Multicomponent meningococcal serogroup B vaccine or 4CMenB (Bexsero, Novartis) was approved in the EU for the immunisation against invasive meningococcal disease (IMD) caused by the bacterium Neisseria meningitidis serogroup B in individuals aged 2 months or older.
Neisseria meningitides, also known as meningococcus, invades the blood and/or the brain causing septicaemia and meningitis, respectively. Despite being a rare disease in Europe, it remains a significant health problem due to its rapid onset, high case fatality and high proportion of survivors with long-term disabilities such as brain damage, limb amputation, hearing loss and renal failure, even after appropriate antibiotic treatment. In addition, the highest rate of meningococcal disease tends to be in infants under 1 year old. Due to these features, preventative vaccination is considered the key strategy to controlling meningococcal disease.
The majority of pathogenic meningococci are encapsulated by a polysaccharide capsule that helps the bacteria resist phagocytosis and complement-mediated lysis. Based on the constituents of these capsules, meningococci have been divided into different serogroups, with groups A, B, C, W-135 and Y being responsible for more than 90 per cent of worldwide IMD. In Europe, serogroups B and C are responsible for most cases, at 71 per cent and 13 per cent in 2009, respectively. Serogroup B is also responsible for approximately one-third of cases in North America.
Monovalent vaccines against serogroup C and quadrivalent vaccines against A, C, W-135 and Y are available. These vaccines have immunogens based on the capsular polysaccharides and they are able to provide broad coverage as the capsule structure is shared by isolates belonging to the same serogroup, regardless of their genotype. The latest of these vaccines conjugate the polysaccharide to a protein that induces a memory response to provide long lasting protection. Since 1999, serogroup C conjugate vaccines have been part of the routine infant immunisation schedule in the United Kingdom and have helped to reduce dramatically the number and proportion of serogroup C infections. In addition, the serogroup C vaccine was able to provide herd immunity by reducing carriage among adolescents and thus providing protection to unvaccinated individuals.
OMV vaccines
Unfortunately the approach of developing polysaccharide conjugate vaccines for serogroup B is not possible as its capsular polysaccharide is too similar to foetal neural cell adhesion molecules and therefore is poorly immunogenic and may induce autoantibodies. To overcome this, approaches using subcapsular antigens have been attempted. A vaccine (MeNZB) that utilised detergent-treated outer-membrane vesicles (OMV) as the immunogen was developed by the Norwegian Institute of Public Health and Novartis to successfully control a serotype B epidemic in New Zealand during the 2000s. OMV vaccines induce an immune response against a strain-specific protein called PorA. The problem with the OMV approach is that PorA is highly variable, and even when several PorA subtypes are used, these types of vaccine do not provide protection against a broad range of circulating serotype B isolates.
4CMenB
In an effort to develop a broadly effective vaccine for meningococcal B, companies have focused on identification of non-polysaccharide bacterial surface antigen targets that are highly conserved. Novartis’ recently approved 4CMenB vaccine was developed using a novel approach called reverse vaccinology. Instead of a traditional approach in which antigenic components from an inactivated pathogen are isolated and purified, Novartis used whole-genome screening to identify highly conserved antigens. 4CMenB contains four main immunogenic components: three recombinant surface-exposed proteins and OMV derived from the NZ98/254 strain (a New Zealand outbreak strain). The vaccine has been tested in clinical trials involving more than 8000 infants, children and adults and was found to induce protective bactericidal antibodies in the majority of infants six months or younger after three doses, in adolescents after two doses, and in adults after two or three doses. The coverage of 4CMenB against meningococcal strains appears to be broad, with one study showing that of 1052 strains collected in Europe between July 2007 and June 2008, the vaccine was able to induce bactericidal antibodies for an estimated 78 per cent of these.
In an effort to develop a broadly effective vaccine for meningococcal B, companies have focused on identification of non-polysaccharide bacterial surface antigen targets that are highly conserved. Novartis’ recently approved 4CMenB vaccine was developed using a novel approach called reverse vaccinology. Instead of a traditional approach in which antigenic components from an inactivated pathogen are isolated and purified, Novartis used whole-genome screening to identify highly conserved antigens. 4CMenB contains four main immunogenic components: three recombinant surface-exposed proteins and OMV derived from the NZ98/254 strain (a New Zealand outbreak strain). The vaccine has been tested in clinical trials involving more than 8000 infants, children and adults and was found to induce protective bactericidal antibodies in the majority of infants six months or younger after three doses, in adolescents after two doses, and in adults after two or three doses. The coverage of 4CMenB against meningococcal strains appears to be broad, with one study showing that of 1052 strains collected in Europe between July 2007 and June 2008, the vaccine was able to induce bactericidal antibodies for an estimated 78 per cent of these.
In the primary phase III trial, 4CMenB was administered to infants at two, four, and six months of age. One month after the third dose, 84-100 per cent of infants had a protective serological response. One month after the booster dose was administered at 12 months, protection was seen in 95-100 per cent of infants. In an extension study in 12-month old infants who had not previously received 4CMenB, it was found that a 96-100 per cent serological response was achieved one month after two catch-up doses were administered. 4CMenB was able to be co-administered with routine infant vaccines without affecting the immunogenicity of either vaccine; however, it was associated with a higher incidence of fever in infants when done so and this finding could become an important issue with routine use.
In a phase IIb/III trial in adolescents, two doses of 4CMenB administered one month apart were able to increase the serological protection from 34-44 per cent to 93-96 per cent one month after the second dose. A third dose at month 3 or 6 did not offer much additional protection. In those that received two or three doses of 4CMenB, seroprotection persisted at six months in 89-100 per cent of subjects. In those who received only one dose, seroprotection persisted at six months in 69-81 per cent of subjects. 4CMenB was also tested in adults with an increased risk of occupational meningococcal exposure. In a phase II trial, a single dose in this population increased seroprotection rates from 22-27 per cent to 80-88 per cent one month after administration. After a second dose, these rates had risen to 91-100 per cent and after a third dose, to 92-100 per cent.
The key strategy for controlling the disease is primary prevention with effective immunisation
The marketing authorisation application for 4CMenB was submitted to the European Medicines Agency in December 2010 and was approved in January 2013. The launch of 4CMenB is expected in late 2013 or the first half of 2014. Credit Suisse forecasts the vaccine to generate worldwide revenue of $250m during 2014, increasing to $1bn by 2018. Since the key strategy for controlling meningococcal disease is primary prevention with effective immunisation programmes, member states of the EU will be evaluating the vaccine for possible inclusion into national immunisation programmes and reimbursement schemes.
Bivalent rLP2086
Pfizer is developing a broad-spectrum meningococcal group B vaccine (rLP2086) that consists of two highly conserved variants of factor H-binding protein (fHbp). fHbp is also one of the immunogens used in Novartis’ 4CMenB vaccine, however, Pfizer independently identified it using a combined biochemical and immunological screening approach and designated it as LP2086 before it was identified as fHbp. Pfizer has stated that the fHBP gene is present in 100 per cent of 1200 different serotype B strains in its collection from the US and Europe, and therefore the vaccine should provide broad coverage. Serum from rLP2086 vaccinated rabbits was able to kill 87 per cent of 100 serotype B strains in vitro, and similar observations were obtained using serum samples from human vaccinees. Although this vaccine may not be effective against invasive meningococcal strains with truncated fHbp or those lacking fHbp altogether, it has been suggested that these strains are unlikely to survive in vivo as this protein is a key virulence factor that is used by the bacterium to evade complement-mediated bacteriolysis. In a phase II trial in adolescents aged 11 to 18 years, rLP2086 vaccine produced seroprotective rates of between 76 -100 per cent after three doses. It was well tolerated by this population and local pain was the most frequent reported reaction. Pfizer initiated three phase III trials of rLP2086 vaccine in Europe and the USA, in the second quarter of 2011, to assess the vaccine in individuals ranging in age from 10 to 65 years old. These trials are expected to be completed in late 2014/early 2015.
Novartis is also developing a multivalent conjugate vaccine (MenABCWY) that combines 4CMenB with its marketed meningococcal A, C, W-135, and Y conjugate vaccine (Menveo). The MenABCWY vaccine has completed several phase II trials in healthy volunteers aged between 10 to 25 years. Development remains at the phase II stage, according to the company’s pipeline.
Looking ahead
Vaccines against serotype B meningococcal disease have proved difficult to produce, and require a different approach from vaccines against other serotypes. Whereas effective polysaccharide vaccines have been produced against types A, C, W and Y, the capsular polysaccharide on the type B bacterium is too similar to human neural antigens to be a successful target. Development of the first approved broad-spectrum vaccine for meningococcal B has been over 20 years in the making. It remains to be seen if 4CMenB can dramatically reduce the number of cases of serotype B infection in a similar way that the meningococcal C conjugate vaccine did against serotype C infection in Europe, through its ability to create a long-term protective immune response and induce a herd immunity effect. Furthermore, there should also be monitoring for resistant strains of meningococcal B that express variants of the antigens in the vaccine.