The case for a MenB vaccine

With a long history of public health interventions against meningitis in the UK – we are the perfect test bed for a MenB vaccine, but it will need a whole new approach say Linda Glennie and Gillian Currie

Meningitis and septicaemia are deadly diseases that can strike anyone without warning, killing one in ten, and leaving a quarter of survivors with complications. Babies and young children are most at risk and few illnesses in Britain can cause such mutilating injuries.

Meningitis can cause deafness, severe mental impairment, spasticity, paralysis, epilepsy and blindness. Septicaemia can lead to amputations, tissue and skin loss requiring reconstructive surgery, growth arrests and deformities, and permanent damage to other organs such as kidneys, lungs, and endocrine glands¹. Less obvious cognitive problems may not become apparent until school age, limiting educational achievements for survivors.

These illnesses have far-reaching consequences for quality of life, with on-going need for specialist medical care, and impact on education, work, finances and family members who may become life-long carers.

Meningococcal infection, caused by Neisseria meningitidis is the most frequent cause of bacterial meningitis in the United Kingdom and also causes septicaemia which is typically more life threatening. There were 1,100 confirmed cases in 2009/10², but laboratory confirmed cases are likely to underestimate the true number of cases, since not all hospitals send samples for identification. Applying a correction based on admissions for meningococcal disease in Hospital Episode Statistics for England arrives at an estimate closer to 1,400. Although the disease is not common it remains the leading infectious cause of death in UK children³.

There are 12 serogroups of N.meningitidis, classified according to their polysaccharide capsule. Of these, six cause the most invasive disease: A, B, C, W135, X and Y, with serogroups B and C responsible for most cases in Europe.

Many advances have been made in improving the outlook for people affected by meningitis and septicaemia through early recognition, symptoms awareness, better treatment and comprehensive aftercare and support. However, there are limits to the improvements that can be achieved in this way; only prevention through immunisation can eliminate the infection.

Immunisation has been a tremendous success. It has virtually eliminated meningitis and septicaemia due to meningococcal C and Hib (Haemophilus influenzae b), and greatly reduced pneumococcal infections. Meanwhile, meningococcal B (MenB) remains the most common serogroup and has been the leading cause of bacterial meningitis for decades.

MenB infection is currently at a similar level as MenC when the MenC vaccine was introduced in 1999, and it kills more people each year than Hib infection at the time of the Hib vaccine introduction in 1992. Unfortunately, prevention of MenB disease has remained an elusive target as MenB vaccines are much more difficult to develop than vaccines for other kinds of meningitis.

All meningitis vaccines used in the routine UK childhood immunisation programme are based on conjugating the bacterial polysaccharide capsule to an immunogenic carrier protein. These ‘conjugate’ vaccines induce a T-cell dependent immune response, can prime for immune memory (where the immune system produces a booster response on reencountering the antigen) and are immunogenic in infants⁴. However, this approach cannot be applied directly in developing MenB vaccines, since the MenB polysaccharide, composed of ?2-8–linked polysialic acid, is structurally identical to foetal brain-cell adhesion molecules and therefore not immunogenic⁵.

With evident obstacles to the capsule-based approach to meningococcal B vaccine development, attention focused on non-capsular outer membrane structures, in particular outer membrane vesicles (OMVs). OMVs contain many antigens, including outer membrane proteins such as the porin proteins, with PorA the most abundant and immunodominant.   However, although PorA is expressed in nearly all meningococci, it is extremely variable⁶.

Unfortunately, prevention of MenB disease has remained an elusive target as MenB vaccines are much more difficult to develop than vaccines for other kinds of meningitis

This OMV vaccine approach was used in response to epidemics in Chile⁷, Cuba⁸, Norway⁹, and New Zealand¹⁰, but protection was strain-specific, especially in children. To increase coverage of OMV vaccines, other attempts have included using recombinant OMVs to express multiple PorA antigens¹¹, two different bivalent OMV vaccines^12,13, and a vaccine based upon OMVs from Neisseria lactamica¹⁴, a close cousin of the meningococcus.  Alternative approaches continue, including engineering OMVs enriched with different immunotypes of genetically detoxified lipopolysaccharide¹⁵, a native OMV vaccine with enhanced expression of multiple outer membrane antigens and genetically detoxified lipopolysaccharide¹⁶, and an OMV vaccine including six PorA and five FetA variants. Some of these have reached clinical trials.

Meningococcal bacteria are antigenically diverse and have a high capacity to change their surface structures in response to changing environments

There are two MenB vaccines currently in late stage development: 4CMenB from Novartis, submitted for licensure in December 2010, and Bivalent rLP2086 from Pfizer, currently in Phase 2 and 3 clinical trials. Both contain factor H binding protein, also known as lipoprotein 2086 (Pfizer) or GNA1870 (Novartis). Factor H binding protein has been found to be important in resistance to complement-mediated bactericidal activity, particularly by the alternative pathway. It is present in all N. meningitidis strains tested to date¹⁷ as well as N lactamica and N. gonorrhoeae.

Pfizer discovered factor H binding protein using detergent extraction and protein purification. From sequencing 63 isolates they found 21 unique versions of the protein, which they categorised into two subfamilies with low variability within each subfamily. Their bivalent vaccine contains factor H binding protein from Subfamily A and Subfamily B. Phase I trials in adults, teenagers and toddlers have reported encouraging results, and results from phase II trials in teenagers show that the vaccine is well tolerated and induces a robust SBA response against a diverse range of MenB strains. However it has not yet been evaluated in infants.

[caption id="attachment_28266" align="alignleft" width="200" caption="Histopathology of bacterial Meningitis: autopsy case of a patient with pneumococcal meningitis showing leptomeningeal inflammatory infiltrates consisting of neutrophilic granulocytes (inset, higher magnification). Hematoxylin-Eosin stain Credit Wikipedia/Marvin 101"][/caption]

The complete sequencing of a meningococcal genome in 2000¹⁸ led to the ‘reverse vaccinology’ or ‘genome mining’ approach to meningococcal B vaccine development. Using this approach, Novartis identified 600 theoretically surface-exposed and conserved antigens from the genome sequence, expressed them in E coli, and after selection of those with bactericidal activity from animal immunogenicity studies, constructed a composite of the most promising candidates. Their vaccine contains recombinant NadA and two recombinant fusion proteins, one with factor H binding protein, the other with Neisserial Heparin Binding Antigen combined with PorA OMV (MeNZB – the vaccine used in the New Zealand epidemic). Clinical trials in over 8,000 infants, toddlers, adolescents and adults have reported promising results, and further trials are underway.

The latest results from clinical trials and studies estimating potential coverage for both these vaccines was presented at Meningitis Research Foundation’s latest conference (available at www.meningitis.org/conference2011/programme).

Several questions as to how effective these vaccines will be remain unanswered. Laboratory studies¹⁹ suggest that 4CMenB would cover 73–87% of MenB strains in five European countries, but some uncertainty remains. Meningococcal bacteria are antigenically diverse and have a high capacity to change their surface structures in response to changing environments, so that selective pressure due to vaccination or other influences could lead to escape mutations, reducing vaccine coverage in the future. The extent to which these new vaccines will generate herd protection is also unknown. The success of conjugate vaccines has been largely due to their impact on acquisition and carriage of meningococci, something which has not been shown for meningococcal outer membrane protein vaccines. Studies are underway to shed light on all of these questions, but it is unlikely that they will be fully answered until a vaccine is introduced.

The UK could be a test case for a new MenB vaccine: with a relatively high disease incidence, a long history of pioneering public health interventions against meningitis, and central provision of vaccines with consistently high vaccine uptake, as well as expertise in intensive monitoring and surveillance, it could demonstrate to the world the potential for prevention of MenB disease.

[caption id="attachment_28267" align="alignright" width="200" caption="This micrograph depicts the presence of aerobic Gram-negative Neisseria meningitidis diplococcal bacteria; Mag. 1150X. Meningococcal disease is an infection caused by a bacterium called N. meningitidis or the meningococcus. The meningococcus lives in the throat of 5-10% of healthy people. Rarely, it can cause serious illness such as meningitis or blood infection"][/caption]

However, immunisation policy is increasingly guided by economic evaluations. In the current cost-cutting environment, with a recent decision against the implementation of rotavirus vaccine on grounds of cost alone, this could yet present an obstacle to the introduction of a licensed MenB vaccine. Accurate cost of illness data is a fundamental component of economic evaluation, but a study of cost effectiveness of MenC vaccine pointed to a lack of published information on costs of treatment and rehabilitation of meningococcal disease at the severe end of the spectrum²⁰. To address this, Meningitis Research Foundation has undertaken a project to estimate the costs of severe meningococcal disease and launched a campaign calling for the early introduction of meningitis vaccines (www.meningitis.org/counting-cost-campaign) which has garnered over 16,000 signatures to date.

Meningococcal B infection has devastating consequences for families affected. The implementation of a broadly protective MenB vaccine in the event of licensure will be a long awaited first step in solving a significant public health problem in the UK, with global ramifications.

Authors: Linda Glennie and Gillian Currie. Linda is Head of Research and Medical Information, and Gillian is a Research Officer at Meningitis Research Foundation

References:

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