Secondary Logo

Safety and Immunogenicity of DTaP5-IPV Compared With DTaP5 Plus IPV as the Fifth Dose in Children 4–6 Years of Age

Smith, Michael J. MD, MSCE; Jordanov, Emilia MD; Sheng, Xiaohua PhD; Tsang, Peter H. MD, PhD

The Pediatric Infectious Disease Journal: March 2017 - Volume 36 - Issue 3 - p 319–325
doi: 10.1097/INF.0000000000001427
Vaccine Reports
Free

Background: Immunogenicity and safety of stand-alone diphtheria, tetanus toxoid, 5-component acellular pertussis vaccine adsorbed, inactivated poliovirus (IPV) combination vaccine (DTaP5-IPV) was compared with separate DTaP5 plus IPV vaccines as fifth dose in children 4–6 years of age.

Methods: In this phase III, controlled, multicenter, randomized, open-label study, participants were randomized to DTaP5-IPV plus measles/mumps/rubella (MMR) and varicella virus (VZV) vaccines (group 1; N = 324), DTaP5+IPV with MMR and VZV (group 2; N = 327), DTaP5-IPV with/without MMR/VZV (group 3; N = 2419) or DTaP5+IPV with/without MMR/VZV (group 4; N = 302). Immunogenicity endpoints (groups 1 and 2) included booster response rates and antibody geometric mean concentrations (GMCs). Noninferiority of DTaP5-IPV to DTaP5+IPV was evaluated based on differences (groups 1 and 2) in booster rates and postvaccination GMC ratios. Safety endpoints (all groups) included all adverse events.

Results: Noninferiority of DTaP5-IPV compared with DTaP5+IPV for all antigens was achieved. Booster rate differences were 5.4% for pertussis toxoid (PT); 7.4% for filamentous hemagglutinin; 3.7% for pertactin (PRN); 4.8% for fimbriae types 2 and 3; −0.1% for tetanus; −1.9% for diphtheria; 3.7% for poliovirus 1; −0.7% for poliovirus 2 and 0.3% for poliovirus 3. GMC ratios were 1.97 for PT; 1.56 for filamentous hemagglutinin; 1.51 for PRN; 1.33 for fimbriae types 2 and 3; 1.17 for tetanus; 1.20 for diphtheria; 1.27 for poliovirus 1; 0.90 for poliovirus 2 and 1.34 for poliovirus 3. Rates of immediate and unsolicited adverse events, solicited injection site reactions and systemic reactions were similar between groups.

Conclusions: DTaP5-IPV was safe and immunogenic in children 4–6 years of age.

From the *Division of Pediatric Infectious Diseases, University of Louisville School of Medicine, Louisville, Kentucky; and Sanofi Pasteur, Swiftwater, Pennsylvania.

Accepted for publication September 12, 2016.

This study was sponsored by Sanofi Pasteur.

M.J.S. received funding from Sanofi Pasteur to present the data from this study to the Infectious Diseases Society of American Annual Meeting (2014). E.J., X.S. and P.H.T. are employees of Sanofi Pasteur.

Address for correspondence: Michael J. Smith, MD, MSCE, Pediatric Infectious Diseases, University of Louisville School of Medicine, 571 South Floyd Street, Suite 40202, Louisville, KY 40205. E-mail: mjsmit22@louisville.edu.

Diphtheria, tetanus and pertussis vaccines have been the cornerstone of childhood vaccination programs for these diseases. In the US, the primary series of 3 doses of diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed (DTaP) is given to infants, followed by booster doses at 15–18 months of age (fourth dose) and a fifth dose at preschool age.1 Importantly, vaccination at this age can decrease the risk of disease transmission from school-age children to their younger siblings who have not yet been fully vaccinated.2,3 Other vaccinations for children 4–6 years of age include inactivated poliovirus (IPV), measles, mumps and rubella (MMR) and varicella (VZV) vaccines.1

The Advisory Committee on Immunization Practices recommends that, whenever feasible, the same manufacturer’s DTaP product should be used for all pertussis vaccinations.4 Currently, separate vaccinations with DAPTACEL (a 5-component acellular pertussis DTaP5 vaccine manufactured by Sanofi Pasteur, Swiftwater, PA) along with IPOL (a stand-alone IPV vaccine also manufactured by Sanofi Pasteur, Swiftwater, PA) meet the immunization requirements for DTaP and IPV vaccination in children 4–6 years of age.5 DTaP5-IPV is the liquid component of PENTACEL (Sanofi Pasteur, Swiftwater, PA) (DTaP-IPV/Haemophilus influenza b, and licensed in the US in June 2008),6 which is used to reconstitute the lyophilized H. influenza b vaccine [polyribosyl-ribitol-phosphate with tetanus toxoid carrier (PRP-T)]. DTaP5-IPV is known as a stand-alone vaccine in several countries under the marketed name of QUADRACEL (Sanofi Pasteur, Swiftwater, PA) and has been licensed in Canada as a booster dose for children 4–6 years of age since 1999.7 DTaP5-IPV vaccine was approved for use in the US in March 2015.8

Licensure of this combination vaccine in the US as a stand-alone vaccine provides an option as the fifth dose, thus allowing a child to complete the entire pediatric series using 5-component acellular pertussis technology. The Advisory Committee on Immunization Practices recommends the use of combination vaccines rather than individual components when possible.9 Patients can benefit from fewer overall injections, and physicians would appreciate a simplified vaccine administration. From the public health perspective, a combination vaccine for the fifth booster dose may improve vaccination coverage rates and timeliness.10 In this report, we present the safety and immunogenicity of DTaP5-IPV vaccine compared with DAPTACEL plus IPOL (DTaP5+IPV) as a booster dose in children 4–6 years of age.

Back to Top | Article Outline

METHODS

This was a phase III, controlled, multicenter, randomized, open-label study. The study was conducted in compliance with the Declaration of Helsinki. The study protocol and informed consent forms were approved by the institutional ethics committee at each study site. Parent(s) or legal guardian(s) of all participants provided written consent before initiation of any study-specific procedures. This study was registered under ClinicalTrials.gov identifier NCT01346293.

Back to Top | Article Outline

Participants

Participants were ≥4 and <7 years of age at enrollment and had documented completion of the 4-dose infant/toddler vaccination series with DAPTACEL and/or PENTACEL vaccine(s) only. Key exclusion criteria included: receipt of any vaccine in the 4 weeks preceding the trial with the exception of inactivated influenza vaccination, which could be received ≥2 weeks before study vaccine; vaccination or planned receipt of any vaccine in the 4 weeks after trial vaccination; receipt of blood or blood-derived products in the past 3 months; known or suspected congenital or acquired immunodeficiency, receipt of immunosuppressive therapy within the preceding 6 months or long-term systemic corticosteroid therapy (prednisone or equivalent for >2 consecutive weeks within the past 3 months); history of HIV, hepatitis B or hepatitis C infection; history of confirmed diphtheria, tetanus or pertussis infection; known hypersensitivity to any vaccine component; confirmed thrombocytopenia; bleeding disorder or receipt of anticoagulants in the past 3 weeks or chronic illness that could interfere with trial conduct or completion. Temporary exclusions in which participation could be delayed until resolution of the condition included febrile illness (temperature ≥38.0°C) or moderate or severe acute illness/infection within 24 hours of vaccination.

Back to Top | Article Outline

Vaccines

Each 0.5 mL dose of DTaP5-IPV (Sanofi Pasteur Ltd., Toronto, Ontario, Canada) contains diphtheria toxoid (15 Lf), tetanus toxoid (5 Lf), acellular pertussis antigens pertussis toxoid (PT; 20 μg), filamentous hemagglutinin (FHA; 20 μg), pertactin (PRN; 3 μg), fimbriae types 2 and 3 (FIM; 5 μg) and IPV type 1 (40 D-antigen units), type 2 (8 D-antigen units) and type 3 (32 D-antigen units) with adjuvant aluminum phosphate (1.5 mg), excipient 2-phenoxyethanol (0.6% v/v) and polysorbate 80 (10 ppm). Each 0.5 mL dose of DTaP5 (DAPTACEL; Sanofi Pasteur Ltd., Toronto, Ontario, Canada) contains diphtheria (15 Lf), tetanus (5 Lf), acellular pertussis antigens PT (10 μg), FHA (5 μg), PRN (3 μg), FIM (5 μg), aluminum phosphate (1.5 mg) and 2-phenoxyethanol (0.6% v/v). Each 0.5 mL dose of IPOL contains poliovirus type 1 (40 D-antigen units), type 2 (8 D-antigen units) and type 3 (32 D-antigen units), 2-phenoxyethanol (0.5%) and formaldehyde (0.02%). Each 0.5 mL dose of MMR vaccine (M-M-RII; Merck & Co., Inc., Whitehouse Station, NJ) contains measles virus [not less than 1000 × 50% of the median tissue culture infective dose (TCID50)], mumps virus (not less than 12,500 TCID50) and rubella virus (not less than 1000 TCID50). Each 0.5 mL dose of VARIVAX (VZV; Merck & Co., Inc., Whitehouse Station, NJ) contains a minimum of 1350 plaque-forming units of Oka/Merck VZV virus.

Back to Top | Article Outline

Study Design

Participants were randomized into immunogenicity (groups 1 and 2) and safety (groups 3 and 4) groups using an interactive voice response system. Participants received the following vaccines: DTaP5-IPV, MMR and VZV (group 1); DTaP5+IPV, MMR and VZV (group 2); DTaP5-IPV with or without MMR or VZV (group 3) or DTaP5+IPV with or without MMR or VZV (group 4). For participants in groups 3 and 4 who had already received 2 documented doses of MMR and/or VZV vaccines, additional doses of these vaccines were not mandatory. Participants were randomized in a 1:1 ratio to group 1 and group 2 and in an 8:1 ratio to group 3 and group 4.

Participants received their assigned vaccinations on day 0. Participants in group 1 and group 3 received 0.5 mL of DTaP5-IPV administered intramuscularly (IM) in the deltoid of the left arm. Participants in group 2 and group 4 received 0.5 mL of DTaP5 administered IM in the deltoid of the left arm, and IPV administered either IM in the deltoid approximately 30 mm below the site of the DTaP5 injection or subcutaneously in the left outer upper triceps. For participants who received MMR and VZV concomitantly, these vaccines were administered subcutaneously in the right outer upper arm. Participants in groups 1 and 2 provided a blood sample for immunogenicity assessments immediately before vaccination on day 0 and again at approximately 28 (+ 14) days after vaccination.

Back to Top | Article Outline

Endpoints

Primary immunogenicity endpoints included the percentage of participants demonstrating a booster response to pertussis, diphtheria, tetanus and poliovirus antigens and geometric mean concentrations (GMCs) or geometric mean titers (GMTs) of antibodies. A booster response to pertussis antigens was defined as antibody concentrations greater than or equal to 4× the lower limit of quantitation (LLOQ) in participants who had prevaccination levels that were less than LLOQ; a 4-fold rise in antibodies in participants with prevaccination levels that were less than or equal to LLOQ and less than 4× the LLOQ or a 2-fold rise in antibody concentrations in participants with prevaccination antibodies greater than or equal to 4× the LLOQ. A booster response to diphtheria and tetanus antigens was defined as antibody level ≥0.4 IU/mL in participants with prevaccination levels <0.1 IU/mL; 4-fold rise in antibodies in participants with prevaccination levels ≥0.1 and <2.0 IU/mL or a 2-fold rise in antibodies in participants with prevaccination levels ≥2.0 IU/mL. A booster response to poliovirus antigens was defined as antibody concentrations greater than or equal to 1/8 dilution in participants with prevaccination titers less than 1/8 dilution or a 4-fold rise in antibodies in participants with prevaccination titers greater than or equal to 1/8 dilution.

Safety outcomes included the occurrence, intensity and relationship to vaccination of any unsolicited systemic adverse events (AEs) reported within 30 minutes after vaccination; the occurrence, time to onset, duration and intensity of solicited injection site reactions, solicited systemic reactions, adverse reactions (ARs) and unsolicited AEs, occurring from day 0 through day 28 after vaccination and serious AEs (SAEs) through 180 days after vaccination. Solicited injection site reactions included pain, erythema, swelling, upper limb edema and extensive swelling of the vaccinated limb. Solicited systemic reactions included fever, headache, malaise and myalgia. The intensity of solicited injection site pain was rated as grade 1 (easily tolerated), grade 2 (sufficiently discomforting to interfere with normal behavior or activities) or grade 3 (incapacitating, unable to perform usual activities); injection site erythema was rated as grade 1 (>0 to <25 mm), grade 2 (≥25 to <50 mm) or grade 3 (≥50 mm); injection site swelling was rated as grade 1 (>0 to <25 mm), grade 2 (≥25 to <50 mm) or grade 3 (≥50 mm) and upper limb edema (change in limb circumference) was rated as grade 1 (>0 to <25 mm increase over prevaccination measurement), grade 2 (≥25 to <50 mm increase) or grade 3 (≥50 mm increase). The intensity of fever was rated as grade 1 (≥38.0°C to ≤38.4°C), grade 2 (≥38.5°C to ≤38.9°C) or grade 3 (≥39.0°C); headache, malaise and myalgia were rated as grade 1 (no interference with activity), grade 2 (some interference with activity) or grade 3 (significant; prevents daily activity).

Back to Top | Article Outline

Serologic Evaluations

Serum samples were stored at −20°C and batch shipped to Sanofi Pasteur where all testing was performed. Antibodies against pertussis antigens PT, FHA, PRN and FIM (2 and 3) and tetanus toxoids were measured by enzyme-linked immunosorbent assay. Antidiphtheria antibodies were measured by a toxin neutralization test. Antipoliovirus types 1, 2 and 3 titers were measured by neutralization assay.

Back to Top | Article Outline

Statistical Analysis

A sample size of approximately 640 participants (320 each in groups 1 and 2) was estimated to provide 90.1% power with a 1-sided type I error of 0.025 to show noninferiority for all primary immunogenicity endpoints, assuming a drop-out rate of 10%. The statistical analysis was performed using SAS version 9.1 (SAS Institute, Cary, NC).

The hypotheses tested were that antipertussis, antidiphtheria, antitetanus and antipoliovirus booster response rates and GMCs for antibodies against vaccine antigens were noninferior in participants who received DTaP5-IPV (group 1) as a fifth dose compared with participants who received DTaP5+IPV (group 2). Differences in booster rates and their 95% confidence intervals (CIs) were calculated. Noninferiority of postvaccination booster responses was demonstrated if the lower limits of the 2-sided 95% CI of the difference between response rates was > –10%. Noninferiority of postvaccination antibody levels was demonstrated if the lower limits of the 2-sided 95% CI of the ratio between GMCs (pertussis, diphtheria and tetanus antigens) or GMTs (poliovirus antigens) was >2/3.

Safety analyses were performed on the safety analysis set, which included all participants who received study vaccine and for whom safety data were available. Immunogenicity analyses were conducted using the per-protocol analysis set (PPAS), which comprised participants who received study vaccine and complied with all protocol-specified requirements and procedures. The full analysis set consisted of all participants who received the study or control vaccine and had at least 1 valid postvaccination serology result.

Back to Top | Article Outline

RESULTS

Participants

This study was conducted in 70 sites in the US and Puerto Rico between April 28, 2011, (first participant visit) and May 30, 2013 (last participant contact). A total of 3372 participants were randomized, including 324 in group 1, 327 in group 2, 2419 in group 3 and 302 in group 4. There were 3354 participants in the safety analysis set and 516 participants in the PPAS. The mean (standard deviation) age was 4.4 (0.5); 51.5% of participants were male and most (75.7%) participants were white (Table 1). All demographic characteristics were similar between groups. No participant discontinued from the study because of an AE or SAE (Fig. 1).

TABLE 1

TABLE 1

FIGURE 1

FIGURE 1

Back to Top | Article Outline

Immunogenicity Results

Pertussis

For each pertussis antigen (PT, FHA, PRN and FIM), the prevaccination GMCs were low in both treatment groups (Table 2). After the fifth dose vaccination, the GMCs increased, with the participants in group 1 showing consistently higher antibody levels than the participants in group 2 for all 4 pertussis antigens (Table 2). The GMCs for all pertussis antigens were higher in group 1 compared with group 2. Twenty-eight days after vaccination, booster responses to all vaccine antigens ranged from 94.9% to 97.2% for group 1 and from 87.5% to 93.1% for group 2 (Table 3). Noninferiority of DTaP-IPV to DTaP5+IPV was demonstrated by both GMC ratios (Table 2) and booster response rates (Table 3).

TABLE 2

TABLE 2

TABLE 3

TABLE 3

Back to Top | Article Outline

Diphtheria and Tetanus Toxin

Prevaccination levels of antibodies to diphtheria and tetanus toxin were low (Table 2). Following the fifth dose vaccination, the GMCs were higher and noninferiority was achieved for both tetanus and diphtheria (Table 2). Table 3 presents the noninferiority comparisons of the antitetanus and antidiphtheria antibodies based on the booster response rates between groups in the PPAS.

Back to Top | Article Outline

Poliovirus

Antipoliovirus antibody levels were still present at 3 years after the routine dose in the second year of life (Table 2), with at least 93.2% of participants in both groups having prevaccination seroprotection titers greater than or equal 1/8 dilution. The fifth dose elicited GMT levels that were more than 15 times higher than prevaccination levels for all 3 polio antigens (Table 2), with seroprotection rates ranging from 99.6% to 100% (data not shown). Noninferiority between the 2 treatment groups, assessed by the comparison of postvaccination GMT ratios and booster response rates, was achieved.

Back to Top | Article Outline

Safety Results

Immediate AEs

Three participants experienced immediate AEs (within 30 minutes of vaccination) that were considered related to vaccination. One participant (DTaP5-IPV) experienced grade 1 flushing, which lasted 2 days; 1 participant (DTaP5-IPV) experienced grade 1 macular rash, which lasted 3 days and 1 participant (DTaP5+IPV) experienced grade 2 hyperhidrosis and nausea, which lasted 1 day.

Twenty-five participants (0.9%) experienced at least 1 immediate unsolicited AE and 2 participants (0.1%) experienced at least 1 immediate unsolicited AR in the DTaP5-IPV group. Six participants (1.0%) experienced at least 1 immediate unsolicited AE and 1 participant (0.2%) experienced at least 1 immediate unsolicited AR in the DTaP5+IPV group.

Back to Top | Article Outline

Solicited Reactions

Solicited reactions were reported by 93.5% of participants who received DTaP5-IPV and 91.7% of those who received DTaP5+IPV (Table 4). Specific injection site reactions are presented in Table 5. The most common solicited injection site reaction was pain, with 77.4% of participants in the DTaP-IPV group and 76.5% of participants in the DTaP5+IPV group experiencing local pain. The percentage of participants experiencing redness and swelling around the injection site was similar between the 2 groups. Grade 3 solicited reactions were experienced by 24.0% of participants in the DTaP5-IPV group and 19.9% of those in the DTaP5+IPV group, with grade 3 injection site reactions reported more frequently in the DTaP5-IPV than the DTaP5+IPV group, primarily because of the frequency of injection site erythema (Table 5). The incidence of grade 3 solicited systemic reactions was similar between DTaP5-IPV and DTaP5+IPV groups (Table 6).

TABLE 4

TABLE 4

TABLE 5

TABLE 5

TABLE 6

TABLE 6

A change in limb circumference was experienced by 68.1% (1703/2500) of participants in the DTaP-IPV group and 65.1% (302/464) of participants in the DTaP5+IPV group (Table 5). The percentage of participants reporting extensive limb swelling (ELS) within 7 days after vaccination was similar between the vaccination groups: 1.5% (39/2666) of participants in the DTaP5-IPV group and 1.3% (8/598) of participants in the DTaP5+IPV group. The most commonly reported solicited systemic reactions were myalgia and malaise (Table 6). Grade 3 solicited systemic reactions were reported by 4.5% and 6.5% of participants in the DTaP5-IPV and DTaP5+IPV groups, respectively.

Back to Top | Article Outline

Unsolicited Events

Unsolicited AEs within 28 days of vaccination were reported by 34.8% of participants who received DTaP5-IPV and 30.8% of participants who received DTaP5+IPV (Table 4). Of these, 4.1% in the DTaP5-IPV group and 3.5% in the DTaP5+IPV group had at least 1 grade 3 unsolicited non-SAE. The most commonly reported unsolicited AEs were cough (5.2% DTaP5-IPV; 4.2% DTaP5+IPV), injection site induration (5.1% DTaP5-IPV; 3.2% DTaP5+IPV) and vomiting (3.3% DTaP5-IPV; 3.9% DTaP5+IPV).

Unsolicited ARs within 28 days of vaccination were reported by 11.6% of participants who received DTaP5-IPV and 9.2% of participants who received DTaP5+IPV (Table 4). Of these, 0.5% in the DTaP5-IPV group and 0.6% in the DTaP5+IPV group had at least 1 grade 3 unsolicited nonserious AR. The most commonly reported unsolicited systemic ARs were vomiting (0.5% DTaP5-IPV; 0% DTaP5+IPV), somnolence (0.3% DTaP5-IPV; 0% DTaP5+IPV) and rash (0.1% DTaP5-IPV; 0% DTaP5+IPV). There were no reports of anaphylactic reactions, convulsions or hypotonic-hyporesponsive episodes.

Back to Top | Article Outline

SAEs

Three participants on the DTaP5-IPV group reported an SAE within 28 days of vaccination, including a case of lobar pneumonia (duration, 23 days), a case of asthma (duration, 53 days) and a participant with new-onset type 1 diabetes mellitus. All required hospitalization but none was deemed to be related to vaccination by the investigator. One participant in the DTaP5+IPV group reported viral synovitis (duration, 16 days).

SAEs reported through day 180 of the study included 21 (0.8%; 18 requiring hospitalization) participants in the DTaP5-IPV group and 3 (0.5%; all requiring hospitalization) in the DTaP5+IPV group. One participant (DTaP5-IPV) experienced life-threatening respiratory failure secondary to croup/laryngotracheitis at 161 days postvaccination and recovered after 6 days. One participant (DTaP5-IPV) was hospitalized 93 days postvaccination and subsequently diagnosed with Kawasaki disease, and recovered by the end of the study. One participant (DTaP5-IPV) was diagnosed with asthma and common variable immune deficiency at 50 days postvaccination. One participant (DTaP5-IPV) presented with symptoms of autism at 158 days postvaccination, which was confirmed by a developmental pediatrician. One participant (DTaP5-IPV) was diagnosed with petit mal epilepsy (absence seizure) at 168 days postvaccination.

Back to Top | Article Outline

DISCUSSION

This phase III study showed that in children 4–6 years of age, vaccination with DTaP5-IPV as a fifth dose booster was noninferior to DTaP5+IPV for responses to all pertussis, diphtheria, tetanus and poliovirus antigens and that local and systemic reactions to vaccines were comparable among all groups.

An important aspect of this study was the use of pertussis immunization as a fifth dose. The prevaccination GMCs were very low in both treatment groups, supporting the need for a preschool pertussis booster. Noninferiority of DTaP5-IPV to DTaP5+IPV was demonstrated by both the booster response rates and the GMC ratios. For PT and FHA, this was not unexpected given the 2-fold higher concentration in vaccine composition of DTaP5-IPV (20 µg PT and 20 µg FHA) compared with DAPTACEL (10 µg PT and 5 µg FHA). The immune responses for the PRN and FIM components of the DTaP5-IPV group were also higher, even though the amounts of antigens for these components are the same in the 2 vaccines. The mechanism for this observation is unknown, but this result may suggest a possible synergistic effect of PT/FHA on the other antigens. Overall, the levels of immune responses described in both treatment groups in the current study are above the levels described in the Swedish infant efficacy study,11–14 which demonstrated 85% protective efficacy against World Health Organization World Health Organization–defined pertussis disease. Thus, it is reasonable to conclude that protective efficacy against pertussis will be achieved when either DTaP5-IPV or DTaP5+IPV is given as a booster dose to children 4–6 years of age.

Prevaccination levels of antibodies to diphtheria toxin had declined in these children after their 18-month dose, and although most still had levels in excess of the 0.1 IU/mL protective level, only 29.2% and 36.1% of participants had antidiphtheria and antitetanus concentrations, respectively, of 1.0 IU/mL and above, levels associated with long-term protection for diphtheria and for tetanus. After vaccination, 100% of participants in the DTaP5-IPV group and at least 99.2% in the DTaP5+IPV group achieved seroprotection of ≥0.1 IU/mL against both diphtheria and tetanus. Noninferiority between the DTaP5-IPV- and DTaP5+IPV-vaccinated participants, as assessed by the comparison of postvaccination GMC ratios and the percentage of subjects achieving booster response, was met. The diphtheria booster results are notable in that a good response was demonstrated with both 5-component DTaP vaccines, which contain a lower diphtheria content (l5 Lf) than what is commonly used in Pediarix and Kinrix (25 Lf), 3-component vaccines.15

The fifth dose elicited more than 15 times higher GMCs than prevaccination levels for all 3 polio antigens, with seroprotection rates ranging from 99.6% to 100%. Although polio has been eradicated from the Western hemisphere, it is important to maintain high levels of protection in the population until global eradication is achieved.

Prevaccination antibody levels did not differ by race or gender. Analysis of the GMCs by race for the pertussis antigens postvaccination showed that in the DTaP5-IPV group, Caucasians had the lowest titers for PT, FHA and FIM antigens and Blacks had the highest titers for these antigens (data not shown). In general, the comparisons of GMCs and GMTs between DTaP5-IPV and DTaP5+IPV across all ethnic groups and both sexes for each vaccine component were similar to those of the PPAS and full analysis set. Blacks show slightly higher pre- and postvaccination GMCs for pertussis antigens than Caucasians and Hispanics, which is consistent with findings in a previous study of the fourth dose of PENTACEL.6 Because the participants were randomly assigned to vaccine groups in the present study, these covariates should not have had a substantial impact on the noninferiority analysis.

The administration of DTaP5-IPV in children 4–6 years old as the fifth dose was found to be well-tolerated, with no safety concerns identified and a safety profile similar to DTaP5+IPV. There were no AEs of special interest or vaccine-related deaths and no life-threatening immediate reactions such as anaphylaxis, difficulties in breathing or hives. This is consistent with the established safety profile of DTaP5+IPV vaccine based on 16 years of postmarketing surveillance and more than 7 million doses distributed.6 Similarly, vaccination with DTaP5-IPV has been associated with generally mild and self-limiting AEs.7 Most solicited reactions in both groups were mild and transient, and few (<0.4%) participants reported unsolicited immediate AEs, all of which were mild or moderate in severity. Injection site reactions were transient, usually resolved spontaneously, and did not require medical intervention. ELS, defined as swelling of the injected limb including the adjacent joint (ie, elbow and/or shoulder), as compared to baseline, is an expected AE. ELS occurs rarely and usually is seen in children receiving a booster dose of DTaP. The pathogenesis of ELS is poorly understood.16 In an analysis of fourth and fifth dose follow-up studies that examined 12 different DTaP vaccines, 2% of 1015 children who received consecutive doses of the same DTaP vaccine reported entire thigh swelling, which resolved completely.17 Others estimated an incidence range of 1%–3% and correlated that with the amount of diphtheria toxoid antigen in the vaccine.18 In the current study, a modified set of the criteria described by Rennels et al19 was used. Daily measurements of limb circumference were collected after vaccination, and the difference of >50 mm from baseline (prevaccination measurement) was intended to serve as a marker for this event. A second marker was the parent’s report of postvaccination soft tissue swelling that extended from the injection site to involve an adjacent joint (eg, the elbow, the shoulder joint or both) of either arm during the 7-day solicited event period. The percentage of participants reporting any (>0 mm) change in limb circumference within 3 days after the vaccination of DTaP5-IPV was 68.1% compared with 65.1% for DTaP5+IPV. In the DTaP5-IPV group, 4 participants experienced at least 1 grade 3 change in limb circumference; in the DTaP5+IPV group, no participant reported a grade 3 reaction. Information was also collected on joint (shoulder, elbow and both) involvement. There were 39 reports of such postimmunization limb swelling captured as solicited reactions by the parents in the DTaP5-IPV group (1.5%) and 8 cases in the DTaP5+IPV group (1.3%). The overall incidence of ELS detected after vaccination administered as the fifth dose in this study compared favorably to the incidence observed by Rennels.17,20

Back to Top | Article Outline

ACKNOWLEDGMENTS

We thank Robert Lersch (Sanofi Pasteur) and Julia R. Gage (Gage Medical Writing, LLC) for their assistance with preparation of the manuscript.

Back to Top | Article Outline

REFERENCES

1. Centers for Disease Control and PreventionBirth-18 Years & “Catch-Up” Immunization Schedules-United States, 20152015Atlanta, GACenters for Disease Control and PreventionAvailable at: http://www.cdc.gov/vaccines/schedules/hcp/child-adolescent.html. Accessed September 9, 2015
2. Bertilone C, Wallace T, Selvey LAFinding the ‘who’ in whooping cough: vaccinated siblings are important pertussis sources in infants 6 months of age and under.Commun Dis Intell Q Rep201438E195–E200
3. Skoff TH, Kenyon C, Cocoros N, et alSources of infant pertussis infection in the United States.Pediatrics2015136635–641
4. Advisory Committee on Immunization PracticesCombination vaccines for childhood immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians (AAFP).MMWR Recomm Rep1999481–15
5. DAPTACEL® Prescribing InformationToronto, Ontario, CanadaSanofi Pasteur LtdAvailable at: http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM103037.pdf. Accessed September 9, 2015
6. PENTACEL® Full Prescribing InformationSwiftwater, PASanofi Pasteur LtdAvailable at: http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM109810.pdf. Accessed September 9, 2015
7. QUADRACEL® Product MonographToronto, Ontario, CanadaSanofi Pasteur LtdAvailable at: https://www.vaccineshoppecanada.com/document.cfm?file=Quadracel_E.pdf. Accessed September 9, 2015
8. Liang J, Wallace G, Mootrey GLicensure of a diphtheria and tetanus toxoids and acellular pertussis adsorbed and inactivated poliovirus vaccine and guidance for use as a booster dose.MMWR Morb Mortal Wkly Rep201564948–949
9. Centers for Disease Control and PreventionCombination vaccines for childhood immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians (AAFP).MMWR199948No. RR-51–16
10. Marshall GS, Happe LE, Lunacsek OE, et alUse of combination vaccines is associated with improved coverage rates.Pediatr Infect Dis J200726496–500
11. Storsaeter J, Hallander HO, Gustafsson L, et alLevels of anti-pertussis antibodies related to protection after household exposure to Bordetella pertussis.Vaccine1998161907–1916
12. Cherry JDComparative efficacy of acellular pertussis vaccines: an analysis of recent trials.Pediatr Infect Dis J1997164 supplS90–S96
13. Gustafsson L, Hallander HO, Gustafsson L, et alEfficacy Trial of Acellular Pertussis Vaccine. Technical Report Trial 11995Stockholm, SwedenSwedish Institute for Infectious Disease Control
14. Cherry JD, Olin PThe science and fiction of pertussis vaccines.Pediatrics19991041381–1383
15. Decker MD, Edwards KM, Bogaerts HHPlotkin S, Orenstein WACombination vaccines.In: Vaccines20085th edPhiladelphiaElsevier1069–1101
16. Woo EJ, Burwen DR, Gatumu SN, et alVaccine Adverse Event Reporting System Working GroupExtensive limb swelling after immunization: reports to the Vaccine Adverse Event Reporting System.Clin Infect Dis200337351–358
17. Rennels MB, Deloria MA, Pichichero ME, et alExtensive swelling after booster doses of acellular pertussis-tetanus-diphtheria vaccines.Pediatrics2000105e12
18. Slade BA, Edwards KM, Rock MReactiogenicity of fifth dose of diphtheria, tetanus, acellular pertussis (DTaP) vaccine: relationship to post-vaccination antibody titers and cytokine levels.2006In: 8th International Symposium: Saga of the Genus Bordetella, 1906–2006Paris, France
19. Rennels MB, Black S, Woo EJ, et alSafety of a fifth dose of diphtheria and tetanus toxoid and acellular pertussis vaccine in children experiencing extensive, local reactions to the fourth dose.Pediatr Infect Dis J200827464–465
20. Rennels MBExtensive swelling reactions occurring after booster doses of diphtheria-tetanus-acellular pertussis vaccines.Semin Pediatr Infect Dis200314196–198
Keywords:

DTaP5; fifth dose; safety; immunogenicity

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.