• No results found

Immunogenicity, Safety, and Tolerability of a Hexavalent Vaccine in Infants

N/A
N/A
Protected

Academic year: 2020

Share "Immunogenicity, Safety, and Tolerability of a Hexavalent Vaccine in Infants"

Copied!
12
0
0

Loading.... (view fulltext now)

Full text

(1)

Immunogenicity, Safety, and

Tolerability of a Hexavalent

Vaccine in Infants

Gary S. Marshall, MDa, Gregory L. Adams, MDb, Michael L. Leonardi, MDc, Maria Petrecz, BSd, Sheryl A. Flores, PhDd, Angela L. Ngai, BSd, Jin Xu, PhDd, Guanghan Liu, PhDd, Jon E. Stek, MSd, Ginamarie Foglia, DOe, Andrew W. Lee, MDd

abstract

BACKGROUND:DTaP5-IPV-Hib-HepB is a fully liquid investigational hexavalent vaccine directed against 6 diseases.

METHODS:This multicenter, open-label, comparator-controlled, phase III study randomly assigned healthy infants 2-to-1 as follows: group 1 received DTaP5-IPV-Hib-HepB, PCV13, and RV5 at 2, 4, and 6 months of age followed by DTaP5, Hib-OMP, and PCV13 at 15 months of age; group 2 received DTaP5-IPV/Hib, PCV13, and RV5 at 2, 4, and 6 months of age, with HepB at 2 and 6 months of age, followed by DTaP5, Hib-TT, and PCV13 at 15 months of age.

RESULTS:Overall, 981 participants were vaccinated in group 1 and 484 in group 2. Immune responses in group 1 to all antigens contained in DTaP5-IPV-Hib-HepB 1 month after dose 3 and for concomitant rotavirus vaccine were noninferior to those in group 2, with the exception of antipertussisfilamentous hemagglutinin (FHA) geometric mean concentrations (GMCs). Vaccine response rates for FHA were noninferior to control. After the toddler dose, group 1 immune responses were noninferior to group 2 for all pertussis antigens. Solicited adverse event rates after any dose were similar in both groups, with the exceptions of increased injection-site erythema, increased fever, and decreased appetite in group 1. Fever was not associated with hospitalization or seizures.

CONCLUSIONS:The safety and immunogenicity of DTaP5-IPV-Hib-HepB are comparable with the analogous licensed component vaccines. Decreased FHA GMCs and increased injection-site reactions and fever are unlikely to be clinically significant. DTaP5-IPV-Hib-HepB provides a new combination vaccine option aligned with the recommended US infant immunization schedule.

WHAT’S KNOWN ON THIS SUBJECT:The routine childhood immunization schedule is crowded during the first 2 years, leading to deferred doses and limiting the addition of new vaccines. Combination vaccines can reduce the “shot burden”and improve coverage rates and timeliness.

WHAT THIS STUDY ADDS:Antibody response rates to antigens contained in an investigational hexavalent vaccine (DTaP5-IPV-Hib-HepB) were noninferior to licensed comparator vaccines when given as a 3-dose infant series. The safety profile was similar to control except for increased rates of mild-to-moderate, self-limited fever.

aDepartment of Pediatrics, University of Louisville, Louisville, Kentucky;bBlue Ridge Pediatric and Adolescent Medicine, Boone, North Carolina;cPalmetto Pediatrics, Charleston, South Carolina;dMerck & Co, Inc, Kenilworth, New Jersey; andeSanoPasteur, Swiftwater, Pennsylvania

Dr Marshall and Mr Stek drafted the initial manuscript; Drs Marshall, Adams, and Leonardi contributed to participant enrollment, data collection/acquisition, data interpretation, and they reviewed and revised the manuscript; Drs Flores, Xu, Liu, Foglia, and Lee contributed to the study concept/design, data analysis/interpretation, and they reviewed and revised the manuscript; Mrs Petrecz, Ms Ngai, and Mr Stek contributed to the data analysis/interpretation, and they reviewed and revised the manuscript; and all authors approved thefinal manuscript as submitted. Data from this article were presented in poster format (#1112) at IDWeek-2014 in Philadelphia, PA. Although the sponsors formally reviewed a penultimate draft, the opinions expressed are those of the authors and may not necessarily reflect those of the sponsors.

This trial has been registered at www.clinicaltrials.gov (identifier NCT01337167). www.pediatrics.org/cgi/doi/10.1542/peds.2014-4102

DOI:10.1542/peds.2014-4102 Accepted for publication May 27, 2015

Address correspondence to Andrew W. Lee, MD, Merck & Co, Inc, 2000 Galloping Hill Rd, UG-3D063, Kenilworth, NJ 08889. E-mail: andrew_wen-tseng_lee@merck.com

(2)

The recommended immunization schedule for children in the United States protects infants and toddlers against 14 different diseases.1

Without the use of modern combination vaccines such as DTaP3-HepB-IPV and DTaP5-IPV/Hib, the schedule would call for

as many as 25 separate injections (27 or 28 separate vaccinations including RV1 or RV5) in thefirst 2 years of life (see the Appendix for vaccine abbreviations and

manufacturers).2Even with current

combination vaccines, however, the

“shot burden”is still appreciable: a minimum of 18 injections (20 separate vaccinations) in thefirst 2 years of life.2The high injection

density during these early years is a factor in vaccine hesitancy, leading to the perception that infants receive“too many shots too soon,”3

with downstream consequences including deferred doses and decreased coverage rates.4,5

Moreover, the crowded vaccination schedule makes it difficult to add new vaccines with potential incremental health benefits to young children. For all of these reasons, the Advisory Committee on Immunization Practices,6American

Academy of Pediatrics,7and

American Academy of Family Physicians8all endorse the use of

combination vaccines.

Higher valency combination vaccines have the potential to mitigate these issues and have been shown to improve coverage and

timeliness.9–11The investigational

hexavalent vaccine DTaP5-IPV-Hib-HepB is a fully liquid combination vaccine directed against 6 diseases; incorporating it into the childhood schedule would result in 1 to 4 fewer shots, depending on which DTaP-based combination vaccine was previously used, which monovalent invasiveHaemophilus influenzaetype b (Hib) vaccine was used along with DTaP3-HepB-IPV, and whether the toddler dose was

delivered as DTaP plus monovalent Hib or DTaP5-IPV/Hib. This report presents results from the pivotal US phase III study (NCT01337167), assessing the safety, tolerability, and

immunogenicity of IPV-Hib-HepB compared with DTaP5-Hib-IPV plus HepB when

administered concomitantly with PCV13 and RV5.

METHODS

Population

Healthy infants 46 to 89 days of age who had received 1 dose of hepatitis B vaccine (outside of study) before or at 1 month of age were eligible for the study. Participants were

excluded if they had (1) participated in another study of an

investigational compound or device within 4 weeks of entry, or

planned to enroll in another clinical study during the current study period; (2) received or expected to receive immunosuppressive agents; (3) received systemic steroids (equivalent of.2 mg/kg per day prednisone) since birth, within 7 days before study entry, or expected to receive steroids through the course of the study; (4) a history of leukemia, lymphoma, malignant melanoma, or myeloproliferative disorder; (5) known or suspected hypersensitivity to any vaccine component; (6) received.1 dose of hepatitis B vaccine or.1

combination vaccine containing hepatitis B vaccine; (7) received any vaccines other than hepatitis B vaccine; (8) a febrile illness, or a rectal temperature$38.0°C ($100.4°F), within 24 hours before enrollment; (9) a coagulation disorder

contraindicating intramuscular (IM) vaccination; (10) a maternal or personal history of hepatitis B surface antigen (HBsAg) seropositivity; (11) a history of Hib disease, hepatitis B, diphtheria, tetanus, pertussis,

poliomyelitis, rotavirus gastroenteritis, or pneumococcal disease; or (12) any

contraindication to the concomitant study vaccines. Prematurity was not an exclusion criterion. The protocol was conducted in accordance with principles of Good Clinical Practice, including obtaining written informed consent from each participant’s parent or legal guardian before study entry, and was approved by the human studies committees applicable to each study site.

Vaccines

Table 1 displays characteristics of the vaccines used in this study. Vaccine supplies were shipped, stored, and distributed in accordance with the study protocol and Good

Manufacturing Practice. Of note, DTaP5-IPV-Hib-HepB was

presented in a sterile, single-dose, liquid, preservative-free

formulation. All vaccine doses were 0.5 mL given intramuscularly, except for RV5, which was 2.0 mL given orally.

Design

This was a randomized, open-label, active comparator-controlled study conducted at 40 sites in the United States between April 2011 and May 2013. A total of 1473 healthy infants were randomly assigned by using a computer-generated, site-balanced allocation schedule to receive either DTaP5-IPV-Hib-HepB (group 1) or control vaccines (group 2) in a 2:1 ratio (Table 2).

(3)

conjugate as the Hib component of DTaP5-IPV-Hib-HepB, and Hib-TT contains the same

protein-polysaccharide conjugate as the Hib component of DTaP5-IPV/Hib).

Blood specimens used to assess immunogenicity were collected via venipuncture immediately before administration of dose 1,∼1 month after completion of the infant series (dose 3), immediately before the toddler dose, and∼1 month after the toddler dose.

From day 1 (day of vaccination) to day 5 after each vaccination, the following safety measurements were obtained: temperature; solicited injection-site adverse events (AEs), including injection-site pain, tenderness, redness, and swelling; and solicited systemic AEs, including pyrexia (fever), vomiting, abnormal crying, drowsiness, appetite loss, and irritability. Unsolicited injection-site and systemic AEs were collected through day 15 after each

vaccination. Serious AEs (SAEs), defined as AEs leading to

hospitalization, were recorded from study entry up to 6 months after the last DTaP5-IPV-Hib-HepB vaccination, regardless of causality.

Parents were instructed to not administer antipyretic, analgesic, or nonsteroidal antiinflammatory medications within 48 hours before administration of study vaccines; these medications were allowed after vaccination in response to fever.

TABLE 1 Vaccines Administered

Target Disease Antigen(s) Vaccinesa

Investigational Licensedb

DTaP5-IPV-Hib-HepB DTaP5-IPV/Hib DTaP5 Hib-OMP Hib-TT HepB

Diphtheria DT 15 Lf 15 Lf 15 Lf —e — —

Tetanus TT 5 Lf 5 Lf 5 Lf — — —

Pertussis PT 20mg 20mg 10mg — — —

FHA 20mg 20mg 5mg — — —

PRN 3mg 3mg 3mg — — —

FIM-2,3c 5mg 5mg 5mg — — —

Polio Type 1 (Mahoney) 40 D-antigen units 40 D-antigen units — — — — Type 2 (MEF-1) 8 D-antigen units 8 D-antigen units — — — — Type 3 (Saukett) 32 D-antigen units 32 D-antigen units — — — —

Hib PRP, OMPd 3mg, 50mg — — 7.5mg, 125mg — —

PRP, TTd — 10mg, 24mg — — 10mg, 24mg —

Hepatitis B HBsAg 10mg — — — — 5mg

(Adjuvant) Aluminum 319mg 330mg 330mg 225mg — 250mg

All products were prepared, packaged, and labeled in accordance with Good Manufacturing Practice, guidelines for Good Clinical Practice from The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, as well as applicable local laws and regulations. Expansion of abbreviations for vaccines and their respective manufacturers are given in the Appendix. Lf, limit offlocculation units; OMP,N meningitidisserogroup B outer membrane protein.

aIn the case of licensed vaccines, trade names are used so as to minimize confusion and facilitate understanding of the study. Trademark symbols are not shown. Composition is given

per 0.5 mL dose unless otherwise indicated. Manufacturers: Merck & Co, Inc, Kenilworth, New Jersey; SanofiPasteur Limited, Swiftwater, Pennsylvania; Pfizer, Inc, Philadelphia, Pennsylvania.

bOther licensed vaccines used in the study: RV5, given as a 2.0-mL oral dose; and PCV13, given as a 0.5-mL IM dose.

cFIM-2,3 content in DTaP5-IPV-Hib-HepB, DTaP5-IPV/Hib, and DTaP5 includes bothmbriae 2 andmbriae 3. Although this is counted as 2 antigens (accounting for the nomenclatureDTaP5,

antibody responses to FIM-2 and FIM-3 are not measured separately. Therefore, the immunogenicity text refers to only 4 pertussis antibodies.

dProtein-polysaccharide conjugates.

eAntigen not contained in corresponding vaccine.

TABLE 2 Vaccination Schedule

Antigens Infant Series Toddler Dose

2 mo (Dose 1) 4 mo (Dose 2) 6 mo (Dose 3) 15 mo Group 1 (Investigational),N= 986 Diphtheria, tetanus, pertussis DTaP5-IPV-Hib-HepB DTaP5-IPV-Hib-HepB DTaP5-IPV-Hib-HepB DTaP5

Poliovirus —a

Hib Hib-OMP

Hepatitis B

Pneumococcus PCV13 PCV13 PCV13 PCV13

Rotavirus RV5 RV5 RV5 —

Group 2 (Control),N= 487 Diphtheria, tetanus, pertussis DTaP5-IPV/Hib DTaP5-IPV/Hib DTaP5-IPV/Hib DTaP5

Poliovirus —

Hib Hib-TT

Hepatitis B HepB — HepB —

Pneumococcus PCV13 PCV13 PCV13 PCV13

Rotavirus RV5 RV5 RV5 —

Expansion of abbreviations for vaccines and their respective manufacturers are given in the Appendix.

(4)

Live attenuated vaccines, such as varicella, measles, mumps, and rubella vaccines, were not provided as part of the study, but were permitted as long as they were given more than 30 days before or after any dose of study vaccine. Nonstudy inactivated vaccines, including inactivated influenza vaccine, were permitted more than 14 days before or after any dose of study vaccine.

Objectives

The primary objectives were to (1) compare the immunogenicity of DTaP5-IPV-Hib-HepB with the corresponding control vaccines; (2) compare the immunogenicity of pertussis responses 1 month after the toddler dose of DTaP5 in children whose primary pertussis series was 3 doses of

DTaP5-IPV-Hib-HepB versus 3 doses of DTaP5-IPV/Hib; and (3) demonstrate that the poliovirus response rate is acceptable after 3 infant doses of DTaP5-IPV-Hib-HepB.

The secondary objectives were to (1) compare antibody responses to polyribosylribitol phosphate (PRP; the polysaccharide antigen

component of Hib conjugate vaccines) elicited by DTaP5-IPV-Hib-HepB versus the corresponding control vaccines; (2) evaluate the immunogenicity of RV5 when administered concomitantly with DTaP5-IPV-Hib-HepB; (3) describe the per-dose safety profile of DTaP5-IPV-Hib-HepB and the control vaccines when given concomitantly with PCV13 and RV5; (4) describe the fever profile after any dose of

DTaP5-IPV-Hib-HepB and control vaccines when given concomitantly with PCV13 and RV5; (5) describe the percentage of participants with solicited injection-site and systemic AEs within 5 days after any dose of DTaP5-IPV-Hib-HepB or control vaccines when coadministered with other recommended vaccines; and (6) describe the incidence of SAEs up to 6 months after the last dose of DTaP5-IPV-Hib-HepB or control vaccines.

The tertiary objectives were to describe (1) the geometric mean concentrations (GMCs) of antibody against all antigens in DTaP5-IPV-Hib-HepB and corresponding control vaccines after 3 doses; (2) the proportion of participants with anti-PRP concentration$0.15mg/mL (considered the short-term correlate of protection12,13) before the toddler

dose of Hib-OMP or Hib-TT and the proportion of participants with anti-PRP$1.0mg/mL (considered the long-term correlate of

protection12,13) 1 month after the

toddler dose of either vaccine; and (3) the response rates to all antigens except pertussis 1 month after the toddler dose.

Analyses

Power

The study planned to enroll∼1440 subjects (960 in group 1 and 480 in group 2). Assuming 85% of the randomly assigned subjects were evaluable after dose 3 and 80% 1 month after the toddler dose, the study had∼92.6% power for testing all the primary objectives.

Immunogenicity

Antibody responses were defined based on accepted immune correlates of protection,14or

previously accepted definitions of vaccine response for licensed vaccines (Supplemental Table 8). The primary and key secondary end points, analysis populations, and statistical methods for

immunogenicity analyses are

FIGURE 1

Participant disposition. Reasons for discontinuation:aAE (death due to asphyxia; 1); lost to follow-up (13); noncompliance (2); physician decision (3); protocol violation (22); withdrawal of consent (15).bAE (death due to pneumonia, aspiration, and cardiopulmonary arrest; 1); lost to follow-up (7); non-compliance (1); physician decision (1); protocol violation (9); withdrawal of consent (4).cLost to follow-up (51); noncompliance (1); physician decision (6); protocol violation (5); withdrawal of consent (18).

d

(5)

provided in Supplemental Table 9. The per-protocol analyses included all participants who met the inclusion criteria, did not deviate from the protocol, and had serology results within the specified day ranges. The per-protocol, original windows population consisted of the per-protocol population who

had vaccination windows of 46 to 74 days after the previous vaccination and blood draw sample windows of 28 to 44 days after the infant series (dose 3) or toddler dose. The per-protocol, revised windows population consisted of the per-protocol population who had vaccination windows of 42 to 84

days after the previous vaccination and blood draw sample windows of 28 to 51 days after the infant series (dose 3) or toddler dose. The revised windows were prespecified in an amendment to the protocol and statistical analysis plan before database lock and knowledge of immunogenicity results. They were based on earlier phase II studies of DTaP5-IPV-Hib-HepB and allowed for inclusion of immunogenicity data from more vaccinated participants in the per-protocol analysis. The success of immunogenicity hypothesis testing was based on results from the per-protocol, revised windows population. Key immunogenicity summaries and analyses were also provided for all end points associated with hypotheses by using the full analysis set population, which included all randomly assigned participants with available serology data at postvaccination regardless of protocol deviation.

Safety

All randomly assigned participants who received$1 dose of study vaccine and had safety follow-up were included in the safety analysis. The AE and fever profiles were described for study vaccines after each vaccination and the entire vaccination period. Incidence rates of solicited AEs (days 1 to 5 after any infant dose), elevated temperatures ($38°C, days 1 to 5 after any infant dose), and unsolicited AEs (days 1 to 15 after any infant dose and occurring in more than 1% of the participants in either vaccination group), were compared by using point estimates and 95% confidence interval (CI; unstratified Miettinen and Nurminen method).15Other safety end points

were summarized by using frequency counts and percentages.

RESULTS

Participant Accounting and Demographics

As shown in Fig 1, 1237 (83.9%) randomly assigned participants

TABLE 3 Participant Demographics and Baseline Characteristics

Characteristic Group 1, DTaP5-IPV-Hib-HepB,N= 986 Group 2, Control,N= 487 Gender,n(%)

Boy 507 (51.4) 273 (56.1)

Girl 479 (48.6) 214 (43.9)

Age, d

Mean (6SD) 65.667.5 65.066.9

Range 46–89 47–87

Race, n (%)

White 765 (77.6) 402 (82.5)

Black 154 (15.6) 53 (10.9)

Asian 13 (1.3) 4 (0.8)

Other 54 (5.5) 28 (5.8)

Ethnicity,n(%)

Hispanic 77 (7.8) 29 (6.0)

Not Hispanic 895 (90.8) 451 (92.6)

Other/not reported 14 (1.4) 7 (1.4)

Weight, kg

Mean (6SD) 5.260.7 5.260.7

Range 3–8 3–8

Neonatal conditions,n(%)

Prematurity 29 (3.0) 18 (3.7)

Low birth weight 2 (0.2) 1 (0.2)

Expansion of the vaccine abbreviation is given in the Appendix.

FIGURE 2

(6)

completed the study. Participants in both groups were comparable with respect to baseline characteristics (Table 3). The most common underlying medical conditions were neonatal jaundice (27.5% of group 1, 27.7% of group 2) and

gastroesophageal reflux disease (19.2% of group 1, 21.9% of group 2). The most frequently reported concomitant medications

administered during the study were analgesics (64.0% of group 1, 60.1%

of group 2) and antiinflammatory products (26.1% of group 1, 21.5% of group 2).

Immunogenicity

Antibody response rates after the infant series for all antigens contained in DTaP5-IPV-Hib-HepB are shown in Fig 2. One month after the infant series, the lower bound of the 2-sided 95% CI for the group difference in response rates (group 1 minus group 2) was above

the prespecified noninferiority margins for all antigens. GMCs of antibody responses to pertussis antigens, PRP, and rotavirus after the infant series and for pertussis antigens after the toddler dose are given in Table 4. The GMC ratio (group 1/group 2) was above the prespecified noninferiority margin for all antibodies except for

pertussisfilamentous hemagglutinin (FHA).

Antibody response rates and GMCs to pertussis antigens after the toddler dose are shown in Fig 3 and Table 4, respectively. The lower bounds of the 2-sided 95% CI for response rates (group 1 minus group 2) and GMC ratios (group 1/group 2) were above noninferiority margins, indicating that both response rates and GMCs in group 1 were noninferior to group 2 for all pertussis antibodies 1 month after the toddler dose.

Figure 2 also reveals antibody response rates to poliovirus antigens after the infant series. The lower bound of the 2-sided 95% CI for the response rates in group 1 was$90%, indicating that

responses for poliovirus types 1, 2, and 3 were acceptable. In addition, Fig 2 reveals anti-PRP response rates after the infant series. The estimated difference in response

TABLE 4 GMCs and GMC Noninferiority Evaluation of Antibody for Selected Antigens

Antigen Group 1, DTaP5-IPV-Hib-HepB,N= 924

Group 2, Control,

N= 460

Estimated GMC Ratio (95% CI) Noninferiority Criterion

n Estimated GMC n Estimated GMC One month after infant series (dose 3)

PT 810 109.61 400 85.41 1.28 (1.20 to 1.38) Met

FHA 810 46.59 400 72.28 0.64 (0.59 to 0.70) Not meta

PRN 808 55.77 400 66.81 0.83 (0.73 to 0.95) Met

FIM-2,3 809 235.87 400 184.40 1.28 (1.15 to 1.42) Met

PRP 765 4.94 382 3.05 1.62 (1.32 to 1.98) Met

Rotavirus IgA 522 282.54 274 277.95 1.02 (0.83 to 1.24) Met One month after the toddler dose

PT 713 126.90 356 90.78 1.40 (1.28 to 1.52) Met

FHA 710 87.52 357 87.54 1.00 (0.91 to 1.10) Met

PRN 713 108.48 358 139.71 0.78 (0.68 to 0.89) Met

FIM-2,3 713 657.28 358 415.00 1.58 (1.41 to 1.78) Met

Expansion of the vaccine abbreviation is given in the Appendix.

aNoninferiority criterion for FHA response rate was met.

FIGURE 3

(7)

rate at the 0.15-mg/mL level was 4.87% (95% CI: 2.23 to 8.14), satisfying the criterion for noninferiority (.25%). At the 1.0-mg/mL level, the estimated difference was 9.68% (95% CI: 4.83 to 14.83), which also met the prespecified noninferiority criterion (.210%).

Table 4 also reveals GMCs of antibody responses to

concomitantly administered RV5 after the infant series. The lower bound of the 95% CI for the GMC ratio (group 1/group 2) of antirotavirus immunoglobulin A (IgA) was 0.83, satisfying the noninferiority criterion

(.0.67).

Results discussed in this section refer to the per-protocol, revised windows population; results on the

basis of the per-protocol, original windows and full analysis set populations were consistent with the results for per-protocol, revised windows for all immunogenicity end points.

Adverse Events

Safety follow-up was obtained for

$99% of participants in each group. As seen in Table 5, 95.5% of participants in group 1 and 93.4% in group 2 reported$1 AE after any dose in the infant vaccination series. In general, the proportion of participants reporting injection-site AEs (days 1–15), solicited injection-site AEs (days 1–5), systemic AEs (days 1–15), and solicited systemic AEs (days 1–5) were similar between groups 1 and 2. The most notable exceptions were solicited reports of decreased appetite on days 1 to 5, which were more common in group 1 (48.9%) than group 2 (43.4%), and solicited reports of pyrexia on days 1 to 5, which were more common in group 1 (47.4%) than group 2 (34.4%). Most of these reports were mild to moderate in intensity and did not lead to medical intervention. During the entire study, 1 participant in group 1 and 1 participant in group 2 discontinued because of vaccine-related non-SAEs.

Table 5 also reveals that 5.4% of participants in group 1 and 6.4% of participants in group 2 reported at least 1 SAE after any dose in the infant vaccination series. There were no discontinuations because of vaccine-related SAEs. One participant in group 1 and 1 in group 2 died during the study; neither death was considered by the investigator to be related to study vaccinations.

Fever of any degree after any infant series vaccine dose was more common in group 1 than group 2 (Table 6, difference 13.1

[7.7%–18.4%]). This was due to a statistically significantly higher incidence of mild and moderate fever in group 1. However, the

TABLE 5 AEs After Any Infant Series Dose in All Participants Who Received at Least 1 Dose of Vaccine

AE Group 1, DTaP5-IPV-Hib-HepB,N= 980a

Group 2, Control,

N= 483a

Number Percent Number Percent

$1 AE (days 1–15) 936 95.5 451 93.4

Injection-site AE (days 1–15) 824 84.1 390 80.7 Solicited injection-site AE (days 1–5) 821 83.8 389 80.5 Systemic AE (days 1–15) 918 93.7 439 90.9 Solicited systemic AE (days 1–5) 905 92.3 432 89.4

Crying 733 74.8 349 72.3

Decreased appetite 479 48.9 209 43.3

Irritability 814 83.1 395 81.8

Pyrexia 465 47.4 166 34.4

Somnolence 726 74.1 346 71.6

Vomiting 252 25.7 104 21.5

$1 vaccine-relatedbAE (days 1–15) 926 94.5 446 92.3 Injection-site AE (days 1–15) 824 84.1 390 80.7 Solicited injection-site AE (days 1–5) 821 83.8 389 80.5

Erythema 478 48.8 204 42.2

Pain 719 73.4 347 71.8

Swelling 393 40.1 168 34.8

Systemic AE (days 1–15) 873 89.1 415 85.9 Solicited systemic AE (days 1–5) 872 89.0 415 85.9

$1 SAE (days 1–15) 21 2.1 8 1.7

$1 SAE (day 1 at dose 1 to day 181 after dose 3) 53 5.4 31 6.4

$1 vaccine-related SAE (days 1–15) 1 0.1 0 0

Deathc 1 0.1 1 0.2

Expansion of the vaccine abbreviation is given in the Appendix.

aNumber of participants vaccinated and with safety follow-up.

bDetermined by the investigator to be possibly, probably, or denitely related to the vaccination. cAll deaths were determined by the investigator to be unrelated to the study vaccines.

TABLE 6 Fever Summary (Any Infant Dose)

Fever (Temperature, °C)a Group 1, DTaP5-IPV-Hib-HepB,N= 949b

Group 2, Control,

N= 470c

Percent Difference Estimate (95% CI)

Number Percent Number Percent

Any ($38.0) 464 48.9 168 35.7 13.1 (7.7 to 18.4) Mild ($38.0 and,38.5) 230 24.2 90 19.1 5.1 (0.5 to 9.5) Moderate ($38.5 and,39.5) 215 22.7 73 15.5 7.1 (2.8 to 11.2) Severe ($39.5) 19 2.0 5 1.1 0.9 (20.6 to 2.2)

Expansion of the vaccine abbreviation is given in the Appendix.

aTemperatures were measured by any method. Approximately 90% of measurements were rectal and 10% axillary for both

groups. Temperatures shown were based on actual temperatures recorded with no adjustments made for the measurement method.

(8)

rates of severe fever were not statistically significantly different. Fever was of brief duration (#2 days for the vast majority), and fever-related SAEs were rare and similar between groups (Table 7).

DISCUSSION

In this large, randomized, open-label, multicenter, controlled clinical trial, antibody response rates to the 12 antigens (diphtheria toxoid [DT], tetanus toxoid [TT], pertussis toxoid [PT], FHA, pertussis pertactin [PRN], pertussisfimbriae types 2 and 3 [FIM-2,3; considered as 2 antigens], inactivated polio vaccine [IPV] 1, IPV2, IPV3, PRP, and HBsAg) contained in DTaP5-IPV-Hib-HepB were noninferior to those for licensed comparators when the vaccines were given as a 3-dose infant series. IgG antibody GMCs to all of the antigens except pertussis FHA were also noninferior. However, antibody response rates and GMCs to all pertussis antigens were noninferior to control after the toddler dose of DTaP5. These results suggest that efficacy against the respective diseases (diphtheria, tetanus, pertussis, polio, Hib, and hepatitis B) would be expected to be similar to the demonstrated efficacy of the licensed comparator vaccines. Responses to rotavirus vaccine given with DTaP5-IPV-Hib-HepB

were noninferior to responses when given with control vaccine. Overall, 26 of 27 primary

immunogenicity end points in this study were met. The failure to meet noninferiority criteria for FHA GMC after the infant series, while meeting criteria for postinfant series response rate and for both response rate and GMC after the toddler dose, is likely of no clinical significance, especially because the other pertussis components (PT, PRN, and FIM-2,3) have been more clearly correlated with pertussis protection.14,16–18In a previous

phase IIB study, over 70% of subjects receiving DTaP5-IPV-Hib-HepB achieved a fourfold rise in antibody responses to PT, FHA, PRN, and FIM-2,3, but acceptability criteria for FHA and PRN were not met.16

The safety profile of DTaP5-IPV-Hib-HepB was similar to control and in line with that expected for routine childhood vaccines. It is noteworthy that DTaP5-IPV-Hib-HepB

administration was associated with increased rates of mild and moderate, self-limited fever that was not associated with an increase in fever-related medical events. Increased rates of fever have been noted before with multivalent combination vaccines. For example, prelicensure studies revealed higher rates of fever (solicited temperature

$38°C) among infants given

DTaP3-HepB-IPV plus PCV7 as compared with those given the corresponding component vaccines plus PCV7, although higher fever (temperature$39.5°C) was rare and occurred with similar frequency in both groups.19There was some

concern early on that increased rates of even low-grade fever might prompt emergency department visits, invasive diagnostic workups, and hospital admissions.20

However, in a managed care-based cohort study of over 61 000 infants who received DTaP3-HepB-IPV (a total of 120 000 doses) plus PCV7, there was no increase in medically attended events associated with fever, including seizure, as

compared with a historical control that received the component vaccines.21In this context, it is

worth noting that high

temperatures ($39.5°C) occurred in only 2% of infants who received DTaP5-IPV-Hib-HepB in the current study. Fever-related AEs were also rare. As with other licensed vaccines, the safety profile of DTaP5-IPV-Hib-HepB will be monitored after approval.

Virtually all doses of DTaP in the United States are given to infants as either DTaP3-HepB-IPV or DTaP5-IPV/Hib, both 5-valent combination vaccines.22In contrast, a

DTaP-based hexavalent vaccine has been used in Europe for over a decade.23

Its adoption was associated with improved immunization

timeliness24and no decrement in

effectiveness in preventing

disease.25Adoption of a hexavalent

combination vaccine in the United States might result in similar benefits: improved coverage and timeliness, sustained protection against disease, and“room” in the schedule for introduction of new vaccines. Given the data presented herein, DTaP5-IPV-Hib-HepB would be an attractive addition to the vaccine armamentarium in the United States.

TABLE 7 Fever-Related AEs

Group 1, DTaP5-IPV-Hib-HepB,N= 980a

Group 2, Control,

N= 483a

Total,N= 1463

Number Percent Number Percent Number Percent AEs (days 1–15)b

Pyrexia 483 49.3 172 35.6 655 44.8

Febrile seizures 0 0 0 0 0 0

Seizures 0 0 0 0 0 0

SAEs (days 1–181)c

Pyrexia 0 0 1 0.2 1 0.1

Febrile seizures 2 0.2 0 0 2 0.1

Seizures 1 0.1 2 0.4 3 0.2

Expansion of the vaccine abbreviation is given in the Appendix.

(9)

ACKNOWLEDGMENTS

The V419 Protocol 005 Study Group participants were as follows: Alabama: Claude Ashley, William H. Johnson; Arkansas: Anthony D. Johnson, Tracy D. Stewart; California: Nicola Klein; Colorado: Robin L. Schaten; Connecticut: Timothy J. Sullivan; Georgia: Wilson P. Andrews; Kansas: Robyn

D. Hartvickson, Paul A. Klaassen; Kentucky: Stanley L. Block, Christopher A. Cunha, Gary S. Marshall; Louisiana: Frank B. Hughes, Thomas G. Latiolais; New York: Robert A. Dracker; North Carolina: Gregory L. Adams, Earl R. Franklin, Karin R. McLelland; Ohio: Julie Shepard; Pennsylvania: Cheryl Duffy, Richard T. Kratz, Anthony P. LaBarbera, Keith S. Reisinger, Edward P. Rothstein, Steven A. Shapiro, David A. Wyszomierski,

Ann M. Zomcik; South Carolina: Michael L. Leonardi, Abe H. Moskow; Tennessee: Donald H. Lewis, Joseph A. Ley; Texas: Khozema A. Palanpurwala; Utah: Matthew J. Cornish, Matthew N. Cox, Martin A. Hollingsworth, Peter E. Silas, Kenneth A. Zollo; and Washington: Timothy E. Crum, Stephen R. Luber.

We thank all of the study

participants, their parents, the study investigators, and their staff. We also thank Dr David R. Johnson of Sanofi Pasteur for helpful review of the draft manuscript and Mrs Karyn Davis for her assistance during author review and submission.

ABBREVIATIONS

AE: adverse event CI: confidence interval DT: diphtheria toxoid FHA: pertussisfilamentous

hemagglutinin

FIM-2,3: pertussisfimbriae types 2 and 3

GMC: geometric mean concentration

HBsAg: hepatitis B surface antigen Hib: invasiveHaemophilus

influenzaetype b IgA: immunoglobulin A IM: intramuscular

IPV: inactivated polio vaccine PRN: pertussis pertactin

PRP: polyribosylribitol phosphate PT: pertussis toxoid

SAE: serious adverse event TT: tetanus toxoid

FINANCIAL DISCLOSURE:Dr Marshall has been an investigator on clinical trials funded by GlaxoSmithKline, Merck, Novartis, Pfizer, and SanofiPasteur, and he also has received honoraria from these companies for service on advisory boards; Dr Adams reports that his major revenue source is private insurance payments and receipts from Medicaid for medical services rendered caring for children in a private pediatric practice, which includes routine recommended immunizations; Drs Marshall, Adams, and Leonardi were investigators for the sponsor supported by research grants; and Mrs Petrecz, Dr Flores, Ms Ngai, Drs Xu and Liu, Mr Stek, and Drs Foglia and Lee are employees of the sponsors and may hold stock and/or stock options from the sponsors.

FUNDING:Funding for this research was provided by Merck & Co, Inc, and SanofiPasteur, Inc (sponsors).

POTENTIAL CONFLICT OF INTEREST:Dr Marshall has been an investigator on clinical trials funded by GlaxoSmithKline, Merck, Novartis, Pfizer, and Sanofi Pasteur, and he also has received honoraria from these companies for service on advisory boards; Dr Adams reports that his major revenue source is private insurance payments and receipts from Medicaid for medical services rendered caring for children in a private pediatric practice, which includes

APPENDIX: VACCINE ABBREVIATIONS, TRADE NAMES, AND MANUFACTURERS

DTaP3-HepB-IPV: diphtheria and tetanus toxoids and acellular (3-component) pertussis adsorbed, hepatitis B (recombinant) and inactivated poliovirus vaccine (PediarixÔ; GlaxoSmithKline, Rixensart, Belgium).

DTaP5: diphtheria and tetanus toxoids and acellular (5-component) pertussis vaccine absorbed (DaptacelÔ; Sanofi Pasteur, Swiftwater, PA).

DTaP5-IPV/Hib: diphtheria and tetanus toxoids and acellular (5-component) pertussis absorbed, inactivated polio, andHaemophilus

b conjugate (tetanus toxoid conjugate) vaccine (PentacelÔ; SanofiPasteur).

DTaP5-IPV-Hib-HepB: diphtheria, tetanus, acellular pertussis (5-component), inactivated polio,

Haemophilus influenzaetype b (polyribosylribitol

phosphate-Neisseria meningitidisouter membrane protein conjugate), and hepatitis B vaccine (investigational hexavalent vaccine).

HepB: hepatitis B vaccine (recombinant; Recombivax HBÔ; Merck, Kenilworth, NJ).

Hib-OMP:Haemophilusb conjugate vaccine (meningococcal protein [N meningitidisserogroup B outer membrane protein] conjugate; PedvaxHIBÔ; Merck).

Hib-TT:Haemophilusb conjugate vaccine (tetanus toxoid conjugate; ActHIBÔ; SanofiPasteur).

IPV: inactivated polio vaccine (no trade name; used as a component of combination vaccines by various manufacturers).

PCV7: pneumococcal 7-valent conjugate vaccine (diphtheria CRM197

protein; PrevnarÔ; Pfizer, Philadelphia, PA).

PCV13: pneumococcal 13-valent conjugate vaccine (diphtheria CRM197

protein; Prevnar 13Ô; Pfizer).

RV1: rotavirus vaccine, live, oral (monovalent; RotarixÔ;

GlaxoSmithKline).

(10)

routine recommended immunizations; Drs Marshall, Adams, and Leonardi were investigators for the sponsor supported by research grants; and Mrs Petrecz, Dr Flores, Ms Ngai, Drs Xu and Liu, Mr Stek, and Drs Foglia and Lee are employees of the sponsors and may hold stock and/or stock options from the sponsors.

REFERENCES

1. Akinsanya-Beysolow I; Advisory Committee on Immunization Practices (ACIP), ACIP Child/Adolescent Immunization Work Group. Advisory Committee on Immunization Practices recommended immunization schedules for persons aged 0 through 18 years— United States, 2014.MMWR Morbid Mortal Wkly Rep. 2014;63(5):108–109

2. Centers for Disease Control and Prevention. Immunization schedules. Available at: www.cdc.gov/vaccines/ schedules/hcp/child-adolescent.html. Accessed December 10, 2014

3. Kennedy A, Basket M, Sheedy K. Vaccine attitudes, concerns, and information sources reported by parents of young children: results from the 2009 HealthStyles survey. Pediatrics. 2011;127(Suppl 1):S92–S99

4. Strine TW, Luman ET, Okoro CA, McCauley MM, Barker LE. Predictors of age-appropriate receipt of DTaP dose 4.Am J Prev Med. 2003;25(1):45–49

5. Meyerhoff AS, Jacobs RJ. Do too many shots due lead to missed vaccination opportunities? Does it matter?Prev Med. 2005;41(2):540–544

6. Kroger AT, Sumaya CV, Pickering LK, Atkinson WL; National Center for Immunization and Respiratory Diseases. General recommendations on

immunization—recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR Recomm Rep. 2011;60(2 RR-2):1–64

7. American Academy of Pediatrics. Combination vaccines. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds. Red Book Online: Report of the Committee on Infectious Diseases. Available at: http:// redbook.solutions.aap.org/chapter.aspx? sectionid=56798095&bookid=886. Accessed October 31, 2014

8. American Academy of Family Physicians Web site. Immunization schedules. Available

at: www.aafp.org/patient-care/

immunizations/schedules.html. Accessed October 31, 2014

9. Marshall GS, Happe LE, Lunacsek OE, et al. Use of combination vaccines is associated with improved coverage rates.Pediatr Infect Dis J. 2007;26(6):496–500

10. Happe LE, Lunacsek OE, Marshall GS, Lewis T, Spencer S. Combination vaccine use and vaccination quality in

a managed care population.Am J Manag Care. 2007;13(9):506–512

11. Happe LE, Lunacsek OE, Kruzikas DT, Marshall GS. Impact of a pentavalent combination vaccine on immunization timeliness in a state Medicaid population. Pediatr Infect Dis J. 2009;28(2):98–101

12. Anderson P. The protective level of serum antibodies to the capsular

polysaccharide ofHaemophilus influenzaetype b.J Infect Dis. 1984; 149(6):1034–1035

13. Käyhty H, Peltola H, Karanko V, Mäkelä PH. The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzaetype b.J Infect Dis. 1983;147(6):1100

14. Storsaeter J, Hallander HO, Gustafsson L, Olin P. Levels of anti-pertussis

antibodies related to protection after household exposure toBordetella pertussis. Vaccine. 1998;16(20): 1907–1916

15. Miettinen O, Nurminen M. Comparative analysis of two rates.Stat Med. 1985; 4(2):213–226

16. Tapiéro B, Halperin SA, Dionne M, et al. Safety and immunogenicity of a hexavalent vaccine administered at 2, 4 and 6 months of age with or without a heptavalent pneumococcal conjugate vaccine: a randomized, open-label study.Pediatr Infect Dis J. 2013; 32(1):54–61

17. Plotkin SA. Vaccines: correlates of vaccine-induced immunity.Clin Infect Dis. 2008;47(3):401–409

18. Kohberger RC, Jemiolo D, Noriega F. Prediction of pertussis vaccine efficacy using a correlates of protection model. Vaccine. 2008;26(27–28):3516–3521

19. Pediarix. Package Insert, November 2013. Rixensart, Belgium: GlaxoSmithKline Biologicals; 2013

20. Thompson LA, Irigoyen M, Matiz LA, LaRussa PS, Chen S, Chimkin F. The impact of DTaP-IPV-HB vaccine on use of health services for young infants. Pediatr Infect Dis J. 2006;25(9):826–831

21. Zangwill KM, Eriksen E, Lee M, et al. A population-based, postlicensure evaluation of the safety of a combination diphtheria, tetanus, acellular pertussis, hepatitis B, and inactivated poliovirus vaccine in a large managed care organization. Pediatrics. 2008;122(6). Available at: www. pediatrics.org/cgi/content/full/122/6/e1179

22. Immunization Action Coalition. Ask the experts: diseases & vaccines. Diphtheria, tetanus, pertussis. Available at: www. immunize.org/askexperts/experts_per. asp. Accessed December 3, 2014

23. Zepp F, Schmitt HJ, Cleerbout J, Verstraeten T, Schuerman L, Jacquet JM. Review of 8 years of experience with Infanrix hexa (DTPa-HBV-IPV/Hib hexavalent vaccine). Expert Rev Vaccines. 2009;8(6):663–678

24. Kalies H, Grote V, Verstraeten T, Hessel L, Schmitt H-J, von Kries R. The use of combination vaccines has improved timeliness of vaccination in children. Pediatr Infect Dis J. 2006;25(6):507–512

(11)

DOI: 10.1542/peds.2014-4102 originally published online July 27, 2015;

2015;136;e323

Pediatrics

Andrew W. Lee

Flores, Angela L. Ngai, Jin Xu, Guanghan Liu, Jon E. Stek, Ginamarie Foglia and

Gary S. Marshall, Gregory L. Adams, Michael L. Leonardi, Maria Petrecz, Sheryl A.

Immunogenicity, Safety, and Tolerability of a Hexavalent Vaccine in Infants

Services

Updated Information &

http://pediatrics.aappublications.org/content/136/2/e323 including high resolution figures, can be found at:

References

http://pediatrics.aappublications.org/content/136/2/e323#BIBL This article cites 20 articles, 2 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

(12)

DOI: 10.1542/peds.2014-4102 originally published online July 27, 2015;

2015;136;e323

Pediatrics

Andrew W. Lee

Flores, Angela L. Ngai, Jin Xu, Guanghan Liu, Jon E. Stek, Ginamarie Foglia and

Gary S. Marshall, Gregory L. Adams, Michael L. Leonardi, Maria Petrecz, Sheryl A.

Immunogenicity, Safety, and Tolerability of a Hexavalent Vaccine in Infants

http://pediatrics.aappublications.org/content/136/2/e323

located on the World Wide Web at:

The online version of this article, along with updated information and services, is

http://pediatrics.aappublications.org/content/suppl/2015/07/21/peds.2014-4102.DCSupplemental Data Supplement at:

by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Figure

TABLE 1 Vaccines Administered
FIGURE 1Participant disposition. Reasons for discontinuation: aAE (death due to asphyxia; 1); lost to follow-up(13); noncompliance (2); physician decision (3); protocol violation (22); withdrawal of consent (15)
TABLE 3 Participant Demographics and Baseline Characteristics
TABLE 4 GMCs and GMC Noninferiority Evaluation of Antibody for Selected Antigens
+3

References

Related documents

2008 E.Casalicchio , E.Galli, S.Tucci, Modeling and simulation of Complex Interdependent Systems: a federated agent-based approach, 3rd International Workshop on Critical

Finally, all the respondents, whether they operate a website or not, agreed that web marketing is an important tool that can help Greek Small and Medium-sized Tourism Enterprises

 Increased bleeding risk when used with aspirin or clopidogrel  Similar bleeding rate with warfarin + antiplatelet vs.. Slide 52 Dabigatran and Dronedarone Interaction-

Supplementary Figure 1: ezetimibe protects againts the increase on total cholesterol in plasma, cholesterol content in heart and heart weight induced by a high cholesterol diet..

•Both the Missing Persons/DVI-module of CODIS 7 and Bonaparte have been used to find possible parents, children and sibblings in the first Dutch familial.

Abstract: Previously chemically characterized Juniperus communis essential oil (EO) and post-distillation waste (PDW) were tested for cytotoxicity and antimicrobial activity

Recent federal circuit and district court cases have interpreted the scope of the ECPA narrowly, effectively expanding both the ability of employers to monitor the workplace and

In addition, OWLS-iMatcher2 [31] is a hybrid discovery approach who opts for both deductive matching of inputs/outputs concepts and algebraic matching used to