Interchangeability of 2 Diphtheria-Tetanus-Acellular
Pertussis Vaccines in Infancy
David P. Greenberg, MD*; Larry K. Pickering, MD‡; Shelly D. Senders, MD§; Jeffrey D. Bissey, MD储; Robert A. Howard, MD¶; Mark M. Blatter, MD#; Keith Reisinger, MD#; Michael E. Pichichero, MD**; and
Barbara J. Howe, MD‡‡
ABSTRACT. Objective. Currently, 4 diphtheria-teta-nus-acellular pertussis (DTaP) vaccines are licensed for pediatric use in the United States, and 2 are commercially available. Although a single manufacturer’s DTaP vac-cine should be used for all 3 doses of the primary immu-nization series, some circumstances result in infants re-ceiving DTaP vaccines from more than 1 manufacturer. The purpose of this study was to evaluate the safety and immunogenicity of a mixed sequence of 2 different DTaP vaccines.
Methods. In this multicenter, observer-blinded, con-trolled study, 449 infants were randomized into 1 of 3 groups (1:1:1 ratio) to receive Tripedia at 2, 4, and 6 months of age (control group); Tripedia at 2 and 4 months of age and Infanrix at 6 months of age; or Tripedia at 2 months and Infanrix at 4 and 6 months of age. Other vaccines were administered concurrently as separate in-jections according to the recommended childhood immu-nization schedule. Safety was monitored closely, and standard enzyme immunoassays were used to measure antibody concentrations to each antigen of the DTaP vaccines.
Results. The rates of injection-site and systemic ad-verse events were similar in each study group, and there were no clinically significant differences among groups after any dose. Infants in all 3 groups responded well to each antigen contained in both vaccines, with 97% to 100% seroprotection or vaccine response rates after the 3-dose primary series. Postvaccination geometric mean antibody concentrations and seroprotection or vaccine response rates to nearly all vaccine antigens were as high or higher in the mixed-sequence groups as in the control group.
Conclusion. Initiating the primary immunization se-ries with 1 or 2 doses of Tripedia and completing the 3-dose series with Infanrix is as safe and at least as immunogenic as administering Tripedia for all 3 doses.
Pediatrics2002;109:666 – 672;diphtheria-tetanus-pertussis vaccine, immunogenicity, infant, interchangeability.
ABBREVIATIONS. DTaP, diphtheria-tetanus-acellular pertussis; DTwP, diphtheria-tetanus-whole cell pertussis; Hib,Haemophilus influenzaetype b; OPV, oral poliovirus vaccine; IPV, inactivated poliovirus vaccine; D, diphtheria toxoid; T, tetanus toxoid; PT, pertussis toxoid; FHA, filamentous hemagglutinin; PRN, pertac-tin; EIA, enzyme immunoassay; EU, enzyme immunoassay units; IU, international units; AE, adverse event; CI, confidence interval; GMC, geometric mean antibody concentration; ANOVA, analysis of variance; NIH, National Institutes of Health.
S
ince 1997, diphtheria-tetanus-acellular pertussis (DTaP) vaccines have replaced diphtheria-teta-nus-whole cell pertussis (DTwP) vaccines in the United States, primarily because of reduced reacto-genicity.1– 4 In 1991, the first DTaP vaccine wasli-censed in the United States for booster immunization at 15 to 18 months and 4 to 6 years of age5and in 1996
for primary immunization beginning at 2 months of age.6Currently, DTaP vaccines from 4 different
man-ufacturers are licensed in the United States,7but only
the 2 evaluated in this study are in use. Additional DTaP vaccines are available in other countries. Each DTaP vaccine differs in the number ofBordetella per-tussis antigens and quantity of each antigen. All of the licensed DTaP vaccines were efficacious in 1 or more clinical trials conducted in Sweden, Germany, and/or Italy.8 –12
Because each DTaP vaccine is considered distinct with regard to antigen content and immunogenicity, the American Academy of Pediatrics and the Advi-sory Committee on Immunization Practices recom-mend that a single manufacturer’s vaccine be given, whenever feasible, for all 3 doses of the primary immunization series.6,13 The reason for this
recom-mendation is that only limited data are available on the safety, immunogenicity, or efficacy of mixed se-quences of different manufacturers’ DTaP vaccines administered during the primary series. However, on a practical level, practitioners cannot always ad-here to this recommendation because they may not know which DTaP vaccine was given previously or may not have the particular brand available. The most common situations for this occurrence are when infants move from one health care provider to another or when a physician’s office or health care system changes from stocking DTaP from one man-ufacturer to another. In such circumstances, the phy-From the *University of Pittsburgh School of Medicine, Children’s Hospital
of Pittsburgh, Pittsburgh, Pennsylvania; ‡Eastern Virginia Medical School, Children’s Hospital of the King’s Daughters, Norfolk, Virginia; §Dr Shelly Senders and Associates, University Heights, Ohio;储Everett Clinic, Everett, Washington; ¶Sciman Biomedical Research, Bryan, Texas; #Primary Physi-cians Research, Pittsburgh, Pennsylvania; **Rochester University School of Medicine, Rochester, New York; and ‡‡GlaxoSmithKline, Collegeville, Pennsylvania.
This work was presented, in part, at the 36th Annual Meeting of the Infectious Diseases Society of America; November 12–15, 1998; Denver, CO. Received for publication Jun 7, 2001; accepted Nov 1, 2001.
sician often has no choice but to switch brands dur-ing the primary series.
This trial is the largest study designed to evaluate the safety and immunogenicity of mixed sequences of 2 different US-licensed DTaP vaccines. When the study was initiated in 1997, Tripedia (Aventis Pas-teur, Swiftwater, PA) was licensed in the United States and was the most widely used DTaP vaccine, and Infanrix (SB Biologicals, Rixensart, Belgium) had recently been licensed. The objective of this study was to evaluate the likely scenario at the time when the primary series would start with Tripedia and end with Infanrix. The primary objective was to assess the immunogenicity of each of the 2 mixed sequences compared with the all-Tripedia series.
METHODS Participants
Healthy infants 6 to 12 weeks of age were recruited from 6 investigative sites in the United States after protocol approval by the institutional review board at each site. Informed consent to participate in the study was obtained from 1 or both parents before any experimental procedures were initiated. To be eligible for the study, infants must have received 1 dose of a hepatitis B vaccine at least 2 weeks before enrollment. Participants were excluded from participation if any of the following criteria were met: premature birth (⬍36 weeks’ gestation), known or suspected immune dysfunction, birth to a hepatitis B surface antigen–posi-tive or human immunodeficiency virus–posiantigen–posi-tive mother, presence of a major congenital defect or serious illness, history of any neurologic or seizure disorder, receipt of any blood product or immunoglobulin preparation, history of previous immunization with any vaccine except hepatitis B vaccine, or current rectal temperatureⱖ100.4°F (38°C).
Study Design
In a single-blind, controlled manner, 449 infants were enrolled and randomized into 3 groups in a 1:1:1 ratio using a computer-generated list. In group 1, Tripedia was administered at 2, 4, and 6 months of age. In group 2, Tripedia was administered at 2 and 4 months of age followed by Infanrix at 6 months of age. In group 3, Tripedia was administered at 2 months of age, followed by Infanrix at 4 and 6 months of age. Each DTaP vaccine was admin-istered by intramuscular injection in the upper right anterolateral thigh. All participants concurrently receivedHaemophilus influen-zaetype b (Hib) conjugate vaccine (OmniHIB; Hib tetanus conju-gate, PRP-T, Aventis Pasteur) in the upper left anterolateral thigh. Hepatitis B vaccine (Engerix-B, SB Biologicals) was adminis-tered in the lower left anterolateral thigh; the first dose had previously been administered at least 2 weeks before study en-rollment, and the second and third doses were administered at 2 and 7 to 9 months of age to complete the series. Participants received poliovirus vaccine in a schedule determined by each investigator. When oral poliovirus vaccine (OPV; Orimune, Led-erle Laboratories, Pearl River, NY) was used exclusively, study participants were vaccinated concurrently with the DTaP vaccines at 2, 4, and 6 months of age. When a sequential inactivated poliovirus vaccine (IPV)-OPV regimen was used, IPV (IPOL, Aventis Pasteur) was given concurrently with the study vaccines at 2 and 4 months of age, no polio vaccine was given at 6 months, and OPV was given after study completion. When IPV was given, it was administered subcutaneously in the lower right anterolat-eral thigh.
Because the DTaP vaccines could not be supplied in identical packaging, the research nurses who administered the study vac-cines were not blinded. However, the parents and all study per-sonnel who collected infant diary and safety information were blinded throughout the study. In addition, laboratory personnel who performed antibody assays were blinded to group assign-ment.
Vaccines
Single lots each of DTaP vaccine and PRP-T vaccine and 2 lots of hepatitis B vaccine were supplied. Tripedia vaccine (lot 7G81491) contained diphtheria and tetanus toxoids manufactured by Aventis Pasteur and acellular pertussis components manufac-tured by the Research Foundation for Microbial Diseases of Osaka University (Biken, Osaka, Japan). Each 0.5-mL dose of Tripedia contained 6.7 Lf of diphtheria toxoid (D), 5 Lf of tetanus toxoid (T), 23.4g of pertussis toxoid (PT), 23.4g of filamentous hemag-glutinin (FHA), and 0.17 mg of aluminum as salts. Infanrix vaccine (lot DTPa833A2/M) contained D and T manufactured by Chiron Behring (Marburg, Germany) and acellular pertussis components manufactured by SB Biologicals. Each 0.5-mL dose of Infanrix contained 25 Lf of D, 10 Lf of T, 25g of PT, 25g of FHA, 8g of pertactin (PRN), and 0.5 mg aluminum as salts. Engerix-B (lots ENG2283A2 and ENG2617A2), manufactured by SB Biologicals, contained 10 g of hepatitis B surface antigen and 0.25 mg of aluminum as salts. OmniHIB vaccine (lot MO293) manufactured by Aventis Pasteur was supplied in lyophilized form and required reconstitution with diluent (0.4% NaCl solution). Each 0.5-mL dose contained 10g ofH influenzaetype b polysaccharide bound to 24g of T protein. Trivalent live OPV (Orimune) was obtained commercially from Lederle Laboratories, and IPV (IPOL) was obtained commercially from Aventis Pasteur (no lot control for these 2 vaccines).
Antibody Response
To evaluate responses to the study vaccines, we obtained blood specimens just before the first dose at 2 months of age and 1 month after the third dose at 7 months of age. Standard laboratory procedures were followed to separate and store the serum speci-mens at⫺20°C until assayed. Concentrations of serum antibodies to vaccine antigens were assessed at the University of Rochester using standardized laboratory assay methods by personnel who were unaware of the vaccine group assignments. To assess re-sponse to pertussis antigens, we measured antibody concentra-tions to PT, FHA, and PRN by enzyme immunoassay (EIA); re-sults were expressed in enzyme immunoassay units (EU) per milliliter.14The EIA plates were coated with purified PT, FHA,
and PRN supplied by SB Biologicals, and, for each antigen, the cutoff for detection was set at 5 EU/mL. EIA methods also were used to assess responses to D and T, with the results expressed in international units (IU) per milliliter.14Purified D and T for
coat-ing the plates were supplied by SB Biologicals; the cutoff for detection was set at 0.10 IU/mL.
Safety Evaluation
Study participants were observed for 15 minutes after each vaccination. Parents were instructed to record potential adverse events (AEs) on standardized diary cards at bedtime on the day of vaccination and for the following 3 evenings. Solicited signs and symptoms recorded by the parents included the child’s rectal temperature, reactions at the injection sites, and systemic symp-toms. Signs and symptoms were considered grade 3 (severe) for fever ⬎39.5°C, irritability (persistent crying that could not be comforted), any other systemic symptom that was incapacitating and prevented normal everyday activities, soreness (cried with limb movement), and redness and swelling (affected area⬎20 mm in its largest diameter). Research personnel contacted all parents by telephone between 1 and 3 days after each immunization to inquire about serious AEs and to remind them to complete the diary cards. Parents were asked to mail the completed diary cards back to the investigator using preaddressed and stamped enve-lopes. When parents failed to mail the cards, the information was collected by telephone interview. At each visit, parents were ques-tioned about the occurrence of potentially serious AEs. Additional information regarding illnesses between visits was obtained from the child’s medical record and parent interviews.
Statistical Analysis
In addition, assuming ␣ ⫽ 0.05 and a 2-sided test of the null hypothesis that the rate of AE among the 3 groups was different, a sample size of 125 participants per group was sufficient to detect a 2-fold difference in AE rates with 90% power given an expected AE rate in the control group of 20%.
Concentrations of antibodies were log transformed, and geo-metric mean antibody concentrations (GMCs) were compared us-ing analysis of variance (ANOVA). Antibody concentrations be-low the be-lower limit of detection were assigned a value of one half of the lower limit. The definition of vaccine response to pertussis antigens (PT, FHA, and PRN) depended on the serostatus of the participant at 2 months of age. For initially seronegative partici-pants (⬍5 EU/mL), vaccine response was defined as the appear-ance of antibodiesⱖ5 EU/mL at 7 months of age. For initially seropositive participants (ⱖ5 EU/mL), vaccine response was de-fined as at least maintenance of prevaccination antibody concen-trations to reflect the natural waning of maternal antibodies. For antibody response to D and T, seroprotection status (at 2 and/or 7 months of age) was defined as antibody concentrations ofⱖ0.10 IU/mL. The proportions of participants who responded to each of the vaccine antigens were compared using2. The frequencies of
AEs after each vaccine dose were compared among groups using
2or Fisher exact test, as appropriate.
In addition to traditional statistics, the immunogenicity data were analyzed for noninferiority. The objective was to rule out that the mixed sequence groups were inferior to the all-Tripedia group with respect to the immune responses to the vaccine anti-gens (except PRN). For vaccine response rates to PT and FHA and seroprotection rates to D and T, 90% CIs were calculated for the rate differences (mixed sequence groups minus the control group). Noninferiority was demonstrated when the lower limit of the 90% CI wasⱖ⫺10% (not more than a 10% decrease in vaccine response or seroprotection rates between the mixed regimen groups and the all-Tripedia control group). For evaluation of the GMCs to PT and FHA, the 90% CI was calculated for the GMC ratio of each mixed-sequence group over the control group using a 1-way ANOVA
model of the log-titers. Noninferiority with respect to PT and FHA was demonstrated when the lower limit of the 90% CI wasⱖ0.67 (not more than a 50% decrease in the GMCs).
RESULTS Participants
A total of 449 infants were enrolled; 151 in group 1 and 149 each in groups 2 and 3. A total of 28 partic-ipants withdrew from the study (12 in group 1; 10 in group 2; 6 in group 3) for the following reasons: 14 moved or were lost to follow-up, 11 did not adhere to the protocol, and 3 withdrew consent. No participant withdrew because of an AE. There were no statisti-cally significant demographic differences among treatment groups; 53% of participants were boys; and 75% were white, 15% were black, and 10% were of other ethnic backgrounds. Mean age at the time of first vaccination was 9 weeks.
Immunogenicity
At 2 months of age, prevaccination GMCs to each DTaP antigen were not significantly different among the 3 treatment groups (Table 1). After 3 vaccine doses, infants in all 3 groups developed significant antibody responses to the pertussis, tetanus, and diphtheria antigens. Infants who received mixed se-quences of DTaP vaccines achieved significantly higher GMCs to FHA and D compared with infants who received only Tripedia (Pⱕ.005 for each
com-TABLE 1. Antibody Responses to Vaccine Antigens for Subjects in Each of 3 Study Groups at 2 (Prevaccination) and 7 (Postvacci-nation) Months of Age
Antigen Group*
2 Months 7 Months
n GMC
(EU/mL)
n GMC
(EU/mL)
95% CI GMC Ratio (Divided by Group 1)
90% CI % Vaccine Response or Seroprotection†
95% CI Rate Difference (Minus Group 1)
90% CI
PT
Group 1 148 3.2 137 87.3 78.1–97.5 NA NA 100.0 97.3–100.0 NA NA
Group 2 146 3.0 137 87.7 79.5–96.8 1.00 0.90, 1.17 100.0 97.3–100.0 0 ⫺3.9, 3.9
Group 3 144 2.9 139 70.9‡ 62.2–80.9 0.81 0.75, 0.98 99.3 96.1–100.0 ⫺0.7 ⫺5.6, 2.8
FHA
Group 1 148 7.5 137 104§ 94.6–113 NA NA 99.3 96.0–100.0 NA NA
Group 2 146 7.3 137 126 114–138 1.21 1.08, 1.35 97.8 93.7–99.5 ⫺1.5 ⫺6.6, 3.3
Group 3 144 7.1 139 128 116–142 1.24 1.12, 1.40 97.1 92.8–99.2 ⫺2.1 ⫺8.0, 2.2
PRN
Group 1 148 7.6 137 27.6§ 23.9–32.0 㛳 㛳 79.6§ 71.8–86.0 㛳 㛳
Group 2 146 6.4 137 69.0¶ 59.9–79.5 㛳 㛳 96.4 91.7–98.8 㛳 㛳
Group 3 144 6.9 139 117 102–135 㛳 㛳 96.4 91.8–98.8 㛳 㛳
D
Group 1 148 0.14 137 0.58§ 0.50–0.67 㛳 㛳 97.8 93.7–99.5 NA NA
Group 2 146 0.14 137 0.81 0.70–0.93 㛳 㛳 98.5 94.8–99.8 0.7 ⫺4.4, 6.0
Group 3 144 0.15 139 0.81 0.71–0.93 㛳 㛳 98.6 94.9–99.8 0.8 ⫺4.3, 6.1
T
Group 1 148 0.53 137 3.24 2.84–3.70 㛳 㛳 100.0 97.3–100.0 NA NA
Group 2 146 0.58 137 3.72 3.29–4.21 㛳 㛳 100.0 97.3–100.0 0 ⫺3.9, 3.9
Group 3 144 0.55 139 2.74# 2.41–3.12 㛳 㛳 100.0 97.4–100.0 0 ⫺4.3, 3.3
NA indicates not applicable.
* Group 1 received Tripedia for all 3 doses; group 2 received Tripedia for doses 1 and 2 and Infanrix for dose 3; group 3 received Tripedia for dose 1 and Infanrix for doses 2 and 3.
† For PT, FHA, and PRN: vaccine response⫽appearance of antibodyⱖ5 EU/mL in subjects who were initially seronegative; for subjects with prevaccination antibody concentrationsⱖ5 EU/mL, vaccine response refers to at least maintenance of prevaccination antibody concentrations. Seroprotection for D and T⫽subjects with antibody titersⱖ0.1 IU/mL.
‡ Group 3 vs group 1 or 2;P⫽.01. § Group 1 vs group 2 or 3;Pⱕ.005.
㛳GMC ratios for PRN, D, and T and rate differences for PRN were not calculated (see Statistical Analysis). ¶ Group 2 vs group 3;P⫽.0001.
parison). The postvaccination GMC to PT was signif-icantly lower among infants in group 3 compared with infants in the other 2 groups (P ⫽ .01). In addition, infants in group 3 had a significantly lower GMC to T than infants in group 2 (P⫽.001). Despite the observed differences in GMCs, the rates of vac-cine response or seroprotection were ⱖ97% to PT, FHA, D, and T among infants in all 3 groups, with no significant difference in antibody response rates among groups.
It is interesting that although Tripedia does not contain PRN, infants who received only Tripedia demonstrated a response to this antigen. Although relatively low antibody concentrations were noted in the all-Tripedia control group, 80% of infants in this group fulfilled the criteria for vaccine response, in-cluding 44 (96%) of 46 infants who were initially seronegative. As would be expected, incrementally higher GMCs were noted in infants who received 1 or 2 doses of Infanrix, which contains PRN.
With respect to noninferiority analyses, the lower limits of the 90% CIs of the seroprotection (D and T) and vaccine response (PT and FHA) rate differences (group 2 minus group 1; group 3 minus group 1) were above the⫺10% cutoff value for clinical signif-icance; therefore, the mixed-sequence groups were noninferior to the control group for vaccine response and seroprotection rates to these vaccine antigens.
In addition, the lower limits of the 90% CIs of the GMC ratios for PT and FHA (group 2 divided by group 1; group 3 divided by group 1) were above the 0.67 cutoff value for clinical significance; therefore, the mixed-sequence groups were noninferior to the control group for GMCs to PT and FHA.
Safety
Both vaccines were considered to be well tolerated, although at least 1 systemic event was reported after 74%, 74%, and 76% of vaccinations in groups 1, 2,
and 3, respectively (differences were not significant). In addition, at least 1 injection-site reaction occurred after 35%, 39%, and 37% of vaccinations, respectively (not significant). Among groups, there were essen-tially no statistically significant differences in sys-temic or injection-site AEs occurring within 3 days after each of the 3 immunizations (Tables 2 and 3), except for irritability after the second dose, reported more often in group 2 (63%) than in group 1 (50%). There was no consistent pattern of systemic or injec-tion-site reactions occurring more or less often in the mixed-sequence vaccine groups relative to the con-trol group. In addition, there was no apparent in-crease in systemic or injection-site symptoms at the time of switch from Tripedia to Infanrix when com-pared with giving Tripedia throughout the primary series. However, after the second and third doses, slightly higher rates of injection-site tenderness were reported in groups 2 and 3 (not significant), and, after the third dose, slightly higher rates of fever were reported with Infanrix compared with Tripedia (not significant).
Parents reported irritability as the most common systemic event, occurring after 47% to 63% of vacci-nations (Table 2). In general, the rates of drowsiness and vomiting decreased, fever increased, and other systemic events remained largely unchanged after the second and third doses compared with after the first dose. Irritability was also reported as the most frequent grade 3 systemic AE, occurring after 0.7% to 3.6% of vaccinations. All other systemic AEs were reported infrequently as grade 3 (ⱕ3% after each vaccination).
The most common injection-site reaction was ten-derness, reported after 21% to 34% of vaccinations (Table 3). In general, the frequency of injection-site redness and swelling progressively increased, whereas tenderness remained largely unchanged be-tween the first and third doses. Grade 3 tenderness
TABLE 2. Frequency of Solicited Systemic AEs During the 4-Day Follow-up Period After Vaccination
Event (%) First Dose Second Dose Third Dose
Group 1 (n⫽145) Tripedia
Group 2 (n⫽140)
Tripedia
Group 3 (n⫽140)
Tripedia
Group 1 (n⫽139)
Tripedia
Group 2 (n⫽134)
Tripedia
Group 3 (n⫽132)
Infanrix
Group 1 (n⫽133) Tripedia
Group 2 (n⫽130) Infanrix
Group 3 (n⫽126)
Infanrix
Fever* (ⱖ38.0°C) 2.8 7.1 5.0 11.5 8.2 15.2 12.8 20.0 17.5
Grade 3 (ⱖ39.5°C) 0.7 0.7 0.0 0.7 0.7 0.0 0.8 2.3 0.0
Irritability 55.9 51.4 57.8 50.4 63.4† 58.3 46.6 46.9 50.8
Grade 3‡ 0.7 2.1 3.6 1.4 0.7 1.5 1.5 1.5 1.6
Unusual crying 22.1 27.8 31.4 19.4 26.1 29.5 20.3 22.3 19.8
Grade 3§ 2.1 2.1 2.1 0.0 0.7 3.0 1.5 0.0 1.6
Sleeplessness 24.8 24.3 27.1 21.6 24.6 21.2 27.1 24.6 21.4
Grade 3§ 0.7 1.4 1.4 0.7 0.7 2.3 1.5 0.0 0.8
Drowsiness 52.4 48.6 55.0 36.7 34.3 32.6 24.1 25.4 28.6
Grade 3§ 0.7 0.7 0.7 0.7 2.2 0.0 0.0 0.8 2.4
Poor appetite 19.3 21.4 27.8 13.7 19.4 20.4 23.3 20.8 18.2
Grade 3§ 0.0 0.7 0.0 0.0 0.7 0.0 0.8 0.0 0.8
Vomiting 16.6 12.8 10.7 8.6 15.7 12.9 8.3 6.2 8.7
Grade 3§ 0.7 0.0 0.0 0.7 0.7 1.5 0.8 0.0 0.8
Diarrhea 17.9 15.0 11.4 12.9 10.4 15.9 12.8 11.5 14.3
Grade 3§ 0.0 0.7 0.0 0.0 0.0 0.0 0.0 0.0 0.0
P⫽NS for all comparisons except where noted. * Rectal temperature.
† Group 2 vs group 1;P⫽.03.
was rarely reported (⬍1%) after any dose. After the third dose, grade 3 redness was reported in 1.5% to 2.4% of participants and grade 3 swelling was re-ported in 1.5% to 3.2% of participants (not signifi-cant).
Serious AEs were reported for 15 infants in the study; 6 in group 1, 5 in group 2, and 4 in group 3. All participants with serious AEs were hospitalized, ex-cept for 1 participant, who experienced seizures. None of the events was considered by the investiga-tor to be causally related to vaccination because of an alternative diagnosis and/or the interval between vaccination and occurrence of the event, and no par-ticipant withdrew from the study because of a seri-ous AE.
DISCUSSION
This is the first study to evaluate the safety and immunogenicity of mixed sequences of Infanrix and Tripedia for the primary immunization series in in-fants. Despite recommendations from the American Academy of Pediatrics Committee on Infectious Dis-eases and the Advisory Committee on Immunization Practices, it is not always feasible or practical to give infants a single manufacturer’s DTaP vaccine for the entire primary series. Physicians are faced with the necessity of giving mixed sequences without know-ing whether the schedules will be well tolerated and protective. This study demonstrated that switching from Tripedia to Infanrix during the primary series is an acceptable alternative to using only Tripedia throughout.
In general, except for PRN, the immune responses to Tripedia observed in our study were similar to the responses seen in previous studies of this vaccine when similar laboratory methods were used to mea-sure antibody concentrations.15,16 In a multicenter
study sponsored by the National Institutes of Health (NIH), 13 DTaP vaccines were evaluated, including prelicensure lots of Tripedia (CB-2) and Infanrix (SKB-3P). The GMCs and vaccine response rates to CB-2 and SKB-3P were as follows: PT, 127 EU/mL (99%) and 54 EU/mL (91%), respectively; FHA, 84 EU/mL (86%) and 103 EU/mL (83%), respectively; and PRN, 3.5 EU/mL (0.8%) and 185 EU/mL (85%), respectively.16 In the present study, infants who
re-ceived 2 doses of Infanrix (group 3) achieved a slightly lower GMC to PT than infants who received 2 or 3 doses of Tripedia (group 1 or 2). This finding
is consistent with the NIH trial, demonstrating that SKB-3P induced a lower PT antibody response com-pared with CB-2. Also, in the present study, infants who received 1 or 2 doses of Infanrix achieved a slightly higher GMC to FHA compared with infants who received 3 doses of Tripedia. These findings also are consistent with the NIH trial, which demon-strated a higher immune response to FHA with SKB-3P compared with CB-2. A similar correlation of antibody responses was observed to D. In the present study, the response to D was higher in the 2 mixed-sequence groups than in the all-Tripedia group. In the NIH trial, SKB-3P generated a slightly higher anti-D response than CB-2, although the difference was not statistically different. No consistent pattern of responses to T was observed in either study. De-spite that consistent correlates of immunity to per-tussis antigens have not been identified, response to individual vaccines has been demonstrated. For mixed-sequence DTaP vaccines, such response is based on similar patterns of immunogenicity.
It is interesting that despite claims that Tripedia does not contain PRN, 80% of participants who re-ceived 3 doses of Tripedia in this study fulfilled the criteria for vaccine response to PRN. Two possible explanations are that Tripedia contains trace quanti-ties of PRN or that the results of the EIA are inaccu-rate. All sera in this study were tested in the same laboratory (University of Rochester) using the same reagents and methods as in previous studies of DTaP vaccines, including evaluations of booster doses of DTaP vaccines in the NIH-sponsored trial of 13 acel-lular pertussis vaccines.17,18The interlaboratory
cor-relation of coefficients for the pertussis antibody as-says exceeded 0.90 between the laboratories in Rochester and the US Food and Drug Administra-tion. There have been no previous problems with false-positive antibody results to PRN reported from these laboratories. Therefore, it seems that many in-fants in the all-Tripedia group truly had an immu-nologic response to PRN.
In the NIH-sponsored study of 13 DTaP vaccines, no antibody response to PRN was observed after the 3-dose primary series of the prelicensure Tripedia (CB-2) vaccine.16 However, with the fourth dose of
CB-2 vaccine, a small but significant increase in an-tibody to PRN was demonstrated (GMC ⫽ 3.5 EU/mL and 6.6 EU/mL, prevaccination and post-vaccination, respectively).17 In infants who were TABLE 3. Frequency of Solicited Injection-Site AEs During the 4-Day Follow-up Period After Vaccination
Event (%) First Dose Second Dose Third Dose
Group 1 (n⫽145)
Tripedia
Group 2 (n⫽140) Tripedia
Group 3 (n⫽140) Tripedia
Group 1 (n⫽139)
Tripedia
Group 2 (n⫽134)
Tripedia
Group 3 (n⫽132)
Infanrix
Group 1 (n⫽133)
Tripedia
Group 2 (n⫽130)
Infanrix
Group 3 (n⫽126)
Infanrix
Redness 14.5 15.0 10.7 23.7 19.4 19.7 26.3 23.1 25.4
⬎20 mm 0.0 0.7 0.0 1.4 0.0 1.5 1.5 1.5 2.4
Swelling 14.5 10.0 10.0 15.8 13.4 14.4 21.0 20.0 20.6
⬎20 mm 0.7 2.1 0.0 0.0 0.0 3.0 1.5 3.1 3.2
Tenderness 33.8 34.3 30.0 20.9 28.4 31.1 22.6 29.2 31.0
Grade 3* 0.0 0.0 0.7 0.0 0.7 0.0 0.0 0.0 0.0
given a primary series with DTwP vaccine, a booster dose of CB-2 vaccine induced a marked increase in PRN antibody (GMC⫽7.8 EU/mL and 32.8 EU/mL, prevaccination and postvaccination, respectively), with 6 of 19 infants demonstrating a 4-fold increase in antibody. Finally, a significant increase in PRN was noted in children who were given a fifth dose of CB-2 vaccine (44% demonstrated a 4-fold re-sponse).18 A randomized, open-label study from
Germany evaluated the interchangeability of 2 acel-lular pertussis vaccines, one containing PT and FHA (equivalent to Tripedia, but without D and T) and the other containing PT, FHA, PRN, and fimbriae type 2 (equivalent to Acel-Imune, but without D and T; Lederle Laboratories).19Three doses of vaccine were
given at monthly intervals beginning at 2 to 4 months of age. Infants in one group were given 3 doses of the 2-component vaccine, and infants in the other 2 groups began the primary series with the 4-component vaccine and completed the series with the 2-component vaccine. Infants in the group that was given the 2-component vaccine (PT and FHA) demonstrated a 96% response rate to PRN. The re-sults from each of these studies support the hypoth-esis that Tripedia contains small amounts of PRN, although we are unaware of any attempts to confirm the hypothesis.
Overall, the mixed sequences of DTaP vaccines were well tolerated. The proportion of infants who experienced systemic AEs and injection-site reactions generally was not increased in the mixed-sequence groups compared with the all-Tripedia control group. The rates of AEs reported in this study are comparable with rates published in earlier studies of DTaP vaccines.4,15,20 –25In the NIH multicenter study
of 13 acellular pertussis vaccines, vomiting and in-jection-site redness and swelling were reported slightly more frequently and fussiness slightly less frequently among infants who were given SKB-3P compared with infants who were given CB-2, al-though the differences were not statistically signifi-cant.4In the present study, no such differences were
observed, although there was no group of infants who received 3 doses of Infanrix. In the NIH study, all of the DTaP vaccines caused significantly fewer AEs compared with the DTwP vaccine. In the Ger-man study of 3 different sequences of acellular per-tussis vaccines, injection-site and systemic events oc-curred with similar frequency in all 3 groups, although the total study population was only 149.19
Two different sets of statistical analyses were per-formed with the immunogenicity data from this study. Most investigators are accustomed to tradi-tional analyses such as Student’sttest or ANOVA for continuous values and 2 or Fisher’s exact test for
categorical values. However, noninferiority testing is appearing more frequently in the literature.26 –30The
goal of noninferiority testing is to show that a new treatment is not inferior to an established treatment using a priori defined parameters for clinically sig-nificant differences between groups. In our study, noninferiority was demonstrated as long as 1) the vaccine response and seroprotection rates for the mixed-sequence groups were not ⬎10% below the
rates for the all-Tripedia control group (PT, FHA, D, and T) and 2) the GMCs for the mixed-sequence groups were not⬍1.5-fold lower than the GMCs of the control group (PT and FHA). These parameters were chosen because smaller differences between groups would have been considered too small to be clinically relevant.
There are advantages and disadvantages to each of the statistical methods. Although noninferiority test-ing should demonstrate whether a new treatment is as good as an old one, it may not be sensitive enough to find important but subtle differences between groups. Traditional testing should identify all signif-icant differences between groups, but it may be too sensitive in finding trivial differences that occur by chance alone and have no clinical significance de-spite having a P value ⬍.05. For example, in our study, the GMC to PT after the third dose in one mixed-sequence group (group 3, 71 EU/mL) was statistically less than in the control group (group 1, 87 EU/mL; P⫽ .01). However, group 3 was nonin-ferior to group 1 because the lower limit of the 90% CI of the ratio of these GMCs was ⬎0.67 (0.75). In another example, after the second dose, the rate of irritability was significantly higher in group 2 (63%) than in group 1 (50%;P ⫽.03). However, all of the infants in both groups had received 2 doses of Tripe-dia. Therefore, the statistical difference had no clini-cal relevance and the difference occurred by chance alone or was caused by factors unrelated to the vac-cine.
CONCLUSION
This study provides evidence that beginning the primary DTaP immunization series with Tripedia and completing it with Infanrix is safe and immuno-genic. Although no correlate of immunity has been established, it is important to demonstrate compara-ble immunogenicity because an efficacy study of the mixed sequences of DTaP vaccines tested here will never be conducted. The results of the present study cannot predict the results of other mixed sequences using Tripedia, Infanrix, and/or other DTaP vac-cines. Factors such as the number of pertussis anti-gens in each vaccine and the order in which the vaccines are given may result in some mixed se-quences having different profiles of safety or immu-nogenicity.
ACKNOWLEDGMENT
This study was funded by a grant from SmithKline Beecham Biologicals.
REFERENCES
1. Edwards KM, Lawrence E, Wright PF. Diphtheria, tetanus, and pertus-sis vaccine: a comparison of the immune response and adverse reactions to conventional and acellular pertussis components.Am J Dis Child. 1986;140:867– 871
2. Edwards KM, Bradley RB, Decker MD, et al. Evaluation of a new highly purified pertussis vaccine in infants and children.J Infect Dis. 1989;160: 832– 837
3. Feldman S, Perry CS, Andrew M, et al. Primary immunization series for infants: comparison of two-component acellular and standard whole-cell pertussis vaccines combined with diphtheria-tetanus toxoids.South Med J. 1993;86:269 –275
acellular pertussis vaccines: adverse reactions.Pediatrics. 1995;96(suppl): 557–566
5. Pertussis vaccination: acellular pertussis vaccine for the fourth and fifth doses of the DTP series. Update to supplementary ACIP recommenda-tions of the Advisory Committee on Immunization Practices.MMWR Morb Mortal Wkly Rep. 1992;41(RR-15):1–5
6. Pertussis vaccination: use of acellular pertussis vaccines among infants and young children. Recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR Morb Mortal Wkly Rep. 1997; 46(RR-7):1–25
7. Notice to readers. FDA approval of a fourth acellular pertussis vaccine for use among infants and young children.MMWR Morb Mortal Wkly Rep. 1998;47:934 –936
8. Greco D, Salmaso S, Mastrantonio P, et al. A controlled trial of two acellular vaccines and one whole-cell vaccine against pertussis. The Progetto Pertosse Working Group.N Engl J Med. 1996;334:341–348 9. Schmitt H-J, Wirsing von Ko¨nig CH, Neiss A, et al. Efficacy of acellular
pertussis vaccine in early childhood after household exposure.JAMA. 1996;275:37– 41
10. Stehr K, Cherry JD, Heininger U, et al. A comparative efficacy trial in Germany in infants who received either the Lederle/Takeda acellular pertussis component DTP (DTaP) vaccine, the Lederle whole-cell com-ponent DTP vaccine, or DT vaccine. The Pertussis Vaccine Study Group. Pediatrics. 1998;101:1–11
11. Liese JG, Meschievitz CK, Harzer E, et al. Efficacy of a two-component acellular pertussis vaccine in infants. The Munich Pertussis Study Group.Pediatr Infect Dis J. 1997;16:1038 –1044
12. Trollfors B, Taranger J, Lagergård T, et al. A placebo-controlled trial of a pertussis-toxoid vaccine.N Engl J Med. 1995;333:1045–1050 13. American Academy of Pediatrics. Pertussis. In: Pickering LK, ed.Red
Book 2000: Report of the Committee on Infectious Diseases.25th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2000:440 14. Pichichero ME, Passador S. Administration of combined diphtheria and
tetanus toxoids and pertussis vaccine, hepatitis B vaccine, and Hae-mophilus influenzaetype b (Hib) vaccine to infants and response to a booster dose of Hib conjugate vaccine.Clin Infect Dis. 1997;25:1378 –1384 15. Pichichero ME, Francis AB, Blatter MM, et al. Acellular pertussis vac-cination of 2-month-old infants in the United States.Pediatrics. 1992;89: 882– 887
16. Edwards KM, Meade BD, Decker MD, et al. Comparison of 13 acellular pertussis vaccines: overview and serologic response.Pediatrics.1995; 96(suppl 3):548 –557
17. Pichichero ME, Deloria MA, Rennels MB, et al. A safety and immuno-genicity 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;100:772–788
18. Pichichero ME, Edwards KM, Anderson EL, et al. Safety and immuno-genicity of six acellular pertussis vaccines and one whole-cell pertussis vaccine given as a fifth dose in four- to six-year-old children [abstract]. Pediatrics.2000;105(1). Available at: http://www.pediatrics.org/cgi/ content/full/105/1/e11
19. Wirsing von Ko¨nig CH, Herden P, Palitzsch D, Schneeweiss B, Bier N. Immunogenicity of acellular pertussis vaccines using two vaccines for primary immunization.Pediatr Infect Dis J.2000;19:757–759
20. Anderson EL, Belshe RB, Bartram J. Differences in reactogenicity and antigenicity of acellular and standard pertussis vaccines combined with diphtheria and tetanus in infants.J Infect Dis. 1988;157:731–737 21. Blumberg DA, Mink CM, Cherry JD, et al. Comparison of acellular and
whole-cell pertussis-component diphtheria-tetanus-pertussis vaccines in infants. The APDT Vaccine Study Group.J Pediatr. 1991;119:194 –204 22. Pichichero ME, Francis AB, Marsocci SM, Green JL, Disney FA. Com-parison of diphtheria and tetanus toxoids and bicomponent acellular pertussis vaccine with diphtheria and tetanus toxoids and whole-cell pertussis vaccine in infants.Am J Dis Child. 1993;147:295–299 23. Bernstein HH, Rothstein EP, Pichichero ME, et al. Reactogenicity and
immunogenicity of a three-component acellular pertussis vaccine ad-ministered as the primary series to 2, 4, and 6 month old infants in the United States.Vaccine. 1995;13:1631–1635
24. Rothstein EP, Kamiya H, Nii R, et al. Comparison of diphtheria-tetanus-2 component acellular pertussis vaccines in United States and Japanese infants at 2, 4, and 6 months of age.Pediatrics. 1996;97:236 –242 25. Patel SS, Wagstaff AJ. Acellular pertussis vaccine (Infanrix-DTPa; SB-3): a review of its immunogenicity, protective efficacy and tolerability in the prevention ofBordetella pertussisinfection.Drugs. 1996;52:254 –275 26. Eron JJ, Yetzer ES, Ruane PJ, et al. Efficacy, safety, and adherence with
a twice-daily combination lamivudine/zidovudine tablet formulation, plus a protease inhibitor, in HIV infection.AIDS. 2000;14:671– 681 27. Gylca R, Gylca V, Benes O, et al. A new DTPa-HBV-IPV vaccine
co-administered with Hib, compared to commercially available DTPw-IPV/Hib vaccine co-administered with HBV, given at 6, 10, and 14 weeks following HBV at birth.Vaccine.2001;19:825– 833
28. Mallet E, Fabre P, Pines E, et al. Immunogenicity and safety of a new liquid hexavalent combined vaccine compared with separate adminis-tration of reference licensed vaccines in infants. The Hexavalent Vaccine Trial Study Group.Pediatr Infect Dis J.2000;19:1119 –1127
29. Schmitt HJ, Knuf M, Ortiz E, Sanger R, Uwamwezi MC, Kaufhold A. Primary vaccination of infants with diphtheria-tetanus-acellular pertus-sis-hepatitis B virus-inactivated poliovirus andHaemophilus influenzae type b vaccines given as either separate or mixed injections.J Pediatr. 2000;137:304 –312
30. Siegel JP. Equivalence and noninferiority trials.Am Heart J. 2000;139: S166 –S170
NET GAIN OF KNOWLEDGE
“When President Lowell of Harvard was asked whether knowledge was on the increase at his institution, he answered, ‘Certainly. The freshman all bring with them a certain amount of knowledge, and they take none away.’”
Barzun J.Doing Research—Should the Sport be Regulated?Columbia, February 1987
DOI: 10.1542/peds.109.4.666
2002;109;666
Pediatrics
Howe
A. Howard, Mark M. Blatter, Keith Reisinger, Michael E. Pichichero and Barbara J.
David P. Greenberg, Larry K. Pickering, Shelly D. Senders, Jeffrey D. Bissey, Robert
Infancy
Interchangeability of 2 Diphtheria-Tetanus-Acellular Pertussis Vaccines in
Services
Updated Information &
http://pediatrics.aappublications.org/content/109/4/666
including high resolution figures, can be found at:
References
http://pediatrics.aappublications.org/content/109/4/666#BIBL
This article cites 28 articles, 4 of which you can access for free at:
Subspecialty Collections
sub
http://www.aappublications.org/cgi/collection/vaccine:immunization_
Vaccine/Immunization
b
http://www.aappublications.org/cgi/collection/infectious_diseases_su
Infectious Disease
following collection(s):
This article, along with others on similar topics, appears in the
Permissions & Licensing
http://www.aappublications.org/site/misc/Permissions.xhtml
in its entirety can be found online at:
Information about reproducing this article in parts (figures, tables) or
Reprints
http://www.aappublications.org/site/misc/reprints.xhtml
DOI: 10.1542/peds.109.4.666
2002;109;666
Pediatrics
Howe
A. Howard, Mark M. Blatter, Keith Reisinger, Michael E. Pichichero and Barbara J.
David P. Greenberg, Larry K. Pickering, Shelly D. Senders, Jeffrey D. Bissey, Robert
Infancy
Interchangeability of 2 Diphtheria-Tetanus-Acellular Pertussis Vaccines in
http://pediatrics.aappublications.org/content/109/4/666
located on the World Wide Web at:
The online version of this article, along with updated information and services, is
by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.
