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Pediatric Infectious Disease Journal:
doi: 10.1097/INF.0b013e318268dfe4
Vaccine Reports

Safety and Immunogenicity of a Quadrivalent Meningococcal Polysaccharide Diphtheria Toxoid Conjugate Vaccine in Infants and Toddlers: Three Multicenter Phase III Studies

Pina, L. Miriam MD; Bassily, Ehab MSc; Machmer, Agnes MS; Hou, Victor PhD; Reinhardt, Albert PhD

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Author Information

From Sanofi Pasteur, Swiftwater, PA.

Accepted for publication July 09, 2012.

This research was funded by Sanofi Pasteur Inc. The authors are employees Of Sanofi Pasteur Inc., and have no other funding or conflicts of interest to disclose.

Address for correspondence: L. Miriam Pina, MD, Sanofi Pasteur, Discovery Drive, Swiftwater, PA 18370. E-mail: miriam.pina@sanofipasteur.com.

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Abstract

Background: Quadrivalent meningococcal conjugate vaccine (Menactra [MenACWY-D]), was licensed in the United States in 2005 to prevent meningococcal disease in adolescents and adults. The license was extended to children aged 2–10 years in 2007 and extended again in 2011 to infants aged 9 months and older based, in part, on results from 3 phase III studies presented herein.

Methods: The safety and immunogenicity of 2 doses of MenACWY-D was assessed in study-eligible children: dose 1 was administered at 9 months of age and dose 2 was administered 3 months later with or without routine childhood vaccines.

Results: Thirty days after vaccination, protective serum bactericidal assay-human complement titers ≥1:8 for meningococcal serogroups A, C, Y and W-135 were achieved by 86–100% of children receiving 2 doses of MenACWY-D. When MenACWY-D was concomitantly administered with measles, mumps, rubella and varicella or heptavalent pneumococcal conjugate vaccine, 81–98% of participants achieved protective responses (serum bactericidal assay-human complement titers ≥1:8 for all serogroups). All seroprotection rates were >91% when the protective titer was defined as serum bactericidal assay-human complement ≥1:4. MenACWY-D did not interfere with measles, mumps, rubella or varicella vaccine responses (98–100% achieved protective titers). When heptavalent pneumococcal conjugate vaccine was given concomitantly with MenACWY-D, antipneumococcal antibody levels, although decreased, were protective for all serotypes by enzyme-linked immunosorbent assay (98–100% ≥ 0.35 μg/mL) and opsonophagocytic assay (99–100% ≥ 1:8). Adverse events were generally mild and similar across groups. Serious adverse events were uncommon.

Conclusions: MenACWY-D was safe and immunogenic when given in 2 doses to infants and toddlers; this vaccine can be given with other common childhood immunizations.

Meningococcal disease is caused by Neisseria meningitidis, an invasive Gram-negative diplococcus that can produce a wide range of clinical manifestations. The 2 most common presentations are purulent meningitis and meningococcemia, but pneumonia, septic arthritis and purulent pericarditis are also possible.1 Meningococcal disease is a global health problem with an annual disease burden of 1.2 million cases worldwide2; however, the incidence of meningococcal disease is unpredictable and varies by geography. In the United States and Europe, the incidence has been in decline over the last decade. Recently, the annual US incidence has averaged less than 1 case per 100,000 persons.3 Disease incidence peaks first in infancy, with a second peak occurring between 15 and 18 years of age in the United States and Europe.

The case-fatality rate is approximately 10–15% in the United States.4 Among persons presenting meningococcemia with shock (5–20% of meningococcal cases),5 mortality can range up to 40%.6 About 20% of patients surviving meningococcal disease suffer from sequelae such as hearing loss, neurologic disability or loss of limbs due to ischemia.5

Twelve serogroups of meningococci have been identified based on their capsular polysaccharides. Of these, serogroups A, B and C have long been recognized as predominant causes of meningococcal disease, whereas cases caused by serogroups Y and W-135 have increased in recent years.2,7–9 Serogroup Y disease accounts for 30% of cases in the United States. Serogroup W-135 disease has circulated globally and has increased in frequency in Saudi Arabia (Hajj 2000–2001), Burkina Faso (2002), Argentina (2006–2009) and Florida (2008–2009).2,3,7,10,11

Early meningococcal vaccines, composed of purified capsular polysaccharides, were shown to be safe and effective against serogroups A, C, Y and W-135 disease in older children and adults. However, polysaccharide vaccines stimulate T cell–independent immune responses that do not induce memory or sufficient levels of protection in children younger than 2 years of age. In contrast, where successfully developed, polysaccharide antigens conjugated to protein carriers induce T cell–dependent immune responses, leading to higher antibody titers (especially in young populations), enhanced antibody avidity and immunologic memory.

The first quadrivalent meningococcal conjugate vaccine—Menactra vaccine (Sanofi Pasteur Inc., Swiftwater, PA [MenACWY-D])—contains 4 meningococcal capsular polysaccharides, each covalently bound to diphtheria toxoid protein; MenACWY-D was licensed in 2005 in the United States for the prevention of meningococcal disease caused by N. meningitidis serogroups A, C, Y and W-135 in adolescents and adults 11–55 years of age.12–14 MenACWY-D was licensed in 2006 for use in Canada and has subsequently been licensed in over 30 countries. In a staged approach, the vaccine was next licensed to those as young as 2 years of age in 2007 and most recently to those as young as 9 months of age in 2011 in the United States.15 Evidence of a reduction in meningococcal disease burden among US adolescents after introduction of MenACWY-D has recently been reported by the Centers for Disease Control and Prevention.16

A second vaccine licensed in the United States to prevent invasive meningococcal disease caused by N. meningitidis serogroups A, C, Y and W-135 was approved in 2010 for use in persons 11–55 years of age (MenACWY-CRM; MENVEO, Novartis Vaccine and Diagnostics, Inc, Cambridge, MA).17 The MenACWY-CRM license was expanded in 2011 to include children as young as 2 years of age. Quadrivalent meningococcal conjugate vaccines are recommended in the United States for all adolescents and for individuals 2–55 years of age who are at high risk for meningococcal disease.18 MenACWY-D is also recommended for individuals 9 months through 2 years of age who are at high risk for meningococcal disease.18

The serum bactericidal assay in the presence of human complement (hSBA) has been directly correlated to protection (hSBA titer ≥ 4) against developing meningococcal disease due to serogroup C and has been extended to serogroups A, Y and W-135.19,20 This assay measures the concentration of functional antibodies and remains the assay of choice when evaluating vulnerable populations such as infants and toddlers.

A 2-dose schedule of MenACWY-D administration in infants and toddlers was assessed in 3 pivotal phase III trials conducted between 2006 and 2009. For these 3 studies, the first dose was administered at 9 months of age, which corresponds to an established US well-baby visit and provides an opportunity to add a new vaccine without the risk of interference with other vaccines. We present here safety assessments and the immunogenicity results as measured by hSBA when dose 2 of MenACWY-D was administered alone or concomitantly with common childhood vaccines.

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Materials and Methods

Children aged 9 months (249–305 days) and 12 months (365–400 days) were enrolled into 1 of 3 parallel-group, multicenter comparative trials (Fig. 1). Trials were conducted in accordance with the Edinburgh revision of the Declaration of Helsinki, Good Clinical Practice, International Conference on Harmonization guidelines and national and local requirements regarding ethics committee review and other statutes or regulations regarding the protection of the rights and welfare of participants in biomedical research. Institutional review board approval was obtained for each trial protocol before study initiation and for all protocol amendments before implementation. The parents/legal guardians of the participants gave written informed consent when their children were included. Before consent form signing, study personnel provided information regarding the nature and purpose of the study and allowed sufficient time and opportunity for questions. Parents/legal guardians who brought a child to a study site for a routine visit were invited to enroll an eligible child. Participants could also be drawn from the general population.

Figure 1
Figure 1
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Healthy children were recruited. Key exclusion criteria were serious acute or chronic illness that could interfere with trial conduct, documented history of invasive meningococcal disease, a history of previous meningococcal vaccination, known or suspected impairment of immunologic function and planned receipt of oral or injected antibiotic therapy 72 hours before any blood draw. Complete inclusion and exclusion criteria are available at ClinicalTrials.gov.21–23

For all studies, an interactive voice-response system assigned study groups and numbers. Block randomization was generated by computer. Participants received 2 doses (0.5 mL each) of MenACWY-D 3 months apart; each dose contained 5 μg of each of the meningococcal polysaccharides (A, C, Y and W-135) conjugated to ~48 μg diphtheria toxoid protein carrier in phosphate buffered saline 3 months apart.

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Study A and Study B

Study A [NCT00384397; MTA44] and Study B [NCT00422292; MTA37] were randomized, modified single-blind trials (only the laboratory personnel were blinded) at 64 (Study A) and 82 (Study B) US-based clinics. In Study A, children received MenACWY-D at 9 and 12 months; the 12-month vaccination was given alone in group 1 or concomitantly with either the first dose of a measles, mumps, rubella and varicella vaccine (MMRV [ProQuad], Merck & Co, Inc., Whitehouse Station, NJ) in group 2 or with a catch-up or booster dose of a pneumococcal conjugate vaccine (PCV7 [Prevnar], Wyeth Pharmaceuticals Inc, Philadelphia, PA) in group 3. Study B was similarly designed, but with the addition of a control group at 12 months receiving only MMRV and a fourth dose of PCV7 (group 4). In Study B, subjects were also allowed to receive a measles, mumps and rubella vaccine (MMR [M-M-RII], Merck & Co, Inc.) and a varicella vaccine (V [VARIVAX], Merck & Co, Inc.) instead of MMRV. A subset of participants in Study A and Study B also received a fourth dose of Haemophilus influenzae type b (Hib) vaccine (ActHIB, Sanofi Pasteur SA, Lyon, France; groups 2A and 4A; Table 1).

Table 1
Table 1
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Study A evaluated the hSBA-measured antibody responses to meningococcal serogroups A, C, Y and W-135 induced by 2 doses of MenACWY-D and assessed the effect of concomitant vaccination with either MMRV, MMRV + Hib or PCV7. Study B evaluated the antibody responses induced by MMRV, MMRV + Hib or PCV7 vaccines when administered concomitantly with MenACWY-D (Table 1). Titers were determined 30–44 days after the 12-month vaccination(s). Safety assessment of MenACWY-D given alone or concomitantly with other pediatric vaccines was a secondary objective of both trials.

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Study C

Study C (NCT00483574; MTA48) was an open-label study among 72 clinical sites in the United States examining MenACWY-D safety. At enrollment, 9-month-old children were assigned to group 1 and 12-month-old children to group 2. Group 1 received MenACWY-D at both 9 and 12 months, with the second dose administered concomitantly with other pediatric vaccines (MMRV [or MMR + V], PCV7, and hepatitis A [HepA;Vaqta], Merck & Co, Inc.). Group 2 participants received only pediatric vaccines and no MenACWY-D (Table 1).

Study A used MenACWY-D vaccine lots U2139AA and US10105; Study B used vaccine lots U2172AA, UD10166 and UD1053; Study C used U2359AA. All other study vaccines were from commercial lots. The size and length of needles to be used were at the discretion of the site’s own practice and procedures.

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Laboratory Methods

Study A and Study B serum was collected 30–44 days postvaccination. All assays were performed at the sponsor’s laboratory (or its designee) by laboratory personnel blinded to study-group assignment using methods derived from Maslanka et al.24

The hSBA was performed with the following reference strains: A (F8238), C (C-11), Y (3021) and W-135 (2515).25 For the hSBA, 2-fold dilutions of test sera were added to microtiter plates containing serogroup-specific meningococcal bacteria and human complement. After initial incubation, an agar overlay medium was added, allowed to harden and incubated overnight at 37°C in the presence of 5% CO2. Bacterial colonies were counted, and the endpoint titer determined by the reciprocal serum dilution yielding ≥50% killing compared with the mean of the complement control wells.

MMRV IgG antibodies were measured by enzyme-linked immunosorbent assay (ELISA; Enzygnost; Dade Behring, Schwalbach, Germany) or plaque reduction neutralization tests. IgG ELISA concentrations were compared with the World Health Organization International Reference Standards for antimeasles, antimumps and antirubella antibodies. Antivaricella IgG ELISA concentrations were compared with a commercial reference. Antivaricella functional antibodies were also measured by indirect immunofluorescence assay in the laboratory of Professor A. Gershon at Columbia University, New York City.26–28

A pneumococcal capsular polysaccharide IgG ELISA measured the concentration of anti-Streptococcus pneumoniae polysaccharide (serotypes 4, 6B, 9V, 14, 18C, 19F, 23F) IgG antibodies in human serum,29 and functional antipneumococcal antibodies were measured by a multiplex opsonophagocytic assay (MOPA).30 All pneumococcal assays were performed at the laboratory of Professor D. Goldblatt, Institute of Child Health, University College, London, United Kingdom.

Serum levels of anti-Hib capsular polysaccharide antibodies were determined by a radioimmunoassay.31–33 Concentrations were compared with the Center for Biologics Evaluation and Research Lot No. 1983 reference standard.

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Safety Assessment

Safety evaluations included immediate adverse events (AEs) reported within 30 minutes after each vaccination, solicited injection-site and systemic reactions reported within 7 days, any unsolicited AEs (including medically significant events [medical events other than common medical ailments resulting in an unscheduled physician’s office or emergency room visit]) reported within 30 days postvaccination, medically significant events reported from day 30 to 6 months after the last vaccination(s), and serious adverse events (SAEs) reported throughout the trial up to 6 months after the last vaccination (Fig. 2). Solicited reactions were reported by diary card and included injection-site tenderness, erythema and swelling, and fever, vomiting, abnormal crying, drowsiness, lost appetite and irritability. All AEs were coded using MedDRA version 9.0.

Figure 2
Figure 2
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Data Analysis

In Study A, the percentages of children (with 95% confidence intervals [CIs]) who developed protective titers (≥1:8) to meningococcal A, C, Y and W-135 serogroups ~30 days after the second dose were calculated. The 95% CIs were computed using the Clopper-Pearson exact method. Based on the proportion of children who had protective titers to the A, C, Y and W-135 serogroups, the antibody responses to MenACWY-D administered concomitantly with MMRV or PCV7 were compared with the responses to MenACWY-D administered alone. Noninferiority was assumed if the upper 95% CI of the difference between the proportions (pMenACWY-DpMenACWY-D+MMRV or pMenACWY-DpMenACWY-D+PCV7) was <10%. Each serogroup was tested separately.

In Study B, immunogenicity was measured by the proportion of children who developed protective MMRV and PCV7 titers ~30 days after vaccination. Antibody responses elicited after the concomitant administration of MMRV, Hib or PCV7 with MenACWY-D were judged to be noninferior to those elicited after the administration of MMRV, Hib and PCV7 without MenACWY-D, based on the proportions of children within each group who achieved protective titers to each antigen. Noninferiority of the antibody responses to MMRV when administered concomitantly with MenACWY-D was demonstrated if the upper limit of the 95% CI for the proportional difference (pMenACWY-D+MMRVpMMRV+PCV7 or MMRV+PCV7+Hib) was <10% (<5% if pMMRV+PCV7 or MMRV+PCV7+Hib was >95%). Each antigen was tested separately.

Noninferiority of the antibody responses to PCV7 when administered concomitantly with MenACWY-D was demonstrated if the upper limit of the 2-sided 95% CI of the ratio of the 2 geometric mean concentrations (GMCs; GMCMMRV+PCV7/GMCMenACWY-D+PCV7 or GMCMMRV+PCV7+Hib/GMCMenACWY-D+PCV7) was <2 for each pneumococcal serotype. Each PCV7 serotype was tested separately.

The immunogenicity per-protocol sets for Study A and Study B included those who satisfied all inclusion/exclusion criteria, received all assigned injections at the proper times, provided blood samples at the specified times and had no protocol violations that would affect assay results. An immunogenicity full-analysis/intent-to-treat set included those who received MenACWY-D or another study vaccine (Study B only) and provided valid immunogenicity results.

Safety analyses were based on data from children who received at least 1 vaccine dose; the data from each study were analyzed separately and were not pooled unless otherwise noted. For any specific child, undocumented safety data were reported as missing.

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Results

The 3 trials were conducted between September 2006 and January 2009. Sex, age and ethnicity demographic data by study group for all 3 studies are presented in Table 2. The ratio of boys to girls was generally 1:1, and most participants were white.

Table 2
Table 2
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In Study A, 49 investigators at 64 clinical sites enrolled 1257 infants at 9 months of age (Fig. 1). Participants were randomized to 1 of 3 groups, and the overall vaccination schedule is presented in Table 1. Of the group 2 participants, 129 received a concomitant Hib vaccine at 12 months of age (group 2A).

In Study B, 60 investigators at 82 clinical sites enrolled 2289 participants at 9 or 12 months of age. Those 9 months of age were randomized to either groups 1, 2 or 3; those 12 months of age were assigned to group 4. A subset of group 1 (1B) was randomized to provide sera after a single dose of MenACWY-D (data not presented). Of the 2289 participants, 24 in group 2 received Men-D + MMRV + Hib vaccines (group 2A). Also, 586 participants in group 4 received MMRV + PCV7 + Hib (group 4A). Immunogenicity results in study groups 2, 2A and 3 were compared with the results in both control groups 4 and 4A (see Table 1 for the vaccination schedule). Study C enrolled 1378 children at 72 US clinical sites by 60 investigators (see Table 1 for the vaccination schedule).

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Immunogenicity

The results from the immunogenicity per-protocol analysis set are presented; the immunogenicity full analysis/intent-to-treat analysis set produced similar results (data not shown). No immunogenicity results are presented for Study C as it was a safety study only.

After 2 doses of MenACWY-D in Study A, the percentage of participants achieving a postvaccination hSBA titer ≥1:8 thirty days after vaccination ranged from 86.4% to 100% (Table 3). Comparing the percentages of participants achieving an hSBA titer ≥1:8, antibody responses to serogroups A, C, Y and W-135 after the concomitant administration of MenACWY-D and MMRV vaccine were noninferior to responses after administration of MenACWY-D alone (ie, the upper limit of the 95% CI of the difference was <10%). When MenACWY-D was given with PCV7, the percentage achieving a protective titer was comparable for serogroups A, C and Y. For serogroup W-135, the difference between the 2 proportions was <10% (5.2%), but the upper limit of the 2-sided 95% CI of the difference was 11.5%. For all study groups, the percentages of participants with an hSBA titer ≥1:4 were >90% for all serogroups: 97.3–97.8% (A), 98.9–100.0% (C), 95.1–96.6% (Y) and 91.0–95.5% (W-135).

Table 3
Table 3
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In Study B, measles, mumps, rubella and varicella vaccine responses after concomitant administration of MenACWY-D and MMRV (or MMR+V) at 12 months of age were noninferior to those after administration of MMRV and PCV7 (without MenACWY-D). The upper limit of the 2-sided 95% CI of the difference between the percentages of participants with protective antibody concentrations was <5% for measles and <10% for mumps, rubella and varicella antibody concentrations. The percentages of participants achieving protective titers to MMRV or Hib antigens were similar whether the vaccines were given alone or concomitantly with MenACWY-D (Table 4).

Table 4
Table 4
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For PCV7 IgG ELISA responses at 12 months, GMC ratios (GMCMMRV+PCV7 or MMRV+PCV7+Hib/GMC MenACWY-D+PCV7) were <2 for all serotypes (1.59–1.83 for serotype 4, 1.52–1.99 for serotype 6B, 1.25–1.74 for serotype 9V, 1.56–1.58 for serotype 14, 1.45–1.84 for serotype 18C, 1.55–1.61 for serotype 19F and 1.41–1.52 for serotype 23F). The antipneumococcal antibody responses after concomitant PCV7 and MenACWY-D administration were noninferior to those after concomitant PCV7 and MMRV or PCV7, MMRV and Hib administration for 11 of the 14 response comparisons (the upper limits of the 2-sided 95% CIs of the ratios of the antipneumococcal antibody GMCs [GMCMMRV+PCV7 or MMRV+PCV7+Hib/GMCMenACWY-D+PCV7] were <2). For serotypes 4, 6B and 18C, the ratios of the antipneumococcal antibody GMCs (GMCPCV7+MMRV/GMCPCV7+MenACWY-D) were <2, but the upper limits of the 2-sided 95% CI of the ratios were >2 (Fig. 3).

Figure 3
Figure 3
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Geometric mean titers by MOPA were high for all serotypes, and any divergence between study groups was observed at titers higher than the protective threshold of 1:8. Although geometric mean titer or GMC responses were lower when PCV7 was administered with MenACWY-D, more than 98% of participants achieved pneumococcal MOPA titers ≥1:8 and ELISA antibody concentrations ≥0.35 μg/mL (Table 5).

Table 5
Table 5
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Safety

More than 3000 children received MenACWY-D alone or concomitant with standard pediatric vaccines (Table 6). Study B and Study C participants received either a single vaccination with MMRV vaccine (ProQuad) or 2 separate vaccinations with MMR and varicella vaccines (MMR+V). Most (97.0%) received a single MMRV vaccination, and such recipients provided most of the Study B and Study C safety data.

Table 6
Table 6
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No immediate unsolicited systemic reactions were reported in Study A and Study B. Two immediate unsolicited systemic reactions were reported in Study C, a case of diarrhea after a 9-month vaccination and a case of urticaria after a 12-month vaccination. The percentages of participants reporting solicited injection-site reactions at the MenACWY-D site were similar when MenACWY-D was administered alone at 9 months (46.8%) or at 12 months (43.2%). These percentages were similar to those observed when MenACWY-D was administered with MMRV (46.8%) or with MMRV and Hib (44.4%) at 12 months and tended to be lower than when MenACWY-D was administered with PCV7 (54.6%) or with PCV7 + MMRV + HepA (57.5%). Solicited injection-site reactions reported at the non–MenACWY-D vaccination sites were similar in all study groups. The most frequently solicited reaction at the MenACWY-D injection site was tenderness, reported more frequently when MenACWY-D was administered with PCV7 (48.9%) or with MMRV + PCV7 + HepA (48.5%) at 12 months than when administered alone at 9 months (34.9%), alone at 12 months (35.2%) or with MMRV (38.1%) or MMRV + Hib (40.3%) at 12 months (Fig. 4). The percentages of participants reporting erythema (23.3–30.1%) and swelling (10.1–16.2%) were similar across study groups. Most solicited injection-site reactions were reported before day 3 postvaccination, resolved in 1–3 days and were grade 1 (mild) in intensity.

Figure 4
Figure 4
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The percentage of participants with solicited systemic reactions after MenACWY-D administration alone at 12 months (60.6%) was lower than after the 9-month MenACWY-D vaccination (68.2%) and lower than what was observed in the control groups at 12 months (76.6% of participants who received MMRV + PCV7, 75.2% of participants who received MMRV + PCV7 + HepA and 84.1% of participants who received MMRV + PCV7 + Hib). The percentage of participants with solicited systemic reactions after MenACWY-D administration alone at 12 months (60.6%) was also lower than that observed after MenACWY-D was given concomitantly with MMRV (71.1%), PCV7 (68.3%) or MMRV + PCV7 + HepA (73.2%). Grade 3 solicited systemic reactions were reported in <8.1% of participants in each vaccination group.

Fever was reported at similar (or lower) rates among participants who received MenACWY-D concomitantly with routine childhood vaccines (20.2–24.5%) compared with recipients of routine vaccines without MenACWY-D (21.8–31.7%); fever was reported less frequently when MenACWY-D was given alone at 9 months or 12 months (12.4% and 13.7%, respectively). Rates of grade 3 fever were also similar between recipients of MenACWY-D and concomitant vaccines (1.7–2.7%) and control vaccines alone (2.0–3.6%; Fig. 5).

Figure 5
Figure 5
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The most frequently reported solicited systemic reaction was irritability. The rate of irritability was lower in participants who received MenACWY-D at 9 and 12 months (55.4% and 48.5%, respectively) compared with recipients of MenACWY-D and concomitant vaccine(s) or concomitant vaccines only (58.3–71.8%). Abnormal crying and drowsiness were reported in 30.1–48.0% and 27.2–44.0% of participants, respectively. Solicited reactions after the first or second MenACWY-D dose were similar in frequency and intensity. The majority of systemic reactions were of grade 1 or grade 2 intensity and resolved within 3 days. Slight differences in rates of these events by gender and ethnic origin were not considered clinically relevant.

Unsolicited AEs were reported in ~40–50% of children. Most AEs were systemic in nature, with fewer than 5% experiencing an unsolicited injection-site AE (usually bruising). The most common systemic reactions were infectious processes such as otitis media and upper respiratory infection. Most unsolicited AEs were grade 1 or 2 in intensity and unrelated to study vaccines. Rates of unsolicited reactions were comparable across groups.

SAEs were reported in each treatment group in 3–5% of participants who received MenACWY-D alone or with concomitant vaccine(s) after the 9-month or 12-month vaccination(s). SAEs were also reported in 2% and 4% of controls after the 12-month vaccinations. In the 3 studies combined, 4 SAEs were considered related to the study vaccine by investigators: insulin-dependent diabetes mellitus (Study A), respiratory distress (Study C) and 2 cases of febrile seizures (Study B). Insulin-dependent diabetes mellitus occurred 183 days after MenACWY-D + PCV7 vaccinations at 12 months. The investigator reported the SAE as related to the investigational vaccine due to inability to exclude a potential association. A case of respiratory distress occurred 7.5 hours after vaccination with MenACWY-D at 9 months. The child recovered and continued in the study. The 2 cases of febrile seizure occurred 1 and 5 days after MenACWY-D vaccination, respectively. Both participants recovered; one continued the trial and the other continued but withdrew 61 days after vaccination for reasons unrelated to AEs. No unexpected trends or risks were identified.

Medically significant AEs occurred in approximately 2–4% of children, but none of these were considered related to administration of study vaccines.

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Discussion

A previous phase II study (NCT00643916; MTA26) assessed the safety and immunogenicity of 2 doses of MenACWY-D versus a single dose when administered in a variety of schedules to infants and toddlers aged 9–18 months.34 The immunogenicity results from that study demonstrated that a 2-dose schedule, with the first dose given at 9 or 12 months of age and the second dose at least 3 months later, induced protective levels of antibodies for all 4 serogroups, as measured by hSBA, in 92–100% of participants. MenACWY-D was well tolerated after each dose.

The results from the 3 phase III studies presented herein are consistent with this earlier phase II study. The data from these 4 studies show that MenACWY-D is both safe and immunogenic when 2 doses are administered 3 months apart to children 9 months of age or older. The MenACWY-D license extension for 9–23 months of age was based on the phase II and III study data.34 The phase III data showed that 2 doses of MenACWY-D given at least 3 months apart had safety and immunogenicity profiles that were similar to those observed in children from 9 –18 months of age. Specifically:

* Injection-site and systemic events were similar to those of currently licensed, routinely administered pediatric vaccines.

* Approximately 1 month after the second dose, protective hSBA titers ≥1:8 to serogroups A, C, Y and W-135 were present in 81–100% of children. An hSBA titer ≥1:4 (established in the 1960s as a correlate of protection)19,20 to each serogroup was achieved by >91% of vaccinated children (data not shown).

Results from Studies A and B suggest that there is no clinically relevant loss in immunogenicity when MenACWY-D is given concomitantly with other childhood vaccines. Antibody responses were reduced slightly for serogroup W-135 when MenACWY-D was administered with PCV7, potentially due to the use of carrier proteins with extensive amino acid similarity (diphtheria toxoid for MenACWY-D and CRM 197 for PCV7),35 but >81% of children still had serogroup-specific titers ≥1:8, and >91% had titers ≥1:4.

Comparisons of the hSBA immune response to MenACWY-D in the infant, or any age group, with other published data are unreliable due to differences in study populations, use of concomitant vaccines and study designs. Such comparisons are problematic especially when testing is performed in different laboratories. Variability in vaccines, study populations and assay methods can all affect the reported data. Although most laboratories follow the basic methods for the serum bactericidal assay (SBA) as described in Maslanka et al.24 and use the same N. meningitidis strains for serogroups A and C, the various manufacturers of quadrivalent conjugate vaccines use different N. meningitidis in their SBAs for serogroups Y and W-135.36,37 There are no internationally recognized standards on which to base between-study comparisons. It is unknown whether variable titer measurements across studies result from varying N. meningitidis strains used in the SBA. However, in an interlaboratory study, even when the same SBA method with the same serogroup strain of N. meningitidis was used with the same complement source, discrepant titers were observed.38 When the percentage of sera samples achieving an SBA titer ≥1:4 was calculated across 4 laboratories, prevaccination sera percentages ranged from 10% to 90% and postvaccination sera percentages ranged from 38% to 100%. These variances are thought to be related to how assay bacteria were grown and maintained in different laboratories as well as how the reaction mixing and incubation was performed.38 The methods for titer determination can also vary between laboratories as some interpolate their data37,39 versus the more conservative endpoint titer determinations used in this report. Further, there are no standardized methods for qualifying use of human and/or baby rabbit complement in the SBA, and inherent variability in results may be introduced by these critical assay reagents.

MenACWY-D does not appear to interfere with MMRV vaccination. Pneumococcal vaccine responses were reduced when PCV7 was given concomitantly with MenACWY-D instead of MMRV or MMRV and Hib vaccines, but this decrease should have little clinical significance given the relatively high pneumococcal titers reported. Antipneumococcal IgG (ELISA) concentrations ≥0.35 µg/mL or functional MOPA titers ≥1:8 are thought to be protective.33 Using these benchmarks, >98% of children concomitantly vaccinated with MenACWY-D had protective titers to the 7 serotypes in PCV7. Our findings suggest that MenACWY-D administration to infants and toddlers will not interfere with the public health goal of efficiently administering a variety of childhood vaccines in the current recommended immunization schedule.

Pelton and Gilmet have acknowledged that the idea of an “older infant-toddler” strategy (ie, initiating vaccination of children at 6 months of age or older) has benefits over an “early-infant” strategy (a 3-dose primary series given at 2, 4 and 6 months, followed by a booster dose at 12–15 months of age, termed a 3+1 strategy). When Ortega-Sanchez modeled the cost-effectiveness of a meningococcal vaccination program in infants and toddlers in the United States, they demonstrated that, with the current historic lows in meningococcal disease incidence, the cost per quality-adjusted life year saved for a 2-dose strategy was similar to a 3+1 strategy.40 A similar finding has already been borne out through real-world experience. Evaluation of meningococcal C conjugate immunization programs in Europe and Canada have demonstrated that 1-dose toddler programs, 2-dose infant-toddler programs and 3-dose infant programs produced equivalent reductions in meningococcal disease.41–43 In this light, a 2-dose MenACWY-D schedule not only shows promise at the individual level, but at a programmatic level as well.

The data from these 3 phase III studies assess the immune response 1 month after dose 2 administered at 12 months of age. Analyses from other studies in infants and toddlers have indicated that the overall immune response wanes rapidly in these younger age groups. The vaccine response durability has been assessed in a separate study (NCT00700713), and the results will be published shortly.

An additional study evaluating MenACWY-D concomitant administration with the fourth dose of Pentacel vaccine in the 15–18 months of age population will be initiated in 2012. This study will evaluate the safety and immunogenicity of both vaccines when they are given together and will provide additional information on the use of MenACWY-D in the second year of life.

There are some limitations to the presented phase III study data. Although the MenACWY-D US license now specifies a 2-dose schedule for children between the ages of 9 and 23 months, MenACWY-D vaccine compatibility with other vaccines was examined with dose 2 only. A further limitation on the assessment of immunogenicity data is that the subsets of participants in Study A and Study B who received MenACWY-D +MMRV+Hib were not as large as in the other study arms (~150 versus 650–1050 participants). Finally, the immune response induced by MenACWY-D was only assessed 1 month after final vaccination. However, an assessment of antibody persistence was assessed in a separate study (NCT00700713; MTA62), and the results will be published shortly.

In summary, MenACWY-D offers the broad protection of a quadrivalent vaccine among children 9–23 months of age when administered as a 2-dose schedule, 3 months apart. This schedule can protect infants with fewer doses than a classic 3+1 infant schedule, and it minimizes the risk of interference and the difficulties associated with the introduction of another vaccine into an already crowded infant vaccination schedule.

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Acknowledgments

The authors acknowledge the investigators and study-site personnel who contributed to the conduct of these studies. The principal investigators were as follows: W. Andrews, M. Blatter, B. Blue, J. Blumer, L. Butler, K. Coopersmith, M. Cornish, W. Daly, D. Devenport, J. Fling, R. Geller, M. Gerber, M. Glover, E. Gotlieb, S. Grogg, L. Hazen, J. Hedrick, D. Johnson, M. Johnson, S. Keathley, K. Koranyi, R. Kratz, J. Kratzer, J. Leader, M. Levin, D. Lewis, J. Ley, S. Luber, F. Mabry, S. Manson, C. Nassim, A. Naz, L. Sass, R. O’Hern, M. Pichichero, JT Robinson, M. Saunders, S. Senders, J. Sneed, C. Spiegel, D. Tayloe, P. Tebbe, J. Tenney, C. Toledo, L. Vermont, L. Weiner, P. Wisman, P. Zollo, G. Adams, E. Anderson, M. Benbow, K. Bromberg, K. Burgess, S. Chandwani, A. Chatterjee, B. Comstock, K. Concannon, M. Cox, C. Deseda, F. Guerra, L. Harris-Ford, C. Harrison, J. Hubbard, A. Johnson, N. Klein, W. Koch, L. Krilov, T. Latiolais, J. Lauzon, L. Lello, H. Lessin, M. Macknin, M. McNerney, M. Mufson, M. Rey, K. Roberts, K. Roche, C. Rupp, W. Spencer, A. Suliman, B. Sullivan, R. Tull, J. Twiggs, T. Villalobos, S. Wall, E. Walter, S. Yeh, R. Yogev, K. Zollo, C. Ashley, S. Baucom, B. Belcher, S. Bhuchar, T. Borrell, C. Brasher, S. Christensen, C. J. Cortopassi, C. Crismon, M. Cruz, P. Dennehy, D. DeSantis, R. Dracker, R. Evans, C. Fisher, R. Fishman, R. Ford, V. Frumin, J. Garner, E. Goldblatt, B. Grunstra, P. Harmon, B. Harvey, D. Henry, W. Hitchcock, S. Hunt, K. Iqbal, W. Johnston, L. Jones, S. Kamdar, T. Klein, B. Lewis, R. Litov, C. Marchant, J. Marshall, J. Martin, M. Martin, S. Mattson, S. Medford, I. Melamed, A. Moskow, R. Ohnmacht, K. Palanpurwala, N. Parkerson, C. Peltier, D. Procter, P. Qaqundah, R. Rosenberg, S. Scott-Zieminick, C. Seyler, J. Shepard, M. Sperling, W. Stepp, J. Tillisch, L. Turner, S. Wallace, W. Webb, J N Widerman, C. Woods, E. Zissman Review and editorial assistance was provided by Robert Lersch, PhD, Julia Moffat, Corwin Robertson, MD, MPH, David Greenberg, MD, David Johnson, MD, MPH and Philipp Oster, MD, from Sanofi Pasteur. Editorial assistance was also provided by John Bukowski, PhD, MPH, of Words World Consulting.

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conjugate vaccine; meningococcal; safety; immunogenicity

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