A randomised controlled trial with a diphtheria–tetanus–acellular pertussis (dTpa) vaccine in adults

Vaccine 18 (2000) 2075±2082

www.elsevier.com/locate/vaccine

A randomised controlled trial with a diphtheria±tetanus±acellular pertussis (dTpa) vaccine in adults M. Van der Wielen a, P. Van Damme a,*, E. Joossens a, G. Franc° ois a, F. Meurice b, A. Ramalho b a

Centre for the Evaluation of Vaccination, Epidemiology and Community Medicine, University of Antwerp, Antwerp, Belgium b SmithKline Beecham Biologicals, Rixensart, Belgium Received 15 July 1999; received in revised form 23 November 1999; accepted 7 December 1999

Abstract The aim of this assessor-blinded trial was to compare the immunogenicity and reactogenicity of a candidate diphtheria, tetanus toxoids and acellular pertussis vaccine with reduced antigen content for diphtheria and pertussis (dTpa) with a licensed reduced adult-type diphtheria±tetanus vaccine Td (reduced diphtheria content) and with an experimental candidate monovalent acellular pertussis vaccine with reduced antigen content (pa). The dTpa and pa vaccines had identical pertussis antigen content. A total of 299 healthy adults (e18 years, mean age: 30.1 years210.7) were randomised into 3 groups to receive a single dose of one of the study vaccines. In all groups, clinically signi®cant reactions (severe) were infrequent (0±6%) and no serious adverse events were reported during the study. The incidence of local and systemic reactions following the administration of dTpa was comparable to the Td vaccine group. Of the total study group, prior to vaccination 52.3 and 93.2% of the subjects had antidiphtheria and anti-tetanus antibody levels e0.1 IU/ml, respectively; and 73.1, 98.2 and 74.5% of the subjects were seropositive for pertussis toxin (PT), ®lamentous hemagglutinin (FHA) and pertactin (PRN) antibodies, respectively. One month after vaccination, a similar percentage of subjects in the dTpa and Td groups had anti-diphtheria (88.4% vs 90.1%) and anti-tetanus (100% vs 98.9%) antibody levels e0.1 IU/ml. Similar anti-FHA (100%) and anti-PRN (98.9%) vaccine response rates were seen in the dTpa and pa groups, while the anti-PT vaccine response rates were 96.8 and 100.0%, respectively. The dTpa vaccine is as well tolerated and immunogenic as the licensed Td vaccine, and additionally, can also boost antibodies against pertussis. 7 2000 Elsevier Science Ltd. All rights reserved. Keywords: Vaccines; Pertussis; Adult immunisation

1. Introduction Universal infant immunisation against diphtheria, tetanus, and pertussis is one of the major goals of the World Health Organisation (WHO) Expanded Programme on Immunisation (EPI). Diphtheria±tetanus± pertussis (DTP) primary vaccination of infants followed by a booster dose in the second year of life is almost universal practice [1]. In many countries, immu* Corresponding author. Tel.: +32-3-820-26-52; fax: +32-3-82026-40. E-mail address: [email protected] (P. Van Damme).

nity to diphtheria and tetanus is currently maintained by booster vaccination at 5- to 10-year intervals. A reduced-antigen content diphtheria±tetanus (Td) vaccine is used in order to improve tolerability while eliciting an adequate immune response. However, pertussis vaccine boosters have not been recommended after seven years of age, mainly due to the high reactogenicity of traditional whole-cell vaccines in older children and the belief that pertussis was both uncommon and mild in older children, adolescents, and adults. In the pre-vaccination era, pertussis infection commonly occurred in early life. The subsequent natural immunity was then maintained by periodic exposure to

0264-410X/00/$ - see front matter 7 2000 Elsevier Science Ltd. All rights reserved. PII: S 0 2 6 4 - 4 1 0 X ( 9 9 ) 0 0 5 6 8 - X

2076

M. Van der Wielen et al. / Vaccine 18 (2000) 2075±2082

the organism (Bordetella pertussis ) which acted as a natural booster [2]. Although the incidence of pertussis in young children has been markedly reduced following the successful implementation of infant immunisation programs, there has been a subsequent increase in the incidence in adults and adolescents [3±6]. Indeed, vaccine-induced immunity to pertussis wanes, leaving older children, adolescents and adults susceptible to reinfection [3,7±10]. The major cause for concern is the potential for older infected individuals to serve as reservoir of infection to young infants [7±9]. Furthermore, because the symptoms are generally atypical in adults [11], adult infection is often dicult to diagnose [12] and this situation creates the potential for further spread. In addition, treatment with antibiotics is only e€ective within the ®rst three weeks after onset of symptoms [13]. All these factors have prompted the development of a suitable vaccination strategy for older populations. This in part has been facilitated by the availability of acellular pertussis vaccines which are less reactogenic than whole-cell vaccines [14,15]. Although combined diphtheria±tetanus±pertussis (DTPa) vaccines have become routine paediatric vaccines in many developed countries, their reactogenicity increases with successive doses, making the paediatric formulation less suitable for older individuals [16]. However reducing the content of the acellular pertussis antigens and formulating it with an established adult Td booster vaccine could result in a new candidate combination vaccine with improved tolerability and the potential to boost titres against all three diseases. The purpose of this study was to assess the reactogenicity and immunogenicity of a diphtheria±tetanus± acellular pertussis candidate vaccine with reduced antigen content for diphtheria and pertussis (dTpa) in comparison with a standard, licensed adult reducedantigen-content diphtheria±tetanus (Td) vaccine and an experimental candidate monovalent acellular pertussis vaccine with reduced antigen content (pa), respectively. The dTpa and pa vaccines had identical pertussis antigen content.

2. Materials and methods 2.1. Subjects This single (assessor) blinded, parallel group study was conducted at the Centre for the Evaluation of Vaccination, Epidemiology and Community Medicine, University of Antwerp, Belgium. The protocol was 1 Tedivax pro Adulto/Td-Rix is a Trade Mark of the SmithKline Beecham group of companies, Rixensart, Belgium.

approved by the ``Commissie voor Medische Ethiek'', Universitair Ziekenhuis Antwerpen, on October 2, 1997. Written informed consent was obtained from all subjects prior to enrolment. The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice in operation at the time. A total of 299 healthy male and female volunteers (e18 years) were enrolled at two study sites, one site enrolled 143 factory workers and employees of SmithKline Beecham Biologicals, while the other site, co-ordinated by the same investigator, enrolled 156 students from the University of Antwerp. Each subject's medical history was taken (including axillary body temperature and record of any medication). Exclusion criteria were: previous vaccination against either diphtheria or tetanus within ®ve years or vaccination against pertussis since childhood; a known history of diphtheria or tetanus; a known exposure to diphtheria or pertussis within the previous ®ve years; or a known history of non-response to diphtheria, tetanus or pertussis vaccination. Additional exclusion criteria were: administration of immunosuppressive/ immune-modifying drugs, of vaccines not foreseen by the protocol (one month before or after the start of the trial), of immunoglobulins and blood products (3 months prior or during the trial); history of allergic disease or reactions likely to be exacerbated by any component of the vaccine; or previous record, following DTP vaccination, of any serious adverse reaction or precautionary indication for DTP vaccination [17]. 2.2. Vaccines and administration Subjects were randomly enrolled into 3 groups in a 1:1:1 ratio using an algorithm of pseudo-random numbers and received either a single intramuscular dose of dTpa, pa or Td vaccine. A description of the vaccines is given in Table 1. Clinical studies with another candidate dTpa vaccine with lower diphtheria content compared to the current candidate dTpa vaccine in this study, showed that the anti-diphtheria antibody response could be improved. For this reason the diphtheria content was increased in the current candidate dTpa vaccine (e2.5 Lf) compared to the Td vaccine (e1.5 Lf) [Data on ®le, SmithKline Beecham Biologicals]. On the other hand, the lower tetanus toxoid content in the current candidate dTpa vaccine induced a similar immunological response as with the Td vaccine [18,19]. Licensed Td vaccine (Tedivax pro Adulto1) was supplied in a pre-®lled syringe, whereas the dTpa and pa vaccines were in solution contained in identical vials. Consequently, dTpa and pa vaccines were administered in a double-blinded and Td in a single blinded fashion. In order to keep both the subjects and the physician administering the vaccine blinded, a non-assessor prepared the vaccines so that

M. Van der Wielen et al. / Vaccine 18 (2000) 2075±2082

all three vaccines were visually identical prior to vaccination. All vaccines were administered by deep intramuscular injection using a 24 mm needle in the deltoid region of the non-dominant side. Vaccinees were observed closely for at least 15 min after vaccination according to the protocol. All vaccines were manufactured by SmithKline Beecham Biologicals (Rixensart, Belgium). 2.3. Assessment of reactogenicity Subjects used diary cards to record solicited local (redness, swelling, and pain on digital pressure) or general (dizziness, fatigue, fever, headache, malaise, and vomiting) signs and symptoms occurring on the day of vaccination and during the 14 subsequent days. Redness and swelling with a diameter e50 mm and fever e39.18C (oral route) were considered as severe. For all other symptoms, `severe' was de®ned as a symptom which prevented normal everyday activities and required medical advice. The follow-up period for unsolicited symptoms and serious adverse events was 0±30 days. The investigator assessed the relationship of all symptoms to vaccination. 2.4. Assessment of immunogenicity Blood was drawn immediately prior to and approximately one month (27±35 days) after vaccination and sera were stored, under code, at ÿ20 to ÿ308C immediately after centrifugation until they could be analysed. Pertussis IgG antibodies were determined by ELISA as described by GranstroÈm et al. [20] for antiPT and anti-FHA; and by Kanra et al. [21] for antiPRN. Antibody levels were expressed in ELISA Units (EL.U/ml), with an assay cut-o€ of 5 EL.U/ml. Antibodies against diphtheria and tetanus toxoids were measured using a modi®ed sandwich ELISA, as described by Camargo et al. [22] and Melville-Smith et

2077

al. [23], respectively. The cut-o€ of the assays was conservatively set at 0.1 IU/ml. Although a good correlation exists between the ELISA and the micro-cellculture neutralising test (VERO cell assay) for antidiphtheria measurements, this may be reduced at antibody levels below 0.1 IU/ml. Therefore, anti-diphtheria levels below ELISA cut-o€ value were reassessed using an in vitro neutralisation assay (VERO cell assay) [24,25]. In the present study, anti-diphtheria and antitetanus antibody levels e0.1 IU/ml were considered to be fully protective [26±29]. For geometric mean concentration (GMC) calculations, antibody levels below the cut-o€ of the assay were given an arbitrary value of half the cut-o€. Seroconversion was de®ned as the appearance of antibodies above the assay cut-o€. A vaccine response to the pertussis antigens was de®ned as seroconversion in initially seronegative subjects, or as at least a two-fold increase of a positive pre-vaccination level. 2.5. Statistical methods Statistical analyses were performed using SAS (version 6.11). The incidence of all local and general symptoms, anti-pertussis vaccine response rates (for each antigen), and the percentage of subjects with post vaccination levels e0.1 IU/ml were compared between the three groups using a two-sided Fisher's exact test. Di€erences were considered signi®cant at p < 0.05. Post vaccination GMCs for all antigens were compared between the three vaccines using the Wilcoxon test. For all values 95% con®dence intervals (CI) were calculated as an additional means of comparison. The three vaccine groups were compared with respect to age and gender using a two-way analysis of variance model with gender and vaccine group e€ect and a twosided Fisher's exact test, to verify for the possible e€ects of demographics on the randomisation procedure.

Table 1 Vaccine formulation Preservative Vaccinea

PTb

FHAc

PRNd

Diphtheria toxoid

Tetanus toxoid

2-Phenoe

Thiomf

pa dTpa Tdh

8 mg 8 mg ±

8 mg 8 mg ±

2.5 mg 2.5 mg ±

± e2.5 Lfg e1.5 Lf

± e5 Lf e10 Lf

2.5 mg 2.5 mg ±

± ± 2.5 mg

a

All vaccines contained 0.5 mg aluminium salts (Al+ ) as adjuvant. Pertussis toxin. c Filamentous hemagglutinin. d Pertactin. e 2-phenoxyethanol. f Thiomersal. g Limits of ¯occulation. h Licensed diphtheria±tetanus vaccine (Tedivax pro Adulto1/Td-Rix).. b

2078

M. Van der Wielen et al. / Vaccine 18 (2000) 2075±2082

3. Results Of the 299 subjects enrolled, all but three completed the study. Two were lost to follow-up and one subject withdrew his consent (not due to an adverse event). In the study cohort the male/female ratio was 147/152; the mean age was 30.1 years (range: 18±73 years). There were no statistically signi®cant di€erences in these parameters between groups. 3.1. Reactogenicity A total of 295 subjects were eligible for the reactogenicity analysis; three subjects (one in each group) had no follow-up and the randomisation code of another subject was broken. For the 295 doses, a total of 290 diary cards were returned for both solicited local symptoms and solicited general symptoms. The most frequently reported local symptom was pain at the injection site (Table 2). However, there were no reports of severe pain, and redness and swelling with a diameter e50 mm were infrequent. The incidences for local symptoms were similar following dTpa and Td vaccination. The onset of almost all (98.4%) local symptoms were within 48 h of vaccination. The pa vaccine showed the lowest

incidence of local symptoms, with a signi®cantly lower ( p < 0.005) incidence of pain, redness, and swelling compared with dTpa. The incidences of general solicited symptoms were low (range 20±40%) following vaccination with pa, dTpa, and Td (Table 2). The incidence was the lowest in the pa group, with a similar incidence in the dTpa and Td groups. The most frequently reported general solicited symptoms were headache and fatigue. There were no reports of fever e39.18C, severe vomiting, or dizziness. No other symptom had a reported incidence, graded as severe, of >1% in any group. Approximately half of the general solicited symptoms were considered as probably or suspected to be related to vaccination. The incidence of reactions occurring 3 days after vaccination (late onset reactions) was similar between groups. The most frequently mentioned unsolicited symptom was myalgia, which was generally considered as probably related/suspected to be related to vaccination. In total, 15 unsolicited signs and symptoms in the pa group, 21 in the dTpa group, and 16 in the Td group were assessed as probably or suspected to be related to vaccination. No serious adverse events were reported during the study.

Table 2 Percentage of volunteers with solicited adverse (local and general) symptoms during the 15 day follow-up period after immunisation Vaccine group Adverse event Local symptoms Pain Redness Swelling General symptoms Dizziness Fatigue Fever Headache Malaise Vomiting a

Grade

dTpa (na=96) (95% CIb)

Any Severec Any e50 mm Any e50 mm

88.5 0.0 33.3 5.2 28.1 5.2

Any Severe Any Severe e37.58C e39.18C Any Severe Any Severe Any Severe

8.3 0.0 40.6 1.0 5.2 0.0 32.3 0.0 16.7 0.0 3.1 0.0

Td (n = 98) (95% CI)

pa (n = 96) (95% CI)

(80.4±94.1)d (0.0±3.8) (24.1±43.7)e (1.7±11.7) (19.4±38.2)f (1.7±11.7)

82.7 0.0 34.7 6.1 26.5 5.1

(73.7±89.6) (0.0±3.7) (25.4±45.0) (2.3±12.9) (18.1±36.4) (1.7±11.5)

71.9 0.0 12.5 0.0 10.4 1.0

(61.8±80.6)d (0.0±3.8) (6.6±20.8)e (0.0±3.8) (5.1±18.3)f (0.0±5.7)

(3.7±15.8) (0.0±3.8) (30.7±51.1) (0.0±5.7) (1.7±11.7) (0.0±3.8) (23.1±42.6) (0.0±3.8) (9.8±25.7) (0.0±3.8) (0.7±8.9) (0.0±3.8)

7.1 0.0 35.7 0.0 9.2 0.0 33.7 1.0 17.3 1.0 2.0 0.0

(2.9±14.2) (0.0±3.7) (26.3±46.0) (0.0±3.7) (4.3±16.7) (0.0±3.7) (24.4±43.9) (0.0±5.6) (10.4±26.3) (0.0±5.6) (0.3±0.7) (0.0±3.7)

6.2 0.0 27.1 1.0 4.2 0.0 33.3 1.0 8.3 0.0 4.2 0.0

(2.3±13.1) (0.0±5.7) (18.5±37.1) (0.0±5.7) (1.2±10.3) (0.0±3.8) (24.0±43.7) (0.0±5.7) (3.7±15.8) (0.0±3.8) (1.2±10.3) (0.0±3.8)

Number of documented doses. 95% con®dence interval. c Severe was de®ned as: preventing normal everyday activities. d,e,f Statistically signi®cant di€erence ( p < 0.05, Fisher's exact test). b

M. Van der Wielen et al. / Vaccine 18 (2000) 2075±2082

2079

3.2. Immunogenicity

4. Discussion

A total of 279 subjects were eligible for the immunogenicity analysis. Twenty subjects were excluded: broken randomisation code (1 subject), non-compliance with inclusion/exclusion criteria (5 subjects), and non-compliance with blood sampling schedule (14 subjects). All groups had a similar pre-vaccination serological status. Considering the total study group (prior to vaccination), the majority of subjects was seropositive for antibodies to tetanus toxoid (93.2%) and pertussis antigens (73.1, 98.2 and 74.5% for PT, FHA, and PRN, respectively). However, approximately half of the subjects was seropositive for antibodies to diphtheria toxoid (52.3%). When ELISA seronegative subjects were re-evaluated by VERO, 73% were shown to be seropositive [24,25]. Nearly all subjects demonstrated a vaccine response (as de®ned above) against each of the three pertussis antigens with similar vaccine response rates observed between the dTpa and pa group (Table 3). A large increase in GMCs following vaccination was observed in both dTpa and pa groups for anti-PT (8- and 13fold increases, respectively), anti-FHA (18-fold increase in both groups), and anti-PRN (40- and 34-fold increases, respectively) antibodies. The only signi®cant di€erence between groups was the occurrence of higher anti-PT GMCs in the group receiving pa. One month after vaccination, a similar percentage of subjects in the dTpa and Td groups had antidiphtheria (88.4% vs 90.1%) and anti-tetanus (100.0% vs 98.9%) antibody levels e0.1 IU/ml (Table 4). There was no di€erence in post vaccination anti-diphtheria GMCs following Td and dTpa vaccination. However, anti-tetanus GMCs were signi®cantly higher ( p < 0.05) following vaccination with Td vaccine.

Vaccination of adolescents and adults against pertussis is now being proposed by some authorities in order to manage the recently observed epidemiological shift in the incidence of the disease to older age groups [3]. In order to achieve continuous protection, it is probable that subsequent doses of pertussis vaccine are required at regular intervals throughout life, irrespective of both past immunisation history and exposure to the natural infection [30]. As it is the case for most vaccine-preventable diseases, a high vaccination coverage must be achieved before herd immunity can be acquired and control of infection is a€orded in the entire population [31]. Combination with an already widely used vaccine is generally accepted as not only the most ecient, but also the most cost-e€ective means of achieving high coverage [32,33]. Therefore the adult Td vaccine, which has been in routine use for a number of years, provides a convenient delivery vehicle for the pertussis antigens. However, as with the development of any combination vaccine, measures must be taken to ensure that neither the immunogenicity of any component nor the reactogenicity pro®le of the vaccine is compromised. Furthermore, the assessment of the immune response is particularly pertinent to adult boosters, where the antigen content has been reduced in order to improve tolerability. The design of this particular trial allowed for the direct comparison of dTpa vaccine with both a licensed Td vaccine and the monovalent pa component. Both the pa and dTpa vaccine were capable of eliciting an anamnestic type response against all pertussis antigens as manifested by the large increase in titres from pre- to post-vaccination and the high percentage of subjects demonstrating a vaccine response.

Table 3 Vaccine response (VR) to pertussis antigens and geometric mean concentrations before and one month after vaccination dTpa group (na=95b) Antibody

Timing

Anti-PT

Pre Post Pre Post Pre Post

Anti-FHA Anti-PRN a

% VRc 93.7 96.8 97.9

pa group (n = 92) GMCd (95% CIe) 10 (8.3±12.9) 76 (62.0±92.8)f 42 (33.6±51.6) 750 (637.3±881.5) 14.8 (11.3±19.3) 587.6 (419.9±822.1)

% VR 96.7 98.9 97.8

GMC (95% CI) 10 (7.8±12.1) 125 (104.9±149.3)f 46 (37.1±56.8) 822 (705.8±958.4) 15.7 (11.2±21.9) 534.4 (364.9±782.8)

Number of subjects. One subject in the dTpa group had missing anti-FHA results. c Vaccine response to pertussis antigens was de®ned as seroconversion in initially seronegative subjects or at least a two-fold increase of positive pre-vaccination titers. d Geometric mean concentrations for all subjects. e 95% con®dence interval. f Statistically signi®cant ( p < 0.05, Wilcoxon test). b

2080

M. Van der Wielen et al. / Vaccine 18 (2000) 2075±2082

Table 4 Anti-tetanus and anti-diphtheria concentrations before and one month after vaccination dTpa (na=95)

Td (n = 92)

Antibody

Timing

% e0.1 IU/ml (SCb)

GMCc (95% CId)

% e0.1 IU/ml (SC)

GMC (95% CI)

Anti-diphtheria

Pre Post Pre Post

53.8 88.4 91.6 100.0

0.2 1.7 1.3 9.9

53.3 90.1 91.3 98.9

0.1 2.0 1.6 11.8

Anti-tetanus

(0.1±0.2) (1.2±2.5) (1.0±1.7) (8.6±11.3)e

(0.1±0.2) (1.4±2.9) (1.2±2.2) (9.9±14.1)e

a

Number of subjects. Seroconversion = appearance of antibodies above or equal to 0.1 IU/ml. c GMC: geometric mean concentrations for all subjects. d 95% con®dence interval. e Statistically signi®cant ( p < 0.05, Wilcoxon test). b

The only di€erence between the two vaccine groups was the higher anti-PT post-vaccination GMCs observed in the group receiving monovalent pa. It can be expected that demonstration of ecacy of a given acellular pertussis vaccine as a primary vaccination course can serve as a basis for ecacy when given as a booster dose later in life. Furthermore given that the antibodies to PT, PRN and Fimbriae have recently been associated with protection, demonstration of antibody responses in adults comparable to those seen in infants may be indicative of protection in adults [34,35]. The components of the dTpa and pa vaccines are identical, and are approximately one third of the dose of the paediatric vaccine (Infanrix2). This paediatric vaccine has been shown to be ecacious in two prospective studies in infants [36±39]. Furthermore, the GMCs following administration of dTpa and pa in the currently reported study exceeded GMCs (as measured by identical laboratory methods) in the household contact study [39]. Therefore these results are suggestive of protection against pertussis in adults, although no conclusions as to the degree of protection can be drawn. Analysis of the CMI response to the vaccine will add further to the understanding of the pertussis response, currently these studies are underway. The licensed Td vaccine elicited signi®cantly higher anti-tetanus titres, presumably due to the di€erence in tetanus toxoid content. Perhaps of more clinical relevance is that all but one subject in the dTpa and Td group had levels e1.0 IU/ml, which is approximately 100 times the generally accepted protective level (e0.01 IU/ml) [40]. In addition, the levels observed in this study were in the range previously reported following vaccination of adults with licensed Td vaccines [41±44]. The high response to tetanus is itself not surprising as 91% of subjects had pre-vaccination levels e0.1 IU/ml 2 Infanrix is a Trade Mark of the SmithKline Beecham group of companies, Rixensart, Belgium.

which in turn is a re¯ection of the longstanding practice of adult tetanus boosters given at regular 5±10 year intervals. When considering pre-vaccination status of diphtheria immunity, by contrast, it is noteworthy that only 53% of the subjects in both groups had levels e0.1 IU/ml. This is comparable to the situation in other European countries such as the United Kingdom (62%), France (51%), and Poland (47%) [45]. In 1989, the WHO recommended the evaluation of diphtheria serological status in all age groups. It is likely that lack of booster vaccination in the past and waning immunity are the plausible reasons for the low diphtheria pre-vaccination antibody levels [46]. It is generally believed that there is a signi®cant risk of diphtheria epidemic when more than 30% of the population have non-protective antibody levels [47,48]. In this study further analysis of the pre-vaccination status using the more sensitive VERO test [24,25], demonstrated that the degree of seroprotection in this study population is approaching this level (21.5 and 32.2% in dTpa and Td groups, respectively). This observation emphasises the continued need for diphtheria revaccination in adults. Given the evident acceptance of adult re-vaccination of tetanus, it is not surprising that a Td vaccine has already been developed. This adds further support to the rationale for including the pertussis antigens. As mentioned, increasing reactogenicity has been associated with successive doses of both diphtheria toxoids and pertussis antigens in children [16]. Although all three vaccines appeared to cause a relatively high incidence of pain at the injection site (72±86% total incidence), no signi®cant increase was observed by the addition of the pa component to the Td vaccine, by comparison of the Td with dTpa group. Furthermore, the incidence of late onset reactions, which have previously been reported with acellular pertussis vaccination in adults [20,49], were similar in all three

M. Van der Wielen et al. / Vaccine 18 (2000) 2075±2082

groups, including the Td group. In this trial no substantial di€erence was seen between the pa and dTpa groups with respect to any general symptom. Again both pa-containing vaccines showed a similar incidence of general symptoms to the Td vaccine. In conclusion, the tolerability of the new dTpa vaccine appears to be acceptable for an adult vaccine. In industrialised countries, routine immunisation schedules should provide high levels of immunity to all age groups. At present industrialised countries only recommend primary series of DTP vaccines in the ®rst year of life, with a single booster of DT or Td vaccine at 4±10 years of age. However, given the recent epidemiological data showing an increase in the susceptibility of older age groups to pertussis and the apparent lack of protection against diphtheria, there is a need for harmonised, universal primary vaccination followed by a booster policy. A dTpa vaccine for adolescents and adults could deserve an important place in a revised booster strategy.

References [1] Davey S. The vaccine challenge. In: State of the world's vaccines and immunization. Geneva: World Health Organisation and United Nations Children's Fund, 1996. p. 1±25. [2] Giammanco A, Chiarini A, Stro€olini T, et al. Seroepidemiology of pertussis in Italy. Rev Infect Dis 1991;13:1216±20. [3] Keitel WA, Edwards KM. Pertussis in adolescents and adults: time to reimmunize? Semin Respir Infect 1995;10:51±7. [4] Nennig ME, Shine®eld HR, Edwards KM, Black SB, Fireman BH. Prevalence and incidence of adult pertussis in an urban population. JAMA 1996;275:1672±4. [5] Centres for Disease Control. Resurgence of Pertussis in the United States 1993. Morbid Mortal Wkly Rep 1993;42:952±60. [6] Baron S, Njamkepo E, Grimprel E, et al. Epidemiology of pertussis in French hospitals in 1993 and 1994: thirty years after a routine use of vaccination. Pediatr Infect Dis J 1998;17:412±8. [7] Cherry JD, Bara€ LJ, Hewlett E. The past, present and future of pertussis. The role of adults in epidemiology and future control. West J Med 1989;150:319±28. [8] Mortimer Jr EA. Pertussis and its prevention: a family a€air. J Infect Dis 1990;161:473±9. [9] Bass JW, Wittler RR. Return of epidemic pertussis in the United States. Pediatr Infect Dis J 1994;13:343±5. [10] Hoppe JE. Update on epidemiology, diagnosis, and treatment of pertussis. Eur J Clin Microbiol Infect Dis 1996;15:189±93. [11] Fine PE. Adult pertussis: a salesman's dream±and an epidemiologist's nightmare. Biologicals 1997;25:195±8. [12] Deville JG, Cherry JD, Christenson PD, et al. Frequency of unrecognized Bordetella pertussis infections in adults. Clin Infect Dis 1995;21:639±42. [13] National Advisory Committee on Immunization, the Advisory Committee on Epidemiology, the Canadian Paediatric Society. Statement on management of persons exposed to pertussis and pertussis outbreak control. Can Med Assoc J 1995;152:712±6. [14] Decker MD, Edwards KM, Steinho€ MC, et al. Comparison of 13 acellular pertussis vaccines: adverse reactions. Pediatrics 1995;96:557±66.

2081

[15] Pichichero ME. Acellular pertussis vaccines. Towards an improved safety pro®le. Drug Saf 1996;15:311±24. [16] Kimura M, Kuno-Sakai H, Sato Y, et al. A comparative trial of the reactogenicity and immunogenicity of Takeda acellular pertussis vaccine combined with tetanus and diphtheria toxoids. Outcome in 3- to 8-month-old infants, 9- to 23-month-old infants and children, and 24- to 30-month-old children. Am J Dis Child 1991;145:734±41. [17] Recommendations of the Advisory Committee on Immunization Practices (ACIP). UpdateVaccine side e€ects, adverse reactions, contraindications, and precautions. Morbid Mortal Wkly Rep 1996;45(RR12):1±35. [18] Tran Minh NN, Edelman K, He Q, Viljanen MK, Arvilommi H, Mertsola J. Antibody and cell-mediated immune responses to booster immunization with a new acellular pertussis vaccine in school children. Vaccine 1998;16:1604±10. [19] Dagan R, Igbaria K, Piglansky L, Van Brusteghem F, Melot V, Kaufhold A. Reactogenicity and immunogenicity of reduced antigen content diphtheria±tetanus±acellular pertussis vaccines as a booster in 4-7-year-old children primed with diphtheria± tetanus±whole cell pertussis vaccine before 2 years of age. Vaccine 1999;17:2620±7. [20] GranstroÈm M, Thoren M, Blennow M, Tiru M, Sato Y. Acellular pertussis vaccine in adults: adverse reactions and immune response. Eur J Clin Microbiol 1987;6:18±21. [21] Kanra G, Ceyhan M, Vandevoorde D, Bogaerts H. Acellular pertussis diphtheria-tetanus-pertussis vaccine containing separately puri®ed pertussis toxoid, ®lamentous haemagglutinin and 69 kDa outer membrane protein as a booster in children. Eur J Pediatr 1993;152:478±83. [22] Camargo ME, Silveira L, Furuta JA, Oliveira EP, Germek OA. Immunoenzymatic assay of anti-diphtheric toxin antibodies in human serum. J Clin Microbiol 1984;20:772±4. [23] Melville-Smith ME, Seagroatt VA, Watkins JT. A comparison of enzyme-linked immunosorbent assay (ELISA) with the toxin neutralization test in mice as a method for the estimation of tetanus antitoxin in human sera. J Biol Stand 1983;11:137±44. [24] Miyamura K, Nishio S, Ito A, Murata R, Kono R. Micro cell culture method for determination of diphtheria toxin and antitoxin titres using Vero cells. I. Studies on factors a€ecting the toxin and antitoxin titration. J Biol Stand 1974;2:189±201. [25] Miyamura K, Tajiri E, Ito A, Murata R, Kono R. Micro cell culture method for determination of diphtheria toxin and antitoxin titres using Vero cells. II. Comparison with the rabbit skin method and practical application for seroepidemiological studies. J Biol Stand 1974;2:203±9. [26] World Health Organization 1989. Second meeting of national programme managers on the Expanded Programme on Immunization, 1989 May, Istanbul, Turkey, Report EUR/ICP/ EPI 021 1905 r. [27] World Health Organization 1990. The control of diphtheria in Europe; 1990 April, Geneva, Switzerland. Report EUR/ICP/ EPI 024 5582 r. [28] Pasetti M, Eriksson P, Ferrero F, Manghi M. Serum antibodies to diphtheria±tetanus±pertussis vaccine components in Argentine children. Infection 1997;25:339±45. [29] Stark K, SchoÈnfeld C, Barg J, Molz B, Vornwald A, Bienzle U. Seroprevalence and determinants of diphtheria, tetanus and poliomyelitis antibodies among adults in Berlin, Germany. Vaccine 1999;17:844±50. [30] Liese JG, Stojanov S, Belohradsky BH. Pertussis vaccination with acellular vaccines. Tolerance±e€ectiveness Ð current vaccination recommendations. Fortschr Med 1997;115:22±7. [31] Anderson RM, May RM. Immunisation and herd immunity. Lancet 1990;335:641±5. [32] Hadler SC. Cost bene®t of combining antigens. Biologicals 1994;22:415±8.

2082

M. Van der Wielen et al. / Vaccine 18 (2000) 2075±2082

[33] Begue P, Grimprel E. Future combined vaccines. J Infect Dis 1996;174(Suppl 3):S295±S297. [34] Storsaeter J, Hallander HO, Gustafsson L, Olin P. Levels of anti-pertussis antibodies related to protection after household exposure to Bordetella pertussis. Vaccine 1998;16:1907±16. [35] Cherry JD, Gornbein J, Heininger U, Stehr K. A search for serologic correlates of immunity to Bordetella pertussis cough illnesses. Vaccine 1998;16:1901±6. [36] Greco D, Salmaso S, Mastrantonio P, et al. A controlled trial of two acellular vaccines and one whole-cell vaccine against pertussis. Progetto Pertosse Working Group. N Engl J Med 1996;334:341±8. [37] Salmaso S, Mastrantonio P, Wassilak SGF, et al. Persistence of protection through 33 months of age provided by immunization in infancy with two three-component acellular pertussis vaccines. Vaccine 1998;16:1270±5. [38] Schmitt HJ, Wirsing von KoÈnig CH, Neiss A, et al. Ecacy of acellular pertussis vaccine in early childhood after household exposure. JAMA 1996;275:37±41. [39] Schmitt HJ, Schuind A, Knuf M, et al. Clinical experience of a tricomponent acellular pertussis vaccine combined with diphtheria and tetanus toxoids for primary vaccination in 22,505 infants. J Pediatr 1996;129:695±701. [40] Wassilak SGF, Orenstein WA, Sutter RW. Tetanus toxoid. In: Plotkin SA, Mortimer Jr EA, editors. Vaccines, 2nd ed. Philadelphia: Saunders, 1994. p. 57±90. [41] Simonsen O, Klñrke M, Klñrke A, et al. Revaccination of adults against diphtheria. II: Combined diphtheria and tetanus revaccination with di€erent doses of diphtheria toxoid 20 years

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

after primary vaccination. Acta Pathol Microbiol Immunol Scand 1986;94:219±25. Aggerbeck H, Fenger C, Heron I. Booster vaccination against diphtheria and tetanus in man. Comparison of calcium phosphate and aluminium hydroxide as adjuvants Ð II. Vaccine 1995;13:1366±74. Aggerbeck H, Wantzin J, Heron I. Booster vaccination against diphtheria and tetanus in man. Comparison of three di€erent vaccine formulations Ð III. Vaccine 1996;14:1265±72. Dal-Re R, Gil A, Gonzalez A, Lasheras L. Does tetanus immune globulin interfere with the immune response to simultaneous administration of tetanus-diphtheria vaccine? A comparative clinical trial in adults. J Clin Pharmacol 1995;35:420±5. Galazka AM, Robertson SE. Immunization against diphtheria with special emphasis on immunization of adults. Vaccine 1996;14:845±57. MatheõÈ C, Van Damme P, Bruynseels P, Goossens H, Vranckx R, Meheus A. Diphtheria immunity in Flanders. Eur J Clin Microbiol Infect Dis 1997;16:631±6. Cohen D, Green MS, Katzenelson E, Slepon R, Bercovier H, Wiener M. Long-term persistence of anti-diphtheria toxin antibodies among adults in Israel. Eur J Epidemiol 1994;10:267±70. Mortimer Jr EA. Diphtheria Toxoid. In: Plotkin SA, Mortimer Jr EA, editors. Vaccines, 2nd ed. Philadelphia: Saunders, 1994. p. 41±56. Hederstedt B, GranstroÈm M. Adverse reactions and antibody response to an acellular pertussis toxoid vaccine in adult volunteers. Vaccine 1989;7:349±50.