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Immunogenicity and reactogenicity of combined versus separately administered DTPw-HBV and Hib vaccines given to healthy infants at 2, 4 and 6 months of age, with a booster at 18 months
Original Report
Immunogenicity and reactogenicity of combined versus separately administered DTPw-HBV and Hib vaccines given to healthy infants at 2,4 and 6 months of age, with a booster at 18 months Stella Riedemann,(‘) German Reinhardt,(‘) Jaime Jara, Richard Rios,(‘) Maria Soledad Wenzel,(l) Paul Willems, and Hans L. Bockc2) Objectives: To determine the immunogenicity and reactogenicity of a combined DTPw-HBV/Hib parison with DTPw-HBV and Hib vaccines given as separate concomitant injections.
vaccine, in com-
In an open, randomized study, healthy infants were injected with either DTPw-HBV/Hib separate DTPw-HBV and Hib vaccines at 2,4 and 6 months of age, with a booster at 18 months.
Methods:
vaccine or
Results: Both vaccination regimens were immunogenic, with seropositivity rates of 100% after the booster vaccination
for all vaccine components. Even as early as 2 months after the second dose of the primary vaccination, most patients had seroprotective antibody titers, the proportion of seropositive subjects approaching 100% for tetanus, hepatitis B, and Hib. Post-primary and post-booster geometric mean titers (GMTs) were well above seroprotective thresholds for each vaccine antigen in both groups, with no clinically relevant differences in the groups. The separate and combined administrations showed comparable reactogenicity profiles, and neither showed a significant increase in reactogenicity with successive doses. Conclusions: The results of this study support the combination of Hib and DTPw-HBV vaccination in routine infant immunization at 2,4 and 6 months of age with a booster at 18 months. Maximum benefit is obtained from compliance with the full course, but substantial benefit is likely to be achieved even in partially compliant patients, provided they receive at least two doses. Furthermore, these results demonstrate the tolerability of a fourth (booster) administration, where the addition of the Hib vaccine to DTPw-HBV did not lead to an increase in the overall reactogenicity. Int J Infect
Dis 2002;
6: 215-222
INTRODUCTION
Vaccination during childhood provides an effective and cost-effective method of protecting against many diseases. Consequently, programs for mass vaccination of children are widespread in both developed and developing countries. However, with the increasing number of diseases for which effective vaccines can be given, vaccination programs have the potential to involve a large numbers of injections. A common strategy to reduce the number of injections is the use of combination vaccines, in which a single injection contains more than one vaccine.1,2 Combination vaccines in widespread use include diphtheria, tetanus and pertussis (DTP) vaccine, and measles, mumps and rubella (MMR) vaccine. There are many advantages to combining vaccines in this way: not only does it reduce discomfort for patients by sparing them (‘)Universidad Biologicals, Address logicals, E-mail:
Austral Rixensart,
de Chile, Belgium.
Valdivia,
Chile;
(Z)GlaxoSmithKline
correspondence to: Hans L. Bock, GlaxoSmithKline Bio260 Orchard Road, 10-01 The Heeren, Singapore 238855. [email protected]
Corresponding
Editorial
Of&e:
New
York
multiple injections, but it also reduces costs. Reduced costs come from many factors, such as fewer clinic visits, fewer syringes and needles, and a reduced requirement for cold storage of vaccines.3 Moreover, when vaccinations are given separately, there is greater scope for missed doses,4 so combination vaccines can also increase compliance, and hence the overall effectiveness of vaccination programs. However, before combination vaccines can be routinely incorporated into vaccination programs, it is essential to demonstrate that the combination is well tolerated and does not adversely affect the immunogenicity of any of the vaccine components. The World Health Organization (WHO), through its expanded Programme on Immunization (EPI), has recently recommended that Haemophilus influenzae type b (Hib) vaccine should be included in routine infant immunization programs.5 H. influenzae type b (Hib) is responsible for a substantial burden of disease in developed and developing countries, with about 3 million cases of serious disease and 400 000-700 000 deaths annually in young children.5 It can cause various diseases, including meningitis and pneumonia.6 Meningitis caused by Hib can have severe neurologic sequelae, even when promptly treated with appropriate antibiotics,’ so it is highly desirable that children should be
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protected against Hib infection by vaccination. Vaccination programs can be effective in preventing Hib infection: the incidence of invasive H. influenzae infection in children aged less than 5 years fell by 97% during the period 1987-97 in the USA, where routine immunization with Hib conjugate vaccines was introduced in 1988.8 There is also evidence that Hib vaccination can be effective in preventing invasive disease in developing countries.‘,iO The strategy of combination with DTP vaccine has already been adopted for including hepatitis B vaccination (HBV) into immunization prograes. The WHO has recommended that all children should be vaccinated against hepatitis B, and stresses the benefits of combined DTPw-HBV vaccination.” Tritanrix-HB is a combined DTPw-HBV vaccine manufactured by GlaxoSmithKline Biologicals, in accordance with that recommendation, and its immunogenicity and favorable reactogenicity profile have been well established.12-l6 This study was done to investigate the immunogenicity and reactogenicity of Hib vaccination when given in combination with a DTPw-HBV vaccine, in comparison with separate administration. MATERIALS
AND METHODS
Ethics The study was approved by the Ethics Review Committee of the Valdivia Hospital before any patients were enrolled, and was conducted in accordance with the Declaration of Helsinki (Hong Kong revision, 1989) and the Good Clinical Practice guidelines in force at the time. The parents or guardians of all subjects gave written informed consent to participate. Study population,
trial design, and vaccines
Subjects included in the study were healthy male and female infants, aged 6-12 weeks at the time of the first vaccination. Exclusion criteria were presence or history of significant disease, history of allergic disease, immunosuppressive therapy, and any previous vaccination other than with oral polio vaccine or BCG vaccine. Subjects were excluded from further participation in the study if they experienced severe systemic adverse reactions to vaccination. The study was a randomized controlled trial with an open comparative parallel-group design. Vaccinations were given at approximately 2,4 and 6 months of age. The interval between vaccinations ranged from 5 to 11 weeks. A booster vaccination was given at approximately 18 months of age. Subjects were randomly allocated to one of two groups, in a ratio of 1 : 1. Subjects in group 1 received a combined diphtheria, tetanus, whole-cell pertussis, hepatitis B and H. influenzae type b (DTPw-HB/Hib) vaccine, prepared extemporaneously by reconstituting a
lyophilized Hib-tetanus conjugate vaccine (Hiberix, GlaxoSmithKline Biologicals) with a liquid DTPwHBV vaccine (Tritanrix-HB, GlaxoSmithKline Biologicals). The vaccine was given by intramuscular injection in the right arm. Subjects in group 2 received the same vaccines, but given in two separate intramuscular injections: Hib in the left deltoid, and DTPw-HBV in the right deltoid. For the booster dose at 18 months of age, all subjects received the combined vaccine. Data collection Parents took subjects to health care centers, or the study nurse visited the subject’s home. The study nurses then used diary cards to record local and systemic signs and symptoms for the day of each vaccination and the 3 following days (a total of 4 days per vaccination). Nurses were asked to rate the severity of pain at the injection site, and the size of any redness or swelling. They were also asked to record the child’s rectal temperature and rate the severity of the following systemic symptoms: irritability, unusual crying, drowsiness, feeding problems, diarrhea, and vomiting. After establishment by the investigator of their relationship with vaccination in terms of related, possibly related or unrelated, systemic symptoms were classified, together with pain at the injection site, as mild (easily tolerated), moderate (sufficiently discomforting to interfere with the infant’s daily activities), or severe (prevents normal daily activities). In addition, they recorded any other adverse experiences occurring during the first 4 days after vaccination on the diary cards. At each subsequent visit, the investigator transcribed information from the diary cards onto the Case Report Form, and asked about any other adverse experiences that occurred after the period covered by the diary card. Serology Venous blood samples were collected for immunologic assays immediately before the first vaccination, 610 weeks after the second dose, 3-6 weeks after the third dose, and immediately before and 3-6 weeks after the booster dose. The serum collected from those samples was stored at -20°C until it was analyzed, with a blinding procedure, at GlaxoSmithKline Biologicals in Rixensart, Belgium. Antidiphtheria and antitetanus antibodies were determined by enzyme-linked immunosorbent assay (ELISA), with a cutoff of 0.1 IU/mL. Although antidiphtheria and antitetanus titers >O.Ol IU/mL are generally considered to be protective, and the ELISA results are well correlated with in vivo neutralization tests,17Js this correlation may be reduced at antibody titers ~0.1 IU/mL. Therefore, a titer of 0.1 IU/mL by ELISA was conservatively set as the cutoff. AntiBordetella pertussis antibodies were determined using a
Immunogenicity and reactogenicity of combined versus separately administered DTPw-HBV / Riedemann et al
pertussis was defined as an antibody titer above the assay cutoff in subjects who were seronegative before the booster, and a post-booster titer r2 times the prebooster titer in initially seropositive subjects.The second statistical test of immunogenicity was a comparison of the postvaccination antibody titers using Student’s t-test with log-transformed data. Antibody titers are presented as geometric means, with confidence intervals calculated from the log-transformed data.
whole-cell based commercial ELISA kit with an assay cutoff of 1.5 EL.U/mL (Labsystem, ICNFLOW, Helsinki, Finland). Anti-HBs antibody titers were measured using a commercial radioimmunoassay kit (AUSAB, Abbott Laboratories, North Chicago, IL, USA), with a cutoff of 10 mIU/mL. A radiolabeled antigen-binding assay (RABA) was used to measure the antibodies against the Hib polysaccharide, PRP, with a cutoff of 0.15 ug/mL. All cutoff values were considered to be seroprotective titers, with the exception of B. pertussis, for which a seroprotective level is not established. In this case, a vaccine response was measured and defined as a postvaccination antibody titer above the cutoff of 15 EL.U/mL in initially seronegative subjects, and a post-primary vaccination antibody titer equal to or greater than the initial titer (post-booster titer 12 times greater) in initially seropositive subjects.
RESULTS Patients studied In total, 120 infants entered the study, 52 females and 68 males. The mean age was 9.9 (range S-12) weeks. Each treatment group comprised 60 subjects, and there were no significant differences in sex ratio or age between the groups. Only one subject was excluded from the reactogenicity analysis, for having received a vaccine other than the study vaccine. The analysis of immunogenicity for the initial series of three vaccinations included 101 subjects (84% of those entering the study); the most common reason for exclusion from the analysis was failure to comply with the vaccination schedule. Ninety-one subjects received all three vaccinations according to the protocol. Seventy subjects (36 from group 1 and 34 from group 2) received the booster injection at 18 months. Of those subjects, 62 (89 ‘0/ ) were included in the immunogenicity analysis, the remainder being excluded for failure to comply with the blood-sampling schedule.
Statistical methods To test the baseline comparability of the two groups, the ratios of males to females were compared using Fisher’s exact test, and age was compared between groups by two-way ANOVA with the factors group, sex, and group x sex interaction. The null hypothesis that the two treatments were equally reactogenic was tested by comparing the proportions of subjects with specific symptoms between groups using Fisher’s exact test. The null hypothesis that the two treatments were equally immunogenic was tested in two ways. The proportions of patients with seroprotective titers after vaccination were compared between groups using Fisher’s exact test. For pertussis, there is no serologic correlate of protection, so the statistical test for this component instead compared the proportions of patients fulfilling the criterion for a vaccine response. A vaccine response was defined as a postvaccination antibody titer above the cutoff of 1.5 EL.U/mL in initially seronegative subjects, and a postvaccination antibody titer equal to or greater than the initial titer in initially seropositive subjects, For the booster dose, vaccine response to Table
1. Percentages
of patients Group
with Pre-dose
seroprotective
Immunogenicity Vaccination in both groups was clearly immunogenic for all five vaccine components. Even as early as 2 months after the second vaccination, most patients had seroprotective antibody titers, the proportion of seropositive subjects approaching 100% for tetanus, hepatitis B, and Hib (Table 1). Seropositivity rates increased after
antibody Post-dose
titers II
(or with Post-dose
titers Iii
above
the
Pre-booster
assay
cutoff
for pertussis) Post-booster
N
1 2
47 54”
46b 54c
41 40
32 30
Diphtheria
1 2
12.8% 14.8%
84.8% 73.6%
97.6% 97.5%
68.8% 70.0%
100.0% 100.0%
Tetanus
1 2
4.3% 9.3%
97.8% 98.1%
100.0% 100.0%
96.9% 90.0%
100.0% 100.0%
Pertussis
1 2
6.4% 5.6%
69.6% 81.5%
97.6% 100.0%
65.6% 76.7%
100.0% 100.0%
HB
1 2
4.3% 0.0%
95.7% 94.4%
97.6% 100.0%
90.6% 96.7%
100.0% 100.0%
Hib
1 2
31.9% 38.5%
97.8% 98.1%
100.0%
100.0% 96.7%
100.0%
V/=52 for Hib; bN=47 None of the differences
for HB; CN=53 for diphtheria. between groups 1 and 2 is statistically
217
100.0%
significant.
32 30
100.0%
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subsequent vaccinations, and after the booster vaccination all subjects had seroprotective antibody titers for diphtheria, tetanus, hepatitis B, and Hib. The vaccine response rates to the whole-cell B. pertussis component were 97.6% in group 1 and 100% in group 2 after the third dose, and 100% in group 1 and 96.7% in group 2 after the booster. The percentages of subjects with seropositive antibody titers were very similar in the two groups, and the differences in those percentages between the groups were not significant for any of the components after any vaccination. Reactogenicity
There were no more reactions reported in the combined administration group (53.4% of doses) than in the separate group (62.2% of doses). As can be seen from Tables 2 and 3, showing the incidences of systemic and local reactions, differences between groups 1 and 2 were Table 2. Overall incidence of all and severe solicited local reactions after primary vaccination course (three vaccine doses administered at 2, 4 and 6 months respectively) Group
I (N=162)
Group
Right limb (DTP-HBV-Hib) Pain All Severe
17.9% 1.2%
Redness All >20 mm
12.3% 1.2%
Swelling All >20 mm
9.9% 1.9%
2 (N=172)
Right limb (DTP-HBVj
Left limb (Hib)
13.4% 1.2%
12.8% 1.2%
4 1%” o:o%
6.4% 0.6%
7.0% 0.0%
6.4% 0.0%
asignificantly different from group 1, P=O.OOS. Severe pain was defined as preventing normal daily
Table 3. reactions
Incidence of all and (% of all vaccinations) Primary
severe
solicited
1
systemic
course
vaccination
Group (N=762)
activities.
Group (N=172)
2
Booster Group (N=35)
1
Group 2 (N =33)
Diarrhea Severe
1.9 0.0
1.2 0.0
0.0 0.0
0.0 0.0
Drowsiness Severe
14.8 0.0
15.7 0.0
2.9 0.0
9.1 0.0
6.8 0.0
8.7 0.0
2.9 0.0
3.0 0.0
Irritability Severe
30.2 0.6
36.6 0.6
17.1 0.0
27.3 0.0
Fever t 38°C Fever 2 39.5X
32.1 0.6
39.5 1.2
28.6 2.9
36.4 0.0
2.5 0.0
2.3 0.0
0.0 0.0
0.0 0.0
Feeding Severe
Vomiting Severe
problems
primary vaccination course doses at 2, 4 and 6 months
included administration of age, respectively.
of three
vaccine
not statistically significant, except for redness, which was significantly more common in group 1 than at the site of the DTP-HBV injection in group 2 (P=O.OOS, Fisher’s exact test). However, in spite of the absence of clinically significant differences between the two groups, the separate administration of DTPw-HB and Hib causes local reactions after each injection, in this case 17.4% added to 16.3%, compared to 22.7% in the case of the DTPw-HB/Hib combination. It is noteworthy that the incidence of severe pain at the injection site was low, and no cases of severe pain lasted for more than 24 h. Local reactions after the booster vaccination were similar (data not shown). The incidence of systemic reactions decreased with successive doses of primary vaccination and after the booster dose. For each individual dose, there was a trend towards an increased incidence of systemic symptoms in group 2 (Figure l), although this did not reach statistical significance. The most common solicited symptoms were fever, irritability, and drowsiness (Table 3). Most solicited symptoms were considered ‘related’ or ‘possibly related’ to treatment by the investigator. The majority of symptoms lasted for less than 24 h, and few were classified as severe. In addition to the solicited signs and symptoms, 184 doses during the primary vaccination phase and 26 doses during the booster phase were followed by at least one unsolicited adverse event. They were all considered by the investigator to be unrelated to treatment and they were equally distributed between the two groups. The events were mostly of the kind that are common in children of that age: the most frequent ones included bronchitis (42), pharyngitis (22), respiratory disorders (30), viral infections (23), anemia (14), and conjunctivitis (13). Other unsolicited events were either rare (less than five cases) or isolated. Among the unsolicited adverse events listed above, six were serious adverse events (SAEs), three in each group, reported during the primary vaccination phase of the study. They included five cases of bronchopneumonia accompanied by related manifestations, and one case of apnea due to gastroesophageal reflux. All were considered to be unrelated to the study vaccination, and all patients recovered without sequelae. DISCUSSION
The results of this study show clearly that the combination of Hib vaccine with DTPw-HBV does not compromise the immunogenicity of any of the components. For all five components of the combined vaccine, seroconversion rates and antibody geometric mean titers (GMTs) after each vaccination were similar whether Hib vaccine was given in combination with or separately from the other components. Both administrations proved to be highly immunogenic, and even after only two vaccinations the seroconversion rates were very high.This could be important
Immunogenicity and reactogenicity of combined versus separately administered DTPw-HBV / Riedemann et al
Dose Figure
1. Total
incidence
of symptoms
after
each
1
Dose
T
Figure
2. Geometric
mean
titers
(-c95%
confidence
Dose 3
Booster
vaccination.
in developing countries, where compliance with the full course of injections might not be as high as in a clinical trial setting. Nonetheless, the results of this study do not support a reduction in the recommended number of injections, as seroconversion rates were still higher after the third dose. Serologic measurements immediately before the booster showed that the antibody titers had persisted over a l-year period. Although titers were lower at this time than at 1 month after the third dose, they were still substantially higher than before the primary vaccination, and were still at seroprotective levels in most subjects. The dramatic increases in antibody titers after the booster are typical of an anamnestic response, showing that the immune system was effectively primed by the earlier course of injections. There was no clear difference between the two groups in the response to the booster, which shows that the priming of the immune system is not compromised by combining the Hib vaccine with the other components. The GMTs of antibodies confirmed the similar immunogenicity of the two modes of vaccine administration (Figures 2-6). The only statistically significant difference between the treatment groups was higher
Prevaccination
2
219
anti-PRP titers after the booster vaccination in group 1 (P=O.O07), but that difference is unlikely to be clinically significant, as the GMT in each group was substantially above the seroprotective level, and all subjects had protective antibody titers.19,20 Concern has been raised that the immune response to Hib vaccines might be compromised when given in combination with DTP vaccines.21,22 However, the results of this study show clearly that this is not true of the vaccines used in this study, which has also been shown in earlier studies.23,24However, this phenomenon appears to be confined to DTPa;25,26 it may be possible that the adjuvant effect of the Pw component compensates for any suppression of the Hib response.27 The addition of the Hib vaccine to the DTPw-HB combination did not lead to an increase in the overall reactogenicity. There was a trend towards a higher incidence of local reactions for the combination vaccine, which was significant for redness. However, it must be borne in mind that giving the Hib vaccine separately requires twice as many injections as the combination vaccine, so the overall burden of local reactions may be lower for the combined vaccine. In any case, local tolerability was good for both regimens, with a low
T
Post-dose intervals)
2 Post-dose of antidiphtheria
3
Pre-booster antibodies.
Post-booster
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10 iE 3z
1
CG s-7 1 E 6
0.1
0.01
Prevaccination Figure
3.
Geometric
mean
titers
(?95%
confidence
Post-dose
2 Post-dose
intervals)
of antitetanus
Post-dose
2 Post-dose
3 Pre-booster
Post-booster
antibodies,
1000
1 Pre-
3 Pre-booster
vaccination Figure
4.
Geometric
mean
titers
(295%
2
10000
E 3 E.
1000
$ C ?
100
0 ii
a
confidence
intervals)
of anti-B.
pertussis
Postbooster
antibodies.
10
1 Pre-
Post-dose
Post-dose
2
3
vaccination Figure
5.
Geometric
mean
titers
(*95%
confidence
Pre-booster
Post-
booster
intervals).
incidence of severe injection site reactions. Moreover, the incidence of local reactions was less than the rates reported by Gustafsson et a128for DTPw vaccine alone; in particular, pain was reported in more than 50% of doses compared to 17.9% in our study. Systemic reactions to the vaccine were also similar in both treatment groups. Most systemic reactions resolved within 24 h, and few
were classified as severe, showing the good tolerability of both treatments. This is the first report of administration of a fourth (booster) dose. Neither the combined nor separate administration of these vaccines caused any significant increase in reactogenicity; in fact, the converse was observed when vaccine was given as a booster in the second year of life.
Immunogenicity and reactogenicity of combined versus separately administered DTPw-HBV / Riedemann
Prevaccination **P < 0.01 Group Figure
6.
Geometric
mean
titers
(+95%
confidence
Post-dose
1 versus intervals)
2 Post-dose
Group
3 Pre-booster
et al
221
Postbooster
2. t-test of anti-PRP
The results of this study are consistent with those of
other studies in which Hib vaccine has been given in combination with DTP-HBV vaccines. Win et al also found that the combined vaccine had similar immunogenicity and reactogenicity to separate vaccinations, with doses given at 1.5,3 and 5 months of age.23 Bravo et al compared combined and separate vaccinations with Hib and DTPw-HBV at the WHO recommended schedule of 6,10 and 14 weeks of age, after a dose of HBV given at birth. 24 Again, there was little difference between the two regimens in either immunogenicity or reactogenicity. Usonis et al also found the combination of Hib with DTPw-HBV to be highly immunogenic with vaccinations at 3,4.5 and 6 months of age.*” In conclusion, the results of this study add to evidence from other studies that the Hib and DTPwHBV vaccines used in this study can be combined in the same syringe without compromising immunogenicity or tolerability. However, the results of this study cannot be generalized to combinations other than that of Hiberix with Tritanrix-HB, which are both, including the combination, WHO approved. Combinations of Hib and DTPw-HBV vaccines from other manufacturers would require separate studies to demonstrate their immunogenicity and tolerability. ACKNOWLEDGMENTS The research described in this manuscript was funded by GlaxoSmithKline Biologicals. REFERENCES 1. Choo S,Finn A. Pediatric combination vaccines.Curr Opin Pediatr 1999; 11:14-20. 2. Centers for Disease Control and Prevention. Combination vaccines for childhood immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians (AAFP). MMWR 1999: 48(No. RR-5):1-16.
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3. Weniger BG, Chen RT, Jacobson SH, et al. Addressing the challenges to immunization practice with an economic algorithm for vaccine selection. Vaccine 1998; 16:1885-1897. F. 4. Ferson MJ, McKenzie KA, Macartney-Bourne Fragmentation of scheduled visits and missed doses among infants receiving multiple injected vaccines. Aust NZ J Public Health 1997; 21:735-738. 5. World Health Organization. Global Programme for Vaccines and Immunization (GPV): The WHO Position
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WER 1998; 73:64-68. 6. Shapiro ED, Ward JI. The epidemiology and prevention of disease caused by Haemophilus injkenzae type b. Epidemiol Rev 1991; 13:113-142. 7. Rauter L, Mutz I. Haemophilus influenzae meningitis 1983 to 1992-epidemiology and sequelae of the disease.Wien Klin Wochenschr 1994; 106:187-192. 8. Centers for Disease Control and Prevention. Progress towards eliminating Haemophilus influenzae type b disease
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MMWR 1998; 47:993-998. 9. Lagos R, Horwitz 1,Toro J, et al. Large scale,postlicensure, selective vaccination of Chilean infants with PRP-T conjugate vaccine: practicality and effectiveness in preventing invasive Haemophilus influenzae type b infections. Pediatr Infect Dis J 1996; 15:21&222. 10. Mulholland K, Hilton S, Adegbola R, et al. Randomised trial of Haemophilus infiuenzae type-b tetanus protein conjugate for prevention of pneumonia and meningitis in Gambian infants. Lancet 1997; 349:1191-1197. 11. World Health Organisation. The children’s vaccine initiative and the global programme for vaccines and immunization: recommendations from the special advisory group of experts, Part I. WER 1996; 71:261-266. 12. Chiu HH, Huang LM, Lee PI, Safary A, Lee CY. Diphtheria, tetanus and whole cell pertussis vaccine combined with hepatitis B vaccines: a comparison of two doses (10 ug and 5 ug). Pediatr Infect Dis J 1998; 17: 206211. 13. Papaevangelou G, Karvelis E,Alexiou D, et al. Evaluation of a combined tetravalent diphtheria, tetanus, whole-cell pertussis and hepatitis B candidate vaccine administered to healthy infants according to a three-dose vaccination schedule. Vaccine 1995: 13:175-178.
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14. Diez-Delgado J, Dal-RC R, Llorente M, Gonzalez A, Lopez J. Hepatitis B component does not interfere with the immune response to diphtheria, tetanus and whole-cell Bordetella pertussis component of a quadrivalent (DTPwHB) vaccine: a controlled trial in healthy infants. Vaccine 1997; 1.5:1418-1422. 1.5. Usonis V, Bakasenas V, Taylor D, Vandepapelibre P Immunogenicity and reactogenicity of a combined DTPwhepatitis B vaccine in Lithuanian infants. Eur J Pediatr 1996; 15.5:189-193. 16. Poovorawan Y, Theamboonler A, Sanpavat S, Chumdermpadetsuk S, Safary A, Vandepapelibre P Longterm antibody persistence after booster vaccination with combined tetravalent diphtheria, tetanus, whole-cell Bordetella pertussis and hepatitis B vaccine in healthy infants. Ann Trop Paediatr 1997; 17:301-308. 17. Melville-Smith ME, Balfour E. Estimation of Corynebacterium diphtheriae antitoxin in human sera: a comparison of enzyme-linked immunosorbent assay with the toxin neutralisation test. J Med Microbial 1988; 25:279283. 18. Melville-Smith ME, Seagroatt VA, Watkins JT. A comparison of enzyme-linked immunosorbent assay (ELISA) with the toxin neutralisation test in mice as a method for the estimation of tetanus antitoxin in human sera. J Biol Stand 1983; 11:137-144. 19. Eskola J,Ward J, Dagan R, Goldblatt D, Zepp F, Siegrist C-A. Combined vaccination of Haemophilus influenzae type b conjugate and diphtheria-tetanus-pertussis containing acellular pertussis. Lancet 1999; 354:2063-2068. 20. Kayhty H, Eskola J, Peltola H, Saarinen L, Makela PH. High antibody responses to booster doses of either Haemophilus influenzae capsular polysaccharide or conjugate vaccine after primary immunization with conjugate vaccines.J Infect Dis 1983; 147:llOO.
21. Eskola J. Analysis of Haemophilus influenzae type b conjugate and diphtheria-tetanus-pertussis combination vaccines.J Infect Dis 1996; 174(suppl3):S302-S305. 22. Begue P, Grimpel E. Future combined vaccines. J Infect Dis 1996; 174(suppl3):S295-S297. 23. Win KM, Aye M, Htay-Htay H, Safary A, Bock HL. Comparison of separate and mixed administration of DTPw-HBV and Hib vaccines: immunogenicity and reactogenicity profiles. Int J Infect Dis 1997; 2:79-84. 24. Bravo L, Carlos J, Gatchalian S, et al. The new DTPwHBV-Hib combination vaccine can be used at the WHO schedule with a monovalent dose of hepatitis B vaccine at birth. SEA J Trop Med Public Health 1998; 29(4):772-778. 25. Granoff D. Challenges for licensure of new diphtheria tetanus toxoid, acellular pertussis (DTaP) combination vaccines: point. Pediatr Infect Dis J 1996; 15:1069-1070. 26. Edwards KM, Decker MD. Challenges for licensure of new diphtheria tetanus toxoid, acellular pertussis (DTaP) combination vaccines: counterpoint. Pediatr Infect Dis J 1996; 15:107t%1073. 27. Vogel FR, Leclerc C, Schutze MP, et al. Modulation of carrier-induced epitopic suppression by Bordetellapertussis components and muramyl peptide. Cell Immunol 1987; 107340-51. 28. Gustafsson L, Hallander HO, Olin P, Reizenstein E, Storsaeter J. A controlled trial of a two-component acellular, a five-component acellular, and a whole-cell pertussis vaccine. N Engl J Med 1996; 334:349-355. 29. Usonis V, Bakasenas V, Willems P,Bock HL. Evaluation of the immunogenicity and reactogenicity of a new combined diphtheria, tetanus, whole-cell B pertussis and hepatitis B vaccine and Haemophilus influenzae type b (DTPwHBV/Hib) vaccine in children at 3, 4.5 and 6 months of age. Acta Med Lith 1999; 6(3):187-191.
Immunogenicity and reactogenicity of combined versus separately administered DTPw-HBV and Hib vaccines given to healthy infants at 2,4 and 6 months of age, with a booster at 18 months Stella Riedemann,(‘) German Reinhardt,(‘) Jaime Jara, Richard Rios,(‘) Maria Soledad Wenzel,(l) Paul Willems, and Hans L. Bockc2) Objectives: To determine the immunogenicity and reactogenicity of a combined DTPw-HBV/Hib parison with DTPw-HBV and Hib vaccines given as separate concomitant injections.
vaccine, in com-
In an open, randomized study, healthy infants were injected with either DTPw-HBV/Hib separate DTPw-HBV and Hib vaccines at 2,4 and 6 months of age, with a booster at 18 months.
Methods:
vaccine or
Results: Both vaccination regimens were immunogenic, with seropositivity rates of 100% after the booster vaccination
for all vaccine components. Even as early as 2 months after the second dose of the primary vaccination, most patients had seroprotective antibody titers, the proportion of seropositive subjects approaching 100% for tetanus, hepatitis B, and Hib. Post-primary and post-booster geometric mean titers (GMTs) were well above seroprotective thresholds for each vaccine antigen in both groups, with no clinically relevant differences in the groups. The separate and combined administrations showed comparable reactogenicity profiles, and neither showed a significant increase in reactogenicity with successive doses. Conclusions: The results of this study support the combination of Hib and DTPw-HBV vaccination in routine infant immunization at 2,4 and 6 months of age with a booster at 18 months. Maximum benefit is obtained from compliance with the full course, but substantial benefit is likely to be achieved even in partially compliant patients, provided they receive at least two doses. Furthermore, these results demonstrate the tolerability of a fourth (booster) administration, where the addition of the Hib vaccine to DTPw-HBV did not lead to an increase in the overall reactogenicity. Int J Infect
Dis 2002;
6: 215-222
INTRODUCTION
Vaccination during childhood provides an effective and cost-effective method of protecting against many diseases. Consequently, programs for mass vaccination of children are widespread in both developed and developing countries. However, with the increasing number of diseases for which effective vaccines can be given, vaccination programs have the potential to involve a large numbers of injections. A common strategy to reduce the number of injections is the use of combination vaccines, in which a single injection contains more than one vaccine.1,2 Combination vaccines in widespread use include diphtheria, tetanus and pertussis (DTP) vaccine, and measles, mumps and rubella (MMR) vaccine. There are many advantages to combining vaccines in this way: not only does it reduce discomfort for patients by sparing them (‘)Universidad Biologicals, Address logicals, E-mail:
Austral Rixensart,
de Chile, Belgium.
Valdivia,
Chile;
(Z)GlaxoSmithKline
correspondence to: Hans L. Bock, GlaxoSmithKline Bio260 Orchard Road, 10-01 The Heeren, Singapore 238855. [email protected]
Corresponding
Editorial
Of&e:
New
York
multiple injections, but it also reduces costs. Reduced costs come from many factors, such as fewer clinic visits, fewer syringes and needles, and a reduced requirement for cold storage of vaccines.3 Moreover, when vaccinations are given separately, there is greater scope for missed doses,4 so combination vaccines can also increase compliance, and hence the overall effectiveness of vaccination programs. However, before combination vaccines can be routinely incorporated into vaccination programs, it is essential to demonstrate that the combination is well tolerated and does not adversely affect the immunogenicity of any of the vaccine components. The World Health Organization (WHO), through its expanded Programme on Immunization (EPI), has recently recommended that Haemophilus influenzae type b (Hib) vaccine should be included in routine infant immunization programs.5 H. influenzae type b (Hib) is responsible for a substantial burden of disease in developed and developing countries, with about 3 million cases of serious disease and 400 000-700 000 deaths annually in young children.5 It can cause various diseases, including meningitis and pneumonia.6 Meningitis caused by Hib can have severe neurologic sequelae, even when promptly treated with appropriate antibiotics,’ so it is highly desirable that children should be
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protected against Hib infection by vaccination. Vaccination programs can be effective in preventing Hib infection: the incidence of invasive H. influenzae infection in children aged less than 5 years fell by 97% during the period 1987-97 in the USA, where routine immunization with Hib conjugate vaccines was introduced in 1988.8 There is also evidence that Hib vaccination can be effective in preventing invasive disease in developing countries.‘,iO The strategy of combination with DTP vaccine has already been adopted for including hepatitis B vaccination (HBV) into immunization prograes. The WHO has recommended that all children should be vaccinated against hepatitis B, and stresses the benefits of combined DTPw-HBV vaccination.” Tritanrix-HB is a combined DTPw-HBV vaccine manufactured by GlaxoSmithKline Biologicals, in accordance with that recommendation, and its immunogenicity and favorable reactogenicity profile have been well established.12-l6 This study was done to investigate the immunogenicity and reactogenicity of Hib vaccination when given in combination with a DTPw-HBV vaccine, in comparison with separate administration. MATERIALS
AND METHODS
Ethics The study was approved by the Ethics Review Committee of the Valdivia Hospital before any patients were enrolled, and was conducted in accordance with the Declaration of Helsinki (Hong Kong revision, 1989) and the Good Clinical Practice guidelines in force at the time. The parents or guardians of all subjects gave written informed consent to participate. Study population,
trial design, and vaccines
Subjects included in the study were healthy male and female infants, aged 6-12 weeks at the time of the first vaccination. Exclusion criteria were presence or history of significant disease, history of allergic disease, immunosuppressive therapy, and any previous vaccination other than with oral polio vaccine or BCG vaccine. Subjects were excluded from further participation in the study if they experienced severe systemic adverse reactions to vaccination. The study was a randomized controlled trial with an open comparative parallel-group design. Vaccinations were given at approximately 2,4 and 6 months of age. The interval between vaccinations ranged from 5 to 11 weeks. A booster vaccination was given at approximately 18 months of age. Subjects were randomly allocated to one of two groups, in a ratio of 1 : 1. Subjects in group 1 received a combined diphtheria, tetanus, whole-cell pertussis, hepatitis B and H. influenzae type b (DTPw-HB/Hib) vaccine, prepared extemporaneously by reconstituting a
lyophilized Hib-tetanus conjugate vaccine (Hiberix, GlaxoSmithKline Biologicals) with a liquid DTPwHBV vaccine (Tritanrix-HB, GlaxoSmithKline Biologicals). The vaccine was given by intramuscular injection in the right arm. Subjects in group 2 received the same vaccines, but given in two separate intramuscular injections: Hib in the left deltoid, and DTPw-HBV in the right deltoid. For the booster dose at 18 months of age, all subjects received the combined vaccine. Data collection Parents took subjects to health care centers, or the study nurse visited the subject’s home. The study nurses then used diary cards to record local and systemic signs and symptoms for the day of each vaccination and the 3 following days (a total of 4 days per vaccination). Nurses were asked to rate the severity of pain at the injection site, and the size of any redness or swelling. They were also asked to record the child’s rectal temperature and rate the severity of the following systemic symptoms: irritability, unusual crying, drowsiness, feeding problems, diarrhea, and vomiting. After establishment by the investigator of their relationship with vaccination in terms of related, possibly related or unrelated, systemic symptoms were classified, together with pain at the injection site, as mild (easily tolerated), moderate (sufficiently discomforting to interfere with the infant’s daily activities), or severe (prevents normal daily activities). In addition, they recorded any other adverse experiences occurring during the first 4 days after vaccination on the diary cards. At each subsequent visit, the investigator transcribed information from the diary cards onto the Case Report Form, and asked about any other adverse experiences that occurred after the period covered by the diary card. Serology Venous blood samples were collected for immunologic assays immediately before the first vaccination, 610 weeks after the second dose, 3-6 weeks after the third dose, and immediately before and 3-6 weeks after the booster dose. The serum collected from those samples was stored at -20°C until it was analyzed, with a blinding procedure, at GlaxoSmithKline Biologicals in Rixensart, Belgium. Antidiphtheria and antitetanus antibodies were determined by enzyme-linked immunosorbent assay (ELISA), with a cutoff of 0.1 IU/mL. Although antidiphtheria and antitetanus titers >O.Ol IU/mL are generally considered to be protective, and the ELISA results are well correlated with in vivo neutralization tests,17Js this correlation may be reduced at antibody titers ~0.1 IU/mL. Therefore, a titer of 0.1 IU/mL by ELISA was conservatively set as the cutoff. AntiBordetella pertussis antibodies were determined using a
Immunogenicity and reactogenicity of combined versus separately administered DTPw-HBV / Riedemann et al
pertussis was defined as an antibody titer above the assay cutoff in subjects who were seronegative before the booster, and a post-booster titer r2 times the prebooster titer in initially seropositive subjects.The second statistical test of immunogenicity was a comparison of the postvaccination antibody titers using Student’s t-test with log-transformed data. Antibody titers are presented as geometric means, with confidence intervals calculated from the log-transformed data.
whole-cell based commercial ELISA kit with an assay cutoff of 1.5 EL.U/mL (Labsystem, ICNFLOW, Helsinki, Finland). Anti-HBs antibody titers were measured using a commercial radioimmunoassay kit (AUSAB, Abbott Laboratories, North Chicago, IL, USA), with a cutoff of 10 mIU/mL. A radiolabeled antigen-binding assay (RABA) was used to measure the antibodies against the Hib polysaccharide, PRP, with a cutoff of 0.15 ug/mL. All cutoff values were considered to be seroprotective titers, with the exception of B. pertussis, for which a seroprotective level is not established. In this case, a vaccine response was measured and defined as a postvaccination antibody titer above the cutoff of 15 EL.U/mL in initially seronegative subjects, and a post-primary vaccination antibody titer equal to or greater than the initial titer (post-booster titer 12 times greater) in initially seropositive subjects.
RESULTS Patients studied In total, 120 infants entered the study, 52 females and 68 males. The mean age was 9.9 (range S-12) weeks. Each treatment group comprised 60 subjects, and there were no significant differences in sex ratio or age between the groups. Only one subject was excluded from the reactogenicity analysis, for having received a vaccine other than the study vaccine. The analysis of immunogenicity for the initial series of three vaccinations included 101 subjects (84% of those entering the study); the most common reason for exclusion from the analysis was failure to comply with the vaccination schedule. Ninety-one subjects received all three vaccinations according to the protocol. Seventy subjects (36 from group 1 and 34 from group 2) received the booster injection at 18 months. Of those subjects, 62 (89 ‘0/ ) were included in the immunogenicity analysis, the remainder being excluded for failure to comply with the blood-sampling schedule.
Statistical methods To test the baseline comparability of the two groups, the ratios of males to females were compared using Fisher’s exact test, and age was compared between groups by two-way ANOVA with the factors group, sex, and group x sex interaction. The null hypothesis that the two treatments were equally reactogenic was tested by comparing the proportions of subjects with specific symptoms between groups using Fisher’s exact test. The null hypothesis that the two treatments were equally immunogenic was tested in two ways. The proportions of patients with seroprotective titers after vaccination were compared between groups using Fisher’s exact test. For pertussis, there is no serologic correlate of protection, so the statistical test for this component instead compared the proportions of patients fulfilling the criterion for a vaccine response. A vaccine response was defined as a postvaccination antibody titer above the cutoff of 1.5 EL.U/mL in initially seronegative subjects, and a postvaccination antibody titer equal to or greater than the initial titer in initially seropositive subjects, For the booster dose, vaccine response to Table
1. Percentages
of patients Group
with Pre-dose
seroprotective
Immunogenicity Vaccination in both groups was clearly immunogenic for all five vaccine components. Even as early as 2 months after the second vaccination, most patients had seroprotective antibody titers, the proportion of seropositive subjects approaching 100% for tetanus, hepatitis B, and Hib (Table 1). Seropositivity rates increased after
antibody Post-dose
titers II
(or with Post-dose
titers Iii
above
the
Pre-booster
assay
cutoff
for pertussis) Post-booster
N
1 2
47 54”
46b 54c
41 40
32 30
Diphtheria
1 2
12.8% 14.8%
84.8% 73.6%
97.6% 97.5%
68.8% 70.0%
100.0% 100.0%
Tetanus
1 2
4.3% 9.3%
97.8% 98.1%
100.0% 100.0%
96.9% 90.0%
100.0% 100.0%
Pertussis
1 2
6.4% 5.6%
69.6% 81.5%
97.6% 100.0%
65.6% 76.7%
100.0% 100.0%
HB
1 2
4.3% 0.0%
95.7% 94.4%
97.6% 100.0%
90.6% 96.7%
100.0% 100.0%
Hib
1 2
31.9% 38.5%
97.8% 98.1%
100.0%
100.0% 96.7%
100.0%
V/=52 for Hib; bN=47 None of the differences
for HB; CN=53 for diphtheria. between groups 1 and 2 is statistically
217
100.0%
significant.
32 30
100.0%
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subsequent vaccinations, and after the booster vaccination all subjects had seroprotective antibody titers for diphtheria, tetanus, hepatitis B, and Hib. The vaccine response rates to the whole-cell B. pertussis component were 97.6% in group 1 and 100% in group 2 after the third dose, and 100% in group 1 and 96.7% in group 2 after the booster. The percentages of subjects with seropositive antibody titers were very similar in the two groups, and the differences in those percentages between the groups were not significant for any of the components after any vaccination. Reactogenicity
There were no more reactions reported in the combined administration group (53.4% of doses) than in the separate group (62.2% of doses). As can be seen from Tables 2 and 3, showing the incidences of systemic and local reactions, differences between groups 1 and 2 were Table 2. Overall incidence of all and severe solicited local reactions after primary vaccination course (three vaccine doses administered at 2, 4 and 6 months respectively) Group
I (N=162)
Group
Right limb (DTP-HBV-Hib) Pain All Severe
17.9% 1.2%
Redness All >20 mm
12.3% 1.2%
Swelling All >20 mm
9.9% 1.9%
2 (N=172)
Right limb (DTP-HBVj
Left limb (Hib)
13.4% 1.2%
12.8% 1.2%
4 1%” o:o%
6.4% 0.6%
7.0% 0.0%
6.4% 0.0%
asignificantly different from group 1, P=O.OOS. Severe pain was defined as preventing normal daily
Table 3. reactions
Incidence of all and (% of all vaccinations) Primary
severe
solicited
1
systemic
course
vaccination
Group (N=762)
activities.
Group (N=172)
2
Booster Group (N=35)
1
Group 2 (N =33)
Diarrhea Severe
1.9 0.0
1.2 0.0
0.0 0.0
0.0 0.0
Drowsiness Severe
14.8 0.0
15.7 0.0
2.9 0.0
9.1 0.0
6.8 0.0
8.7 0.0
2.9 0.0
3.0 0.0
Irritability Severe
30.2 0.6
36.6 0.6
17.1 0.0
27.3 0.0
Fever t 38°C Fever 2 39.5X
32.1 0.6
39.5 1.2
28.6 2.9
36.4 0.0
2.5 0.0
2.3 0.0
0.0 0.0
0.0 0.0
Feeding Severe
Vomiting Severe
problems
primary vaccination course doses at 2, 4 and 6 months
included administration of age, respectively.
of three
vaccine
not statistically significant, except for redness, which was significantly more common in group 1 than at the site of the DTP-HBV injection in group 2 (P=O.OOS, Fisher’s exact test). However, in spite of the absence of clinically significant differences between the two groups, the separate administration of DTPw-HB and Hib causes local reactions after each injection, in this case 17.4% added to 16.3%, compared to 22.7% in the case of the DTPw-HB/Hib combination. It is noteworthy that the incidence of severe pain at the injection site was low, and no cases of severe pain lasted for more than 24 h. Local reactions after the booster vaccination were similar (data not shown). The incidence of systemic reactions decreased with successive doses of primary vaccination and after the booster dose. For each individual dose, there was a trend towards an increased incidence of systemic symptoms in group 2 (Figure l), although this did not reach statistical significance. The most common solicited symptoms were fever, irritability, and drowsiness (Table 3). Most solicited symptoms were considered ‘related’ or ‘possibly related’ to treatment by the investigator. The majority of symptoms lasted for less than 24 h, and few were classified as severe. In addition to the solicited signs and symptoms, 184 doses during the primary vaccination phase and 26 doses during the booster phase were followed by at least one unsolicited adverse event. They were all considered by the investigator to be unrelated to treatment and they were equally distributed between the two groups. The events were mostly of the kind that are common in children of that age: the most frequent ones included bronchitis (42), pharyngitis (22), respiratory disorders (30), viral infections (23), anemia (14), and conjunctivitis (13). Other unsolicited events were either rare (less than five cases) or isolated. Among the unsolicited adverse events listed above, six were serious adverse events (SAEs), three in each group, reported during the primary vaccination phase of the study. They included five cases of bronchopneumonia accompanied by related manifestations, and one case of apnea due to gastroesophageal reflux. All were considered to be unrelated to the study vaccination, and all patients recovered without sequelae. DISCUSSION
The results of this study show clearly that the combination of Hib vaccine with DTPw-HBV does not compromise the immunogenicity of any of the components. For all five components of the combined vaccine, seroconversion rates and antibody geometric mean titers (GMTs) after each vaccination were similar whether Hib vaccine was given in combination with or separately from the other components. Both administrations proved to be highly immunogenic, and even after only two vaccinations the seroconversion rates were very high.This could be important
Immunogenicity and reactogenicity of combined versus separately administered DTPw-HBV / Riedemann et al
Dose Figure
1. Total
incidence
of symptoms
after
each
1
Dose
T
Figure
2. Geometric
mean
titers
(-c95%
confidence
Dose 3
Booster
vaccination.
in developing countries, where compliance with the full course of injections might not be as high as in a clinical trial setting. Nonetheless, the results of this study do not support a reduction in the recommended number of injections, as seroconversion rates were still higher after the third dose. Serologic measurements immediately before the booster showed that the antibody titers had persisted over a l-year period. Although titers were lower at this time than at 1 month after the third dose, they were still substantially higher than before the primary vaccination, and were still at seroprotective levels in most subjects. The dramatic increases in antibody titers after the booster are typical of an anamnestic response, showing that the immune system was effectively primed by the earlier course of injections. There was no clear difference between the two groups in the response to the booster, which shows that the priming of the immune system is not compromised by combining the Hib vaccine with the other components. The GMTs of antibodies confirmed the similar immunogenicity of the two modes of vaccine administration (Figures 2-6). The only statistically significant difference between the treatment groups was higher
Prevaccination
2
219
anti-PRP titers after the booster vaccination in group 1 (P=O.O07), but that difference is unlikely to be clinically significant, as the GMT in each group was substantially above the seroprotective level, and all subjects had protective antibody titers.19,20 Concern has been raised that the immune response to Hib vaccines might be compromised when given in combination with DTP vaccines.21,22 However, the results of this study show clearly that this is not true of the vaccines used in this study, which has also been shown in earlier studies.23,24However, this phenomenon appears to be confined to DTPa;25,26 it may be possible that the adjuvant effect of the Pw component compensates for any suppression of the Hib response.27 The addition of the Hib vaccine to the DTPw-HB combination did not lead to an increase in the overall reactogenicity. There was a trend towards a higher incidence of local reactions for the combination vaccine, which was significant for redness. However, it must be borne in mind that giving the Hib vaccine separately requires twice as many injections as the combination vaccine, so the overall burden of local reactions may be lower for the combined vaccine. In any case, local tolerability was good for both regimens, with a low
T
Post-dose intervals)
2 Post-dose of antidiphtheria
3
Pre-booster antibodies.
Post-booster
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International
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10 iE 3z
1
CG s-7 1 E 6
0.1
0.01
Prevaccination Figure
3.
Geometric
mean
titers
(?95%
confidence
Post-dose
2 Post-dose
intervals)
of antitetanus
Post-dose
2 Post-dose
3 Pre-booster
Post-booster
antibodies,
1000
1 Pre-
3 Pre-booster
vaccination Figure
4.
Geometric
mean
titers
(295%
2
10000
E 3 E.
1000
$ C ?
100
0 ii
a
confidence
intervals)
of anti-B.
pertussis
Postbooster
antibodies.
10
1 Pre-
Post-dose
Post-dose
2
3
vaccination Figure
5.
Geometric
mean
titers
(*95%
confidence
Pre-booster
Post-
booster
intervals).
incidence of severe injection site reactions. Moreover, the incidence of local reactions was less than the rates reported by Gustafsson et a128for DTPw vaccine alone; in particular, pain was reported in more than 50% of doses compared to 17.9% in our study. Systemic reactions to the vaccine were also similar in both treatment groups. Most systemic reactions resolved within 24 h, and few
were classified as severe, showing the good tolerability of both treatments. This is the first report of administration of a fourth (booster) dose. Neither the combined nor separate administration of these vaccines caused any significant increase in reactogenicity; in fact, the converse was observed when vaccine was given as a booster in the second year of life.
Immunogenicity and reactogenicity of combined versus separately administered DTPw-HBV / Riedemann
Prevaccination **P < 0.01 Group Figure
6.
Geometric
mean
titers
(+95%
confidence
Post-dose
1 versus intervals)
2 Post-dose
Group
3 Pre-booster
et al
221
Postbooster
2. t-test of anti-PRP
The results of this study are consistent with those of
other studies in which Hib vaccine has been given in combination with DTP-HBV vaccines. Win et al also found that the combined vaccine had similar immunogenicity and reactogenicity to separate vaccinations, with doses given at 1.5,3 and 5 months of age.23 Bravo et al compared combined and separate vaccinations with Hib and DTPw-HBV at the WHO recommended schedule of 6,10 and 14 weeks of age, after a dose of HBV given at birth. 24 Again, there was little difference between the two regimens in either immunogenicity or reactogenicity. Usonis et al also found the combination of Hib with DTPw-HBV to be highly immunogenic with vaccinations at 3,4.5 and 6 months of age.*” In conclusion, the results of this study add to evidence from other studies that the Hib and DTPwHBV vaccines used in this study can be combined in the same syringe without compromising immunogenicity or tolerability. However, the results of this study cannot be generalized to combinations other than that of Hiberix with Tritanrix-HB, which are both, including the combination, WHO approved. Combinations of Hib and DTPw-HBV vaccines from other manufacturers would require separate studies to demonstrate their immunogenicity and tolerability. ACKNOWLEDGMENTS The research described in this manuscript was funded by GlaxoSmithKline Biologicals. REFERENCES 1. Choo S,Finn A. Pediatric combination vaccines.Curr Opin Pediatr 1999; 11:14-20. 2. Centers for Disease Control and Prevention. Combination vaccines for childhood immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians (AAFP). MMWR 1999: 48(No. RR-5):1-16.
antibodies.
3. Weniger BG, Chen RT, Jacobson SH, et al. Addressing the challenges to immunization practice with an economic algorithm for vaccine selection. Vaccine 1998; 16:1885-1897. F. 4. Ferson MJ, McKenzie KA, Macartney-Bourne Fragmentation of scheduled visits and missed doses among infants receiving multiple injected vaccines. Aust NZ J Public Health 1997; 21:735-738. 5. World Health Organization. Global Programme for Vaccines and Immunization (GPV): The WHO Position
Paper on Haemophilus
influenzae
type b conjugate vaccines.
WER 1998; 73:64-68. 6. Shapiro ED, Ward JI. The epidemiology and prevention of disease caused by Haemophilus injkenzae type b. Epidemiol Rev 1991; 13:113-142. 7. Rauter L, Mutz I. Haemophilus influenzae meningitis 1983 to 1992-epidemiology and sequelae of the disease.Wien Klin Wochenschr 1994; 106:187-192. 8. Centers for Disease Control and Prevention. Progress towards eliminating Haemophilus influenzae type b disease
among infants and children-United
States, 1987-1997.
MMWR 1998; 47:993-998. 9. Lagos R, Horwitz 1,Toro J, et al. Large scale,postlicensure, selective vaccination of Chilean infants with PRP-T conjugate vaccine: practicality and effectiveness in preventing invasive Haemophilus influenzae type b infections. Pediatr Infect Dis J 1996; 15:21&222. 10. Mulholland K, Hilton S, Adegbola R, et al. Randomised trial of Haemophilus infiuenzae type-b tetanus protein conjugate for prevention of pneumonia and meningitis in Gambian infants. Lancet 1997; 349:1191-1197. 11. World Health Organisation. The children’s vaccine initiative and the global programme for vaccines and immunization: recommendations from the special advisory group of experts, Part I. WER 1996; 71:261-266. 12. Chiu HH, Huang LM, Lee PI, Safary A, Lee CY. Diphtheria, tetanus and whole cell pertussis vaccine combined with hepatitis B vaccines: a comparison of two doses (10 ug and 5 ug). Pediatr Infect Dis J 1998; 17: 206211. 13. Papaevangelou G, Karvelis E,Alexiou D, et al. Evaluation of a combined tetravalent diphtheria, tetanus, whole-cell pertussis and hepatitis B candidate vaccine administered to healthy infants according to a three-dose vaccination schedule. Vaccine 1995: 13:175-178.
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14. Diez-Delgado J, Dal-RC R, Llorente M, Gonzalez A, Lopez J. Hepatitis B component does not interfere with the immune response to diphtheria, tetanus and whole-cell Bordetella pertussis component of a quadrivalent (DTPwHB) vaccine: a controlled trial in healthy infants. Vaccine 1997; 1.5:1418-1422. 1.5. Usonis V, Bakasenas V, Taylor D, Vandepapelibre P Immunogenicity and reactogenicity of a combined DTPwhepatitis B vaccine in Lithuanian infants. Eur J Pediatr 1996; 15.5:189-193. 16. Poovorawan Y, Theamboonler A, Sanpavat S, Chumdermpadetsuk S, Safary A, Vandepapelibre P Longterm antibody persistence after booster vaccination with combined tetravalent diphtheria, tetanus, whole-cell Bordetella pertussis and hepatitis B vaccine in healthy infants. Ann Trop Paediatr 1997; 17:301-308. 17. Melville-Smith ME, Balfour E. Estimation of Corynebacterium diphtheriae antitoxin in human sera: a comparison of enzyme-linked immunosorbent assay with the toxin neutralisation test. J Med Microbial 1988; 25:279283. 18. Melville-Smith ME, Seagroatt VA, Watkins JT. A comparison of enzyme-linked immunosorbent assay (ELISA) with the toxin neutralisation test in mice as a method for the estimation of tetanus antitoxin in human sera. J Biol Stand 1983; 11:137-144. 19. Eskola J,Ward J, Dagan R, Goldblatt D, Zepp F, Siegrist C-A. Combined vaccination of Haemophilus influenzae type b conjugate and diphtheria-tetanus-pertussis containing acellular pertussis. Lancet 1999; 354:2063-2068. 20. Kayhty H, Eskola J, Peltola H, Saarinen L, Makela PH. High antibody responses to booster doses of either Haemophilus influenzae capsular polysaccharide or conjugate vaccine after primary immunization with conjugate vaccines.J Infect Dis 1983; 147:llOO.
21. Eskola J. Analysis of Haemophilus influenzae type b conjugate and diphtheria-tetanus-pertussis combination vaccines.J Infect Dis 1996; 174(suppl3):S302-S305. 22. Begue P, Grimpel E. Future combined vaccines. J Infect Dis 1996; 174(suppl3):S295-S297. 23. Win KM, Aye M, Htay-Htay H, Safary A, Bock HL. Comparison of separate and mixed administration of DTPw-HBV and Hib vaccines: immunogenicity and reactogenicity profiles. Int J Infect Dis 1997; 2:79-84. 24. Bravo L, Carlos J, Gatchalian S, et al. The new DTPwHBV-Hib combination vaccine can be used at the WHO schedule with a monovalent dose of hepatitis B vaccine at birth. SEA J Trop Med Public Health 1998; 29(4):772-778. 25. Granoff D. Challenges for licensure of new diphtheria tetanus toxoid, acellular pertussis (DTaP) combination vaccines: point. Pediatr Infect Dis J 1996; 15:1069-1070. 26. Edwards KM, Decker MD. Challenges for licensure of new diphtheria tetanus toxoid, acellular pertussis (DTaP) combination vaccines: counterpoint. Pediatr Infect Dis J 1996; 15:107t%1073. 27. Vogel FR, Leclerc C, Schutze MP, et al. Modulation of carrier-induced epitopic suppression by Bordetellapertussis components and muramyl peptide. Cell Immunol 1987; 107340-51. 28. Gustafsson L, Hallander HO, Olin P, Reizenstein E, Storsaeter J. A controlled trial of a two-component acellular, a five-component acellular, and a whole-cell pertussis vaccine. N Engl J Med 1996; 334:349-355. 29. Usonis V, Bakasenas V, Willems P,Bock HL. Evaluation of the immunogenicity and reactogenicity of a new combined diphtheria, tetanus, whole-cell B pertussis and hepatitis B vaccine and Haemophilus influenzae type b (DTPwHBV/Hib) vaccine in children at 3, 4.5 and 6 months of age. Acta Med Lith 1999; 6(3):187-191.