Menb JAMA.Pdf

ORIGINAL CONTRIBUTION

Immunogenicity and Tolerability of Recombinant Serogroup B Meningococcal Vaccine Administered With or Without Routine Infant Vaccinations According to Different Immunization Schedules A Randomized Controlled Trial

Nicoletta Gossger, MD Context In the absence of an effective vaccine, serogroup B Neisseria meningitidis (MenB) Matthew D. Snape, MD, FRCPCH remains a major cause of invasive disease in early childhood in developed countries. Ly-Mee Yu, MSc Objective To determine the immunogenicity and reactogenicity of a multicomponent Adam Finn, PhD, FRCP MenB vaccine (4CMenB) and routine infant vaccines when given either concomitantly or separately. Gianni Bona, MD Design, Setting, and Participants Phase 2b, multicenter, open-label, parallel- Susanna Esposito, MD group, randomized controlled study of 1885 infants enrolled at age 2 months from Nicola Principi, MD August 2008 to July 2010 in Europe. Javier Diez-Domingo, MD, PhD Intervention Participants were randomized 2:2:1:1 to receive (1) 4CMenB at 2, 4, and 6 months with routine vaccines (7-valent pneumococcal and combined diphthe- Etienne Sokal, MD, PhD ria, tetanus, acellular pertussis, inactivated polio, hepatitis B, Haemophilus influenzae Birgitta Becker, MD type b vaccines); (2) 4CMenB at 2, 4, and 6 months and routine vaccines at 3, 5, and Dorothee Kieninger, MD 7 months; (3) 4CMenB with routine vaccines at 2, 3, and 4 months; or (4) routine vaccines alone at 2, 3, and 4 months. Roman Prymula, MD, PhD Main Outcome Measures Percentage of participants with human complement se- Peter Dull, MD rum bactericidal activity (hSBA) titer of 1:5 or greater against 3 MenB strains specific Ellen Ypma, MSc for vaccine antigens (NZ98/254, 44/76-SL, and 5/99). Daniela Toneatto, MD Results After three 4CMenB vaccinations, 99% or more of infants developed hSBA titers of 1:5 or greater against strains 44/76-SL and 5/99. For NZ98/254, this proportion Alan Kimura, MD, PhD was 79% (95% CI, 75.2%-82.4%) for vaccination at 2, 4, and 6 months with routine Andrew J. Pollard, PhD, FRCPCH vaccines, 86.1% (95% CI, 82.9%-89.0%) for vaccination at 2, 4, and 6 months without routine vaccines, and 81.7% (95% CI, 76.6%-86.2%) for vaccination at 2, 3, and 4 months for the European MenB Vaccine with routine vaccines. Responses to routine vaccines given with 4CMenB were noninfe- Study Group rior to routine vaccines alone for all antigens, except for the responses to pertactin and serotype 6B pneumococcal polysaccharide. Fever was seen following 26% (158/602) to ENINGOCOCCAL DISEASE 41% (247/607) of 4CMenB doses when administered alone, compared with 23% (69/ occurs with an inci- 304) to 36% (109/306) after routine vaccines given alone and 51% (306/605) to 61% dence of 0.2 to 14 per (380/624) after 4CMenB and routine vaccines administered together. 100 000 population in in- Conclusion A 4CMenB vaccine is immunogenic against reference strains when ad- dustrializedM countries.1 Effective vac- ministered with routine vaccines at 2, 4, and 6 or at 2, 3, and 4 months of age, pro- cines based on capsular polysaccha- ducing minimal interference with the response to routine infant vaccinations. rides for meningococcal serogroups A, Trial Registration clinicaltrials.gov Identifier: NCT00721396 C, W-135, and Y are available,2 but sero- JAMA. 2012;307(6):573-582 www.jama.com group B capsular polysaccharide is an- tigenically similar to human neural cell Serogroup B Neisseria meningitidis Author Affiliations are listed at the end of this article. glycopeptides containing polysialic acid A List of the European MenB Vaccine Study Group and poorly immunogenic in humans. (MenB) vaccines based on detergent- Members is available at http://www.jama.com. extracted outer membrane vesicles Corresponding Author: Matthew Snape, MD, FRCPCH, (OMVs) containing outer membrane Oxford Vaccine Group, CCVTM, Churchill Hospital, Uni- For editorial comment see p 614. versity of Oxford, Old Rd, Oxford OX3 7LJ, United King- proteins, including porin protein A, dom ([email protected]).

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proved effective in clinical trials and someone experiencing meningococcal Participants were randomized to the controlled a clonal MenB outbreak in disease; prior receipt of meningococcal 4 vaccination groups in a 2:2:1:1 ratio New Zealand.3,4 However, the high B or C vaccines or any of the nationally according to a centrally held random- strain specificity of these vaccines lim- recommended routine infant vaccines; ization list (Biostatistics and Clinical its their usefulness, especially in in- acute or chronic illness; known reac- Data Management, Novartis) using a fants and young children.5,6 tions to vaccine components; known or fixed block size of 6. The unequal To develop a vaccine with broader suspected immune disease or impair- allocation ratio was chosen to effi- protection, novel antigens identified by ment, including the administration of ciently assess primary as well as sec- sequencing the MenB genome— steroids; receipt of antibiotics 6 days ondary objectives. This was an open- factor-H binding protein variant 1 prior to enrollment; receipt of blood label study; ie, study personnel and (fHbp1), Neisserial adhesin A (NadA), products; or planned receipt of non- parents both knew which vaccines were and Neisseria heparin binding antigen study vaccines. Investigator-defined op- being administered. (NHBA)—were combined with OMVs tions for race/ethnicity were chosen by from the New Zealand epidemic strain the participants’ parents for demo- Immunology NZ98/254 in a multicomponent sero- graphic description of the study popu- Sera obtained before the first vaccina- group B meningococcal vaccine lation. tion and 30 (−4/ϩ7) days after the third (4CMenB).7 To facilitate manufacture dose of 4CMenB (or routine vaccines in and enhance protein stability, fHbp1 Intervention the control group) were shipped to the and NHBA were combined with other The 4CMenB vaccine consisted of 50 Novartis Vaccines Serology Laboratory, proteins identified during genome se- µg each of fHbp1, NadA, and NHBA fu- Marburg, Germany, for blinded immu- quencing to create 2 fusion pro- sion proteins, 25 µg of detoxified OMV nology assessments. Human comple- teins.8,9 Small studies in infants dem- from N meningitidis strain NZ98/254, ment serum bactericidal activity (hSBA) onstrated immunogenicity of 4CMenB 1.5 of mg aluminum hydroxide, and was assessed against 3 target strains cho- against reference strains.8,9 histidine 10mM in 0.5 mL of water for sen to determine the immunogenicity of In this study we assessed the immu- injection. Participants also received a individual vaccine components— nogenicity and reactogenicity of combined diphtheria, tetanus, acellu- strain 44/76-SL for fHBP1, strain 5/99 for 4CMenB in a large cohort of infants lar pertussis, inactivated polio, hepati- NadA, and strain NZ98/254 for OMV. when given in 2 different schedules, and tis B, and Haemophilus influenzae type The hSBA was expressed as interpo- concomitantly or separately from rou- b vaccine (DTaP-HBV-IPV/Hib) (In- lated titers according to reciprocal se- tine vaccines. fanrix Hexa; GlaxoSmithKline) and rum dilutions yielding 50% or greater 7-valent pneumococcal glycoconju- killing of the target strain after 60 min- METHODS gate vaccine (PCV7) (Prevnar; Wyeth utes of incubation compared with growth Study Participants and Trial Design Pharmaceuticals). These are referred to at time 0. An interpolated titer of 1:5 or This phase 2b, open-label, parallel- as routine vaccines, although they do greater represented 95% confidence that group, randomized controlled trial was not necessarily reflect the routine vac- participants achieving this titer had a pro- conducted between August 2008 and cines used in each study country. tective hSBA titer (Ն1:4).10 July 2010 in Belgium (6 centers), United The study design allowed assess- Because no hSBA strain specific for Kingdom (4 centers), Czech Republic (4 ment of 3 primary 4CMenB sched- NHBA was available at the time of centers), Germany (25 centers), Italy (5 ules: ages 2, 4, and 6 months, together analysis, antibodies to NHBA were mea- centers), and Spain (16 centers). Ap- with routine infant vaccines (concomi- sured by enzyme-linked immunosor- propriate regulatory authorities in each tant); 2, 4, and 6 months, with routine bent assay and expressed as geometric participating country granted approval vaccines given separately at 3, 5, and 7 mean concentrations (GMCs). for the trial. Participants were healthy, months (intercalated); and 2, 3, and 4 Responses to routine vaccines were full-term, 2-month-old infants with a months, concomitantly with routine in- determined for participants in the ac- birth weight of 2.5 kg or greater, whose fant vaccines (accelerated). A control celerated and control groups only, ac- parent(s) or legal guardian(s) provided group received DTaP-HBV-IPV/Hib and cording to availability of serum, using written informed consent. In the United PCV7 only at 2, 3, and 4 months. These standard correlates of protection to in- Kingdom, participants were recruited by immunization time points were cho- terpret responses. Geometric mean ti- information letters sent via National sen to reflect schedules currently used ters (GMTs) of hSBA, routine vaccine Health Service child health computer da- in different countries. All vaccines were antigen-specific IgG GMCs, and the be- tabases; participants in other study cen- administered by intramuscular injec- tween-group ratios of GMT and GMC ters were recruited through pediatric tion in the anterolateral thigh; 4CMenB were calculated (with 2-sided 95% CIs) hospitals or private practices. Exclu- and routine vaccines given concomi- using 2-way analysis of variance with sion criteria were any history of menin- tantly were administered in opposite a factor for vaccine group and immu- gococcal infection or close contact with limbs. nization center.

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Safety rately. The percentage of 4CMenB re- ing the third dose), and IgG GMC Parents recorded local injection site recipients achieving hSBA titers of 1:5 or against NHBA using the adjusted Wald actions (pain, erythema, swelling, and greater in the concomitant group, ob- test proposed by Agresti and Coull.14 induration) and systemic reactions (ie, tained from a categorical linear model, The sample size calculation for the pri- fever [axillary temperature Ն38°C], was considered noninferior to that in mary outcome was determined using a change in eating habits, sleepiness, un- the intercalated group if the lower lim- simulation approach to estimate that 300 usual crying, vomiting, diarrhea, irri- its of the 95% CI for the differences in participants in the accelerated group tability, rash) for 7 days after each vac- these percentages (concomitant mi- would yield 95% power to demonstrate cination. Injection site pain was nus intercalated) was greater than that the lower limit of the 2-sided 95% classified by the parents as mild (mini- −10%.12 The same criteria were used to CI for the true percentage of partici- mal discomfort when the child’s leg was determine noninferiority between the pants with hSBA titer of 1:5 or greater touched), moderate (obvious discom- control and accelerated groups for the was 70% or greater. A sample size of 600 fort when the leg was touched), or se- response to routine vaccines. in the concomitant and intercalated vere (pain on movement of the leg). Additionally, a post hoc noninferior- groups was calculated to provide 87% Erythema, induration, and swelling ity criterion for the geometric mean ra- power to demonstrate noninferiority in were summarized by maximal sever- tios of 4CMenB response (intercalated di- response rates for all 3 MenB strains (as- ity (1-25 mm, 25-50 mm, and Ͼ50 mm, vided by concomitant) obtained from suming only 80% provided evaluable respectively). analysis of variance adjusting for center sera, response rates to 4CMenB given to- Adverse event recording was en- was defined as the lower limit of the 95% gether with routine immunizations were hanced by telephone contact in the CI being greater than 0.5 for all 3 strains. similar to those in previously published week after study vaccination. Safety fol- For pertussis antigens, noninferiority of studies,8,9 and that response rates to low-ups were completed 6 months af- the accelerated compared with the con- 4CMenB given without routine immu- ter the last dose of 4CMenB (and at age trol group was achieved if the lower limit nizations were 2% higher for each strain). 10 months in the control group). All se- of the 2-sided 95% CI for the ratio of the Individuals who received at least 1 rious adverse events reported during the antigen-specific IgG GMCs after vacci- dose of vaccine and provided postbase- study were recorded. Determination of nation was greater than 0.67. All anti- line safety data were included in the the relationship between adverse events gen thresholds were chosen based on tra- safety analyses, for which results were and the study vaccine was made by a ditional use and acceptance by regulatory reported descriptively with no formal study investigator’s judgment based on authorities. Responses to antigens ad- statistical analyses. temporal relationship and biological ministered at the same time were ana- Statistical analysis was performed plausibility criteria. lyzed in a per-protocol population, ie, using SAS version 9.1. those who received all designated vac- Statistics cines on time and provided sera within RESULTS The primary outcome was assessment the scheduled window (23-55 days post A total of 1885 participants were en- of percentages of participants with hSBA vaccination) and who received no pro- rolled (United Kingdom, 561; Italy, 371; titers of 1:5 or greater 1 month after im- hibited medications (systemic antibiot- Germany, 317; Czech Republic, 283; munization with 4CMenB in the con- ics or systemic/high-dose inhaled Belgium, 248; Spain, 105), of whom comitant and accelerated groups, vac- corticosteroids). 1810 (96%) completed the study. Of cine response being sufficient if the Modified intention-to-treat analysis these, 1636 were included in the modi- lower limit of the 2-sided 95% Clopper- was performed as per-randomized fied intention-to-treat immunogenic- Pearson11 CI of this percentage was 70% group; the per-protocol population was ity analysis (FIGURE 1) and 1599 in the or greater for all 3 reference strains. In analyzed as per-immunization course per-protocol immunogenicity analy- addition, hSBA titers were log trans- received. sis. Median age at enrollment was 68.7 formed and their GMTs and 2-sided A post hoc analysis was performed days for all groups, 48.3% to 53.4% of 95% CIs calculated. The prespecified that used all available data and in- each group were boys, and 93.1% of all population for this analysis was the cluded imputed values to replace miss- participants were white. modified intention-to-treat popula- ing data.13 Each missing value was re- tion, including only those who re- placed with a set of plausible values that Immunogenicity ceived a study vaccine and provided represent the uncertainty about the cor- Primary Outcome. After immuniza- evaluable serum samples before and af- rect values to impute. Variables in- tion with 4CMenB and routine vac- ter immunization. cluded in the imputation model were cines together at either 2, 4, and 6 or The main secondary outcomes were actual vaccine administered, center, age, 2, 3, and 4-months, 99% or more of par- noninferiority of immune responses to birth weight, weight, height, sex, race, ticipants had hSBA titers of 1:5 or 4CMenB and routine vaccines admin- hSBA titers for strains 44/76-SL, 5/99, greater for strains 44/76-SL and 5/99 in istered together compared with sepa- and NZ98/254 (at baseline and follow- the modified intention-to-treat analy-

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sis (FIGURE 2 and TABLE 1). For strain ing the predefined criteria of a suffi- intercalated group met the prespeci- NZ98/254, percentages were 79.0% cient immune response. Results from fied noninferiority criterion for (417/528 [95% CI, 75.2% to 82.4%]) multiple imputation analysis were simi- 44/76-SL and 5/99 but not NZ98/254 and 81.7% (219/268 [95% CI, 76.6% to lar (Table 1). (−7.1% [95% CI, −11.7% to −2.6%]) 86.2%]) following concomitant or ac- Secondary Outcomes. The differ- (Table 1). Although the lower limit of celerated schedules. Lower limits of the ence in the percentage of participants the 95% CI for the geometric mean 95% CIs were greater than 70% for all with hSBA titers of 1:5 or greater in concomitant to intercalated hSBA 3 tested reference strains, thereby meet- the concomitant group minus the ratios were all above 0.5, thus meeting

Figure 1. Flowchart of the Modified Intention-to-Treat (MITT) Population

1885 Participants randomized

622 Randomized to receive 632 Randomized to receive 317 Randomized to receive 314 Randomized to receive concomitant schedule intercalated schedule accelerated schedule routine schedule (control)

621 Received concomitant schedule 625 Received intercalated schedule 315 Received accelerated schedule 310 Received routine schedule as randomized as randomized as randomized as randomized 1 Received routine schedule 4 Received concomitant schedule 1 Received concomitant schedule 1 Received concomitant schedule 2 Received accelerated schedule 1 Received intercalated schedule 2 Received intercalated schedule 1 Received routine schedule 1 Received accelerated schedule

70 Excluded 88 Excluded 39 Excluded 52 Excluded 45 No serum or no results (before 55 No serum or no results (before 31 No serum or no results (before 43 No serum or no results (before or after immunization) or after immunization) or after immunization) or after immunization) 18 Withdrawn 27 Withdrawn 7 Withdrawn 7 Withdrawn (withdrew consent) 9 Withdrew consent 15 Withdrew consent 3 Withdrew consent 2 Lost to follow-up 4 Adverse event 7 Adverse event 2 Adverse event 2 Protocol deviation 4 Protocol deviation 1 Protocol deviation 3 Administrative reason 1 Inappropriate enrollment 1 Administrative reason 5 Lost to follow-up 5 Lost to follow-up 1 Lost to follow-up 2 Not vaccinated 1 Not vaccinated

552 Included in primary immunogenicity 544 Included in primary immunogenicity 278 Included in primary immunogenicity 262 Included in primary immunogenicity analysis analysis analysis analysis

See “Methods” for definitions of groups. The number of infants approached, assessed for eligibility, and primarily excluded is unknown. Six-month follow-up in the safety population was completed by 597 participants in the concomitant group, 599 in the intercalated group, 309 in the accelerated group, and 305 in the routine (control) group. This chart does not show the flow of participants for the per-protocol population (used for calculations of Neisseria heparin binding antigen enzyme- linked immunosorbent assay data and response to concomitant vaccines).

Figure 2. Reverse Cumulative Distribution of hSBA Titers at 1 Month After the Third 4CMenB Vaccination, by Meningococcal Strain (MITT Population)

Group Concomitant Intercalated Accelerated Control

Strain 44/76-SL Strain 5/99 Strain NZ98/254 100 100 100

80 80 80

60 60 60

40 40 40

20 20 20

Participants, Cumulative % 0 Participants, Cumulative % 0 Participants, Cumulative % 0 0.1 1 10 100 1000 10 000 0.1 1 10 100 1000 10 000 100 000 0.1 1 10 100 1000 10 000 hSBA Titer hSBA Titer hSBA Titer

See “Methods” for definitions of groups. Numbers of participants in each group are as reported in Figure 1. Blue vertical lines indicate reference for hSBA titers of 1:5 or greater. 4CMenB indicates multicomponent serogroup B meningococcal vaccine; hSBA, human complement serum bactericidal activity; MITT, modified intention-to-treat.

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the prespecified noninferiority crite- group compared with the control the study, fewer than 1% of all partici- rion, it is notable that the upper limit group (lower limits of 95% CI of the pants experienced severe erythema, of the 95% CI for these ratios were all differences in these values being swelling, or induration at either of the less than 1 (TABLE 2). greater than −10%), with the excep- vaccination sites. However, 12% to 16% The geometric mean ratios (con- tion of pertactin (difference, −4% in the concomitant and accelerated comitant divided by accelerated) of [95% CI, −11% to 3%]). Noninferior- groups, respectively, experienced se- hSBA titers were similar for strains 44/ ity was demonstrated for 6 of the 7 vere local pain after a dose of 4CMenB, 76-SL and NZ98/254 (confidence in- serotypes in the pneumococcal vac- compared with 1% to 3% after doses of tervals crossing 1) but higher for strain cine (serotypes 4, 9V, 14, 18C, 19F, DTaP-HBV-IPV/Hib or PCV7 in the con- 5/99 (1.61 [95% CI, 1.41 to 1.84]). IgG 23F) but not for serotype 6B (differ- trol group. GMCs against NHBA 1 month after the ence, −5% [95% CI, −14% to 3%]), Fever (Ն38.0°C) after any vaccina- third 4CMenB vaccination were 4342 because the lower limit of the differ- tion was described in 80% (501/624) in (95% CI, 4067-4635) when 4CMenB ence in the percentage of participants the concomitant group and 76% (243/ was administered separately from rou- with antibody response greater or 318) in the accelerated group, com- tine vaccines, compared with 3211 equal to the prespecified cutoff level pared with 51% (160/311) in control (95% CI, 2949-3495) to 3332 (95% CI, was −14% (TABLE 4). group and 71% (447/627) in the inter- 3120-3558) when administered to- calated group. For the intercalated gether (TABLE 3). Reactogenicity and Safety group there were twice as many immu- The percentages of participants The numbers of participants experienc- nization days, and therefore more op- achieving the threshold of response ing adverse reactions after immuniza- portunity for fever to be experienced. for DTaP-HBV-IPV/Hib components tion are shown in the eTable available Rates of fever per 4CMenB dose are were noninferior in the accelerated at http://www.jama.com. Throughout shown in the eTable.

Table 1. Results of the Number of Infants Achieving Bactericidal Titers of 1:5 or Greater and the Percentages at Baseline and 1 Month After the Third Vaccination (MITT Population and Multiple Imputation) and Vaccine Group Differencesa % (95% CI)b

Vaccine Group Differences

Concomitant Concomitant Minus Minus Strain Concomitant Intercalated Accelerated Control Intercalated Accelerated Strain 44/76-SL Baseline, No./totalc 47/525 38/531 16/272 16/248 MITTd 9.0 (6.7 to 11.7) 7.2 (5.1 to 10.0) 5.9 (3.4 to 9.4) 6.5 (3.7 to 10.3) 1.8 (−1.5 to 5.1) 3.1 (−0.6 to 6.8) Multiple imputatione 8.7 (6.8 to 11.2) 6.80 (5.1 to 9.2) 6.8 (4.2 to 9.8) 6.5 (4.1 to 9.7) 1.9 (−1.2 to 4.9) 2.3 (−1.4 to 5.9) Post third dose, No./totalc 521/525 528/531 270/272 11/248 MITTd 99.2 (98.1 to 99.8) 99.4 (98.4 to 99.9) 99.3 (97.4 to 99.9) 4.4 (2.2 to 7.8) −0.2 (−1.2 to 0.8) −0.03 (−1.3 to 1.2) Multiple imputatione 98.9 (96.6 to 99.1) 98.8 (96.4 to 99.1) 98.4 (94.3 to 98.7) 10.5 (8.2 to 16.0) 0.1 (−1.4 to 1.6) 0.5 (−1.5 to 2.4) Strain 5/99 Baseline, No./totalc 28/520 34/517 12/266 15/226 MITTd 5.4 (3.6 to 7.7) 6.6 (4.6 to 9.1) 4.5 (2.3 to 7.7) 6.6 (3.7 to 10.7) −1.2 (−4.1 to 1.7) 0.9 (−2.3 to 4.0) Multiple imputatione 5.5 (4.0 to 7.7) 6.7 (4.9 to 8.9) 4.9 (3.0 to 7.8) 6.0 (3.7 to 9.2) −1.1 (−3.9 to 1.7) 0.7 (−2.4 to 3.8) Post third dose, No./totalc 517/520 513/517 266/266 12/226 MITTd 99.4 (98.3 to 99.9) 99.2 (98.0 to 99.8) 100 (98.6 to 100) 5.3 (2.8 to 9.1) 0.2 (−0.8 to 1.2) −0.6 (−1.2 to 0.01) Multiple imputatione 99.1 (96.8 to 99.3) 98.7 (96.2 to 98.9) 98.6 (94.6 to 98.9) 11.6 (9.0 to 17.2) 0.5 (−1.0 to 2.0) 0.4 (−1.6 to 2.3) Strain NZ98/254 Baseline, No./totalc 18/528 5/526 6/268 2/250 MITTd 3.4 (2.0 to 5.3) 1.0 (0.3 to 2.2) 2.2 (0.8 to 4.8) 0.8 (0.1 to 2.9) 2.5 (0.7 to 4.2) 1.2 (−1.2 to 3.5) Multiple imputatione 3.2 (1.9 to 5.0) 1.0 (0.4 to 2.3) 2.0 (0.8 to 4.3) 0.8 (0.1 to 2.8) 2.2 (0.5 to 3.8) 1.2 (−1.0 to 3.4) Post third dose, No./totalc 417/528 453/526 219/268 11/250 MITTd 79.0 (75.2 to 82.4) 86.1 (82.9 to 89.0) 81.7 (76.6 to 86.2) 4.4 (2.2 to 7.7) −7.1 (−11.7 to −2.6) −2.7 (−8.5 to 3.05) Multiple imputatione 79.0 (74.8 to 81.5) 86.1 (82.0 to 88.1) 79.1 (73.5 to 82.9) 9.7 (7.2 to 14.7) −7.0 (−11.6 to −2.44) −0.76 (−6.5 to 5.0) Abbreviation: MITT, modified intention-to-treat. aSee “Methods” for definition of groups. bTwo-sided 95% CI calculated using Clopper-Pearson method. cTotal numbers may differ from MITT population in Figure 1 because human complement serum bactericidal activities failed for individual strains. dUnadjusted for center effect. en=610 for the concomitant group; n=613 for the intercalated group; n=306 for the accelerated group; and n=309 for the routine group. See “Methods” for variables included in imputation model.

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Over the 8- to 10-month study, 166 Of these, 20 (9 concomitant, 7 interca- routine vaccination in the intercalated serious adverse events were reported in lated, 3 accelerated, and 1 control) were and accelerated groups, and 2 following 158 participants: 63 (10%) in the con- thought to be possibly related to vaccination with 4CMenB in the inter- comitant group, 57 (9%) in the interca- 4CMenB or routine vaccinations. calated group, 1 of the latter being a lated group, 19 (6%) in the accelerated Four possibly related serious adverse febrile seizure 2 days after the second group, and 19 (6%) in the control group. events were seizures, 1 each following 4CMenB dose. Two hypotonic hypore-

Table 2. Geometric Mean Titers and Ratios (MITT Population), by Vaccination Groupa GMT (95% CI) GMR (95% CI)

Concomitant Concomitant Strain Concomitant Intercalated Accelerated Control to Intercalated to Accelerated Strain 44/76-SLb n = 525 n = 531 n = 272 n = 248 Baseline MITTc 1.51 (1.41-1.61) 1.38 (1.29-1.48) 1.34 (1.23-1.46) 1.27 (1.18-1.37) 1.09 (1.00-1.18) 1.12 (1.01-1.24) Multiple imputationd 1.54 (1.44-1.65) 1.40 (1.32-1.50) 1.39 (1.28-1.51) 1.29 (1.20-1.38) 1.10 (1.01-1.19) 1.11 (1.01-1.22) Post third dose MITTc 83 (77-90) 110 (102-119) 82 (75-91) 1.26 (1.13-1.39) 0.75 (0.69-0.83) 1.01 (0.90-1.49 Multiple imputationd 85 (76-92) 106 (97-116) 80 (72-90) 1.71 (1.45-2.01) 0.80 (0.72-0.88) 1.05 (0.93-1.19) Strain 5/99b n = 520 n = 517 n = 266 n = 226 Baseline MITTc 1.29 (1.20-1.38) 1.28 (1.19-1.37) 1.20 (1.10-1.31) 1.24 (1.14-1.35) 1.01 (0.93-1.10) 1.07 (0.97-1.19) Multiple imputationd 1.28 (2.00-1.37) 1.29 (1.21-1.38) 1.21 (1.11-1.32) 1.24 (1.15-1.33) 1.00 (0.92-1.08) 1.06 (0.97-1.17) Post third dose MITTc 520 (475-570) 669 (611-731) 323 (287-363) 1.43 (1.18-1.74) 0.78 (0.70-0.87) 1.61 (1.41-1.84) Multiple imputationd 533 (475-598) 636 (572-709) 315 (274-361) 1.77 (1.66-2.73) 0.84 (0.74-0.95) 1.69 (1.44-1.99) Strain NZ98/254b n = 528 n = 526 n = 268 n = 250 Baseline MITTc 1.14 (1.09-1.19) 1.08 (1.04-1.13) 1.07 (1.01-1.13) 1.06 (1.03-1.10) 1.05 (0.90-1.11) 1.06 (1.00-1.14) Multiple imputationd 1.13 (1.08-1.17) 1.08 (1.04-1.13) 1.06 (1.01-1.12) 1.06 (1.02-1.10) 1.04 (0.99-1.10) 1.06 (1.00-1.12) Post third dose MITTc 12 (10-13) 17 (15-19) 11 (9-12) 1.16 (1.06-1.25) 0.68 (0.59-0.80) 1.10 (0.91-1.32) Multiple imputationd 12 (10-13) 16 (14-19) 10 (9-12) 1.40 (1.25-1.57) 0.71 (0.61-0.83) 1.15 (0.95-1.38) Abbreviations: GMR, geometric mean ratio; GMT, geometric mean titer; MITT, modified intention-to-treat. aSee “Methods” for definitions of groups. bTotal numbers may differ from MITT population in Figure 1 because human complement serum bactericidal activities failed for individual strains. cAdjusted for center effect. dn=610 for the concomitant group; n=613 for the intercalated group; n=306 for the accelerated group; and n=309 for the routine group. See “Methods” for variables included in imputation model.

Table 3. Geometric Mean Bactericidal Antibody Concentrations Measured by ELISA Against Vaccine Antigen NHBA (per-Protocol Population and Multiple Imputation Analysis)a ELISA Geometric Mean Antibody Concentration

Concomitant Intercalated Accelerated Control

Sample Sample Sample Sample U/mL Size, U/mL Size, U/mL Size, U/mL Size, Group (95% CI) No. (95% CI) No. (95% CI) No. (95% CI) No. Baseline Per-protocol populationb 23 (21-24) 569 23 (22-24) 559 22 (21-24) 293 22 (21-23) 287 Multiple imputationc 23 (22-24) 615 23 (22-24) 615 23 (21-24) 307 22 (21-23) 307 Post third dose Per-protocol populationb 3332 (3120-3558) 545 4342 (4067-4635) 557 3211 (2949-3495) 281 21 (20-21) 269 Multiple imputationc 3261 (2965-3587) 615 4039 (3697-4414) 609 3049 (2732-3402) 307 30 (26-36) 307 Ratio of post third dose to baseline Per-protocol populationb 150 (136-165) 531 191 (174-210) 539 145 (128-164) 275 0.94 (0.89-0.99) 257 Multiple imputationc 143 (128-161) 615 175 (157-196) 609 135 (118-156) 307 1.39 (1.17-1.66) 307 Abbreviations: ELISA, enzyme-linked immunosorbent assay; NHBA, Neisseria heparin binding antigen. aSee “Methods” for definitions of groups. bAdjusted for center effect. cn=610 for the concomitant group; n=613 for the intercalated group; n=306 for the accelerated group; and n=309 for the routine group. See “Methods” for variables included in imputation model.

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sponsive episodes were reported, 1 within related serious adverse events were asep- of 4CMenB is immunogenic against 3 12 hours of concomitant 4CMenB and tic meningitis, retinal dystrophy (be- reference strains expressing 1 of 3 vac- routine vaccines and 1 within 6 hours lieved to be congenital), transient syno- cine antigens. Furthermore, 4CMenB after routine vaccines in the interca- vitis of the right hip, a transient hearing was immunogenic when administered lated group. Two cases of Kawasaki dis- loss noted by a parent, and transient in a 2-, 3-, and 4-month schedule, an ease were reported, 1 of which was con- apnea after concomitant vaccination. important finding given the high rates sidered possibly related to the study of MenB disease in the first 6 months vaccine by an independent expert panel. COMMENT of life.15,16 These results suggest that Six children were observed in the hos- This study of more than 1800 infants there can be some flexibility in the in- pital because they had experienced fever shows that when administered to- corporation of 4CMenB into the vari- within 2 days after vaccination with gether with routine vaccines to healthy ous immunization schedules used in 4CMenB. The remaining 5 possibly infants, a primary immunization course different countries.

Table 4. Immunogenicity of Routine Vaccines (DTaP-HBV-IPVHib and 7-Valent Pneumococcal) Given Concomitantly With or Without 4CMenB; Total Number and Percentage of Infants With Seroresponse Greater Than or Equal to a Prespecified Level and Geometric Mean Antibody Concentrations (per-Protocol Population)a No. of Participants With Positive Threshold/Total Geometric Mean Antibody No. Tested (% Participants Achieving Concentration/Titers Threshold of Response) [95% CI] (95% CI)

Vaccine Threshold Accelerated Difference in Accelerated Geometric Mean Antigen of Response Group Control Group Response, % Group Control Group Ratio Diphtheria IgG Ն0.10 IU/mL 238/238 209/210 0 (−1 to 3) 1.43 (1.30 to 1.57) 1.69 (1.53 to 1.87) 0.85 (0.75 to 0.95) (100) [98 to 100] (100) [97 to 100] Tetanus IgG Ն0.10 IU/mL 238/238 210/210 0 (−2 to 2) 1.91 (1.71 to 2.13) 2.00 (1.78 to 2.25) 0.95 (0.83 to 1.09) (100) [98 to 100] (100) [98 to 100] Pertussis Ն4-fold increase in IgG FHA 182/238 156/210 2 (−6 to 10) 71 (65 to 79) 71 (64 to 79) 1.01 (0.89 to 1.14) (76) [71 to 82] (74) [68 to 80] Pertactin 195/238 181/210 −4 (−11 to 3) 143 (125 to 164) 185 (160 to 214) 0.77 (0.65 to 0.91) (82) [76 to 87] (86) [81 to 91] Pertussis 204/238 186/210 −3 (−9 to 4) 35 (31 to 39) 37 (33 to 41) 0.94 (0.82 to 1.08) toxoid (86) [81 to 90] (89) [83 to 93] Polio Titers Ն1: 8 Type 1 174/175 162/164 1 (−2 to 4) 103 (83 to 128) 151 (120 to 189) 0.68 (0.53 to 0.89) (99) [97 to 100] (99) [96 to 100] Type 2 162/174 155/164 −1 (−7 to 4) 62 (48 to 80) 89 (69 to 115) 0.70 (0.52 to 0.94) (93) [88 to 96] (95) [90 to 97] Type 3 175/175 159/164 3 (1 to 7) 257 (201 to 329) 366 (284 to 472) 0.70 (0.52 to 0.94) (100) [98 to 100] (97) [93 to 99] PRP-Hib IgG Ն0.15 µg/mL 233/236 204/209 1 (−2 to 4) 2.39 (2.01 to 2.85) 2.51 (2.10 to 3.01) 0.95 (0.77 to 1.18) (99) [96 to 100] (98) [95 to 99] Hepatitis type B IgG Ն10 mIU/mL 199/206 189/194 −1 (−5 to 3) 243 (193 to 305) 319 (252 to 405) 0.76 (0.58 to 1.01) virus (97) [93 to 99] (97) [94 to 99] Pneumococcal IgG Ն0.35 µg/mL serotype PnC 4 215/228 192/203 0 (−5 to 4) 1.97 (1.67 to 2.32) 2.08 (1.74 to 2.48) 0.95 (0.77 to 1.17) (94) [90 to 97] (95) [91 to 97] PnC 6B 162/228 155/203 −5 (−14 to 3) 0.87 (0.68 to 1.09) 1.16 (0.91 to 1.50) 0.74 (0.55 to 1.00) (71) [65 to 77] (76) [70 to 82] PnC 9V 224/228 198/203 1 (−2 to 4) 4.31 (3.71 to 5.00) 3.61 (3.08 to 4.24) 1.19 (0.99 to 1.44) (98) [96 to 100] (98) [9 to 99] PnC 14 223/228 192/203 3 (0 to 8) 5.06 (4.28 to 6.00) 4.12 (3.44 to 4.93) 1.23 (0.99 to 1.53) (98) [95 to 100] (95) [91 to 97] PnC 18C 223/228 195/203 2 (−2 to 6) 4.61 (3.91 to 5.42) 3.67 (3.09 to 4.37) 1.25 (1.02 to 1.54) (98) [95 to 100] (96) [92 to 98] PnC 19F 224/228 198/203 1 (−2 to 4) 4.58 (3.89 to 5.39) 4.48 (3.77 to 5.34) 1.02 (0.83 to 1.26) (98) [96 to 100] (98) [94 to 99] PnC 23F 212/228 195/203 −3 (−7 to 2) 2.38 (1.98 to 2.87) 2.68 (2.19 to 3.26) 0.89 (0.70 to 1.13) (93) [89 to 96] (96) [92 to 98] Abbreviations: DTaP-HBV-IPV/Hib, combined diphtheria, tetanus, acellular pertussis, inactivated polio, hepatitis B, Haemophilus influenzae type b; FHA, filamentous hemagglutinin; 4CMenB, multicomponent serogroup B meningococcal vaccine; PRP-Hib, polyribosylribitol phosphate Haemophilus influenzae type b polysaccharide. aSee “Methods” for definitions of groups.

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Immunogenicity of 4CMenB cine antigens: pertactin and pneumo- tion of MenB strains likely to be cov- When administered alone in the inter- coccal serotype 6B. This is unlikely to ered by the vaccine on a regional ba- calated group rather than with rou- be of clinical significance, because acel- sis. Recently presented data suggest that tine vaccines, 4CMenB elicited higher lular pertussis vaccines that lack pertac- pooled sera from children immunized hSBA GMTs for all strains. Similarly, ad- tin are known to be effective, and evi- with the 4CMenB vaccine would be bac- ministration of 4CMenB in a 2-, 4-, and dence suggests that pneumococcal tericidal against 78% (95% CI, 66% to 6-month schedule, rather than an ac- disease resulting from the 6B serotype 91%) of invasive strains in Europe29 and celerated 2-, 3-, and 4-month sched- is lower in countries that have imple- against 76% (95% CI, 59% to 87%) of ule, resulted in higher hSBA GMTs for mented vaccination with the PCV7 vac- such strains in Australia.30 However, the the 5/99 strain. However, immuniza- cine, although the putative response ability of these laboratory assays to ac- tion schedules need to balance the ad- threshold of IgG level of 0.35 µg/mL or curately predict the effects of a MenB vantages of optimal immunogenicity greater was achieved only by a rela- vaccine—possibly also on non-MenB and the practical need to minimize im- tively low percentage of the immu- pathogens expressing vaccine anti- munization visits and ensure early im- nized population, possibly resulting gens—is unknown and can only be munization. The clinical significance of from both direct protection and herd evaluated properly following imple- any reduction in hSBA GMTs is uncer- immunity.24 mentation in a program with close sur- tain, given that the proportion of par- veillance. ticipants with an hSBA titer of 1:5 or Breadth of Protection greater was at least 79% for all strains Three strains expressing key vaccine an- Reactogenicity in all 4CMenB recipients. Lower hSBA tigens were used for hSBA analysis, Outer membrane vesicle vaccines (eg, GMTs may lead to shorter persistence demonstrating “proof of principle” im- MeNZB) have been administered to of bactericidal antibodies following pri- munogenicity of these antigens but al- more than 3 million children across mary immunization, as observed with lowing only limited conclusions re- all age groups and are considered well the serogroup C meningococcal vac- garding cross-protection against other tolerated and safe.23 In trials of cines17-19 and with the New Zealand naturally occurring strains. Also, data MeNZB to control clonal outbreaks in MenB vaccine (MeNZB).8,20 A fol- from assays using strains genetically en- New Zealand, fever was the most pro- low-up study of the same participants gineered to express a range of fHbp1 nounced adverse reaction,31 with no assessing antibody persistence and the subvariants25 and from early phase 2 additional reactogenicity burden with response to a booster dose of 4CMenB studies8,9 suggest that genotypic analy- concomitant administration of MenB has been undertaken21 and will fur- sis of panels of invasive strains is not and routine vaccines. In contrast, in ther inform the relative benefits of the sufficient to predict the likely breadth this study 4CMenB appeared to be different immunization schedules. of coverage of 4CMenB immunization less reactogenic when administered 4CMenB immunogenicity in this against invasive meningococcal dis- separately rather than together with study is consistent with previous small ease in infants. routine vaccines (although the study trials that found 4CMenB to be more Further information regarding the made no formal statistical compari- broadly immunogenic when given with breadth of protection could be achieved sons of reactogenicity rates between OMVs,8,9 possibly because of a syner- by testing against a more extended groups). The majority of children in gistic or enhancing effect of the OMV. panel of strains, as in previous 4CMenB this study became febrile after receiv- Furthermore, the OMV component of infant studies,8,9 but the number of ing their first and second dose of con- 4CMenB was used as a vaccine to con- strains that can be tested by hSBA is lim- comitant 4CMenB and routine vac- trol a clonal outbreak of MenB disease ited by the volume of sera available from cines, although only 1 child in our in New Zealand, with an apparent ef- infants, the limited supply of suitable study had a febrile convulsion (2 days fectiveness of 85% in children aged 6 human complement, and the unsuit- following 4CMenB administration). months to 5 years22 after inducing very ability of many strains for hSBA.26 This, There is therefore a need to compare similar hSBA titers against strain NZ98/ combined with the evolutionary and the risk profile of a relatively com- 254.23 This provides confidence that the geographical variation in the target mon, but transient, postimmunization levels of functional antibody induced MenB antigens, makes selection of fever with the benefit of reducing the by this vaccine could indeed induce strain panels difficult.27 The meningo- risk of an uncommon, but potentially protection against strains expressing the coccal antigen testing system28 using an fatal, meningococcal infection. This vaccine antigens. antigen-specific enzyme-linked immu- must be carefully communicated nosorbent assay (evaluating both im- to parents in the event of routine Immunogenicity munological cross-reactivity and anti- implementation if the possibility of of Routine Vaccines gen expression) has an accuracy of 86% increased systemic reactogenicity is to Concomitant 4CMenB impaired the im- in predicting the hSBA response and be an accepted component in the con- munogenicity of only 2 routine vac- might be suitable to assess the propor- trol of this serious disease. Rates and

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magnitude of fever in this study are cine introduction will require detailed expenses for attendance at conferences. Dr Bona reported receiving grants or grants pending from comparable with those seen with assessment of potential vaccine cover- Novartis Vaccines, Pfizer/Wyeth Vaccines, and other pediatric vaccines, notably after age at a regional level and monitoring GlaxoSmithKline Vaccines. Dr Esposito reported serving as a board member for GlaxoSmithKline, Medim- the second dose of ASO3B-adjuvanted after implementation to determine the mune, Johnson & Johnson, and Novartis Vaccines and split virion H1N1 influenza vaccine accuracy of such predictions. Never- receiving grants or grants pending from Crucell, used in children aged 6 months to 5 theless, this vaccine could potentially GlaxoSmithKline, Novartis Vaccines, Tibotec, and Pfizer/Wyeth. Dr Principi reported serving as a board 32 years and whole-cell pertussis vac- provide improved protection for member for Pfizer/Wyeth and receiving grants or cine in 1 study,33 and were actually infants against meningococcal disease grants pending from Crucell, GlaxoSmithKline, Novar- tis Vaccines, and Pfizer/Wyeth. Dr Diez-Domingo re- lower than those observed in another beyond the protection provided by ported providing expert testimony for Novartis and study of the pertussis vaccine.34 currently licensed vaccines. receiving payment for lectures from Novartis and Pfizer. Dr Kieninger reported receiving support for travel to Author Affiliations: Oxford Vaccine Group, NIHR Ox- meetings from Novartis Vaccines and Diagnostics; re- Limitations ford Biomedical Research Centre, and Department of ceiving grants or grants pending from Novartis Vac- Paediatrics, University of Oxford, Oxford, United King- cines, Pfizer/Wyeth Vaccines, GlaxoSmithKline Vac- The open-label design could poten- dom (Drs Gossger, Snape, and Pollard); Centre for Sta- cines, and Sanofi Pasteur; and receiving payment tially bias reporting of adverse events tistics in Medicine, Oxford (Ms Yu); Bristol Children’s for lectures from Pfizer/Wyeth Vaccines and if parents were more alert to subjec- Vaccine Center, University of Bristol, and University GlaxoSmithKline Vaccines. Dr Prymula reported re- Hospitals Bristol NHS Foundation Trust, Bristol, United ceiving support for travel to meetings from Novartis tive reactions such as irritability if their Kingdom (Dr Finn); Division of Pediatrics, Depart- and Pfizer; serving as a board member for Novartis child received 4CMenB rather than rou- ment of Medical Sciences, University of Piemonte Ori- and Pfizer; serving as a consultant for Novartis entale, Azienda Ospedaliero-Universitaria Maggiore and Pfizer; receiving grants or grants pending from tine vaccines. This would be less likely della Carità, Novara, Italy (Dr Bona); Department of Novartis and Pfizer; receiving payment for lectures to influence objective measures such as Maternal and Pediatric Sciences, Università degli Studi from Novartis and Pfizer; and receiving travel/ di Milano, Fondazione IRCCS Ca’ Granda Ospedale accommodations/meeting expenses from Novartis, temperature and extent of swelling or Maggiore Policlinico, Milan, Italy (Drs Esposito and Prin- Pfizer, GlaxoSmithKline, Baxter, and Sanofi Pasteur. erythema. The 3 strains selected for cipi); Centro Superior de Investigacion en Salud Pub- Dr Pollard reported receiving grants or grants pend- hSBA analysis do not specifically evalu- lica (CSISP), Valencia, Spain (Dr Diez-Domingo); De´ par- ing from Novartis Vaccines, Pfizer/Wyeth Vaccines, tement de Pe´ diatrie, Universite´ Catholique de Louvain, GlaxoSmithKline Vaccines, and Sanofi Pasteur; and that ate the immunogenicity of NHBA, be- Cliniques Saint Luc, Brussels, Belgium (Dr Sokal); his institution received payment for lectures or orga- cause the only strain expressing NHBA NETSTAP e.V., Bochum, Germany (Dr Becker); Cen- nization of educational activities, which he coordi- ter for Clinical Studies, Department of Paediatric Im- nated; and that he is a Jenner Investigator and James also contained porin protein A homolo- munology, University of Mainz, Mainz, Germany (Dr Martin Senior Fellow. Drs Finn and Pollard do not re- gous to the OMV component. Concen- Kieninger); University Hospital, Hradec Kra´ love´ , Czech ceive any personal financial support from vaccine Republic (Dr Prymula); and Novartis Vaccines and Di- manufacturers. Ms Yu, an employee of the Centre for trations of IgG specific to NHBA in- agnostics, Cambridge, Massachusetts, and Siena, Italy Statistics in Medicine, Oxford, reported that she pro- creased following administration of (Drs Dull, Toneatto, Kimura, and Ms Ypma). vides general and project-specific statistical support to Author Contributions: Ms Ypma had full access to all the Oxford Vaccine Group. 4CMenB; however, this was also ob- of the data in the study and takes responsibility for Funding/Support: This study was funded by Novar- served following administration of a the integrity of the data and the accuracy of the data tis Vaccines and Diagnostics. vaccine containing the recombinant analysis. Role of the Sponsor: With the lead investigators, Study concept and design: Snape, Finn, Esposito, Novartis was involved in the design of the study as proteins without OMVs in early phase Principi, Prymula, Dull, Ypma, Toneatto, Kimura, well as analysis of the data, review, and comment on 2 studies. This increase in IgG GMCs Pollard. the manuscript. Data collection was undertaken by the Acquisition of data: Gossger, Snape, Finn, Bona, study investigators. Editorial control of the manu- was not associated with an increase in Esposito, Principi, Diez-Domingo, Sokal, Becker, script was assigned to the University of Oxford. Novar- hSBA titers against NZ98/254,8,9 rais- Kieninger, Prymula, Pollard. tis conducted the primary analysis of the data prior Analysis and interpretation of data: Gossger, Snape, to review by Ms Yu. ing doubts about the bactericidal quali- Yu, Finn, Bona, Esposito, Principi, Dull, Ypma, Toneatto, Independent Statistical Review: Ms Yu had access to ties of these antibodies. A naturally oc- Kimura, Pollard. the full raw data set, protocol, and analysis plan and curring strain allowing the assessment Drafting of the manuscript: Gossger, Snape, Yu, performed her own analysis. All results reported in the Esposito, Principi, Ypma, Pollard. article were reanalyzed by her. Ms Yu is independent of NHBA-induced bactericidal activity Critical revision of the manuscript for important in- of the sponsor, employed by the UK National Health has recently been identified35 and will tellectual content: Snape, Yu, Finn, Bona, Esposito, Service, and not compensated by Novartis. Principi, Diez-Domingo, Sokal, Becker, Kieninger, Coordinating Center: Novartis Vaccines and Diag- provide important additional informa- Prymula, Dull, Ypma, Toneatto, Kimura, Pollard. nostics was the coordinator of the study. tion regarding the immunogenicity of Statistical analysis: Yu, Dull, Ypma. Statistical and Data Management Center: Statistical Administrative, technical, or material support: Sokal. evaluation of the results was performed by Bio- this antigen. Obtaining funding: Esposito, Principi, Pollard. statistics and Statistical Reporting, Novartis, and con- Study supervision: Snape, Bona, Esposito, Principi, firmed by an independent statistician at Oxford CONCLUSIONS Prymula, Dull, Toneatto, Pollard. University working for the Centre for Statistics in Conflict of Interest Disclosures: The authors have com- Medicine. In conclusion, 4CMenB was immuno- pleted and submitted the ICMJE Form for Disclosure Online-Only Material: The eTable and a list of the Eu- genic, generally well tolerated, and of Potential Conflicts of Interest. Drs Snape, Finn, Es- ropean MenB Vaccine Study Group members are avail- posito, Principi, Diez-Domingo, Kieninger, Sokal, Pry- able at http://www.jama.com. showed minimal interference with mula, and Pollard reported acting as chief and prin- Additional Contributions: We thank all of the par- routine vaccines in the first year of cipal investigators for clinical studies and receiving ticipants and their families for contributing to this study. funding from noncommercial funding bodies as well life. 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Approximate is better than fluence of sequence variability on bactericidal activ- (6):349-355. “exact” for interval estimation of binomial proportions. ity sera induced by Factor H binding protein variant 35. Biolchi A, Kleinschmidt A, Boccadifuoco G, et al. Am Stat. 1998;52(52):119-126. 1.1. Vaccine. 2011;29(5):1072-1081. Evaluation of the contribution of protein antigen 15. Ramsay ME. Current epidemiology of meningo- 26. Borrow R, Aaberge IS, Santos GF, et al. Interlabo- NHBA to bactericidal antibody responses in sera from coccal disease in the UK and Europe, including issues ratory standardization of the measurement of serum human vaccinees enrolled in clinical trials. Presented for surveillance relating to a MenB vaccine. Pre- bactericidal activity by using human complement at: 17th International Pathogenic Neisseria Confer- sented at: Meningitis Research Foundation Confer- against meningococcal serogroup b, strain 44/76- ence; September 11-16, 2010; Banff, Alberta, Canada.

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