Peter M. Dull

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

CONTEXT In the absence of an effective vaccine, serogroup B Neisseria meningitidis (MenB) remains a major cause of invasive disease in early childhood in developed countries. OBJECTIVE To determine the immunogenicity and reactogenicity of a multicomponent MenB vaccine (4CMenB) and routine infant vaccines when given either concomitantly or separately. DESIGN, SETTING, AND PARTICIPANTS Phase 2b, multicenter, open-label, parallel-group, randomized controlled study of 1885 infants enrolled at age 2 months from August 2008 to July 2010 in Europe. 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 diphtheria, tetanus, acellular pertussis, inactivated polio, hepatitis B, Haemophilus influenzae type b vaccines); (2) 4CMenB at 2, 4, and 6 months and routine vaccines at 3, 5, and 7 months; (3) 4CMenB with routine vaccines at 2, 3, and 4 months; or (4) routine vaccines alone at 2, 3, and 4 months. MAIN OUTCOME MEASURES Percentage of participants with human complement serum bactericidal activity (hSBA) titer of 1:5 or greater against 3 MenB strains specific for vaccine antigens (NZ98/254, 44/76-SL, and 5/99). 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 was 79% (95% CI, 75.2%-82.4%) for vaccination at 2, 4, and 6 months with routine 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 with routine vaccines. Responses to routine vaccines given with 4CMenB were noninferior 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 41% (247/607) of 4CMenB doses when administered alone, compared with 23% (69/304) to 36% (109/306) after routine vaccines given alone and 51% (306/605) to 61% (380/624) after 4CMenB and routine vaccines administered together. CONCLUSION A 4CMenB vaccine is immunogenic against reference strains when administered with routine vaccines at 2, 4, and 6 or at 2, 3, and 4 months of age, producing minimal interference with the response to routine infant vaccinations. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00721396.

Immunogenicity of a tetravalent meningococcal glycoconjugate vaccine in infants: a randomized controlled trial.

CONTEXT Immunization with a meningococcal tetravalent (serogroup ACWY) glycoconjugate vaccine is recommended for all US adolescents. However, the currently licensed vaccine is poorly immunogenic in infancy, when the highest rates of disease are observed. OBJECTIVE To determine the immunogenicity of a novel tetravalent CRM(197)-conjugated meningococcal vaccine (MenACWY) in infants. DESIGN, SETTING, AND PARTICIPANTS Randomized, open-label, controlled study of 225 UK and 196 Canadian 2-month-olds from August 2004 to September 2006. INTERVENTION UK infants received a primary course of MenACWY (at 2, 3, and 4 months or 2 and 4 months) or Neisseria meningitidis serogroup C monovalent meningococcal glycoconjugate vaccine (MenC) (at 2 and 4 months). All received MenACWY at 12 months. Canadian infants received MenACWY at 2, 4, and 6 months or 2 and 4 months; at 12 months they received MenACWY, a plain tetravalent polysaccharide vaccine, or no vaccine. MAIN OUTCOME MEASURE Percentage of infants with a human complement serum bactericidal activity (hSBA) titer >or=1:4 after a primary course of MenACWY and after a 12-month booster. Safety and reactogenicity of MenACWY were also assessed. RESULTS According to the prespecified per-protocol analysis, the percentages (95% CIs) of MenACWY 2-, 3-, and 4-month recipients with hSBA titers >or=1:4 after primary immunization were serogroup A, 93% (84%-98%); C, 96% (89%-99%); W-135, 97% (90%-100%); and Y, 94% (86%-98%). With a post hoc intention-to-treat analysis with imputed values for missing data, these values were unchanged for serogroups C and Y; for serogroup A, values were 92% (84%-97%), and for W-135, 97% (91%-99%). For the per-protocol analysis of MenACWY 2-, 4-, and 6-month recipients, the percentages (95% CIs) of responders were A, 81% (71%-89%); C, 98% (92%-100%); W-135, 99% (93%-100%); and Y, 98% (92%-100%). With the imputed value analysis, these values were A, 83% (74%-89%); C, 98% (93%-99%); W-135, 99% (94%-100%); and Y, 98% (92%-99%). At least 84% of MenACWY 2- and 4-month recipients achieved hSBA titers >or=1:4 for serogroups C, W-135, and Y after primary immunization, as did at least 60% for serogroup A (per-protocol and imputation analysis). At least 95% of primary and booster MenACWY recipients achieved hSBA titers >or=1:4 for serogroups C, W-135, and Y at 13 months, as did at least 84% for serogroup A (per-protocol and imputation analysis). During the primary immunization course, postimmunization pain on leg movement was observed in 2% of UK MenACWY 2- and 4-month recipients and 4% of MenC 2- and 4-month recipients; a temperature of 38 degrees C or greater was observed in 4% and 2% in these groups, respectively. CONCLUSION MenACWY is well tolerated and immunogenic in infancy. Trial Registration clinicaltrials.gov Identifier: NCT00262002.

Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study

BACKGROUND Effective glycoconjugate vaccines against Neisseria meningitidis serogroups A, C, W-135, and Y have been developed, but serogroup B remains a major cause of severe invasive disease in infants and adolescents worldwide. We assessed immunogenicity and tolerability of a four-component vaccine (4CMenB) in adolescents. METHODS We did a randomised, observer-blind, placebo-controlled, study at 12 sites in Santiago and Valparaíso, Chile. Adolescents aged 11-17 years received one, two, or three doses of 4CMenB at 1 month, 2 month, or 6 month intervals. Immunogenicity was assessed as serum bactericidal activity using human complement (hSBA) against three reference strains for individual vaccine antigens, and assessed by ELISA against the fourth strain. Local and systemic reactions were recorded 7 days after each vaccination, and adverse events were monitored throughout the study. Participants were initially randomised to five groups (3:3:3:3:1) during the primary phase to receive either one dose, two doses 1 or 2 months apart, or three doses of 4CMenB, or three doses of placebo, with an additional three groups generated for the booster phase. All subjects received at least one dose of 4CMenB. Geometric mean titres, proportions of participants with serum bactericidal antibody titres of 4 or more, and Clopper-Pearson 95% CIs were calculated. The study is registered with ClinicalTrials.gov, number NCT00661713. FINDINGS Overall, 1631 adolescents (mean age 13·8 [SD 1·9] years) received at least one dose of 4CMenB. After two or three doses, 99-100% of recipients had hSBA titres of 4 or more against test strains, compared with 92-97% after one dose (p<0·0145) and 29-50% after placebo. At 6 months 91-100% of participants still had titres of 4 or more for each strain after two or three doses, but only 73-76% after one dose; seroresponse rates reached 99-100% for each strain after second or third doses at 6 months. Local and systemic reaction rates were similar after each 4CMenB injection and did not increase with subsequent doses, but remained higher than placebo. No vaccine-related serious adverse events were reported and no significant safety signals were identified. INTERPRETATION On the basis of immunogenicity responses this study provides evidence for an adolescent 4CMenB vaccine schedule of two doses, 1-6 months apart, to provide protection against meningococcal B infection. The extent of this protection against meningococcus B variants circulating worldwide will be determined by national surveys. FUNDING Novartis Vaccines and Diagnostics.

Immunogenicity and safety of an investigational multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly with routine infant and child vaccinations: results of two randomised trials

BACKGROUND Meningococcal serogroup B disease disproportionately affects infants. We assessed lot-to-lot consistency, safety and immunogenicity, and the effect of concomitant vaccination on responses to routine vaccines of an investigational multicomponent vaccine (4CMenB) in this population. METHODS We did primary and booster phase 3 studies between March 31, 2008, and Aug 16, 2010, in 70 sites in Europe. We used two series of sponsor-supplied, computer-generated randomisation envelopes to allocate healthy 2 month-old infants to receive routine vaccinations (diphtheria-tetanus-acellular pertussis, inactivated poliovirus, hepatitis B plus Haemophilus influenzae type b, and seven-valent pneumococcal vaccine) at 2, 4, and 6 months of age alone, or concomitantly with 4CMenB or serogroup C conjugate vaccine (MenC) in: 1) an open-label, lot-to-lot immunogenicity and safety substudy of three 4CMenB lots compared with routine vaccines alone (1:1:1:1, block size eight); or 2) an observer-blind, lot-to-lot safety substudy of three 4CMenB lots compared with MenC (1:1:1:3, block size six). At 12 months, 4CMenB-primed children from either substudy were randomised (1:1, block size two) to receive 4CMenB booster, with or without measles-mumps-rubella-varicella (MMRV) vaccine. Immunogenicity was assessed by serum bactericidal assay with human complement (hSBA) against serogroup B test strains, and on randomly selected subsets of serum samples for routine vaccines; laboratory personnel were masked to assignment. The first coprimary outcome was lot-to-lot consistency (hSBA geometric mean ratio of all lots between 0·5 and 2·0), and the second was an immune response (hSBA titre ≥5) for each of the three strains. The primary outcome for the booster study was immune response to booster dose. Immunogenicity data for 4CMenB were for the modified intention-to-treat population, including all infants from the open-label substudy who provided serum samples. The safety population included all participants who contributed safety data after at least one dose of study vaccine. These trials are registered with ClinicalTrials.gov, numbers NCT00657709 and NCT00847145. FINDINGS We enrolled 2627 infants in the open-label phase, 1003 in the observer-blind phase, and 1555 in the booster study. Lot-to-lot consistency was shown for the three 4CMenB lots, with the lowest 95% lower confidence limit being 0·74 and the highest upper limit being 1·33. Of 1181–1184 infants tested 1 month after three 4CMenB doses (all lots pooled), 100% (95% CI 99–100) had hSBA titres of 5 or more against strains selective for factor H binding protein and neisserial adhesin A, and 84% (82–86) for New Zealand outer-membrane vesicle. In a subset (n=100), 84% (75–91) of infants had hSBA titres of 5 or more against neisseria heparin binding antigen. At 12 months of age, waning titres were boosted by a fourth dose, such that 95–100% of children had hSBA titres of 5 or more for all antigens, with or without concomitant MMRV. Immune responses to routine vaccines were much the same with or without concomitant 4CMenB, but concomitant vaccination was associated with increased reactogenicity. 77% (1912 of 2478) of infants had fever of 38·5°C or higher after any 4CMenB dose, compared with 45% (295 of 659) after routine vaccines alone and 47% (228 of 490) with MenC, but only two febrile seizures were deemed probably related to 4CMenB. INTERPRETATION 4CMenB is immunogenic in infants and children aged 12 months with no clinically relevant interference with routine vaccines, but increases reactogenicity when administered concomitantly with routine vaccines. This breakthrough vaccine offers an innovative solution to the major remaining cause of bacterial meningitis in infant and toddlers. FUNDING Novartis Vaccines and Diagnostics.

Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial

BACKGROUND Meningococcal conjugate vaccines protect individuals directly, but can also confer herd protection by interrupting carriage transmission. We assessed the effects of meningococcal quadrivalent glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in 18-24-year-olds. METHODS In this phase 3, observer-blind, randomised controlled trial, university students aged 18-24 years from ten sites in England were randomly assigned (1:1:1, block size of three) to receive two doses 1 month apart of Japanese Encephalitis vaccine (controls), 4CMenB, or one dose of MenACWY-CRM then placebo. Participants were randomised with a validated computer-generated random allocation list. Participants and outcome-assessors were masked to the treatment group. Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over 1 year. Primary outcomes were cross-sectional carriage 1 month after each vaccine course. Secondary outcomes included comparisons of carriage at any timepoint after primary analysis until study termination. Reactogenicity and adverse events were monitored throughout the study. Analysis was done on the modified intention-to-treat population, which included all enrolled participants who received a study vaccination and provided at least one assessable swab after baseline. This trial is registered with ClinicalTrials.gov, registration number NCT01214850. FINDINGS Between Sept 21 and Dec 21, 2010, 2954 participants were randomly assigned (987 assigned to control [984 analysed], 979 assigned to 4CMenB [974 analysed], 988 assigned to MenACWY-CRM [983 analysed]); 33% of the 4CMenB group, 34% of the MenACWY-CRM group, and 31% of the control group were positive for meningococcal carriage at study entry. By 1 month, there was no significant difference in carriage between controls and 4CMenB (odds ratio 1·2, 95% CI 0·8-1·7) or MenACWY-CRM (0·9, [0·6-1·3]) groups. From 3 months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (18·2% [95% CI 3·4-30·8] carriage reduction), capsular groups BCWY (26·6% [10·5-39·9] carriage reduction), capsular groups CWY (29·6% [8·1-46·0] carriage reduction), and serogroups CWY (28·5% [2·8-47·5] carriage reduction) compared with control vaccination. Significantly lower carriage rates were also noted in the MenACWY-CRM group compared with controls: 39·0% (95% CI 17·3-55·0) carriage reduction for serogroup Y and 36·2% (15·6-51·7) carriage reduction for serogroup CWY. Study vaccines were generally well tolerated, with increased rates of transient local injection pain and myalgia in the 4CMenB group. No safety concerns were identified. INTERPRETATION Although we detected no significant difference between groups at 1 month after vaccine course, MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates during 12 months after vaccination and therefore might affect transmission when widely implemented. FUNDING Novartis Vaccines.

Phase III Comparison of an Investigational Quadrivalent Meningococcal Conjugate Vaccine with the Licensed Meningococcal ACWY Conjugate Vaccine in Adolescents

BACKGROUND Neisseria meningitidis is an important cause of invasive bacterial infection in the United States, and disease rates are higher for adolescents than for the general population. Quadrivalent meningococcal conjugate vaccine is recommended for routine vaccination of adolescents and high-risk groups. This study compares the safety and immunogenicity of the Novartis Vaccines investigational quadrivalent meningococcal CRM(197) conjugate vaccine, MenACWY-CRM, with the licensed meningococcal conjugate vaccine, Menactra. METHODS In this multicenter phase III study, 2180 adolescents 11-18 years of age were randomly assigned to 4 groups (1:1:1:1) to receive a single dose of 1 of 3 lots of MenACWY-CRM or a single dose of Menactra. Serum samples obtained before vaccination and 1 month after vaccination were tested for serogroup-specific serum bactericidal activity using human complement (hSBA). The hSBA titers after vaccination with MenACWY-CRM or Menactra were compared in noninferiority and superiority analyses. RESULTS The hSBA geometric mean titers after MenACWY-CRM vaccination were higher than the hSBA geometric mean titers after Menactra vaccination, and criteria for superiority were met for this end point for all 4 serogroups. Also, the criteria for superiority of MenACWY-CRM, compared with Menactra, were met for the end points of proportion of subjects with postvaccination hSBA titers 1:8 and proportion of seroresponders for serogroups A, W-135, and Y. MenACWY-CRM was noninferior to Menactra for serogroup C for these end points. Reactogenicity was similar, with 64% of the MenACWY-CRM recipients and 70% of the Menactra recipients reporting mild and/or moderate solicited reactions. Neither vaccine was associated with a serious adverse event. CONCLUSIONS MenACWY-CRM vaccine is well tolerated in adolescents and generates a stronger immune response than Menactra for all 4 serogroups. TRIAL REGISTRATION Clinicaltrials.gov identifier: NCT00450437 .

Considerations for a phase-III trial to evaluate a group B Streptococcus polysaccharide-protein conjugate vaccine in pregnant women for the prevention of early- and late-onset invasive disease in young-infants

In 2010, an estimated 393,000 infection-related neonatal deaths occurred worldwide with Group B streptococcus (GBS) being a leading cause. Prevention of early-onset disease (0-6 days; EOD) is currently focused on intra-partum antibiotic prophylaxis to mothers identified as being at risk; such strategies reduce EOD by 75-80% but are resource-intensive and logistically-difficult to implement in developing countries. Vaccination of pregnant women is an alternate strategy for preventing both EOD and late-onset disease (7-89 days; LOD). A trivalent GBS polysaccharide-protein conjugate vaccine (GBS-CV) composed of capsular epitopes from serotypes Ia, Ib and III is undergoing phase-II evaluation among pregnant women in Europe, North America and Africa. These serotypes cause 70-80% of all invasive GBS disease in early-infancy. Maternal anti-GBS antibodies are associated with protection from EOD, however, since a correlate of efficacy has not been defined, a phase III efficacy trial may be required for licensure. Criteria for selecting appropriate sites include sufficiently high GBS incidence in large birth cohorts, as well as adequate clinical and microbiological diagnostic skills and capacities. Alternate pathways to licensure should be explored, e.g. identification of serological correlates of protection with subsequent phase IV studies establishing vaccine-effectiveness against invasive GBS disease. Conducting a randomized, placebo-controlled efficacy trial, however, has the additional advantage of also being able to evaluate the role of GBS contributing to neonatal culture-negative sepsis, stillbirths, prematurity and low-birth weight.

Immunogenicity and Safety of a Multicomponent Meningococcal Serogroup B Vaccine and a Quadrivalent Meningococcal CRM197 Conjugate Vaccine against Serogroups A, C, W-135, and Y in Adults Who Are at Increased Risk for Occupational Exposure to Meningococcal Isolates

ABSTRACT Laboratory staff who work with meningococcal isolates are at increased risk for developing invasive disease relative to the general population. This was the first study of laboratory workers who received both a conjugate vaccine against meningococcal serogroups A, C, W-135, and Y (Men ACWY-CRM, Menveo) and an investigational multicomponent vaccine against serogroup B containing factor H binding protein, neisserial adhesin A, Neisseria heparin binding antigen, and New Zealand strain outer membrane vesicles (4CMenB). Healthy adults (18 to 50 years of age) received three doses of 4CMenB at baseline, 2 months, and 6 months followed by a single dose of MenACWY-CRM 1 month later. Immunogenicity was assessed via serum bactericidal assay using human complement (hSBA) at 1 month postvaccination; solicited reactogenicity and adverse events were monitored. Fifty-four participants enrolled. Bactericidal immune responses were evident after each dose of 4CMenB, as assessed by hSBA geometric mean titers and percentages of subjects with hSBA titers of ≥4 against the test strains or a 4-fold rise in titer over baseline. At 1 month postvaccination, most MenACWY-CRM recipients had hSBA titers of ≥8 against serogroups A, C, W-135, and Y. Few participants discontinued due to an adverse event or vaccine reaction. Rates of solicited reactions were lower after MenACWY-CRM than after 4CMenB administration. Sequential administration of 4CMenB and MenACWY-CRM provided robust evidence of an immune response against serogroups A, B, C, W-135, and Y in laboratory workers routinely exposed to meningococcal isolates.

Could the multicomponent meningococcal serogroup B vaccine (4CMenB) control Neisseria meningitidis capsular group X outbreaks in Africa

A new vaccine, 4CMenB, is composed of surface proteins of Neisseria meningitidis and is aimed to target serogroup B (MenB) isolates. The vaccine components are present in meningococcal isolates of other serogroups allowing potential use against meningococcal isolates belonging to non-B serogroups. Isolates of serogroup X (MenX) have been emerged in countries of the African meningitis belt. 4CMenB may offer a vaccine strategy against these isolates as there is no available capsule-based vaccine against MenX. We used the Meningococcal Antigen Typing System (MATS) to determine presence, diversity and levels of expression of 4CMenB antigens among 9 MenX isolates from several African countries in order to estimate the potential coverage of MenX by the 4CMenB vaccine. We performed bactericidal assays against these isolates, using pooled sera from 4CMenB-vaccinated infants, adolescents and adults. The African MenX isolates belonged to the same genotype but showed variation in the vaccine antigens. MATS data and bactericidal assays suggest coverage of the 9 African MenX isolates by 4CMenB but not of two unrelated MenX isolates from France. 4CMenB vaccine can be considered for further investigation to control MenX outbreaks in Africa.

A randomized trial to determine the tolerability and immunogenicity of a quadrivalent meningococcal glycoconjugate vaccine in healthy adolescents.

Background: Because of the well-documented increased risk of meningococcal disease among adolescents, vaccination is recommended for this population in many countries, including the United States. This study compared the tolerability and immunogenicity in adolescents of a candidate quadrivalent meningococcal CRM197 glycoconjugate vaccine against serogroups A, C, W-135, and Y (MenACWY-CRM) with that of the licensed unconjugated quadrivalent polysaccharide vaccine (MPSV4). Methods: This phase II study was conducted in the United States among 524 adolescents aged 11–17 years in 2 stages, with different randomization schemes. The first 334 participants, enrolled in Stage 1, were randomized (1:1) to receive either MenACWY-CRM(+) (with adjuvant) or MPSV4. The next 190 participants, enrolled in Stage 2, were randomized (4:1) to receive either MenACWY-CRM(−) (without adjuvant) or MPSV4. Safety data were collected using diary cards and active surveillance. Human complement serum bactericidal activity (hSBA) titers were measured 1 and 12 months postvaccination. Results: MenACWY-CRM and MPSV4 vaccines were well tolerated (local reactions, 63%–71% vs. 60%–62%; systemic reactions, 44%–56% vs. 46%–59%, respectively). One month postvaccination, similar hSBA titers were observed with the adjuvanted and nonadjuvanted MenACWY-CRM. The immunogenicity of MenACWY-CRM(−), measured by geometric mean titer, was significantly (P < 0.05) greater than that of MPSV4 for all 4 vaccine serogroups at 1 month. The percentage of subjects with hSBA titers ≥1:4 was also significantly greater (P < 0.01) for MenACWY-CRM(−) recipients for serogroups A, C, and Y and noninferior for W-135. The proportions of MenACWY-CRM(−) recipients with hSBA titers ≥1:4 to the vaccine serogroups at 1 month were 84% to 96% and geometric mean titers were 34 to 100. The percentage of subjects with hSBA titers ≥1:4 was significantly (P < 0.01) greater than MPSV4 for serogroups C, W-135, and Y 12 months postvaccination. Conclusions: MenACWY-CRM was well tolerated and immunogenic, with evidence of persistence of bactericidal antibodies for at least 12 months postvaccination.