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Safety and Immunogenicity of a Pentavalent Combination Vaccine (Diphtheria, Tetanus, Acellular Pertussis, Polio and Haemophilus Influenzae Type b Conjugate) When Administered as a Fourth Dose at 15 to 18 Months of Age D. W. Scheifele, Scott A. Halperin, E. Rubin, B. Tapiero, R. Guasparini, W. Meekison, G. Predy, E. Mills & F. Noriega Published online: 04 Nov 2005.
To cite this article: D. W. Scheifele, Scott A. Halperin, E. Rubin, B. Tapiero, R. Guasparini, W. Meekison, G. Predy, E. Mills & F. Noriega (2005) Safety and Immunogenicity of a Pentavalent Combination Vaccine (Diphtheria, Tetanus, Acellular Pertussis, Polio and Haemophilus Influenzae Type b Conjugate) When Administered as a Fourth Dose at 15 to 18 Months of Age, Human Vaccines, 1:5, 180-186, DOI: 10.4161/hv.1.5.2079 To link to this article: http://dx.doi.org/10.4161/hv.1.5.2079
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[Human Vaccines 1:5, 180-186, September/October 2005]; ©2005 Landes Bioscience
Safety and Immunogenicity of a Pentavalent Combination Vaccine (Diphtheria, Tetanus, Acellular Pertussis, Polio, and Haemophilus Influenzae Type b Conjugate) when Administered as a Fourth Dose at 15 to 18 Months of Age
UT E
.
ABSTRACT
A DTaP-IPV//PRP-T combination vaccine (Pentacel™) has been universally used in Canada to provide immunization against diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae type b with single injections at 2, 4, 6 and 18 months of age. This randomized, multicenter study was conducted to evaluate administration of a fourth dose of DTaP-IPV//PRP-T at 15 to 18 months of age, similar to the US immunization schedule. Participants who had received three doses of DTaP-IPV//PRP-T by 8 months of age were enrolled at 12 months and randomized to receive a fourth dose at 15, 16, 17 or 18 months. Antibody levels for each vaccine antigen were measured prior to and four weeks following booster vaccination. Overall, 1782 subjects were immunized and monitored for adverse events, and 735 were evaluated for immune responses. Preimmunization antibody levels differed minimally by age, for all antigens. The immune responses elicited by DTaP-IPV//PRP-T were comparable between participants vaccinated at 15 or 16 months and those vaccinated at 17 or 18 months, as demonstrated by specific antibody geometric mean titers, seroprotection/seroresponse rates, and reverse cumulative distribution curves. The fourth dose was well tolerated in all age groups. Toddlers at 15, 16, 17 or 18 months of age are equally suitable recipients for booster immunization with the DTaP-IPV//PRP-T vaccine.
Evaluation Center; British Columbia’s Children’s Hospital; Vancouver, British Columbia, Canada
2Clinical Trials Research Center; IWK Health Centre; Dalhousie University; Halifax,
Nova Scotia, Canada
5The Associated Study Centre; Surrey, British Columbia, Canada 7Capital Health Authority; Edmonton, Alberta, Canada
In 2003, the National Immunization Survey from the US Centers for Disease Control and Prevention (CDC) found that the rate at which children 19–35 months of age completed the standard immunization series for young children had increased to 79%,1,2 but that nearly 1 million children in the United States failed to complete the schedule. Although various factors are known to affect vaccination coverage, including socioeconomic class, age, and parental concerns about vaccine safety,3-5 the complexity of the childhood vaccination schedule has received less attention. The current US schedule requires up to 22 injections administered during four to six office visits, during the first 18 months of life and the number of injections may increase as new vaccines become available.6 The use of combination parenteral vaccines, in which multiple antigens are delivered in a single vial or syringe, is common worldwide.7 Since 1997, a DTaP-IPV//PRP-T combination vaccine (Pentacel™) has been administered universally to Canadian children at 2, 4, 6 and 18 months of age, providing protection against diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae type b (Hib). Since its introduction in Canada, this combination vaccine has maintained control over vaccine-preventable infections in young children, including invasive Hib disease.8 The addition of newer vaccines to the Canadian immunization schedule may necessitate more flexibility in the timing of the fourth dose of DTaP-IPV//PRP-T vaccine. In the United States, the CDC Advisory Committee on Immunization Practices,6 the American Academy of Pediatrics, and the American Academy of Family Physicians recommend infant vaccination with DTaP and Hib vaccines at 2, 4 and 6 months of age, with a fourth dose of DTaP at 15–18 and Hib at 12–15 months of age. This differs from the primary series for IPV, with recommended administration at 2, 4 and 6–18 months of age.6 To support the inclusion of DTaP-IPV//PRP-T vaccine in the US schedule, data
BIO
8Sanofi Pasteur Limited; Toronto, Ontario, Canada
INTRODUCTION
SC
6Westcoast Clinical Research; Port Coquitlam, British Columbia, Canada
IEN
4Hôpital Ste-Justine pour les Enfants; Montreal, Quebec, Canada
CE
3Montreal Children’s Hospital; Montreal, Quebec, Canada
.D
1Vaccine
ON
OT D
IST
RIB
D.W. Scheifele1 S.A. Halperin2 E. Rubin3 B. Tapiero4 R. Guasparini5 W. Meekison6 G. Predy7 E. Mills8 F. Noriega9
9Sanofi Pasteur Inc..; Swiftwater, Pennsylvania, USA
ES
*Correspondence to: D.W. Scheifele; Vaccine Evaluation Center; British Columbia’s Children's Hospital; Vancouver, British Columbia, Canada; Email:
[email protected]
ND
Received 07/04/05; Accepted 07/29/05
Previously published online as a Human Vaccines E-publication:
LA
http://www.landesbioscience.com/journals/vaccines/abstract.php?id=2079
05
KEY WORDS
20
vaccine, childhood, diphtheria, tetanus, pertussis, poliomyelitis, Haemophilus influenzae
ACKNOWLEDGEMENTS
©
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Research Paper
This study was funded by Sanofi Pasteur Limited. We thank Miggi Tomovici M.D., David Greenberg M.D., David Jemiolo MS, and Lisa DeTora Ph.D. of Sanofi Pasteur for assistance with data analysis and manuscript preparation, and Timothy Voloshen, Ph.D. for performing serology analyses.
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regarding immunogenicity and safety characteristics in the age range of 15–18 months are necessary. This study examined whether a fourth dose of DTaP-IPV//PRP-T, administered at 15, 16, 17 or 18 months, produced consistent immune responses and safety profiles.
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MATERIALS AND METHODS
Table 1
Demographic profiles by age group of subjects immunized*
Total (N) Gender (n [%]) Male Female
15 Months
16 Months
17 Months
18 Months
445
449
450
438
215 (48.3) 230 (51.7)
211 (47.0) 238 (53.0)
222 (49.3) 228 (50.7)
213 (48.6) 225 (51.4)
Study design. This open-label, randomized, multicenter Age (months) study was performed in seven Canadian centers in Mean (SD) 15.4 (0.27) 16.4 (0.26) 17.4 (0.26) 18.3 (0.26) 2000–2001. Eligible participants were randomized (1:1:1:1) Race (n [%]) to receive a fourth dose of DTaP-IPV//PRP-T at 15, 16, 17 Caucasian 383 (86.1) 385 (85.7) 384 (85.3) 380 (86.8) or 18 months of age. Participants at three centers (two in Black 10 (2.2) 7 (1.6) 9 (2.0) 8 (1.8) Montreal and one in Halifax) provided sera for immunoassays Hispanic 6 (1.3) 4 (0.9) 4 (0.9) 1 (0.2) prior to and approximately 30 days after vaccination. The Asian 19 (4.3) 19 (4.2) 28 (6.2) 11 (2.5) trial was conducted in accordance with the principles outlined East Indian 9 (2.0) 10 (2.2) 9 (2.0) 7 (1.6) in the Declaration of Helsinki. Approval was obtained from Native Indian 2 (0.4) 1 (0.2) 2 (0.4) 4 (0.9) the Institutional Review Board or Ethics Committee at each Other 16 (3.6) 23 (5.1) 14 (3.1) 27 (6.2) participating center. Study participants. Study personnel explained the study *ITT population procedures and obtained informed consent from the parents or legal custodians of participants. Eligible participants were healthy toddlers, Adverse events requiring healthcare provider contact (telephone call, office 12 months of age, who had completed a routine three-dose primary series or hospital visit) were recorded for 60 days after immunization. Serious with DTaP-IPV//PRP-T combination vaccine (Pentacel™) by eight months adverse events were documented from enrollment at 12 months to completion of age. Exclusions to enrollment included: a history of developmental delay of follow-up (Day 60). or neurologic disorder; clinically diagnosed or laboratory- confirmed pertussis; Immunogenicity analysis. Blood samples (2.4–5.0 ml) were drawn prior chronic underlying medical, congenital or developmental disorder; known or to and 28–48 days after vaccination at participating centers. Sera were suspected hypersensitivity to any component of the study vaccine; impaired processed and frozen immediately for subsequent analyses. immunologic function or receipt of immunosuppressive therapy or Antibody concentrations (µg/ml) to H. influenzae type b PRP were immunoglobulins; and prior immunization with a fourth dose of diphtheria, determined using a Farr-type radioimmunoassay, following specifications tetanus, pertussis, H. influenzae type b conjugate, or poliovirus vaccine established by the Food and Drug Administration, Center for Biologics (either inactivated or oral). Evaluation and Research (CBER). Antibody concentrations of PT, FHA, Vaccines and vaccination. DTaP-IPV//PRP-T vaccine was prepared by FIM and PRN were determined by an enzyme-linked immunosorbent assay using a dose of liquid DTaP-IPV (QuadracelTM, sanofi pasteur) to reconstitute (ELISA) method; results were expressed in ELISA units (EU)/ml. Poliovirus lyophilized PRP-T (ActHIB®, sanofi pasteur). The DTaP-IPV product antibody titers were determined using a serum neutralization assay, expressed contained in each 0.5 ml dose: diphtheria toxoid (15 limit of flocculation as the reciprocal titration achieving neutralization. Tetanus toxoid antibody [Lf ]), tetanus toxoid (5 Lf ), five acellular pertussis antigens (20 µg pertussis concentrations, determined by ELISA, and diphtheria antibody titers, detertoxoid [PT], 20 µg filamentous hemagglutinin [FHA], 5 µg fimbriae types mined by toxin neutralization assay, were both reported in International 2 and 3 [FIM], and 3 µg pertactin [PRN]), three poliovirus antigens (40 D Units (IU)/ml by comparison to calibrated World Health Organization antigen units poliovirus type 1 [Mahoney], eight D antigen units poliovirus (WHO) reference sera. type 2 [MEF1], and 32 D antigen units poliovirus type 3 [Saukett]), Immune responses were assessed by calculating increases in geometric aluminum phosphate, and 2-phenoxyethanol. The PRP-T component was mean antibody concentrations or titers (GMT), seroresponse to each a sterile, lyophilized powder of 10 µg H. influenzae type b capsular polysac- pertussis antigen (≥ 4-fold post-vaccination rise in antibody), and seroprocharide (PRP) covalently bound to 24 µg tetanus toxoid. A single lot of each tection to diphtheria; tetanus; poliovirus types 1, 2 and 3; and PRP antigens. product was used. Seroprotection was defined as an antibody concentration ≥0.1 IU/ml for Each dose of vaccine was injected into the deltoid muscle using a 25 gauge diphtheria and tetanus, ≥ 1:8 for poliovirus, and ≥ 1.00 µg/ml for PRP. 1-inch needle. No concurrent vaccines were given. No live vaccine was given Reverse cumulative distribution curves were plotted for pre and post-immuwithin 60 days before or after the study vaccination. As a courtesy, the nization antibody concentrations for each vaccine antigen. varicella and combined measles, mumps and rubella (MMR) vaccines were Statistical analysis. The primary objective of the trial was to determine offered upon study entry, at 12 months of age, to participants who had not if antibody responses to a booster dose of DTaP-IPV//PRP-T vaccine were yet received them. similar among children 15, 16, 17 and 18 months of age by comparing Safety assessment. Subjects were observed at the study sites for 30 minutes responses to each antigen for the combined group of 15- or 16-month-olds after vaccination to detect and treat any immediate reactions. Parents recorded relative to the combined group of 17- or 18-month-olds. For the primary prespecified local and systemic reactions, and unsolicted adverse events on evaluation criteria of seroprotection and seroresponse rates, predefined diary cards for seven days following vaccination. Compliance was encouraged equivalence bounds were -10% and 10% for the two-sided 90% confidence by telephone contacts with parents on Days 4 and 8 after vaccination. interval (CI) for the between-group differences. For GMTs one month after Solicited local injection-site reactions included redness, swelling and tenderness. The vaccination, the predefined equivalence bounds were 2/3 and 1.5 for the extent of redness or swelling was measured with a standard ruler. The upper two-sided 90% CI of the ratios of the two combined groups. Similarity of arm circumference of both arms was measured daily at the level of the axilla preimmunization antibody levels was assessed among the four individual age using a standard tape measure. Axillary temperature was measured daily groups. Age at the time of vaccination, in months for each subject was using a standard electronic thermometer. Solicited systemic reactions were calculated as: fussiness, crying, decreased appetite, decreased activity, rash, vomiting, and diarrhea. Parents rated the severity of each symptom as mild, moderate or (vaccination date - date of birth + 1)/(365.25/12). severe based on prespecified descriptive criteria.
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The principal safety outcome was the rate of fever ≥ 38°C during the three days following immunization. Fever data for the two combined age groups were compared. Equivalence was demonstrated if the two-sided 90% CI of the difference in fever rate between the two combined age groups was -10% to 10%. A descriptive comparison was performed on all local and systemic reaction rates within seven days after vaccination for each of the four individual age groups. With a planned enrollment of 1800 participants for the safety assessment and 760 for the immunogenicity assessment, the study was designed to have at least 92% power to identify between-group differences, anticipating a dropout rate of 20%. Power to recognize an increased rate of fever by the combined age groups was >99%, based on an effective sample size of 355 subjects per month of age.
Table 2 Antigens
RESULTS Participants. A total of 1869 participants were enrolled, and 1782 received a fourth dose of DTaP-IPV//PRP-T (safety population). A sixty-day safety follow-up was completed by 1773 subjects: six withdrew voluntarily, two were lost to follow-up, and one was noncompliant with study procedures. Among the 817 participants at the study sites collecting
Geometric mean titers (95% confidence intervals) before and 28 days following a fourth dose of DTaP-IPV//PRP-T
PRP (µg/ml)
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Immunogenicity analyses were based on the “per-protocol” (PP) population (eligible subjects who were immunized and provided two blood samples within the specified window), whereas safety analyses were based on the “intent-to-treat” (ITT) population, using all available data from immunized subjects.
Diphtheria (IU/ml)
Tetanus (IU/ml)
PT (EU/ml)
FHA (EU/ml)
FIM (EU/ml)
PRN (EU/ml)
Polio 1 (1/dil)
Polio 2 (1/dil)
Polio 3 (1/dil)
Time
15 Months n=189*
16 Months n=185*
17 Months n=187*
18 Months n=174*
Prevaccination
0.41 (0.33, 0.51)
0.32 (0.25, 0.41)
0.42 (0.34, 0.53)
0.37 (0.29, 0.47)
Postvaccination
29.92 (24.58, 36.43)
28.42 (23.86, 33.86)
37.15 (31.14, 44.33)
35.71 (28.90, 44.13)
Prevaccination
0.14 (0.12, 0.17)
0.11 (0.09, 0.14)
0.09 (0.08, 0.11)
0.08 (0.07, 0.10)
Postvaccination
4.47 (3.86, 5.18)
4.37 (3.82, 5.00)
4.65 (3.98, 5.43)
5.50 (4.75, 6.37)
Prevaccination
0.51 (0.45, 0.57)
0.43 (0.37, 0.50)
0.45 (0.39, 0.51)
0.42 (0.36, 0.49)
Postvaccination
4.42 (3.98, 4.91)
4.02 (3.58, 4.51)
4.80 (4.30, 5.37)
5.11 (4.60, 5.68)
Prevaccination
15.62 (13.74, 17.76)
15.51 (13.32, 18.05)
11.86 (10.29, 13.67)
10.23 (8.90, 11.76)
Postvaccination
251.45 (221.73, 285.16)
222.77 (194.18, 255.58)
267.99 (238.94, 300.57)
274.59 (242.44, 310.99)
Prevaccination
18.48 (16.13, 21.18)
16.24 (14.28, 18.47)
15.50 (13.40, 17.94)
12.89 (10.96, 15.16)
Postvaccination
172.67 (156.57, 190.42)
182.05 (167.94, 197.34)
205.45 (185.92, 227.02)
217.32 (196.61, 240.20)
Prevaccination
44.15 (37.45, 52.04)
36.95 (31.45, 43.42)
35.46 (30.49, 41.24)
34.92 (29.67, 41.09)
Postvaccination
837.67 (726.21, 966.23)
726.75 (627.57, 841.60)
887.05 (767.89, 1024.70)
837.22 (710.67, 986.31)
Prevaccination
11.31 (9.66, 13.24)
10.01 (8.48, 11.82)
9.89 (8.40, 11.64)
9.44 (7.90, 11.29)
Postvaccination
187.71 (163.39, 215.63)
166.33 (144.52, 191.43)
197.60 (169.98, 229.72)
185.83 (158.83, 217.41)
Prevaccination
161.37 (128.34, 202.91)
96.33 (76.18, 121.80)
84.67 (67.78, 105.77)
79.32 (62.55, 100.59)
Postvaccination
4717.36 (3897.23, 5710.08)
3493.03 (2904.12, 4201.35)
4111.20 (3423.14, 4937.57)
4023.23 (3397.15, 4764.69)
Prevaccination
362.73 (293.33, 448.55)
244.30 (197.44, 302.27)
234.20 (190.20, 288.38)
223.40 (181.09, 275.59)
Postvaccination
8466.90 (7243.23, 9897.29)
6547.12 (5493.76, 7802.46)
7329.91 (6280.39, 8554.82)
7341.98 (6328.46, 8517.83)
Prevaccination
263.03 (206.54, 334.98)
164.15 (129.35, 208.31)
124.52 (99.25, 156.21)
99.45 (77.01, 128.43)
Postvaccination
9372.05 (7960.98, 11033.23)
7362.32 (6169.32, 8786.01)
7023.94 (5784.12, 8529.51)
6213.36 (5113.37, 7549.97)
*Total number with one or more evaluable measurement; N’s for individual measurements varied by up to nine participants for the 15-month age group, and up to four participants in the remaining groups. PRP, polyribosyl-ribitol-phosphate capsular polysaccharide of H. influenzae type b; PT, pertussis toxoid; FHA, filamentous hemagglutinin; FIM, fimbriae types 2 and 3; PRN, pertactin.
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sera, 771 received a fourth dose of DTaPIPV//PRP-T, of which 735 provided both pre Table 3 Summary of geometric mean titer ratios post-fourth dose of DTaP-IPV//PRP-T† and post-immunization blood samples sufficient for a serology test result for at least one antigen GMT GMT within the prescribed window (immunogenicity population). Gender and race distributions 17 + 18 Months 15 + 16 Months 15 + 16 Months were similar among the four treatment groups n = 374 n = 361 17 + 18 Months (Table 1). More than 85% of participants were (90% Confidence Interval) Caucasian. PRP (g/ml) Immunogenicity. Preimmunization GMTs Prevaccination 0.36 0.40 across the four age groups for each antigen 29.2 36.5 0.80 (0.68–0.94) showed some differences for specific pairwise Postvaccination comparisons (diphtheria, PT, FHA and polio Diphtheria (IU/ml) antibodies) as indicated by nonoverlapping Prevaccination 0.13 0.09 95% confidence intervals (Table 2). This was Postvaccination 4.42 5.04 0.88 (0.78–0.99) not unexpected, as lower GMTs were seen at Tetanus (IU/ml) 18 months compared to 15 months. 0.47 0.43 Post-immunization GMTs were similar for the Prevaccination combined group vaccinated at 15 or 16 Postvaccination 4.22 4.95 0.85 (0.78–0.93) months relative to those vaccinated at 17 or 18 PT (EU/ml) months. For each antigen, robust booster 15.6 11.1 responses were observed in all age groups Prevaccination 237 271 0.87 (0.79–0.97) (Table 2). For all antigens except polio, the Postvaccination antibody values were slightly greater in the FHA (EU/ml) group vaccinated at 17 or 18 months relative to Prevaccination 17.3 14.2 those vaccinated at 15 or 16 months, but the Postvaccination 177 211 0.84 (0.78–0.91) values met the predefined equivalence criteria FIM (EU/ml) for the two age groups (Table 3). Reverse cumulative distribution curves for Prevaccination 40.4 35.2 post-immunization antibodies to the five per- Postvaccination 781 863 0.91 (0.80–1.03) tussis antigens were nearly superimposable for PRN (EU/ml) the two combined age groups (Fig. 1), as were 10.7 9.67 the curves for the remaining antigens (data not Prevaccination shown). The seroprotection/seroresponse rates Postvaccination 177 192 0.92 (0.82–1.04) following the booster dose are shown in Polio 1 (1/dil) (Table 4). Children in both combined age Prevaccination 125 82.1 groups produced high levels of antibodies that Postvaccination 4070 4070 1.00 (0.86–1.16) fulfilled the prespecified definition of equivalence between the combined age groups for Polio 2 (1/dil) each vaccine antigen. Prevaccination 297 229 Safety. Nine participants experienced one Postvaccination 7458 7340 1.02 (0.89–1.16) or more reactions within 30 minutes after Polio 3 (1/dil) vaccination, which included injection-site 207 112 redness (n = 4), injection-site bruising (n = 2), Prevaccination rashes or urticaria (n = 2) and tremor (n = 1). Postvaccination 1.26 (1.08–1.46) 6620 8310 All immediate reactions resolved without †Per-protocol immunogenicity population; PRP = polyribosyl-ribitol-phosphate capsular polysaccharide of H. influenzae type b; PT, pertussis toxoid; sequelae. During the first three days after vaccination, FHA, filamentous hemagglutinin; FIM, fimbriae 2 and 3; PRN, pertactin. approximately 16–19% of participants in the combined groups experienced some fever, and approximately 6% had moderate or severe fever (>38.5˚C). Fever rates did (42.1%, 733/1741) and anorexia (31.7%, 552/1741). Most cases were mild. not differ significantly between the two combined age groups. Crying, diarrhea, and decreased activity were reported for 27.4% Most solicited reactions were mild or moderate in intensity. Redness was (477/1740), 23.7% (412/1740) and 25.3% (440/1740) of participants, the most frequently reported injection-site reaction in all age groups, occur- respectively, while vomiting and rash were reported for 6.1% (106/1740) ring in approximately half the participants in the four individual age groups and 4.7% (81/1741) of participants, respectively. Compared with results (Table 5). For all groups combined, severe redness (>50 mm) occurred in obtained three days after immunization, similar proportions of participants 4.1% (72/1735) of subjects. Increased upper arm circumference, tenderness, in the four individual age groups had systemic reactions within seven days and swelling were recorded in 37.7% (647/1714), 33.7% (586/1740) and after immunization. 31.6% (546/1729) of the participants, respectively. Severe upper arm swelling Unsolicited adverse events judged by the investigator to be possibly, (increase in circumference >40 mm) occurred in only 1.1% (18/1714) of probably, or definitely related to the study vaccine occurred in 10.4% participants. Compared with results obtained three days after immunization, (185/1782) of all subjects during the entire sixty-day follow-up period. The similar proportions of participants in the four individual age groups had most common events possibly related to study vaccine involved upper respiinjection-site reactions within seven days after immunization. ratory symptoms and other infections; events probably or definitely related In general, the percentage of participants reporting solicited systemic to vaccination mainly involved the administration site. symptoms was similar for both combined age groups. The most common Twenty-nine participants (1.7%) experienced 42 serious adverse events symptoms occurring during the three days after immunization were fussiness during Days 0 to 60 after vaccination. These events were distributed evenly
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Figure 1. Reverse cumulative antibody distribution curves for pertussis antigens. **Per-protocol immunogenicity population; †PT, pertussis toxoid; ‡FHA, filamentous hemagglutinin; §FIM, fimbriae 2 and 3; PRN, pertactin.
the primary immunization series (number of doses, ages at which they are given, immunogenicity of the vaccine used), the expected decline in antibody levels and protection in subsequent months, timing of routine well-child visits, and parental compliance with the recommended schedule. This study is noteworthy for having considered in detail some potential advantages and disadvantages of booster immunization with DTaP-IPV//PRP-T at 15 or 16 months DISCUSSION versus 17 or 18 months of age, as a wider window for this dose would The timing of first booster dose administration in childhood immu- aid uptake and incorporation in national vaccination schedules. It nization schedules is influenced by many considerations, including was expected that younger children might experience higher rates of injection-site reactions as a result of their higher residual preimmunization Table 4. Seroprotection/seroresponse rates post-fourth dose of DTaP-IPV//PRP-T* antibody levels or that they might experience inferior responses as a result Difference in Rate of their reduced immunologic maturity. Antigen Seroprotection/ 15 + 16 17 + 18 15 + 16 Months – (90% CI) † However, older children might have seroresponse Months Months 17 + 18 Months lower preimmunization antibody levels, Threshold Criteria (%) (%) (%) affording less certain protection, but a greater ability to respond to booster (-2.10, 0.55) -0.77 99.2 ≥ 1.0 µg/ml 98.4 PRP stimuli. This study, therefore, was Diphtheria ≥ 0.1 IU/ml 100.0 100.0 0.00 NA powered to detect relatively small differTetanus ≥ 0.1 IU/ml 100.0 100.0 0.00 NA ences in immune responses and safety PT ≥ 4-fold rise 93.5 97.8 -4.30 (-6.79, -1.82) profiles between the two combined age groups. The results indicate that adminFHA ≥ 4-fold rise 86.8 92.5 -5.71 (-9.39, -2.02) istration of DTaP-IPV//PRP-T at 15, FIM ≥ 4-fold rise 93.5 95.6 -2.10 (-4.87, 0.68) 16, 17 and 18 months of age produces ≥ 4-fold rise 94.3 92.8 1.55 (-1.45, 4.54) PRN generally equivalent responses, in terms Polio 1 ≥ 1:8 dilution 99.7 100.0 -0.27 (-0.71, 0.17) of immunogenicity and safety. Polio 2 ≥ 1:8 dilution 100.0 100.0 0.00 NA Participants in this study had 100.0 100.0 0.00 NA Polio 3 ≥ 1:8 dilution received three doses of a DTaP-IPV// *Per-protocol immunogenicity population; †CI, Confidence interval equivalence was demonstrated if the 2-sided 90% CI for the difference in seropro- PRP-T vaccine at approximately 2, 4 tection/seroresponse rates was between -10% and 10%; PRP, polyribosyl-ribitol-phosphate capsular polysaccharide of H. influenzae type b; PT, and 6 months of age, from community pertussis toxoid; FHA, filamentous hemagglutinin; FIM, fimbriae 2 and 3; PRN, pertactin; NA, not applicable. providers. Prelicensure studies of this across the age groups. The majority (69%, 29/42) were infectious in nature, including five cases of pneumonia. None of the serious adverse events was assessed by the investigator as related to study vaccination. Two subjects had febrile seizures during the week after vaccination, both in conjunction with upper respiratory tract infection. No hypotonic-hyporesponsive episodes were reported.
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vaccine demonstrated high rates of immune responses to each component upon com- Table 5 Percentage of subjects with solicited local and systemic reactions 0 to 3 days after DTaP-IPV//PRP-T administration* pletion of the primary series.9 By enrolling participants at 12 months of age, we were 15 Months 16 Months 17 Months 18 Months All able to ensure compliance with the randomLocal (%) ly assigned booster vaccination schedules. Preimmunization antibody levels differed Redness Any (>5 mm) 51.5 51.4 58.2 56.0 54.2 slightly between 15- and 18-month-old Severe (>50 mm) 2.5 4.8 3.7 5.7 4.1 subjects for some antigens (Table 2), but Swelling there were no significant differences in protective levels. For H. influenzae type b Any (>5 mm) 31.2 29.7 33.6 31.8 31.6 Severe (>50 mm) 2.3 2.3 2.8 1.7 2.3 antibody in particular there were no significant differences in levels between 15- and Pentacel™ Arm Circumference Increase † 18-month-old subjects. Our observations Any (>5 mm) 37.0 39.3 37.5 37.2 37.7 are consistent with previous reports that Severe (>40 mm) 0.7 1.4 1.2 1.0 1.1 describe a tetanus toxoid-related decline in NonPentacel™ Arm Circumference Increase † antibody levels in the first months after Any (>5 mm) 16.3 14.7 12.0 14.4 14.4 completion of primary immunization, Severe (>40 mm) 0.2 0.2 0.5 0.2 0.3 following which levels stabilize and decline Tenderness slowly in subsequent months.10 A previous Any 33.0 33.4 35.3 32.9 33.7 study with a DTP-IPV//PRP-T vaccine Severe 2.5 3.0 2.7 3.3 2.9 (with whole-cell pertussis antigens) showed Systemic (%) that antibody levels for all antigens were relatively stable between 12 and 18 months Fever Any (>38.0°C) 14.7 17.7 19.1 18.5 17.5 of age after primary vaccination at 2, 4 and Severe (>39.5°C) 0.2 0.7 1.6 1.2 0.9 11 6 months of age. ‡ Immune responses to a fourth dose of Less Active Any 26.7 24.5 24.4 25.5 25.3 DTaP-IPV//PRP-T, administered at 15, Severe 1.1 0.2 0.7 0.9 0.7 16, 17 or 18 months of age, were robust and consistent throughout this age range. Vomiting Any 6.6 6.8 5.0 5.9 6.1 Post-immunization GMTs were similar Severe (≥3 episodes) 0.2 0.5 0.2 0.7 0.4 across all four age groups for each antigen, with significant booster responses to all Diarrhea antigens observed. Seroprotection/seroreAny 23.2 25.0 25.1 21.3 23.7 sponse rates were equivalent in all age groups. Severe (>5 stools) 0.2 0.5 0.5 0.7 0.5 Finally, reverse cumulative antibody distri- Crying bution curves for all antigens after boosting 25.7 28.3 25.5 27.4 Any 30.1 were nearly identical for the combined Severe (>3 hours) 1.1 0.7 0.9 0.9 0.9 group vaccinated at 15 or 16 months rela- Fussiness tive to the combined group vaccinated at Any 43.3 41.1 42.8 41.1 42.1 17 or 18 months. A previous study showed Severe (>3 hours) 5.2 2.0 6.4 5.0 4.7 that a booster dose of whole-cell Anorexia DTP-IPV//PRP-T vaccine produced higher Any 29.6 31.8 33.0 32.4 31.7 immunologic responses at 18 months than Severe (skipped 2 meals) 3.4 2.3 2.5 3.3 2.9 at 12 or 15 months for virtually every constituent antigen, but responses were Rash Present 3.6 5.0 5.0 5.0 4.7 satisfactory at each age.11 The fourth dose of DTaP-IPV//PRP-T *Safety population; †Relative to baseline circumference of ipsilateral arm; ‡Mild, daily activity not affected, subject interactive; moderate, interferes had a favorable safety profile, as demon- with and limits daily activity, less interactive; severe, no interested in daily activity, disabling. strated by consistently low fever rates and adverse event profiles in all age groups. Safety findings in this study were similar to those previously reported Local reactions tend to be more frequently observed and more with DTaP-IPV//PRP-T vaccine.9 No participant had a serious severe after the 4th and 5th dose of a DTaP vaccine than in any of the adverse event considered related to study vaccine by the investigator, previous three doses of the infant series.14 Swelling of a large limb and no hypotonic hyporesponsive episodes were reported. While area or of the entire extremity are recognized reactions of DTaP booster doses of some DTaP vaccines were reported to cause large immunizations occasionally observed after a booster dose.15 In a injection-site reactions more often than found with primary retrospective analysis of limb swelling occurring after the 4th and 5th doses,12-13 severe local reactions were infrequent in this study. dose of 12 different DTaP vaccines, limb swelling was reported in 20 Redness ≥50 mm diameter was reported by parents in 4.1% of (2%) of 1,015 children that received a DTaP immunization series subjects, and swelling ≥50 mm occurred in 2.3%. with the same DTaP vaccine.16 In this study, arm circumference www.landesbioscience.com
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increase following a 4th dose of Pentacel™ was calculated as an indirect indication of whole limb swelling. An increase of >5 mm was reported in 37.7% of subjects in the Pentacel™ arm and in 14.4% of subjects in the nonimmunized (control) arm, and an increase of >40 mm was reported in 1.1% of subjects in the Pentacel™ arm and in 0.3% of the control arm. Although, a frequency of 1.1% may seem consistent with a previous report,16 reports of increased measurements in the un-immunized arm highlight the questionable reliability of these measurements. Furthermore, none of the parents of subjects with a “severe” arm circumference increase sought medical attention nor did the subjects have systemic signs of reactogenicity (i.e., fever). Combination vaccines were developed to decrease the number of injections, thereby increasing the ease of administration.7 More inclusive combination vaccines might improve vaccination coverage and decrease costs,7 but could compromise safety. Several factors contribute to the definition of an “ideal” combination vaccine, including safety, efficacy, compatibility with the recommended immunization schedule, and ease of use.7 Compatibility of the component antigens is another key consideration. The immunization series followed here provided four doses of IPV vaccine by age 18 months, one in excess of the current recommendation; this fourth dose of IPV was well-tolerated and resulted in strong antibody responses to poliovirus 1, 2 and 3. Some studies, but not others, have documented lower anti-PRP titers after administration of combinations that include Hib vaccine, and researchers have suggested that increases in invasive Hib disease can be associated with the use of acellular rather than whole-cell pertussis antigens in a combination vaccine.17-18 However, in Germany and Canada, high vaccine efficacy persists with the use of a combination vaccine containing acellular pertussis antigens.8,19 The DTaP-IPV//PRP-T combination vaccine used in this study displayed high immunogenicity and a robust booster response for the Hib antigens in all age groups. Nearly 100% seroprotection rates were achieved in groups vaccinated at 15 or 16 months and at 17 or 18 months, using a conservative definition of protection (anti-PRP level ≥1.0 µg/ml). In addition, all of the other antigens in the vaccine produced significant immunologic responses, as determined by conservative seroprotection rates for diphtheria, tetanus, and polio antigens, and by seroresponse rates for the acellular pertussis antigens. In summary, this study showed that toddlers at 15, 16, 17 or 18 months of age were equally suitable recipients for booster immunization with DTaP-IPV//PRP-T vaccine. The vaccine had a favorable safety profile in each age group, and immune responses to each vaccine component were consistently robust after booster vaccination across the full age range of the study.
7. Decker MD. Principles of pediatric combination vaccines and practical issues related to use in clinical practice. Pediatr Infect Dis J 2001; 20:S10-18. 8. Scheifele D, Halperin S, Law B, et al. Invasive Haemophilus influenzae type b infections in vaccinated and unvaccinated children in Canada, 2001-2003. Can Med Assoc J 2005; 172:53-6. 9. Mills E, Gold R, Thipphawong J, et al. Safety and immunogenicity of a combined fivecomponent pertussis-diphtheria-tetanus-inactivated poliomyelitis-Haemophilus B conjugate vaccine administered to infants at two, four and six months of age. Vaccine 1998; 16:576-585. 10. Simonsen O, Badsberg JH, Kjeldsen K, Moller-Madsen B, Heron I. The fall-off in serum concentration of tetanus antitoxin after primary and booster vaccination. Acta Pathol Microbiol Immunol Scand [C] 1986; 94:77-82. 11. Scheifele DW, Guasparini R, Lavigne P. A comparative study of PENTA vaccine booster doses given at 12, 15, or 18 months of age. Vaccine 1999; 17:543-50. 12. Halperin SA, Scheifele D, Mills E, et al. Nature, evolution, and appraisal of adverse events and antibody response associated with the fifth consecutive dose of a five-component acellular pertussis-based combination vaccine. Vaccine 2003 ; 21:2298-306. 13. Pichichero ME, Deloria MA, Rennels MB, et al. A safety and immunogenicity comparison of 12 acellular pertussis vaccines and one whole-cell pertussis vaccine given as a fourth dose in 15- to 20-month-old children. Pediatrics 1997; 100:772-88. 14. CDC. Use of Diphtheria Toxoid-Tetanus Toxoid-Acellular Pertussis Vaccine as a Five-Dose Series. Supplemental Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2000; 49(RR13):1-8. 15. Schmitt HJ, Beutel K, Schuind A, et al. Reactogenicity and immunogenicity of a booster dose of a combined diphtheria, tetanus, and tricomponent acellular pertussis vaccine at fourteen to twenty-eight months of age. J Pediatr 1997; 130:616-23. 16. Rennels MB, Deloria M, Pichichero M, et al. Extensive swelling after booster doses of acellular pertussis-tetanus-diphtheria vaccines. Pediatrics 2000; 105:e12. 17. Granoff DM. Assessing efficacy of Haemophilus influenzae type b combination vaccines. Clin Infect Dis 2001; 33:S278-287. 18. McVernon J, Andrews N, Slack MP, Ramsay ME. Risk of vaccine failure after Haemophilus influenzae type b (Hib) combination vaccines with acellular pertussis. Lancet 2003; 361:1521-3. 19. Schmitt HJ, von Kries R, Hassenpflug B, et al. Haemophilus influenzae type b disease: Impact and effectiveness of diphtheria-tetanus toxoids-acellular pertussis (-inactivated poliovirus)/H. influenzae type b combination vaccines. Pediatr Infect Dis J 2001; 20:767-74.
References 1. Mitka M. Improvement seen in US immunization rates. JAMA 2004; 292:1167. 2. National Center for Health Statistics, C.f.D.C.a.P. The National Immunization Survey, www.cdc.gov/nis 2004. 3. Hutchins SS, Jiles R, Bernier R. Elimination of measles and of disparities in measles childhood vaccine coverage among racial and ethnic minority populations in the United States. J Infect Dis 2004; 189:S146-52. 4. Ramsay ME, Yarwood J, Lewis D, Campbell H, White JM. Parental confidence in measles, mumps and rubella vaccine: Evidence from vaccine coverage and attitudinal surveys. Br J Gen Pract 2002; 52:912-6. 5. Briss P, Shefer A, Rodewald L. Improving vaccine coverage in communities and healthcare systems. no magic bullets. Am J Prev Med 2002; 23(1):70-71. 6. Centers for Disease Control and Prevention. Recommended Childhood and Adolescent Immunization Schedule - United States, January - June 2004. Available at www.cdc.gov/nip/ recs/child-schedule.PDF, 2005.
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