature, severe headache, 2n5% of subjects received only the Td vaccine. In discomfort, fatigue, nausea and vomiting and others. group II, the dose of Td was administered sim- Fever was considered to a temperature above 38 mC. ultaneously with the following other vaccines: (a) 166 Local signs recorded were: pain at the injection site, together with the first dose of Td: 105 typhoid (100 redness and swelling. oral and 5 parenteral), 40 IPV, 8 hepatitis B, 4 General symptoms and local pain were measured meningococcal A–C, 3 influenza and 2 each of rabies, according to the following scale: 0 l Absent, l l hepatitis A and pneumococcal, with an average of Mild (the adverse reaction did not significantly 1n1p0n8 doses for each dose of Td. 20n5% of cases interfere with normal life), 2 l Moderate (some received only Td vaccine. (b) 14 together with the changes, which were not considered dangerous for the second dose of Td: 9 hepatitis B, 2 rabies and 1 each subject), 3 l Severe (significant changes in general of oral typhoid, IPV and hepatitis A; an average of state or incapacity, which were considered dangerous 0n1p0n3 doses; 90n8% of subjects received only Td to the subject’s health). vaccine. (c) 10 together with the third dose of Td: 6 The statistical analysis was carried out using the hepatitis B, 2 influenza and 1 each of IPV and SPSS computer programme. The association between hepatitis A, an average of 0n1p0n3 doses for each dose antibody levels and the categorical variables (age and of Td, with 93n8% of subjects receiving only the Td gender) and between the number and type of reported vaccine. adverse reactions and the categorical variables (age, # gender, order of dose) was established using the χ test. The association between pre- and postvaccination Prevalence of seroprotection before and after titres was measured by McNemar’s test. A logistical vaccination. Immunogenicity regression analysis was carried out to control the Tetanus presence of possible confounding factors and included all the variables which could be associated with the Table 1 shows the seroprotection prevalence for factor studied. The presence or absence of tetanus and tetanus (titres & 0n1IU\ml) in the pre-vaccination diphtheria antibodies were used as dependent and post-vaccination tests made for each group. variables and age and gender, in the case of pre- Before vaccination, the prevalence of seroprotection vaccination antibody levels, as independent variables. against tetanus in groups I and II was 90n5% # In the reactogenicity analysis, the presence or absence (182\201) and 30n6% (45\147) respectively [χ l of a local reaction and of a general reaction were 131n85, P ! 0n001]. In each of the groups the preva- considered as dependent variables and age, gender, lence was slightly higher in males than females, the number of doses of other vaccines administered although the differences were not statistically simultaneously and the anterior level of tetanus and significant. In group I, 1 month after administration diphtheria antibodies as independent variables. The of one dose of Td vaccine, seroprotective levels were adjusted odds ratios and the 95% confidence intervals detected in 99n5% (182\183) subjects [McNemar, were calculated. P ! 0n0001 with respect to pre-vaccination rates] with

Table 1. Prealence of seroprotection against tetanus and diphtheria before and after accination according to age group and gender

Group I Group II

Determination Prev* Postv* Prev* Postv1* Postv6* Postv7* (No. studied) (201) (183) (147) (137) (119) (102)

Tetanus & 0n1IU\ml 90n5† 99n530n681n783n999n02 Males 91n8 100 32n377n97897n6 (56\61) (55\55) (21\65) (46\59) (39\50) (41\42) Females 90 99n229n384n686n9 100 (126\140) (127\128) (24\82) (66\78) (60\69) (60\60) Diphtheria & 0n1IU\ml 38n385n819n04 65n765n590n2 Males 40n989n116n04 62n76095n2 (25\61) (49\55) (11\65) (37\59) (30\50) (40\42) Females 37n184n420n767n969n688n3 (52\140) (108\128) (17\82) (53\78) (48\69) (53\60)

* Prev, prevaccination; Postvl, Postv6, Postv7, postvaccination, 1, 6 and 7 months after the ﬁrst dose. † Values are percentages with numbers in parentheses.

Table 2. Determinants of protection against tetanus (preaccination titre). Logistic regression analysis

IU\ml Independent variables Adjusted odds ratio (95% CI) P

& 0n1 Age, years " 54 1n00 18–23 30n20 (12n05–75n73) ! 0n00001 24–30 17n91 (7n81–41n05) ! 0n00001 45–54 1n04 (0n51–2n13) n.s.† Gender Female* 1n00 Male 1n23 (0n68–2n23) n.s.†

* Reference group. † n.s., not signiﬁcant.

no diﬀerences between males and females. In group II, in the 18–23 and 24–30 years age groups with respect the proportion of seroprotected subjects 1, 6 and 7 to the " 54 years age group. The 45–54 years age months after the beginning of the 3-dose schedule was group showed a similar proportion of seroprotected 81n7% (112\137) [McNemar, P ! 0n0001 with respect to that of the " 54 years age group. to prevaccination rates], 83n9% (99\l 19) [McNemar, P!0n0001 with respect to prevaccination rates] and Diphtheria 99n0% (101\102) [McNemar, P ! 0n0001 with respect to prevaccination rates] respectively. In all three tests Table 1 also shows the prevalences of seroprotection the results were slightly better for females. for diphtheria (titres & 0n1IU\ml) before and after At the end of each vaccination series, similar rates the vaccination schedule in each of the groups. of seroprotection were found in both groups (99n5% Before vaccination, the prevalence of seroprotection in group I s. 99% in group II). against diphtheria in groups I and II was 38n3% # The logistical regression analysis (Table 2) of the (77\201) and 19% (28\147) [χ l 14n05, P ! 0n0001], prevaccination situation conﬁrmed the greater pro- respectively. In group I, as with tetanus, the prevalence portion of seroprotected subjects (& 0n1IU\ml) in of antibodies was slightly greater in males, whereas the younger age groups, being markedly greater the reverse was true in group II, although the

Table 3. Determinants of protection against diphtheria (preaccination titre). Logistic regression analysis

IU\ml Independent variables Adjusted odds ratio (95% CI) P

& 0n1 Age, years " 54* 1n00 18–23 1n51 (0n76–3n01) n.s.† 24–30 1n59 (0n80–3n16) n.s. 45–54 0n34 (0n14–0n80) ! 0n01 Gender Female* 1n00 Male 0n99 (0n60–1n66) n.s.

* Reference group. † n.s., not signiﬁcant.

differences were not statistically significant. In group P ! 0n00000l]. Within group II, the differences in local I, 1 month after administration of a dose of Td reactogenicity related with each dose of vaccine were vaccine, 85n8% (157\183) of subjects had sero- minimal, oscillating between 40% (second dose) and protective levels of antibodies [McNemar, P ! 0n0001, 47n5% (first dose). with respect to prevaccination levels], the levels being In both age groups and for each dose, females slightly higher in males. In group II, the levels of reported a higher number of adverse local reactions, a seroprotection 1, 6 and 7 months after the beginning finding that was statistically significant in all cases of the 3-dose vaccination schedule were 65n7% except for the third dose in group II. (90\137) [McNemar, P ! 0n0001, with respect to Table 4 shows the number of local reactions prevaccination levels) 65n5% (78\119) [McNemar, (between 1 and 4) in each group and for each dose. P ! 0n0001, with respect to prevaccination levels] and Table 5 shows the type of reaction. 90n2% (92\102) [McNemar, P ! 0n0001, with respect The logistical regression analysis shown in Table 6 to prevaccination levels], respectively, with a slightly confirms the progressively greater reactogenicity of better final result in male subjects (not statistically the Td vaccine in the younger age groups (adjusted significant). OR l 7n03, 95% CI 2n76–17n89) in subjects aged At the end of each vaccination series, similar levels 18–23 years with respect to the reference group (" 54 of seroprotection were found in both groups (85n8% years) and in females (adjusted OR in males l 0n3, in group I s.90n2% in group II). 95% CI 0n17–0n53) when the prevaccination titres of In the logistical regression analysis (Table 3) of the tetanus antibodies are included in the model (adjusted prevaccination situation, the lowest level of sero- OR l 1n6, 95% CI 1n14–2n23). The prevaccination protection (& 0n1IU\ml) corresponded to the 45–54 presence of diphtheria antibodies and the simul- years age group and the highest to the younger age taneous administration of other vaccines were not groups (reference group " 54 years). associated with greater local reactogenicity in the At the end of each vaccination series, similar levels logistical regression analysis. of seroprotection were found in the two groups (95n6% in group I s.98n03% in group II). General reactions Reactogenicity of the Td vaccine The general adverse reactions presumably related to each dose of vaccine are shown in Table 4. As with Local reactions local reactogenicity, general reactogenicity in group I The adverse local reactions which followed the was twice that of group II. In group I, for the first administration of each dose of vaccine are shown in (booster) dose, 40n9% (76\186) subjects reported & 1 Table 4. Local reactogenicity in group I was almost general reactions against 21n6% (30\139) after the # twice that of group II. After administration of the first first dose in group II [χ l 12n59, P ! 0n00000l]. With dose, the proportion of subjects reporting & 1 local respect to the general reactogenicity related to each reactions was 83n3% (155\186) in group I (booster dose of vaccine, the differences were small, oscillating # dose) and 47n5% (66\139) in group II [χ l 45n36, between 17n5% (second dose) and 21n6% (first dose).

Table 4. Reactogenicity: number of reported aderse reactions

Group II Group I 1st dose 1st dose 2nd dose 3rd dose Related doses (No. l 201) (No. l 147) (No. l 137) (No. l 119) Valid cases 186 139 120 104

Local reactions* 83n3 (155\186) 47n5 (66\139) 40n0 (48\120) 46n1 (48\104) One 70n9 (110\155) 75n7 (50\66) 50n0 (14\48) 39n6 (19\48) Two 20n6 (32\155) 10n6(7\66) 29n2 (14\48) 29n2 (14\48) Three 8n4 (13\155) 13n6(9\66) 20n8 (10\48) 29n2 (14\48) Four — — — 2n1(1\48) In males 70n2 (40\57) 31n4 (19\61) 27n4 (14\51) 41n9 (18\43) In females 89n1 (115\129) 60n2 (47\78) 49n3 (34\69) 49n2 (30\61) (P value) P ! 0n002 P! 0n001 P ! 0n003 n.s.† General reactions* 40n9 (76\186) 21n6 (30\139) 17n5 (21\120) 20n2 (21\104) One 65n8 (50\76) 63n3 (19\30) 61n9 (13\21) 52n4 (11\21) Two 25n0 (19\76) 33n3 (10\30) 23n8(5\21) 33n3(7\21) Three 7n9(6\76) 3n3(1\30) 14n3(3\21) 9n5(2\21) Four 1n3(1\76) — — 4n8(1\21) In males 35n1 (20\57) 16n4 (10\61) 13n7(7\51) 13n9(6\43) In females 43n4 (56\129) 38n5 (30\78) 20n3 (14\69) 24n6 (15\61) (P value) n.s. n.s. n.s. n.s.

Values are percentages with numbers in parentheses. * Subjects with one or more reactions. † n.s., not signiﬁcant.

Table 5. Reactogenicity: types of aderse reactions reported

Group II Group I 1st dose 1st dose 2nd dose 3rd dose Related doses (No. l 201) (No. l 147) (No. l 137) (No. l 119) Local reactions (213) (91) (82) (93) Pain* 71n8 (153) 75n8 (69) 61n0 (50) 45n2 (42) Redness 10n3 (22) 8n8 (8) 24n4 (20) 29n0 (27) Swelling 18n3 (38) 15n4 (14) 14n6 (12) 25n8 (24) General reactions (110) (42) (32) (35) Fever 3n6 (4) 0 (0) 0 (0) 2n8 (1) Discomfort† 35n5 (39) 30n9 (13) 31n3 (10) 20n0 (7) Headache‡ 43n6 (48) 54n8 (23) 50n0 (16) 45n7 (16) Nausea\vomiting§ 7n3 (8) 4n8 (2) 12n5 (4) 14n3 (5) Other** 10n0 (11) 9n5 (4) 6n2 (2) 17n1 (6)

Values are percentages with numbers in parentheses. * In group I: 74% mild and 26% moderate. In group II (3 doses): 78% mild and 22% moderate. † In group I: 75% mild and 25% moderate. In group II (3 doses): 68% mild and 32% moderate. ‡ In group I: 79% mild and 21% moderate. In group II (3 doses): 79% mild and 21% moderate. § In group I: 100% mild. In group II (3 doses): 64% mild and 36% moderate. ** In group I: 73% mild and 27% moderate. In group II (3 doses): 67% mild and 33% moderate.

Females reported greater general reactogenicity, Table 5 shows the type of reactions, the most frequent but the differences were not statistically significant in being discomfort and severe headache. any case. The logistical regression analysis in Table 6 con- Table 4 also shows the number of general reactions firms the greater general reactogenicity of the Td (between 1 and 4) in each group and for each dose. vaccine observed in the younger age groups. In the

Table 6. Reactogenicity to the ﬁrst dose of Td accine. Logistic regression analysis

Adjusted odds ratio Variable (reference group) (95% CI) P

Local reactions Age (" 54 years) 18–23 7n03 (2n76–17n89) ! 0n00001 24–30 4n22 (1n63–10n96) ! 0n003 45–54 2n44 (1n15–5n19) ! 0n02 Gender (female) Male 0n30 (0n17–0n53) ! 0n00001 Other vaccines (0 doses) 1n01 (0n74–1n36) n.s.* AntiTET titre† (! 0n1IU\ml) 2n54 (1n31–4n93) ! 0n006 AntiDIP titre‡ (! 0n1IU\ml) 1n42 (0n74–2n73) n.s. General reactions Age (" 54 years) 18–23 3n15 (1n21–8n18) ! 0n02 24–30 2n47 (0n90–6n78) n.s.* 45–54 2n47 (0n99–6n17) ! 0n0535 Gender (female) Male 0n58 (0n33–1n00) ! 0n0511 Other vaccines (0 doses) 1n43 (1n10–1n84) ! 0n007 AntiTET titre† (! 0n1IU\ml) 1n22 (0n62–2n40) n.s. AntiDIP titre‡ (! 0n1IU\ml) 1n15 (0n67–1n97) n.s.

* n.s., not signiﬁcant. † AntiTET, prevaccination antitetanus antibodies. ‡ AntiDIP, prevaccination antidiphtheria antibodies.

model, gender (adjusted OR in males l 0n58, 95% CI vaccination can be considered exceptional, the prob- 0n33–1n0) and the simultaneous administration of ability of recall bias must be considered, meaning that other vaccines (adjusted OR l 1n43, 95% CI 1n10– it is likely that some of these subjects have in fact 1n84) are significantly related. Neither the pre- received tetanus vaccinations in the past. In any case, vaccination presence of tetanus or diphtheria anti- more than one dose of vaccine (three) is required to bodies are associated in the logistical regression reach seroprotection levels comparable to those of the analysis with the appearance of general adverse 18–30 years age group [32], thereby guaranteeing reactions. protection against a disease in which there is no herd immunity. DISCUSSION In each age group, the minimal differences between genders both before vaccination and during the Seroprotection before and after vaccination vaccination period is a recommendation for the use of Tetanus the same vaccination strategies for both sexes. The simultaneous administration of other vaccines does The results of this study confirm a low level of not influence the formation of tetanus antibodies [33]. protection against tetanus in the adult population which can be explained both by the history of low Diphtheria vaccination coverage in infancy in the older age groups and by the absence of periodic revaccinations As previously remarked, the lack of exposure to [18, 22, 23]. In younger subjects such as the 18–30 natural (reduced circulation of toxigenic strains of years age group, the proportion of seroprotected Corynebacterium diphtheriae) and artificial (lack of subjects reaches 90% even though they claim not to periodic revaccination) boosters explains the low have received a booster dose within the last 10 years. levels of protection against diphtheria reported in The administration of a single dose of Td vaccine various European countries [7, 8, 12, 16, 18, 19]. gives protection to almost all subjects vaccinated [31]. Leaving to one side differences in the type of Almost a third of subjects & 45 years who denied population studied, in laboratory tests, in threshold being vaccinated previously possessed tetanus anti- protection levels (absolute or partial) and other bodies. Given that such a situation without previous methodological differences, the results of our study

are consistent with these studies and also show the vaccines is in accordance with the current recommen- need to use vaccination schedules which are differen- dations on the simultaneous administration of tiated with respect to age, the fundamental paradigm vaccines [33] and is also consistent with current trends of antecedents of diphtheria vaccination. We know towards the use of combined vaccines in both children that adults in general have an imprecise idea of their and adults. vaccination history, usually because there is no documented history or because of the span of time or Safety of the Td vaccine inadequate conservation of documents [34]. For this reason it is vital, in addition to encouraging the use of In daily clinical practise we are often faced with the individual immunization registers, to develop group need to administer various vaccines simultaneously, strategies in consonance with the situation of each underlining the importance of carrying out natu- sector of the population. The results of this study may ralistic studies of the type postulated by Lasagna [39] provide useful information in this respect. in 1974. Unlike clinical trials, these studies attempt to The present study also confirms the utility of the Td evaluate the product (in this case a vaccine) in real or vaccine in conferring protection against tetanus and ‘natural’ conditions of use, both for the doctor and diphtheria [13]. In the younger population groups, the subject. This may affect the immunogenicity of presumably vaccinated in infancy (the history of the each vaccine and, of course, the safety profile. In the introduction of the vaccine and the levels of coverage present study, only 2n5% of the younger age group reached in each country are determining factors in this and a progressively greater proportion (20n5%,90n8% respect), a single dose of the vaccine will normally be and 93n85% in doses 1, 2 and 3 respectively) of the sufficient [31, 35]. A recent study by Nicolay et al. [31] & 45 years age group received only the Td vaccine, a carried out in Germany, Austria and Slovenia and fair reflection of the way vaccines are usually limited to the younger population, reaches similar administered in a Vaccination Centre. conclusions. Specific situations such as an imminent The reactogenicity of the tetanus and diphtheria trip to endemic or epidemic areas [36] might require toxoids is related to numerous factors [13, 40–46] such additional individualized doses of vaccine. In subjects as: the formula of the vaccine, previous levels of with a negative or uncertain vaccination history it antitoxin, the route of administration, the adjuvants seems advisable to carry out a 3-dose schedule, as this used, the age of the subjects and, of course, the ensures levels of protection of almost 100% against methods used to measure adverse effects. Although both tetanus and diphtheria. Although the absolute this makes comparisons difficult, the results of our protection levels in the case of diphtheria are study are broadly consistent with other studies [40, somewhat lower (90%), they are sufficient to ensure 46]. The greater local reactogenicity (83% in the herd immunity [27]. 18–30 years age group and between 40% and 47% The logistical regression analysis confirms that the according to the order of the dose in the & 45 years initial vaccination immune situation is primarily age- age group) and general reactogenicity (41% in the dependent [37], presumably because the possibility of 18–30 years age group and 17–21% in the & 45 years previous primovaccination is more certain and closer age group) are clearly associated with age, and this is in time. Neither gender nor the simultaneous adminis- presumably related to the greater number of previous tration of other vaccines play a relevant role in the vaccinations in the younger age group. The logistic response to the diphtheria vaccine. Some studies have model confirms the progressive increase of reacto- found lower levels of diphtheria antibodies in females genicity at a younger age as well as the influence of the [15, 17, 19, 38] which they have taken to indicate a prevaccination titre of tetanus antibodies which leads poor response to the vaccination in females [17]. In to a two-and-a-half fold increase in the number of some countries, but not in Spain, lower levels of adverse local reactions. Curiously, women suffer diphtheria antibodies in females might be related to greater local reactogenicity than males, both in the Td vaccination of male servicemen. Despite the fact raw and logistic analyses. that the dose of Td was administered at the same time The most common local adverse event was pain at as one or more other vaccines, the seroresponse rates the site of inoculation, while the general reactions to a booster dose of Td led to a very high seroresponse included discomfort and headache. In all cases, the rate to tetanus and a relatively high seroresponse rate reactions were of light or moderate intensity. As might to diphtheria. This lack of interference by other be expected, the general reactions were more common

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