MeNZB™: a safe and highly immunogenic tailor-made vaccine against the New Zealand Neisseria meningitidis serogroup B disease epidemic strain
Introduction
Despite public health intervention, the New Zealand epidemic of systemic group B meningococcal disease, dominated by a single subtype and now in its 14th 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) vaccine, MenBvac™, was replaced with the New Zealand epidemic strain (subtype P1.7b,4) [1]. The resulting tailor-made vaccine, MeNZB™, is a meningococcal serogroup B outer membrane vesicle vaccine for intramuscular injection in a 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 disease, 1990 through 2003 [3].
A total of 541 cases of meningococcal disease were reported in New Zealand during 2003, representing an incidence of 14.5/100,000 (1.5/100,000 in 1989–90). Annually, around 75% of cases occur in those under 20 years of age. Infants are at greatest risk with an age-specific rate of 124/100,000 in 2003 for those aged less than 1 year [3]. The average annual case fatality rate is 4.1% [3] and significant morbidity is sustained in 15–20% of the cases, including skin, digit or limb loss, neurological sequelae, such as developmental delay and sensori-neural deafness [4].
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 vaccines, the Norwegian vaccine MenBvac™ and the Cuban vaccine VA-MENGOC-BC™, have been based on OMVs [8], [9] as is the New Zealand vaccine. The seed stock for this tailor-made vaccine, MeNZB™, is derived from the strain NZ98/254, which was chosen among strains representative of the New Zealand epidemic. This strain was isolated from a 15-year-old boy from New Zealand diagnosed with meningitis in October 1998.
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™, across all age groups. This at a time when the vaccine has been licensed and the immunisation campaign with widespread use of MeNZB™ 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.
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Materials and methods
MeNZB™ was prepared from a B:4:P1.7b,4 meningococcal strain (NZ98/254) by fermentor growth followed by inactivation and extraction of the OMPs with the detergent deoxycholate. Intact and fragments of OMVs, containing OMPs and lipopolysaccharide (LPS), were purified by ultracentrifugation and adsorbed on to aluminium hydroxide. MenBvac™ was prepared from a B:15:P1.7,16 meningococcal strain (44/76) in a similar manner to MeNZB™.
In studies in adults, children aged 8–12 years and toddlers 16–24
Results
One thousand two hundred and seventy-eight subjects were enrolled and received at least one vaccination in the four clinical trials over a 27-month period between May 2001 and September 2003.
Two hundred and ninety-four subjects were enrolled in the 6–8-month-old infants study (MeNZB™ 235 subjects, Menjugate™ 59 subjects), 325 subjects were enrolled in the toddler study (MeNZB™ 261 subjects, MenBvac™ 64 subjects), 608 subjects were enrolled in the school children study (MeNZB™ 547 subjects,
Discussion
MeNZB™, intended for control of the New Zealand epidemic, induces production of serogroup B serum bactericidal antibodies directed against the non-capsular protein surface antigens of the vaccine strain, as does the parent vaccine MenBvac™. The low GMTs for infants, toddlers and teenagers seen at baseline suggest that the populations most at risk with high rates of disease pre-vaccination are still immunologically naïve against the epidemic strain. In all age groups, the response rates (at
Acknowledgements
These studies were sponsored by Chiron Vaccines and the New Zealand Ministry of Health. We thank Teuila Percival (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 Managers), Sandrine Tilman, Ellen Ypma (Biostatisticians) Chiron Vaccines; Karen Gewert (Clinical Data Care); Paul
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Members of Meningococcal Management Team.