Properties and clinical performance of vaccines containing outer membrane vesicles from Neisseria meningitidis
Introduction
The obligate human pathogen Neisseria meningitidis is a Gram-negative bacterium that variably colonizes the nasopharynx of healthy individuals, often at a level of 10–20% [1], [2]. On rare occasions an encapsulated strain invades the blood stream leading to meningitis and/or septicaemia. Death occurs in around 5–10% of cases and up to 20% survivors are left with serious injuries including loss of limbs and neural deficits [3]. Invasive meningococcal disease causes a significant public health burden throughout the world, with estimates of 500,000 cases and more than 50,000 deaths reported annually [4].
Meningococci are differentiated on the basis of their capsular type. Effective conjugated capsular polysaccharide–protein vaccines have recently been developed for prevention of disease caused by strains of serogroup A, C, W-135 and Y in all age-groups [5]. However, the capsular vaccine approach is not suitable for strains of serogroup B since that polysaccharide capsule has a structural homology with the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) in the human foetal brain. Such structures can also be found in adult tissues, though in lesser amounts. The serogroup B capsule is poorly immunogenic, but more importantly the concern is that its use could lead to an autoimmune response and tissue damage in vaccinees, or even cause foetal disorders [6]. Therefore, the vaccine approach for group B meningococci has largely focused on outer membrane proteins. Historically in the more developed countries serogroup B disease has tended to dominate, although serogroup C caused more fatalities. Following the gradual increase of global implementation of the glycoconjugate serogroup C vaccines in routine infant immunization programs a reduction of serogroup C cases has occurred [7]. Serogroup Y meningococcal disease which emerged in the USA over the last decade accounted for more than one third of their cases [8]. Recent epidemiological data reveals that serogroup B strains currently are responsible for 40–50% of sporadic meningococcal disease also in USA and more than 90% in certain European countries [9], [10]. Thus with the increasing introduction of a quadrivalent polysaccharide–protein conjugate vaccine against serogroups A, C, W-135 and Y, a vaccine to control serogroup B remains the last meningococcal challenge in the industrialized world. In most countries, the highest rates of serogroup B disease occur in infants less than 1 year of age. The challenge is to develop an optimal vaccine that is safe, effective and has the ability to induce long-term immunity in infants.
To date, wild-type outer membrane vesicle (wtOMV) vaccines are the only formulations that have shown efficacy against serogroup B meningococcal disease. Efficacy has been demonstrated in Cuba, Norway, Chile, Brazil and New Zealand (Table 1); where epidemics dominated by one particular strain of defined clonal type were lasting for decades [11], [12], [13]. Because of their strain specificity wtOMV vaccines are particularly suitable for epidemic control [14]. The most significant limitation of this approach is that the strain-specific immune response, in smaller children and infants, is almost exclusively directed towards the immuno-dominant porin protein, PorA [15], [16], [17].
The present review deals with the physico-chemical properties of wtOMV vaccine formulations, the experience from clinical trials, epidemic control and routine use by conventional OMV vaccines. The potential for various improvements of the “OMV concept” and likely scenarios for future use will also be addressed.
Section snippets
Manufacture, characterization and other pre-clinical data
From the early 1980 various manufacturing methods for OMV vaccines have been presented [18], [19]. The most detailed and comprehensive presentation was published by Frasch et al. [20].
Traditionally the OMV bulk for vaccine production is processed from bacteria that have been grown by fermenter in a semi-synthetic (e.g. modified Frantz’ medium) or a fully synthetic medium (e.g. Catlin-6). The bacterial mass is harvested by centrifugation or tangential flow filtration. Outer membrane vesicles are
Development, use and impact of protein based vaccines for serogroup B meningococci
Already early in the 20th century, the importance of serum bactericidal activity (SBA) for protection against meningococcal disease was noted [47], [48], but the most quoted publication is the 1969 paper by Goldschneider et al. in which a correlation between SBA, disease incidence and age was shown [49]. The same correlation pattern of increasing SBA level, with diminishing disease rates, following increasing ages in the adolescent period was shown for serogroups A, B and C meningococci [49].
Age specific immune responses
The marked and selective differences in the immune response in various age-groups after immunization with OMV vaccines, was first reported following a collaborative trial in Santiago, Chile in 1994 with the Cuban and Norwegian OMV vaccines [15]. When the target organisms in the SBA test were of the same strain type used for vaccine manufacture (i.e. homologous strain), the percentage of vacinees having ≥4-fold rise in SBA titres, was of the same magnitude for the infant group as for adults
Immunization regimens and duration of immunity
Originally, in Cuba and Norway a two-dose primary immunization schedule was used, with 6 weeks (6–8 weeks for the Cuban trial) between the first and the second dose [11], [12]. The study of Tappero et al. in Santiago, Chile [15] indicated a higher and somewhat broader immune response after three doses compared with two doses. Later a three-dose primary immunization schedule has been used in clinical trials undertaken by NIPH and Chiron (later Novartis) and proven beneficial [65]. Immunogenicity
Estimates of efficacy and effectiveness
For wtOMV vaccines it is only the efficacy estimates from the clinical trials in Cuba and Norway that is based on “double-blind-placebo-controlled-randomized trials”. As stated in section 3 the point estimates were presented as 87% and 57% for the Cuban- and the Norwegian vaccine, respectively [11], [12]. It is however, important to keep in mind that the observation periods were 16 months in the Cuban study and 29 months in the Norwegian situation. Moreover, when the Norwegian data was
Reactogenicity and safety
OMV vaccines have been used in various ways since the 1980's and the safety records are substantial. The NIPH vaccine (MenBvac) has been used in more than 400,000 doses, the formulation for New Zealand, MeNZB has been used in more than 3 million doses and the VA-MENGOC-BC from Finlay Institute, Havana has been used in more than 55 million doses in different parts of Latin-America and to a small extent in Europe [66]. The Hib-conjugate vaccine PedvaxHIB with the “Meningococcal Outer Membrane
Potentials for development and future use
The OMV-type vaccine has clearly shown to be suitable for epidemic control and to be used in localised clonal outbreaks. It is also realistic to make a mixture of two (or perhaps even four) OMVs, representing different serosubtypes (PorA variants). Since important hyper-endemic and epidemic serogroup B strains change rather slowly over time (10–20 years), there might be feasible and commercially acceptable to make such formulations for one or more geographical regions [20], [82]. If the
Concluding remarks
The concept of OMV vaccines is not “cutting edge”, sophisticated or refined vaccinology. It harbours a number of “crude features” since being developed in the 1970. They are complex formulations and challenging to manufacture. However, they have a long standing track- and safety record. Of particular importance is the substantial safety and effectiveness documentation that have been made available through a number of important studies [11], [12], [15], [56], [57], [58], [75], [81]. It is also
Acknowledgements
Elisabeth Wedege, Hanne Nøkleby and Dan Granoff are all thanked for helpful comments to the different versions of the manuscript. Ellen Namork and Audun Aase have made the original illustrations used in Fig. 1 and they are thanked for generously accepting the present use.
Discolosed conflicts of interest: JH: Consultant (Wyeth Vaccines Research, Novartis Vaccines and Diagnostics); Advisor (WHO, PAHO). DM: The New Zealand seroprevalence study and laboratory serum antibody analyses of MeNZB
References (85)
- et al.
Meningococcal vaccines
- et al.
Antigenic similarities between brain components and bacteria causing meningitis. Implications for vaccine development and pathogenesis
Lancet
(1983) - et al.
Effect of outer membrane vesicle vaccine against serogroup B meningococcal disease in Norway
Lancet
(1991) - et al.
The concept of “tailor-made”, protein-based, outer membrane vesicle vaccines against meningococcal disease
Vaccine
(2005) - et al.
Measurement of lipopolysaccharide (endotoxin) in meningococcal protein and polysaccharide preparations for vaccine usage
J Biol Stand
(1989) - et al.
Immunogenicity of a combination vaccine containing pneumococcal conjugates and meningococcal PorA OMVs
Vaccine
(2007) - et al.
Production, characterization and control of a Neisseria meningitidis hexavalent class 1 outer membrane protein containing vesicle vaccine
Vaccine
(1996) - et al.
Immunogenicity and reactogenicity in UK infants of a novel meningococcal vesicle vaccine containing multiple class 1 (PorA) outer membrane proteins
Vaccine
(1999) - et al.
Pore formation and mitogenicity in blood cells by the class 2 protein of Neisseria meningitidis
J Biol Chem
(1992) - et al.
Differences in the immunogenicity of three Haemophilus influenza type b conjugate vaccines in infants
J Pediatr
(1992)
Immunogenicity in infants of Haemophilus influenza type b polysaccharide in a conjugate vaccine with Neisseria meningitidis outer-membrane protein
Lancet
Improved immunogenicity of a H44/76 group B outer membrane vesicle vaccine with over-expressed genome-derived Neisserial antigen 1870
Vaccine
Efficacy, safety, and immunogenicity of a meningococcal group B (15:P1.3) outer membrane protein vaccine in Iquique, Chile
Vaccine
Serum bactericidal activity correlates with the vaccine efficacy of outer membrane vesicle vaccines against Neisseria meningitidis serogroup B disease
Vaccine
Safety and immunogenicity of New Zealand strain meningococcal serogroup B OMV vaccine in healthy adults: beginning of epidemic control
Vaccine
MeNZB™: a safe and highly immunogenic tailor-made vaccine against the New Zealand Neisseria meningitidis serogroup B disease epidemic strain
Vaccine
Immunogenicity and safety of a strain-specific MenB OMV vaccine delivered to under 5-year olds in New Zealand
Vaccine
MeNZB™ vaccine and epidemic control: when do you stop vaccinating?
Vaccine
Safety review: two outer membrane vesicle (OMV) vaccines against systemic Neisseria meningitidis serogroup B disease
Vaccine
Use of available outer membrane vesicle vaccines to control serogroup B meningococcal outbreaks
Vaccine
The intensive vaccines monitoring programme (IVMP): an electronic system to monitor vaccine safety in New Zealand
Vaccine
The risk of simple febrile seizures after immunization with a new group B meningococcal vaccine, New Zealand
Vaccine
Vaccination as teenagers against meningococcal disease and risk of chronic fatigue syndrome
Vaccine
Development and characterization of outer membrane vesicle vaccines against serogroup A Neisseria meningitidis
Vaccine
The natural history of meningococcal carriage and disease
Epidemiol Infect
Asymptomatic carriage of Neisseria meningitidis in a randomly sampled population
J Clin Microbiol
Control of epidemic meningococcal disease
WHO practical guidelines
Immunogenicity of a tetravalent meningococcal glycoconjugate vaccine in infants: a randomized controlled trial
JAMA
Planning, registration and implementation of an immunisation campaign against meningococcal serogroup C disease in the UK: a success story
Vaccine
Meningococcal disease
N Engl J Med
Population-based analysis of meningococcal disease mortality in the United States: 1990–2002
Pediatr Infect Dis J
A surveillance network for meningococcal disease in Europe
FEMS Microbiol Rev
Vaccine against group B Neisseria meningitidis: protection trial and mass vaccination results in Cuba
NIPH Ann
New Zealand epidemic of meningococcal disease identified by a strain with phenotype B:4:P1.4
J Infect Dis
Immunogenicity of 2 serogroup B outer-membrane protein meningococcal vaccines. A randomized controlled trial in Chile
JAMA
The VR2 epitope on the PorA P1.7-2 4 protein is the major target for the immune response elicited by the strain-specific Group B meningococcal vaccine MeNZB
Clin Vaccine Immunol
Serotype determinant protein of Neisseria meningitides. Large scale preparation by direct detergent treatment of the bacterial cells
Acta Pathol Microbiol Scand [C]
Polysaccharides and membrane vaccines
Preparation of outer membrane protein vaccines against meningococcal disease
Production, characterization and control of MenB-vaccine “Folkehelsa”: an outer membrane vesicle vaccine against group B meningococcal disease
NIPH Ann
Bactericidal antibodies after vaccination with the Norwegian meningococcal serogroup B outer membrane vesicle vaccine: a brief survey
NIPH Ann
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