Efficacy, safety, and immunogenicity of a meningococcal group B (15:P1.3) outer membrane protein vaccine in Iquique, Chile. Chilean National Committee for Meningococcal Disease. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials From tailor-made to ready-to-wear meningococcal B vaccines: longitudinal study of a clonal meningococcal B outbreak. A prospective study of the effectiveness of the New Zealand meningococcal B vaccine. MeNZB: a safe and highly immunogenic tailor-made vaccine against the New Zealand Neisseria meningitidis serogroup B disease epidemic strain. Immune response of Brazilian children to a Neisseria meningitidis serogroup B outer membrane protein vaccine: comparison with efficacy. Serum bactericidal activity correlates with the vaccine efficacy of outer membrane vesicle vaccines against Neisseria meningitidis serogroup B disease. New Zealand Epidemic Strain Meningococcal B Outer Membrane Vesicle Vaccine in Children Aged 16–24 Months Immunogenicity of a serogroup B meningococcal vaccine against multiple Neisseria meningitidis strains in infants. Immunogenicity of 2 serogroup B outer-membrane protein meningococcal vaccines: a randomized controlled trial in Chile. Vaccine against group B Neisseria meningitidis: protection trial and mass vaccination results in Cuba. 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 Effect of outer membrane vesicle vaccine against group B meningococcal disease in Norway
A meningococcal group B ( 15:P1.3 ) outer membrane protein vaccine was tested for efficacy in a r and omized , double-blind controlled study in Iquique , Chile . A total of 40 811 volunteers , ages 1 - 21 years , enrolled in the study . Volunteers received two doses of vaccine six weeks apart by jet injector . Both the experimental vaccine and the control vaccine ( Menomune , A , C , Y and W135 meningococcal polysaccharide vaccine ) were well tolerated with minor side-effects . Active surveillance for suspected cases of meningococcal disease was conducted for 20 months in Iquique . Eighteen cases of group B meningococcal disease were confirmed during the 20 months . Efficacy was estimated to be 51 % ( p = 0.11 ) for all ages combined . In children aged 1 - 4 no protection was evident , but in volunteers aged 5 - 21 vaccine efficacy was 70 % ( p = 0.045 ) . The IgG antibody response by ELISA was characterized by a large booster effect after the second dose , followed by a substantial drop in antibody levels by 6 months . The youngest children had the highest responses . The bactericidal antibody response , on the other h and , was characterized by the lack of a significant booster response , higher responses in the older children , and an increase in the geometric mean titer in the later months of the study in the older children Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more BACKGROUND Outer-membrane-vesicle vaccines for meningococcal B outbreaks are complex and time consuming to develop . We studied the use of already available vaccine to control an outbreak caused by a genetically close strain . METHODS From 2006 to 2009 , all individuals younger than 20 years living in the region of Norm and y , France , in which an outbreak caused by a B:14:P1.7,16 strain occurred , were eligible to receive MenBvac  , a  Norwegian vaccine  design ed 20 years earlier against a strain sharing the same serosubtype ( B:15:P1.7,16 ) . The immunogenicity ( in a r and omly selected cohort of 400 children aged 1 - 5 years ) , safety , and epidemiological effect of the vaccination were assessed . FINDINGS 26,014 individuals were eligible to receive the vaccine . Shortage of vaccine production prompted start of the campaign in the highest incidence groups ( 1 - 5 years ) . 16,709 ( 64 % ) received a complete vaccination schedule of whom 13,589 ( 81 % ) received a 2 + 1 dose schedule ( week 0 , week 6 , and month 8) . At 6 weeks after the third dose , of 235 vaccinees for whom sample s were available , 206 ( 88 % ) had a seroresponse , and 108 ( 56 % ) of 193 had a seroresponse at 15 months . These results were similar to those described for tailor-made vaccines and their homologous strain . Only previously described adverse effects occurred . The incidence of B:14:P1.7,16 cases decreased significantly in the vaccine targeted population after the primary vaccination period ( from 31·6 per 100,000 to 5·9 per 100,000 ; p=0·001 ) . INTERPRETATION The ready-to-wear approach is reliable if epidemic and vaccine strains are genetically close . Other meningococcal B clonal outbreaks might benefit from this strategy ; and previously described outer-membrane-vesicle vaccines can be effective against various strains . FUNDING French Ministry of Health The effectiveness of a new  group B strain-specific meningococcal vaccine referred to as " MeNZB , " developed by Chiron Vaccines ( Siena , Italy ) in collaboration with the Norwegian Institute of Public Health , was assessed in a prospect i ve observational study following a nationwide vaccination program in New Zeal and . The  vaccination program began in July 2004 , and the study uses data from January 2001 to June 2006 . A generalized estimating equation model was used to estimate vaccine effectiveness that included potential confounding variables , such as disease progression over time , age , ethnicity , socioeconomic status , seasonality , and geographic region . The model provides strong statistical evidence for a vaccine effect ( p < 0.0001 ) , with estimated disease rates 3.7 times higher in the unvaccinated group than in the vaccinated group ( 95 % confidence interval : 2.1 , 6.8 ) and a vaccine effectiveness of 73 % ( 95 % confidence interval : 52 , 85 ) . An estimated 54 epidemic strain meningococcal cases were prevented in the 2 years since the vaccination program began ( 95 % confidence interval assuming a fixed population size : 22 , 115 ) . In a sensitivity analysis , these estimates proved to be robust to modeling assumptions , including population estimates , estimates of the numbers vaccinated , effects of partial vaccination , and temporal autocorrelation Clinical studies have been conducted in New Zeal and evaluating the safety and immunogenicity of an outer membrane vesicle ( OMV ) vaccine , MeNZB , developed to control epidemic disease caused by group B meningococci , subtype P1.7b,4 . MeNZB , administered in a three-dose regimen , was well tolerated and induced a seroresponse , defined as a four-fold rise ( > or = titre 8) in serum bactericidal antibodies against the vaccine strain 4 - 6 weeks after the third vaccination , in 96 % ( 95 % confidence interval ( CI ) : 79 - 100 % ) of adults , 76 % ( 95 % CI : 72 - 80 % ) of children , 75 % ( 95 % CI : 69 - 80 % ) of toddlers and 74 % ( 95 % CI : 67 - 80 % ) of infants receiving MeNZB . In conclusion , these findings suggest that MeNZB is safe and is likely to confer protection against systemic group B meningococcal disease caused by the epidemic strain Since 1986 , serogroup B Neisseria meningitidis has caused approximately 80 % of the meningococcal disease in Brazil . In 1988 , an epidemic caused by N. meningitidis B:4:P1.15 was recognized in the greater São Paulo area of Brazil . The São Paulo state government decided to vaccinate children from 3 to 83 months of age with a vaccine consisting of serotype 4 outer membrane protein and group C meningococcal polysaccharide that was produced in Cuba . About 2.7 million children were vaccinated during two immunization campaigns conducted in 1989 and 1990 . Because of this , a case-control study was design ed to determine vaccine efficacy against group B meningococcal disease . The purpose of our study was to compare the antibody response with the protection from disease estimated from the case-control study . We measured the immune responses of vaccinees by enzyme-linked immunosorbent assay ( ELISA ) , immunoblot , and bactericidal assay . The development of bactericidal antibodies was age dependent and in good agreement with the results of the case-control study . Only 40 % of vaccinees showed fourfold or greater increases in bactericidal antibody titers after vaccination . A poor correlation between antibody levels detected by ELISA and those by bactericidal assay was found . Immunoblot analysis showed that about 50 % of the serum sample s with bactericidal titers higher than 1:4 were reactive with class 1 outer membrane protein . We conclude that the bactericidal assay is a good , laboratory-based , functional assay for the study of vaccine immunogenicity and that an effective solution to group B meningococcal disease remains to be demonstrated For evaluation of serum bactericidal activity ( SBA ) as surrogate for the efficacy of outer membrane vesicle ( OMV ) vaccines against Neisseria meningitidis serogroup B disease , we have reanalyzed data from a r and omized double blind placebo-controlled efficacy trial involving 172000 secondary school students ( aged 13 - 14 years ) in Norway ( 1988 - 1991 ) . A cohort of the efficacy trial consisting of 880 individuals was selected for immunogenicity studies . An efficacy of 87 % was calculated for a 10-month observation period . However , after an observation period of 29 months , the estimated efficacy against group B disease induced by vaccination was 57 % . The immunogenicity study showed that the SBA geometric mean titer ( GMT ) for the vaccinees was 2.4 before vaccination and 19.0 six weeks after the second vaccine dose . One year after vaccination the GMT was reduced to 2.8 . A separate three-dose study with 304 adolescents showed that with a third dose at 10 months after the second dose ( i.e. when cases of disease started to appear ) a strong booster response was induced . Ten months after the second dose the SBA was reduced to near pre-immunization level . Following the third dose the SBA geometric mean titer of 2.7 increased to 62.3 . One year after the third dose , the GMT was markedly higher than 6 weeks after the second dose ( 12.6 versus 8.8 ) . Thus , protection after vaccination corresponds with the level of SBA . In order to reach lasting protective levels of SBA in a population , three vaccine doses are probably required . Measurements of SBA are likely to be useful for evaluating various upcoming formulations and improvements of immunization regimens for OMV vaccines Background : New Zeal and has experienced an epidemic of Neisseria meningitidis dominated by strain B:4:P1.7b,4 since 1991 . Children younger than 5 years are at highest risk . Previous serogroup B outer membrane vesicle ( OMV ) strain specific vaccines have shown variable efficacy in this age group . Objective : To evaluate the immunogenicity , reactogenicity and safety in 16–24-month-old children of an OMV vaccine  developed against the New Zeal and epidemic strain . Methods : Children ( 332 ) aged 16–24 months were r and omized to receive the New Zeal and c and i date vaccine made using strain NZ98/254 ( B:4:P1.7b,4 ) or the Norwegian parent vaccine made using strain 44/76 ( B:15:P1.7,16 ) . Vaccines ( 25 μg/dose ) were administered at 0 , 6 and 12 weeks in this observer-blind trial . Immune response was measured by serum bactericidal assay and enzyme-linked immunosorbent assay . Sero-response was defined as a 4-fold or greater rise in serum bactericidal antibody titer compared with baseline , with titers < 1:4 required to increase to ≥1:8 to be considered a sero-response . Local and systemic reactions were monitored for 7 days after vaccination . Results : Sero-response against NZ98/254 was achieved after 3 doses in 75 % ( 95 % CI : 69–80 % ) receiving the New Zeal and c and i date vaccine by both intention to treat ( ITT ) and per protocol ( PP ) analyses . In Norwegian parent vaccinees this was seen in 3 % ( 0–12 % ) ( ITT ) and 4 % ( 0–13 % ) ( PP ) . Vaccines were well tolerated with no vaccine-related serious adverse events . Conclusion : The New Zeal and c and i date vaccine administered to these 16–24-month-old children in 3 doses was safe and elicited a promising immune response against the c and i date vaccine strain NZ98/254 ( N. meningitidis B:4:P1.7b,4 ) contributing to vaccine licensure for this age group BACKGROUND The serogroup B meningococcus is responsible for the majority of cases of meningococcal disease in temperate countries . Infants and young children < 2 years of age are at greatest risk of disease . This study assessed the immunogenicity in infants of a serogroup B meningococcal outer membrane protein vaccine  that has been used extensively in disease outbreaks in Cuba and several Latin American countries and shown to be efficacious in teenagers . METHOD One hundred five healthy infants entering the routine vaccination schedule in Havana , Cuba , were given either 2 or 3 doses of the serogroup B meningococcal vaccine VA-MENGOC-BC at 3.5 , 5.5 and 7.5 months of age . Immune response pre- and postvaccination was determined by the conventional serum bactericidal assay ( SBA ) , a more sensitive novel whole blood bactericidal assay ( WBA ) and immunoglobulin ELISA . RESULTS In 52 and 46 % of infants > 50 % killing of the vaccine serogroup B strain ( B:4:P1.19,15 ) and serogroup C strain , respectively , was demonstrated by the WBA after 2 doses of the vaccine . Serum bactericidal activity ( 4-fold increase in titer ) was induced in only 27 % against the vaccine serogroup B strain and in 14 % against the serogroup C strain . The changes in WBA and SBA were mirrored by the serogroup B and C immunoglobulin ELISA . Cross-reactive immunogenicity against other ( heterologous ) serogroup B strains was demonstrated for one of the four further strains assessed by WBA . By age 16 to 18 months SBA , WBA and ELISA responses had declined considerably . The addition of a third dose of vaccine did not appear to significantly influence immunogenicity at 17 months of age . CONCLUSION The serogroup B outer membrane protein vaccine VA-MENGOC-BC induces a demonstrable immune response in infants against both the serogroup B vaccine strain and against a serogroup C strain . Cross-reactive immunogenicity against other ( heterologous ) serogroup B strains is limited in this age group CONTEXT Meningococcal disease occurs worldwide , and serogroup B disease accounts for a large proportion of cases . Although persons younger than 4 years are at greatest risk for serogroup B meningococcal disease , vaccine efficacy has not been demonstrated in this age group . OBJECTIVE To evaluate serum bactericidal activity ( SBA ) against homologous vaccine type strains and a heterologous Chilean epidemic strain of Neisseria meningitidis as a potential correlate for vaccine efficacy . DESIGN Double-blind , r and omized controlled trial conducted between March 14 and July 20 , 1994 . All blood sample s were taken by December 1994 . SETTING Santiago , Chile , where a clonal serogroup B meningococcal disease epidemic began in 1993 . PARTICIPANTS Infants younger than 1 year ( n = 187 ) , children aged 2 to 4 years ( n = 183 ) , and adults aged 17 to 30 years ( n = 173 ) . INTERVENTION Participants received 3 doses of outer-membrane protein ( OMP ) meningococcal vaccine developed in either Cuba or Norway or a control vaccine , with each dose given 2 months apart . Blood sample s were obtained at baseline , prior to dose 3 , and at 4 to 6 weeks after dose 3 . MAIN OUTCOME MEASURE Immune response , defined as a 4-fold or greater rise in SBA titer 4 to 6 weeks after dose 3 compared with prevaccination titer . RESULTS Children and adult recipients of either meningococcal vaccine were more likely than controls to develop an immune response to the heterologous epidemic strain . After 3 doses of vaccine , 31 % to 35 % of children responded to the vaccine vs 5 % to placebo ; 37 % to 60 % of adults responded to vaccine vs 4 % to placebo ( P<.05 vs control for all ) . Infants , however , did not respond . In contrast , against homologous vaccine type strains , the response rate was 67 % or higher among children and adults and 90 % or higher among infants ( P<.001 vs control for all ) . Subsequent SBA against 7 isogenic homologous target strains identified class 1 OMP as the immunodominant antigen . CONCLUSIONS These data suggest that neither serogroup B OMP meningococcal vaccine would confer protection during a heterologous epidemic . However , epidemic strain-specific vaccines homologous for class 1 OMP are promising c and i date s for the control of epidemic serogroup B meningococcal disease The  Cuban vaccine , first in the world with proven efficacy against group B-caused disease , is based on outer membrane proteins from B meningococci capable of inducing long-lasting and high-titered bactericidal antibodies in humans . This bactericidal activity has a wide spectrum against all pathogenic group B Neisseria meningitidis tested . A r and omized , double-blind controlled trial of the vaccine efficacy was performed during 1987 - 1989 with 106,000 10 - 14 years old students from 197 boarding schools in seven provinces . The efficacy obtained was 83 % ( chi 2 , p less than 0.002 ; Fischer exact , p less than 0.001 ) . In a second field trial including 133,600 persons from 5 months to 24 years of age in Ciego de Avila province ( 30 cases/10(5 ) inhabitants , the highest incidence rate in Cuba ) by comparing vaccinated and non-vaccinated population after 2.5 years of observation and careful follow-up , the efficacy and safety was confirmed . Because of these results and because of the very low reactogenicity of the vaccine , the Ministry of Public Health took the advice of the Scientific Council to vaccinate all children between 3 months and 6 years of age in the most affected provinces . No severe or long lasting reactions to the vaccine were observed after the millions of doses administered . The efficacy of vaccination varied in the provinces between 83 % and 94 % , among age groups ranging from 3 months and 20 years . After 3 years of massive application no severe reactions occurred and one of the most severe epidemics has been practically eradicated 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 r and omisation 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 sub study 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 sub study of three 4CMenB lots compared with MenC ( 1:1:1:3 , block size six ) . At 12 months , 4CMenB-primed children from either sub study were r and omised ( 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 r and omly selected subsets of serum sample s for routine vaccines ; laboratory personnel were masked to assignment . The first co primary 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 sub study who provided serum sample s. The safety population included all participants who contributed safety data after at least one dose of study vaccine . These trials are registered with Clinical Trials.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 Zeal and 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 clinical ly 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 For more than 15 years , Norway has had the highest incidence of meningococcal disease in northern Europe , with 80 % of cases being due to serogroup B meningococci . The case-fatality has remained high , at about 10 % . In this study , an outer membrane vaccine , which had previously been shown to induce an increase in bactericidal antibodies to the parent strain , was assessed in a large-scale , r and omised , double-blind trial . From October , 1988 , 171,800 students in secondary schools volunteered to take part in a double-blind , placebo-controlled , efficacy trial with school as the r and omisation unit . Hospitals and clinics that routinely receive patients with infectious disease were asked to report urgently all cases of suspected meningitis and /or septicaemia in 13 - 21-year-old students in Norway . These cases were registered and further investigated according to a detailed protocol . 89 out of the 221 cases investigated by June 3 , 1991 , were shown to be severe systemic disease due to group B meningococci . 36 cases in 35 schools took part in the trial ( 11 schools with vaccinated students and 24 with students given placebo ) . The calculated rate of protection was thus 57.2 % ( p = 0.012 , one-sided test ) . The findings suggest that , although the vaccine conferred protection against group B meningococcal disease , the effect was insufficient to justify a public vaccination programme
IMPORTANCE Human serum bactericidal antibody levels ( hSBA ) are commonly used as an immune correlate of protection after vaccination against meningococcal disease .
We performed a systematic review of how well this marker correlates with protection induced by outer membrane vesicle ( OMV ) vaccines against meningococcal B ( MenB ) disease .
OBJECTIVE To compare vaccine effectiveness ( VE ) of OMV vaccines against MenB predicted by hSBA ( predicted protection ) to VE from clinical studies ( observed protection ) .