Klein, Nicola P. MD, PhD*; Reisinger, Keith S. MD†; Johnston, William MD‡; Odrljin, Tatjana MD§; Gill, Christopher J. MD¶; Bedell, Lisa MA**; Dull, Peter MD§
Infections with Neisseria meningitidis can result in permanent disability or death within a matter of hours.1–3 The first year of life represents the highest risk period for invasive meningococcal disease,4,5 and developing a sufficiently immunogenic vaccine suitable for use in young infants has proven challenging.6 Five immunologically distinct serogroups (A, B, C, W-135, and Y) cause most disease globally.5,7
MenACWY-CRM (Menveo, Novartis Vaccines and Diagnostics, Cambridge, MA) is a polysaccharide-CRM197 conjugate vaccine directed against serogroups A, C, W-135, and Y.8 MenACWY-CRM is highly immunogenic and well tolerated in adults,9–11 adolescents,9,12,13 children,14 and infants.15,16 In an earlier phase II study in young infants, MenACWY-CRM was well tolerated and highly immunogenic.15,16 We now present results from our pivotal phase III infant study that assessed the safety and immunogenicity of 4 doses of MenACWY-CRM administered to infants at 2, 4, 6, and 12 months of age. The coprimary objectives were to assess immune response after 4 doses of MenACWY-CRM and to compare immune response after 4 doses of MenACWY-CRM with that after a single dose at 12 months of age. We also present secondary endpoints including immunogenicity after 3 doses of MenACWY-CRM given at 2, 4, and 6 months of age, persistence of immune response at 12 months of age, the effect of concomitant administration of MenACWY-CRM on immune responses to routine infant vaccines, and the safety and tolerability of MenACWY-CRM.
MATERIALS AND METHODS
Novartis study V59P14 was a phase III, open-label, randomized, parallel-group, multicenter study of healthy infants conducted in the United States, Colombia, and Argentina (ClinicalTrials.gov identifier NCT00474526). This current report includes immunogenicity and safety results from US subjects only; results from the Latin American cohort, which followed different vaccination schedules, will be presented as a separate manuscript. The protocol and amendments were approved by local institutional review boards. Informed consent was obtained from a parent or legal guardian. An independent, external data monitoring committee monitored safety throughout the study.
We enrolled and randomized infants 2:1 to receive MenACWY-CRM at 2, 4, 6, and 12 or 13 months of age concomitantly with routine infant vaccines or to receive routine infant vaccines alone followed by MenACWY-CRM in the second year of life (Fig. 1). Subjects were further enrolled into either the immunogenicity cohort (Fig. 1A) or the safety-only cohort (Fig. 1B). We completed enrollment in the immunogenicity cohort before enrolling subjects into the safety-only cohort. We randomized using an interactive voice response system (United Biosource Corporation, San Francisco, CA) with 2 computer-generated lists provided by the sponsor; 1 for the immunogenicity cohort and 1 for the safety-only cohort. Randomization was stratified by site whereby each site was assigned a set of randomization blocks containing the 2:1 ratio within each block, with a block size of 6.
Eligible subjects were healthy 55- to 89-day-old infants with a gestational age ≥37 weeks and a birth weight ≥2.5 kg. We excluded infants with allergy to the vaccine or vaccine components, significant infection in the past 7 days, fever in the past 3 days, or previous exposure to either disease caused by or vaccination against N. meningitidis (serogroups A, C, W-135, or Y), Corynebacterium diphtheriae, Clostridium tetani, Bordetella pertussis, poliovirus, Haemophilus influenzae type B (Hib), pneumococcus, or hepatitis B virus (HBV). A birth vaccination against HBV was permitted.
MenACWY-CRM was prepared by extemporaneous mixing of the lyophilized MenA component with the liquid MenCWY component immediately before intramuscular (IM) injection to the right thigh. Each 0.5-mL dose contained 10 μg of MenA oligosaccharide and 5 μg each of oligosaccharides from MenC, MenW-135, and MenY conjugated to CRM197 (∼50 μg).14 Concomitant vaccines were administered either IM or subcutaneously to the left thigh, as appropriate. In subjects only receiving routine vaccines, Hib vaccine was administered IM to the right thigh as control for local reactogenicity at 2, 4, and 6 months of age, whereas pneumococcal conjugate vaccine (PCV7) served as control for the reactogenicity assessments at 12 months of age.
All subjects received routine vaccines as per the schedule in Figure 1. Concomitant vaccines given during this study were combined DTaP-HBV-IPV (Pediarix, GlaxoSmithKline, Rixensart, Belgium); DTaP booster (Infanrix, GlaxoSmithKline); Hib-TT (ActHIB, Sanofi Pasteur, Swiftwater, PA); PCV7 (Prevnar, Wyeth, Pearl River, NY); rotavirus vaccine (RotaTeq, Merck & Co., Whitehouse Station, NJ); MMRV (ProQuad, Merck & Co.) or measles, mumps, and rubella vaccine (M-M-R II, Merck & Co.) and varicella vaccine (Varivax, Merck & Co.); and HAV. This study was completed before the pneumococcal 13-valent conjugate vaccine was available.
We obtained serum samples before and 1 month after the infant series (at 2 and 7 months of age) and before and 1 month after the 12-month toddler dose (at 12 and 13 months of age). Functional antibodies to each meningococcal serogroup were measured by serum bactericidal assay using human complement (hSBA). Titers were reported as the reciprocal of the dilution resulting in ≥50% killing at T60 (60 minutes) compared with T0 of the test strain in question.17 We measured immunogenicity as the percentage of subjects with hSBA titers ≥8 against each serogroup 1 month after the fourth dose and by geometric mean titers (GMTs).18 We used enzyme-linked immunosorbent assays to evaluate seroresponses to diphtheria, tetanus, Hib, HBV, pneumococcal, and pertussis antigens (pertussis toxin, filamentous hemagglutinin, and pertactin) and assessed seroresponse to poliovirus using a viral neutralization assay.
Given the absence of a US-licensed comparator vaccine, the first coprimary end point was sufficiency of the immune response 1 month after 4 doses of MenACWY-CRM administered at 2, 4, 6, and 12 months of age. Sufficiency of the immune response was prespecified as met if the lower limit (LL) of the 95% confidence interval (CI) for the percentage of infants with hSBA titers ≥8 was ≥80% for serogroup A and ≥85% for C, W, and Y.
The second coprimary objective was to demonstrate superiority of the immune response after 4 doses of MenACWY-CRM administered at 2, 4, 6, and 12 months of age compared with 1 dose at 12 months of age. Superiority was met if the LL of the 2-sided 95% CI for the ratio of GMTs (GMT4-dose series/GMT12-month dose only) was >2.0. Superiority was assessed using analysis of variance, as previously described.14
Secondary immunogenicity endpoints included (1) immune response after 3 doses at 2, 4, and 6 months of age as measured by the percentage of subjects with hSBA titers ≥8 against each serogroup, (2) persistence of immune response at 12 months of age after 3 doses at 2, 4, and 6 months of age, and (3) effect of concomitant administration of MenACWY-CRM with all routine vaccines as measured after 3 doses at 2, 4, and 6 months of age and at 13 months of age for the pneumococcal conjugate booster.
To evaluate the immune response of concomitant vaccines, certain analyses were prespecified as key secondary objectives. We defined noninferiority as being met as follows: for diphtheria, tetanus, Hib, HBV, and PCV7 (through dose 3), noninferiority was achieved if the LL of the 95% CI for the differences in seroresponse rates to the concomitant antigen for the groups ([MenACWY-CRM plus routine vaccines] − [routine vaccines alone]) was >−10%. For poliovirus, the threshold was >−5%. For pertussis antigens, noninferiority was defined as a geometric mean concentration (GMC) ratio (GMCMenACWY-CRM + routine/GMCroutine vaccines alone) >0.67. We defined immunologic noninferiority for the fourth dose of PCV7 as met if the LL of the 2-sided 95% CI for the ratio of the GMCs (GMCMenACWY-CRM + routine/GMCroutine vaccines alone) was >0.50.
For safety evaluations, we solicited all local and systemic reactions up to 7 days after each vaccination. All adverse events (AE) that required an office or emergency room visit, resulted in premature withdrawal from the study, or were considered serious (SAE) were collected during the entire study period. Investigators assigned AE severity and assessed relationship to vaccination.
We calculated sample size based on the first coprimary objective, guided by previous phase II immunogenicity results,16 and determined that 150 subjects per group were needed. The sample size resulted in 92% power for the first coprimary end point and 93% power for the second coprimary end point, for an overall power of 86% for the study. The immunogenicity analysis was based on the per-protocol population, which included all subjects who received all appropriately timed vaccine doses, provided appropriately timed evaluable serum samples, and were without major protocol deviation. The safety cohort included all subjects who received at least 1 dose of vaccine and provided any safety data. No imputations were performed for missing data. Missing data did not contribute to the denominators in means and percentages.
We enrolled 1508 subjects who were randomized 2:1 to receive MenACWY-CRM coadministered with routine vaccines or routine vaccines only followed by MenACWY-CRM in the second year of life (Fig. 1). Of the 1508 enrolled subjects, 479 were enrolled into the immunogenicity cohort (320 randomized to receive 4 doses of MenACWY-CRM with routine vaccines; 159 to receive routine vaccines only followed by MenACWY-CRM at 12 and 15 months of age; Fig. 1A). The remaining 1029 were enrolled into the safety-only cohort (680 to receive 4 doses of MenACWY-CRM with routine vaccines; 349 to receive routine vaccines only followed by MenACWY-CRM in the second year of life; Fig. 1B). Enrollment began on March 29, 2007, and all follow-ups were completed by November 13, 2009. Subject demographics were similar between groups (Table 1). The majority of subjects were male and white. The major reason for discontinuation was withdrawal of informed consent (Fig. 1).
Immunogenicity analyses were performed on the per-protocol data set, which consisted of 323 subjects after the infant series (223 received MenACWY-CRM plus routine vaccines; 100 received routine vaccines only) and 267 subjects after the 4-dose series (183 received MenACWY-CRM plus routine vaccines; 84 received routine vaccines only). One month after the third dose of MenACWY-CRM, the percentage of subjects with hSBA titers ≥8 for serogroups A, C, W, and Y were 67%, 97%, 96%, and 96%, respectively; before the fourth dose at 12 months of age, these percentages decreased to 12%, 52%, 69%, and 60%, respectively (Fig. 2). One month after the fourth dose of MenACWY-CRM administered at 12 months of age, 100% of subjects achieved hSBA titers ≥8 against serogroups W-135 and Y, and 94% and 98% of subjects achieved this level against serogroups A and C, respectively (Fig. 2). The LL of the 2-sided 95% CIs exceeded the prespecified criteria, demonstrating that the first coprimary end point was achieved.
Individuals who received 4 doses of MenACWY-CRM achieved significantly higher GMTs than the group that received only 1 dose at 12 months (Fig. 2B). Subjects who received 4 doses achieved GMTs that were 4.5- to 38-fold higher than subjects who only received 1 dose at 12 months of age. The LL of the 95% CI for the ratio of GMTs was >2.0 for all serogroups (range, 3.0–24), demonstrating that the second coprimary end point was met.
In regard to the secondary end point of immune responses to routine vaccines administered concomitantly with MenACWY-CRM, 1 month after the primary infant series (at 7 months), seroresponse rates were noninferior for diphtheria, tetanus, HBV, Hib antigens and all poliovirus serotypes (Fig. 3A). For pertussis, noninferiority was demonstrated for all antigens using the primary comparator, GMC ratios (Fig. 3B), although noninferiority was narrowly missed for pertactin when using a secondary end point of seroresponse (LL 95% CI, −12%). Similarly, seroresponses 1 month after the primary infant series were noninferior for all pneumococcal serotypes except for PnC 6B (LL 95% CI, −14%; Fig. 3C). However, 1 month after the fourth PCV7 dose at 12 months of age, noninferiority was achieved for all PCV7 serotypes (Fig. 3D).
Of 1508 enrolled subjects, 1500 were exposed to at least 1 vaccination, provided follow-up safety data, and were included in the safety analysis. Within 7 days after the third dose (given at 6 months), rates of erythema and induration after MenACWY-CRM administration were similar to or lower than those after the comparator vaccine Hib administration; rates of erythema and induration were lower within 7 days after MenACWY-CRM than after PCV7 administration at 12 months of age (Table 2). The percentage of subjects who experienced solicited systemic reactions was similar between groups (Table 2). The most common systemic reactions were irritability and sleepiness. Rates of fever were low and similar between groups.
After 3 doses of MenACWY-CRM, the percentages of subjects experiencing any AEs were similar between subjects who received MenACWY-CRM with concomitant vaccines (75%) and those who received routine vaccination only (76%). After 4 doses of MenACWY-CRM, AEs were lower among subjects who received MenACWY-CRM with routine vaccination (55%) compared with those who received routine vaccines alone (62%). The types of AEs were generally similar between groups; the most commonly reported AEs were upper respiratory tract infections (34%–36%).
SAEs were reported with similar frequency among groups. Three SAEs were considered to be at least possibly related to vaccination, 2 of which resulted in withdrawal from the study: 1 subject was diagnosed with Kawasaki disease 29 days after the third dose of MenACWY-CRM and concomitant routine vaccines, and 1 subject had partial complex seizures 31 days after the second dose of MenACWY-CRM with concomitant routine vaccines. The third subject experienced 2 episodes of febrile convulsions 8 and 29 days after the third dose of MenACWY-CRM with concomitant routine vaccines. All 3 conditions resolved within 7 days of event onset. No deaths occurred.
This study demonstrates that a 4-dose series of MenACWY-CRM was highly immunogenic in young infants with 94% to 100% seroresponse rates for all 4 meningococcal serogroups. Furthermore, 4 doses of MenACWY-CRM were significantly more immunogenic than a single dose administered at 12 months of age. Taken together, these results indicate that vaccinating infants with 4 doses of MenACWY-CRM will provide significant protection against meningococcal serogroups A, C, W-135, and Y. In light of infants' high risk from invasive meningococcal disease, the findings from this study represent a major advance toward protecting vulnerable infant populations against meningococcal disease.
An important observation in this study was the finding that more than 96% of subjects had hSBA titers ≥8 against 3 serogroups (C, W-135, and Y) after 3 doses, with 52% to 69% maintaining hSBA titers ≥8 for these same serogroups before a fourth MenACWY-CRM dose at 12 months of age. Although future studies will be needed to assess long-term persistence of immunity beyond the fourth dose, the current study provides evidence that 3 doses administered at 2, 4, and 6 months of age confer substantial protection against 3 of the epidemiologically relevant serogroups in the United States during the first year of life.
The current findings support our previous phase II trial, indicating that the MenACWY-CRM vaccine is highly immunogenic in infants.15,16 Our results contrast with the results of a phase II meningococcal vaccine trial in which a quadrivalent polysaccharide vaccine conjugated to diphtheria toxoid demonstrated suboptimal immune responses in young infants.6 We hypothesize that these differences may be related to differential immunogenicity of the carrier proteins (CRM197 vs. diphtheria toxoid) or to other aspects of the conjugation chemistry and vaccine design, such as the chemical linkers employed, selective sizing of oligosaccharides, and the ratio of oligosaccharides to carrier molecules.19
Antibody seroresponses after the third dose of routine vaccines administered with and without MenACWY-CRM were noninferior for all concomitant vaccine antigens, with the exception of pneumococcal serotype 6B. However, the clinical relevance of this difference is unclear, as subsequent seroresponses were noninferior for 6B after the fourth dose. Similarly, as the main secondary end point of pertactin GMC ratios showed essentially no difference between the 2 groups, the clinical significance of the lower pertactin seroresponse in recipients of concomitant MenACWY-CRM is unclear. Taken together, we conclude that MenACWY-CRM may be given concomitantly with routine pediatric vaccines without substantial concern for clinically relevant immunologic interference.
MenACWY-CRM was well tolerated, with local reactogenicity similar to that seen after vaccination with the comparator vaccine Hib. Furthermore, the majority of systemic reactions after vaccination with MenACWY-CRM were mild to moderate and comparable to those noted after routine vaccines alone. Overall, these results indicate that MenACWY-CRM administered with routine vaccines was safe and well tolerated in infants.
MenACWY-CRM was highly immunogenic in infants, making MenACWY-CRM the first multivalent meningococcal vaccine that can be used in a 4-dose primary immunization series from 2 months of age to offer protection against these 4 meningococcal serotypes. The use of MenACWY-CRM in young infants offers a powerful public health tool for reducing the burden of meningococcal sepsis and meningitis caused by serotypes A, C, W, and Y in infants.
Kathleen Jenks, PhD, and Lisa DeTora, PhD, provided assistance with the manuscript preparation. Susan E. Myers, MSc, and Gerard P. Johnson, PhD, of Complete Healthcare Communications, Inc., whose work was funded by Novartis Vaccines and Diagnostics, also assisted with the manuscript preparation.
US Investigators: Marsha Anderson, Henry Bernstein, Stan L. Block Jr, John L. Buttler, Archana Chatterjee, Shane Glade Christensen, Blaise Congeni, Matthew J. Cornish, Marilou Gegare Cruz, Mary C. Dundon, John P. Frey, Manjusha Gaglani, Ricardo Grillo Paris, William H. Johnston, Nicola Klein, Tsoline Kojaoghlanian, Paul S. Lei, Colin Marchant, Keith S. Reisinger, Mildred S. Rey, Edward Rothstein, Jack Seidel, Shelly Senders, Steven Shapiro, Peter Silas, Ina Stephens, Lisa Turner, Sylvia Yeh, Ram Yogev.
Novartis study team: Jessica Hackett, Giuseppe Ciavarro, Caitlin McCourt, Marielle Migchelsen, Katherine Lanier, Conor Knightly, Felicia Lipansky, Bridget Waluch, Jina Shah, Cynthia Reeves, Niranjan Kanesa-thasan, Matt Hohenboken.
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meningococcal disease; conjugate vaccine; immunogenicity; safety; infants
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