Immunogenicity and safety of a hexavalent meningococcal outer-membrane-vesicle vaccine in children of 2–3 and 7–8 years of age
Introduction
Meningococcal disease forms a major health problem in many countries with still an overall mortality of 7–10%. The clinical picture varies from self-limiting bacteremia, to meningitis or septic shock. In the Netherlands, the annual number of patients with meningococcal disease has increased steadily from the beginning of the eighties. In 1996, these infections were mostly caused by Neisseria meningitidis serogroup B (80%) which predominates also in other European countries with a temperate climate [1], [2]. Therefore, production of a meningococcal vaccine capable of generating long-lasting immunity in all age groups has a high priority in the Netherlands health care programme. Vaccines against Neisseria meningitidis serogroup B have not been widely available yet. Development of such a vaccine has been complicated by the inability of group B capsule polysaccharides to induce significant increases in antibodies [3]. The poor immunogenicity of the antigen is probably associated with immunological tolerance since antibodies against group B polysaccharide cross-react with host antigens [4], [5]. However, conjugate vaccines, in which capsular polysaccharides and proteins are covalently linked, elicit some immune response against the normally nonimmunogenic group B polysaccharide [6], [7], [8], [9]. Fusco et al. showed bactericidal activity in monkeys after three injections of modified N-propionylated group B meningococcal polysaccharide conjugated to a recombinant class 3 porin [10]. Other immunodominant antigens at the cell surface of N. meningitidis are also able to induce strong bactericidal activity and are widely used as candidate for vaccine development. Patients with meningococcal disease have shown immune responses to various meningococcal outer-membrane proteins (OMP), suggesting that these proteins could be an important component of meningococcal vaccines [11], [12], [13], [14], [15], [16], [17]. Vaccines consisting of membrane vesicles containing a mixture of OMPs were safe and immunogenic in volunteers [18], [19], [20], [21]. Efficacy studies with these vaccines demonstrated that antibodies to these antigens do provide a significant protection against serogroup B meningococcal disease [22], [23], [24], [25], [26]. However, these studies showed that the protective efficacy was between 50 and 80%, age dependent and of limited duration [24], [25], [26]. Class 1 proteins (PorA) appeared to be better inducers of bactericidal antibodies than class 2 or class 3 proteins. These bactericidal antibodies were shown to be the best correlates for protection against group B meningococcal disease [20], [21], [27], [28], [29], [30], [31], [32], [33], [34], [35]. In the National Institute of Public Health and the Environment (RIVM) in the Netherlands, two trivalent vaccine strains have been developed containing and expressing genes encoding the prevalent PorA 6 serosubtypes [36], [37]. The PorA serosubtypes represent together 80% of current isolates from blood and cerebrospinal fluid of patients in the Netherlands [1]. Using the two trivalent vaccine strains a hexavalent meningococcal outer-membrane vesicle (OMV) vaccine was produced including the serosubtype antigens: P1.7,16; P1.5,2; P1.19,15 and P1.5c,10; P1.12,13; P1.7h,4. The vaccine consisted for 90% of PorA OMPs and had very low expression of class 4 and 5 OMPs. Classes 2/3 OMPs as well as the B-capsular polysaccharide are not expressed due to gene deletions. Phase I clinical trials with this vaccine showed that the vaccine is safe and that after one vaccination with the highest dose (15 μg of the individual PorA proteins) 50% of the volunteers showed a fourfold increase in bactericidal antibody activity against six test-strains expressing the specific serosubtypes [21]. In infants in the UK, this hexavalent OMV vaccine was safe and evoked encouraging immune responses [38]. The current phase II study was designed to analyse the safety and the immunogenicity of two different dose of this hexavalent meningococcal OMV vaccine in healthy Netherlands toddlers and school children.
Section snippets
Study population
Healthy children living in Rotterdam (the Netherlands) 7–8 years old (born in 1988) or 2–3 years old (born in 1993) were recruited by letter to participate in this trial. Children were included in the study after a positive reply, a health check and written informed consent. The study subjects did not receive a hepatitis B or meningococcal vaccine prior to entry in the study, were known not to be allergic to vaccine-components, had no immunodeficiency and were never diagnosed with meningococcal
Study populations
After written informed consent by their parents or their legal representatives, a total of 165 healthy children of 7 year old (78 female, 87 male: group A) and 172 healthy toddlers of 2–3 year old (76 female, 96 male: group B) were willing to participate. In group A, three participants dropped out after the first vaccination, without any serious adverse event (two of the high dose meningococcal vaccine and one of the HepB vaccinated children). Two additional children were excluded because they
Discussion
The hexavalent RIVM meningococcal OMV vaccine used in this study was shown to be safe and able to induce bactericidal antibodies in 2–3 and 7–8 years old children. Adverse reactions, mostly mild local inflammation were seen more frequently after meningococcal vaccination than after hepatitis B vaccination. Side-effects after both high and low dose of meningococcal OMV vaccine were minimal and comparable with meningococcal OMP vaccines in children [38], [41], [42]. In this study, the IgG
Conclusion
Hexavalent meningococcal OMV vaccine is considered to be safe. After three hexavalent meningococcal vaccinations increased levels of IgG against OMV and increased bactericidal activity were measured with the highest levels in the youngest children. Fourfold rise in bactericidal antibody titre in vaccinated children assumed to be indicative for protection varied for the different meningococcal serosubtypes. SBA activity against the wild type isolates were comparable to the isogenic strains.
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