Vaccine23(2005)
2191–2196
MeNZB TM:a safe and highly immunogenic tailor-made vaccine
against the New Zealand Neisseria meningitidis serogroup B disease
epidemic strain
Philipp Oster a,1,Diana Lennon b,1,Jane O’Hallahan c,∗,1,Kim Mulholland d,
Stewart Reid e,Diana Martin f
a Chiron Vaccines,Siena,Italy
b University of Auckland,Auckland1020,New Zealand
c Meningococcal Vaccine Strategy,Ministry of Health,Level1,Ol
d Bank Chambers,Customhous
e Quay,P.O.Box5013,Wellington,New Zealand
d Centr
e for International Child Health,University o
f Melbourne,Australia
e Ropata Medical Centre,Lower Hutt,New Zealand
f Institute of Environmental Science and Research,Porirua,New Zealand
Available online26January2005
Abstract
Clinical studies have been conducted in New Zealand evaluating the safety and immunogenicity of an outer membrane vesicle(OMV) vaccine,MeNZB TM,developed to control epidemic disease caused by group B meningococci,subtype P1.7b,4.MeNZB TM,administered in a three-dose regimen,was well tolerated and induced a seroresponse,defined as a four-fold rise(≥titre8)in serum bactericidal antibodies against the vaccine strain4–6weeks after the third vaccination,in96%(95%confidence interval(CI):79–100%)of adults,76%(95%CI: 72–80%)of children,75%(95%CI:69–80%)of toddlers and74%(95%CI:67–80%)of infants receiving MeNZB TM.In conclusion,these findings suggest that MeNZB TM is safe and is likely to confer protection against systemic group B
meningococcal disease caused by the epidemic strain.
©2005Elsevier Ltd.All rights reserved.
Keywords:Serum bactericidal assay(SBA);Outer membrane vesicle(OMV)vaccine;Epidemic control
1.Introduction
Despite public health intervention,the New Zealand epi-demic of systemic group B meningococcal disease,domi-nated by a single subtype and now in its14th year,has not been abated,and therefore,the best option for its control is the use of a strain-specific vaccine.For that purpose,the vaccine strain of an outer membrane vesicle(OMV)vac-cine,MenBvac TM,was replaced with the New Zealand epi-demic strain(subtype P1.7b,4)[1].The resulting tailor-made vaccine,MeNZB TM,is a meningococcal serogroup B outer membrane vesicle vaccine for intramuscular injection in a ∗Corresponding author.Tel.:+6444954432;fax:+6444954401.
E-mail address:jane vt.nz(J.O’Hallahan).
1Members of Meningococcal Management Team.three-dose regimen,intended to provide immunity against serious systemic disease caused by Neisseria meningitidis serogroup B subtype P1.7b,4[2].
This subtype accounted for 86%of all group B meningococci isolated from cases of dis-ease,1990through2003[3].
A total of541cases of meningococcal disease were re-ported in New Zealand during2003,representing an in-cidence of14.5/100,000(1.5/100,000in1989–90).Annu-ally,around75%of cases occur in those under20years of age.Infants are at greatest risk with an age-specific rate of124/100,000in2003for those aged less than1 year[3].The average annual case fatality rate is4.1% [3]and significant morbidity is sustained in15–20%of the cases,including skin,digit or limb loss,neurological sequelae,such as developmental delay and sensori-neural deafness[4].
0264-410X/$–see front matter©2005Elsevier Ltd.All rights reserved. doi:10.1016/j.vaccine.2005.01.063
2192P.Oster et al./Vaccine23(2005)2191–2196
A number of surface-expressed outer membrane proteins eliciting antibody responses have been identified,although the relative contribution of these antibodies to protection has not been fully elucidated.Antibodies to the Por A protein, have been identified in convalescent sera[5]and have also been identified as immunodominant following vaccination with group
B OMV vaccines[6,7].
The most extensively studied meningococcal group B vac-cines,the Norwegian vaccine MenBvac TM and the Cuban vaccine V A-MENGOC-BC TM,have been based on OMVs [8,9]as is the New Zealand vaccine.The seed stock for this tailor-made vaccine,MeNZB TM,is derived from the strain NZ98/254,which was chosen among strains representative of the New Zealand epidemic.This strain was isolated from a15-year-old boy from New Zealand diagnosed with menin-gitis in October1998.
The aim of this paper is to give a preliminary overview of the results from a series of clinical trials conducted in New Zealand to evaluate the immunogenicity and safety of this candidate vaccine,MeNZB TM,across all age groups. This at a time when the vaccine has been licensed and the immunisation campaign with widespread use of MeNZB TM to control the epidemic in New Zealand is under way.It is the intention of the authors to present further results in the future discussing the outcome of each single study in detail.
2.Materials and methods
MeNZB TM was prepared from a B:4:P1.7b,4meningo-coccal strain(NZ98/254)by fermentor growth followed by inactivation and extraction of the OMPs with the detergent deoxycholate.Intact and frag
聚合度ments of OMVs,containing OMPs and lipopolysaccharide(LPS),were purified by ul-tracentrifugation and adsorbed on to aluminium hydroxide. MenBvac TM was prepared from a B:15:P1.7,16meningococ-cal strain(44/76)in a similar manner to MeNZB TM.
In studies in adults,children aged8–12years and toddlers 16–24months of age,the parent vaccine,MenBvac TM,was the control vaccine.In a fourth study in infants aged6–8 months,the control group received Meningococcal C con-jugate vaccine(Menjugate TM).The New Zealand Standing Committee on Therapeutic Trials approved the vaccines for use in these trials.The studies were conducted in accordance with the Declaration of Helsinki guidelines on good clini-cal practice and local regulations for clinical trials including prior approval from the appropriate Ethics Committee.To be eligible for participation in the studies,healthy subjects had to fulfil all study-specific inclusion criteria(regarding age, prior exposure to the antigen,recent antibiotic use,etc.)and give written informed consent.
2.1.Study design
All studies were designed to evaluate the safety,tolera-bility and immunogenicity of MeNZB TM in a range of age groups.Each study population was randomised in a4:1ra-tio to either receive MeNZB T
M or control vaccine,except in the adult study.Three doses were administered at6-week intervals intramuscularly either in the deltoid region of the non-dominant arm or in the antero-lateral thigh.Blood samples for serological assays were collected by venepunc-ture before thefirst vaccination and4–6weeks after the second and third vaccinations.The studies were conducted as follows:
•A phase I/II,single-centre,randomised,observer-blind study in healthy adults aged18–50years.Subjects re-ceived MeNZB TM25or50g/dose or the parent vaccine MenBvac TM25g/dose.A third arm receiving50g/dose is not included in this report.
受众心理•A phase II,single-centre,randomised,observer-blind study in healthy school children aged8–12years.Sub-jects received MeNZB TM25g/dose or the parent vac-cine MenBvac TM25g/dose.This study was conducted as a two-cohort study,evaluating vaccines manufactured at different sites. •A phase II,single-centre,randomised,observer-blind study in healthy toddlers aged16–24months.Subjects received MeNZB TM25g/dose or the parent vaccine MenBvac TM25g/dose.
•A phase II,single centre,randomised,observer-blind study in healthy infants aged6–8months.Subject
s received 25g/dose of MeNZB TM or Menjugate TM.
A study in infants aged6–10weeks at enrolment is yet to be completed.
2.2.Immunogenicity
The primary immunogenicity outcome was whether the vaccines induced an immune response,as measured by the serum bactericidal assay(SBA).This assay measures func-tional antibodies with bactericidal activity acquired through vaccination against or by contact ingitidis serogroup B.
The SBA was performed on vaccinees sera to measure the level of bactericidal antibodies[10].The serum dilution sequence started at1:2.The bactericidal antibody titre was calculated as the reciprocal of the dilution of serum that kills 50%of the organisms determined against the average zero count for the assay.An interpolated titre value was calcu-lated for each serum,since interpolated titres allow greater precision.Seroconversion was defined as at least a four-fold rise(seroresponse)in SBA titre(≥8)as compared with base-line pre-vaccination titre.
2.3.Safety monitoring
Subjects were observed for30min following the vaccina-tions for evidence of immediate reactions.Age-appropriate local and systemic reactions,including body temperature for7days following each vaccination,including the day
P.Oster et al./Vaccine23(2005)2191–21962193
of the vaccination were recorded on standardised diary cards by the subject or the subject’s caregiver and veri-fied by study staff.Information on any other adverse event, including serious adverse events and/or adverse events ne-cessitating a physician’s visit and/or resulting in the sub-ject’s withdrawal from the study,were collected throughout the trials.
2.4.Statistical methods
Statistical methods used for the immunogenicity analyses were similar in the various studies.Descriptive statistics for percentage of seroresponders,defined as subjects showing at least a four-fold increase in bactericidal activity as com-pared to baseline titres,as measured by SBA,at4–6weeks after the second and the third vaccination,and associated 95%Clopper–Pearson confidence intervals(CIs)were cal-culated by vaccine group in each study.Geometric mean antibody titres(GMTs)for SBA and associated95%CIs were calculated by vaccine group in each individual stud
代理httpy. The GMTs and95%CIs were constructed by exponentiat-ing(base10)the least square means of the logarithmically transformed(base10)titres and their95%CIs obtained from a one-way analysis of variance(ANOV A)with a factor for vaccine group.The results of the cohorts A and B in the 8–12-year-old study were pooled.This is justified because the populations of the two cohorts were from the same area of New Zealand,and their immunogenicity and safety results were similar for each vaccine lot administered regardless of manufacturing site.
3.Results
One thousand two hundred and seventy-eight subjects were enrolled and received at least one vaccination in the four clinical trials over a27-month period between May2001and September2003.
Two hundred and ninety-four subjects were enrolled in the6–8-month-old infants study(MeNZB TM235subjects, Menjugate TM59subjects),325subjects were enrolled in the toddler study(MeNZB TM261subjects,MenBvac TM64sub-jects),608subjects were enrolled in the school children study (MeNZB TM547subjects,MenBvac TM61subjects),and75 subjects were enrolled in the adult study(MeNZB TM25sub-jects(25g),24subjects(50g),MenBvac TM26subjects). All juvenile subjects were resident in metropolitan Auckland, New Zealand.
3.1.Immunogenicity
Seroresponse,as measured by a four-fold increase in SBA titre compared with baseline titre against the candidate vaccine strain NZ98/254was high in all age groups,4–6 weeks following the third dose of MeNZB TM:74%(95% CI:67–80%)of infants,75%(95%CI:69–80%)of toddlers,Table1
Percentage of seroresponders to MeNZB TM in each age-group study as mea-sured by SBA using NZ98/254as target strain
Age group Variable MeNZB TM Control Adults N2426
%responders a9642
95%CI79–10023–63 8–12years old N48556
%responders a7632
95%CI72–8020–46 16–24months old N23155
%responders a754
95%CI69–800–13 6–8months old N20152
%responders a740
95%CI67–800–7
a Seroresponders are defined as subjects showing at least a four-fold in-crease in SBA antibody titres from day1.If titre is<4on day1,one needs a titre of8to be considered a responder.
76%(95%CI:72–80%)of school children and96%(95%CI: 79–100%)of adults were seroresponders.For all age groups, the percentage of seroresponders was higher after the third dose than after the second dose(data not shown).In the con-trol groups,the corresponding percentages of seroresponders were much lower;0%(95%CI:0–7%)among infants receiv-ing Menjugate TM,4%(95%CI:0–13%)among toddlers re-ceiving MenBvac TM,32%(95%CI:20–46%)among school children receiving MenBvac TM and42%(95%CI:23–63%) among adults receiving MenBvac TM(Table1).Six weeks after the third vaccination the SBA anti-meningococcus B GMTs had increased from a baseline of≤1.06to≥16for infants and toddlers who had received MeNZB TM(Table2). The SBA GMT of the control group did not rise significantly from baseline when measured at6weeks after the third dose (Table3).
3.2.Safety
The safety database for MeNZB TM comprises1068sub-jects.There were no serious adverse events possibly or prob-ably related to the administration of MeNZB TM.Other non-related serious adverse events resulted from hospitalisation following accidents or illness.
3.2.1.Injection-site reactions
The injection-site reactions across the age groups are dis-played in Table3;it should be remembered that observation methods differed across the age groups.In all age groups, injection-site reactions(including tenderness/pain,redness, swelling,and induration)occurred frequently with tender-ness/pain being the most frequent(Table3).The injection-site reactions seen were not usually clinically significant and severe injection-site reactions persisting for more than7days were uncommon.Reactions were similarly distributed after first,second and third doses.
2194P.Oster et al./Vaccine23(2005)2191–2196
Table2
Geometric mean SBAb titres(GMTs)against NZ98/254after vaccination with MeNZB TM achieved in
each age-group study
Age group Variable MeNZB TM Control
Adults N2426
GMT at baseline(95%CI) 2.2(1.29–3.76) 2.19(1.31–3.65)
GMT after third dose(95%CI)44(22–88)11(5.85–22)
8–12years old N48556
GMT at baseline(95%CI) 1.5(1.36–1.65) 2.04(1.4–2.97)
GMT after third dose(95%CI)23(20–27)7.44(4.38–13) 16–24months old N23155
GMT at baseline(95%CI) 1.06(1.01–1.11) 1.14(0.98–1.34)
GMT after third dose(95%CI)16(14–18) 1.56(1.16–2.10) 6–8months old N20152
GMT at baseline(95%CI)1(1–1.01) 1.05(0.95–1.15)
GMT after third dose(95%CI)16(14–19) 1.07(0.97–1.18)
3.2.2.Systemic reactions
Most systemic reactions were mild or moderate in severity and transient.The frequency of all reactions was generally similar between those who received MeNZB TM and those who received the control vaccines.
Among infants and toddlers,irritability was the most fre-quent reaction(Table5).Other reactions included change in eating habits,impaired sleeping,diarrhoea and vomiting (Table4).Temperature of>38◦C was recorded in approxi-mately15%of toddlers and infants.However,these occurred at a similar rate in the control vaccine group.In adults,re-ported adverse events included headache,malaise,myalgia, nausea,arthralgia and fever(Table5).
4.Discussion
MeNZB TM,intended for control of the New Zealand epi-demic,induces production of serogroup B serum bacteri-cidal antibodies directed against the non-capsular protein surface antigens of the vaccine strain,as does the parent vaccine MenBvac TM.The low GMTs for infants,toddlers and teena
gers seen at baseline suggest that the populations most at risk with high rates of disease pre-vaccination are still immunologically na¨ıve against the epidemic strain.In all age groups,the response rates(at least a four-fold rise above the baseline titre)after the third MeNZB TM vaccina-tion were consistently over70%and reached96%in adults. In addition,most individuals who did not sustain a four-fold rise did demonstrate an increase in serum bacterici-dal activity after the third dose when compared to base-line(data not shown).This is consistent with the view that the percentage of individuals in a population sustain-ing a four-fold rise in SBA following vaccination prob-ably underestimates the protection afforded by the vac-cine[11].There was a trend towards higher response rates among adults than younger people and natural priming may be of importance for the ability to respond with an at
Table3
Injection-site reactions reported across all age-group studies after vaccination with MeNZB TM Reaction Age group MeNZB TM Control
Total number of doses given Percentage of doses followed
by the specified reaction(%)
Total number of doses
given
Percentage of doses followed
by the specified reaction(%)
Tenderness/pain Infants7003717721 Toddlers7727318870
Children16067817681
Adults73967892 Induration Infants7004317717 Toddlers7725818845长江三角洲经济 Children1606101767
Adults73197814 Redness Infants7003317716 Toddlers7725518847
Children1606111767
Adults73167815 Swelling Infants700151773 Toddlers7723418827
Children160671762
Adults73107822
P.Oster et al./Vaccine23(2005)2191–21962195 Table4
Systemic reactions commonly reported in infants and toddlers age-group studies after vaccination with MeNZB TM
Reaction Age group MeNZB TM Control
Total number of doses given Percentage of doses followed
by the specified reaction(%)
Total number
of doses given
Percentage of doses followed
by the specified reaction(%)
Fever(>38.5◦C)axillary Infants7001517712 Toddlers772101888
Irritability Infants7004917735 Toddlers7724118840
Change in eating habits Infants7002317715 Toddlers7721918820 Sleepiness Infants7001817710 Toddlers7721918818
Diarrhoea Infants7001117710 Toddlers7721218814 V omiting Infants7001117711 Toddlers772618810
least four-fold increase in SBA titre if only two doses are given.
As is common for intramuscularly administered alu-minium hydroxide containing vaccines,the frequency of lo-cal(injection site)and systemic reactions after administration of MeNZB TM,MenBvac TM or Menjugate TM was high.Oc-currence of local reactions is very common for meningococ-cal OMV vaccines,and therefore,MeNZB TM was expected to have such a profile.The most common adverse reaction was local pain,which is consistent with the Norwegian parent vaccine data[12].Most of the local and systemic reactions were of mild or moderate intensity.The frequency and in-tensity where assessed,of local and systemic reactions were similar across age groups and similarly distrib
uted after the first,second and third dose.Among those subjects who ex-perienced local reactions of severe intensity after thefirst dose of MeNZB TM,local reactions of severe intensity were not frequently reported after the subsequent doses.The re-actogenicity data suggest that MeNZB TM is better tolerated in infants and that the overall reactogenicity profile of the vaccine in this age group compares well to a Meningococcal C conjugate vaccine.This is in line with other infant vac-cines that cause higher reactogenicity when administered to children of older age.No serious adverse events possibly or probably related to the administration of MeNZB TM have been reported.All data on MeNZB TM indicate that the only difference between MeNZB TM,and the parent vaccine is the strain used in its production.
The mechanism for specific protection against the invasion of infectious agents is immunity,and the serum bactericidal assay is currently the best laboratory test used to measure antibodies considered protective against meningococci.For the parent vaccine MenBvac TM,the protection rate among secondary school students was57%(95%CI21–87%)for a 29-month follow-up period after only two doses[13],and the protection rate was as high as87%(95%CI:62–100%)after
Table5
Systemic reactions commonly reported in school children(8–12years)and adults age-group studies after vaccination with MeNZB TM Reaction Age group MeNZB TM Control
Total number of doses given Percentage of doses followed
大型超市
管理by the specified reaction(%)Total number
of doses given丝锥夹头
Percentage of doses followed
by the specified reaction(%)
Headache8–12years16062317614 Adults73227831
Malaise8–12years16061817614 Adults73227828
Myalgia8–12years160691768 Adults73217817 Nausea8–12years1606917611 Adults73147815
Arthralgia8–12yrs160661766 Adults733785 Fever(>38.5◦C)axillary8–12years160631763 Adults730781
2196P.Oster et al./Vaccine23(2005)2191–2196
10months[13].For this vaccine and others based on outer membrane proteins(V A-MENGOC-BC and the Walter Reed vaccine),it has been shown that there is some correlation between immune responses and protection rates in efficacy studies[13–15].Given that a four-fold rise in serum bacte-ricidal titre in the New Zealand assay requires that a titre of at least8be achieved post-vaccination,we consider that the satisfactory immune responses demonstrated in the studies with MeNZB TM indicate that a high proportion of the vac-cinated New Zealand population will be protected.In con-clusion,these studies showed that MeNZB TM is a safe and immunogenic vaccine and that,if a high percentage of the target population is vaccinated,it will have a significant im-pact on the epidemic of serogroup B meningococcal disease in New Zealand.
Acknowledgements
These studies were sponsored by Chiron Vaccines and the New Zealand Ministry of Health.We thank Teuila Per-cival(Paediatrician),Middlemore Hospital;Joanna Stewart (Statistician),Florina Chan
Mow,Jamie Hosking,Kumanan Rasanathan,Viliame Sotutu,Vanessa Thornton,Sharon Wong(Clinical Research Fellows),University of Auckland; Mark Wakefield,Benedetta Ghezzi(Clinical Trial Man-agers),Sandrine Tilman,Ellen Ypma(Biostatisticians)Ch-iron Vaccines;Karen Gewert(Clinical Data Care);Paul Blatchford,Anne Glennie,Lisa McCallum,Nicola Ruijne (Vaccine Antibody Testing Laboratory),Institute of Environ-mental Science and Research Limited and particularly the Norwegian Institute of Public Health for experitise around OMV vaccine development.
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