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PEDIATRICS Vol. 109 No. 4 April 2002, pp. 666-672

Interchangeability of 2 Diphtheria-Tetanus-Acellular Pertussis Vaccines in Infancy

David P. Greenberg, MD*, Larry K. Pickering, MD{ddagger}, Shelly D. Senders, MD§, Jeffrey D. Bissey, MD||, Robert A. Howard, MD, Mark M. Blatter, MD#, Keith Reisinger, MD#, Michael E. Pichichero, MD** and Barbara J. Howe, MD{ddagger}{ddagger}

* University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania
{ddagger} Eastern Virginia Medical School, Children’s Hospital of the King’s Daughters, Norfolk, Virginia
§ Dr Shelly Senders and Associates, University Heights, Ohio
|| Everett Clinic, Everett, Washington
Sciman Biomedical Research, Bryan, Texas
# Primary Physicians Research, Pittsburgh, Pennsylvania
** Rochester University School of Medicine, Rochester, New York
{ddagger}{ddagger} GlaxoSmithKline, Collegeville, Pennsylvania

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   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 NET GAIN OF KNOWLEDGE
 REFERENCES
 
Objective. Currently, 4 diphtheria-tetanus-acellular pertussis (DTaP) vaccines are licensed for pediatric use in the United States, and 2 are commercially available. Although a single manufacturer’s DTaP vaccine should be used for all 3 doses of the primary immunization series, some circumstances result in infants receiving 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, controlled 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 injections according to the recommended childhood immunization 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 adverse 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 series 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.

Key Words: diphtheria-tetanus-pertussis vaccine • immunogenicity • infant • interchangeability

Abbreviations: DTaP, diphtheria-tetanus-acellular pertussis • DTwP, diphtheria-tetanus-whole cell pertussis • Hib, Haemophilus influenzae type b • OPV, oral poliovirus vaccine • IPV, inactivated poliovirus vaccine • D, diphtheria toxoid • T, tetanus toxoid • PT, pertussis toxoid • FHA, filamentous hemagglutinin • PRN, pertactin • 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


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 NET GAIN OF KNOWLEDGE
 REFERENCES
 
Since 1997, diphtheria-tetanus-acellular pertussis (DTaP) vaccines have replaced diphtheria-tetanus-whole cell pertussis (DTwP) vaccines in the United States, primarily because of reduced reactogenicity.1–4 In 1991, the first DTaP vaccine was licensed in the United States for booster immunization at 15 to 18 months and 4 to 6 years of age5 and in 1996 for primary immunization beginning at 2 months of age.6 Currently, DTaP vaccines from 4 different manufacturers are licensed in the United States,7 but 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 of Bordetella pertussis 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 Advisory Committee on Immunization Practices recommend 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 recommendation is that only limited data are available on the safety, immunogenicity, or efficacy of mixed sequences of different manufacturers’ DTaP vaccines administered during the primary series. However, on a practical level, practitioners cannot always adhere 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 manufacturer to another. In such circumstances, the physician often has no choice but to switch brands during 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 Pasteur, 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
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 NET GAIN OF KNOWLEDGE
 REFERENCES
 
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–positive or human immunodeficiency virus–positive 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 temperature >=100.4°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 administered by intramuscular injection in the upper right anterolateral thigh. All participants concurrently received Haemophilus influenzae type b (Hib) conjugate vaccine (OmniHIB; Hib tetanus conjugate, PRP-T, Aventis Pasteur) in the upper left anterolateral thigh.

Hepatitis B vaccine (Engerix-B, SB Biologicals) was administered in the lower left anterolateral thigh; the first dose had previously been administered at least 2 weeks before study enrollment, 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, Lederle 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 anterolateral thigh.

Because the DTaP vaccines could not be supplied in identical packaging, the research nurses who administered the study vaccines were not blinded. However, the parents and all study personnel who collected infant diary and safety information were blinded throughout the study. In addition, laboratory personnel who performed antibody assays were blinded to group assignment.

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 manufactured 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), 23.4 µg of pertussis toxoid (PT), 23.4 µg of filamentous hemagglutinin (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, 25 µg of PT, 25 µg of FHA, 8 µg of pertactin (PRN), and 0.5 mg aluminum as salts. Engerix-B (lots ENG2283A2 and ENG2617A2), manufactured by SB Biologicals, contained 10 µg 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 10 µg of H influenzae type b polysaccharide bound to 24 µg 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 specimens 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 response to pertussis antigens, we measured antibody concentrations to PT, FHA, and PRN by enzyme immunoassay (EIA); results were expressed in enzyme immunoassay units (EU) per milliliter.14 The 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.14 Purified D and T for coating 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 symptoms. 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 envelopes. When parents failed to mail the cards, the information was collected by telephone interview. At each visit, parents were questioned 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
The sample size for this study was based on the predicted immune response to FHA (85% after a 3-dose primary series of Tripedia). A sample size of 125 evaluable participants per group provided an 80% probability that the 1-sided 95% confidence interval (CI) would exclude a difference of 85% response to FHA after 3 doses of Tripedia versus 74% for a mixed vaccine schedule. In addition, assuming {alpha} = 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 geometric mean antibody concentrations (GMCs) were compared using analysis of variance (ANOVA). Antibody concentrations below the 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 participants (<5 EU/mL), vaccine response was defined as the appearance of antibodies >=5 EU/mL at 7 months of age. For initially seropositive participants (>=5 EU/mL), vaccine response was defined as at least maintenance of prevaccination antibody concentrations 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 of >=0.10 IU/mL. The proportions of participants who responded to each of the vaccine antigens were compared using {chi}2. The frequencies of AEs after each vaccine dose were compared among groups using {chi}2 or 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 antigens (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 was >=-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 was >=0.67 (not more than a 50% decrease in the GMCs).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 NET GAIN OF KNOWLEDGE
 REFERENCES
 
Participants
A total of 449 infants were enrolled; 151 in group 1 and 149 each in groups 2 and 3. A total of 28 participants 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 statistically 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 sequences of DTaP vaccines achieved significantly higher GMCs to FHA and D compared with infants who received only Tripedia (P <= .005 for each comparison). The postvaccination GMC to PT was significantly 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 vaccine response or seroprotection were >=97% to PT, FHA, D, and T among infants in all 3 groups, with no significant difference in antibody response rates among groups.


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  		TABLE 1. Antibody Responses to Vaccine Antigens for Subjects in Each of 3 Study Groups at 2 (Prevaccination) and 7 (Postvaccination) Months of Age

 
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, including 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 significance; 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 essentially no statistically significant differences in systemic 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 injection-site reactions occurring more or less often in the mixed-sequence vaccine groups relative to the control group. In addition, there was no apparent increase in systemic or injection-site symptoms at the time of switch from Tripedia to Infanrix when compared 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).


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  		TABLE 2. Frequency of Solicited Systemic AEs During the 4-Day Follow-up Period After Vaccination

 

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  		TABLE 3. Frequency of Solicited Injection-Site AEs During the 4-Day Follow-up Period After Vaccination

 
Parents reported irritability as the most common systemic event, occurring after 47% to 63% of vaccinations (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 (<=3% after each vaccination).

The most common injection-site reaction was tenderness, 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 between the first and third doses. Grade 3 tenderness 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 reported in 1.5% to 3.2% of participants (not significant).

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, except for 1 participant, who experienced seizures. None of the events was considered by the investigator to be causally related to vaccination because of an alternative diagnosis and/or the interval between vaccination and occurrence of the event, and no participant withdrew from the study because of a serious AE.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 NET GAIN OF KNOWLEDGE
 REFERENCES
 
This is the first study to evaluate the safety and immunogenicity of mixed sequences of Infanrix and Tripedia for the primary immunization series in infants. Despite recommendations from the American Academy of Pediatrics Committee on Infectious Diseases 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 knowing 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 measure 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 received 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 compared 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 demonstrated 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. Despite that consistent correlates of immunity to pertussis 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 received 3 doses of Tripedia in this study fulfilled the criteria for vaccine response to PRN. Two possible explanations are that Tripedia contains trace quantities of PRN or that the results of the EIA are inaccurate. 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 acellular pertussis vaccines.17,18 The interlaboratory correlation of coefficients for the pertussis antibody assays exceeded 0.90 between the laboratories in Rochester and the US Food and Drug Administration. There have been no previous problems with false-positive antibody results to PRN reported from these laboratories. Therefore, it seems that many infants in the all-Tripedia group truly had an immunologic 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 antibody to PRN was demonstrated (GMC = 3.5 EU/mL and 6.6 EU/mL, prevaccination and postvaccination, respectively).17 In infants who were 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 response).18 A randomized, open-label study from Germany evaluated the interchangeability of 2 acellular 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).19 Three 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 results from each of these studies support the hypothesis 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.4,15,20–25 In the NIH multicenter study of 13 acellular pertussis vaccines, vomiting and injection-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, although the differences were not statistically significant.4 In 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 German study of 3 different sequences of acellular pertussis vaccines, injection-site and systemic events occurred with similar frequency in all 3 groups, although the total study population was only 149.19

Two different sets of statistical analyses were performed with the immunogenicity data from this study. Most investigators are accustomed to traditional analyses such as Student’s t test or ANOVA for continuous values and {chi}2 or Fisher’s exact test for categorical values. However, noninferiority testing is appearing more frequently in the literature.26–30 The 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 significant 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 testing 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 significant differences between groups, but it may be too sensitive in finding trivial differences that occur by chance alone and have no clinical significance despite 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 noninferior 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 Tripedia. Therefore, the statistical difference had no clinical relevance and the difference occurred by chance alone or was caused by factors unrelated to the vaccine.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
NET GAIN OF KNOWLEDGE
 REFERENCES
 
This study provides evidence that beginning the primary DTaP immunization series with Tripedia and completing it with Infanrix is safe and immunogenic. Although no correlate of immunity has been established, it is important to demonstrate comparable 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 vaccines. Factors such as the number of pertussis antigens in each vaccine and the order in which the vaccines are given may result in some mixed sequences having different profiles of safety or immunogenicity.


   NET GAIN OF KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 NET GAIN OF KNOWLEDGE
REFERENCES
 

"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

Submitted by Student


   ACKNOWLEDGMENTS
 
This study was funded by a grant from SmithKline Beecham Biologicals.


   FOOTNOTES
 
Received for publication Jun 7, 2001; Accepted Nov 1, 2001.

Reprints requests to (D.P.G.) Division of Allergy, Immunology and Infectious Diseases, Rm 4B-320, Children’s Hospital of Pittsburgh, 3705 Fifth Ave, Pittsburgh, PA 15213-2583; E-mail: greenbd{at}chplink.chp.edu

This work was presented, in part, at the 36th Annual Meeting of the Infectious Diseases Society of America; November 12–15, 1998; Denver, CO.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 NET GAIN OF KNOWLEDGE
 REFERENCES
 

  1. Edwards KM, Lawrence E, Wright PF. Diphtheria, tetanus, and pertussis vaccine: a comparison of the immune response and adverse reactions to conventional and acellular pertussis components. Am J Dis Child.1986; 140 :867 –871[Medline]
  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[Medline]
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PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics

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