Meningitis B and the future of vaccines

This week is a good week for vaccines. Indeed it is a good week for society, at least in Europe, for we have just got word that the European Medicines Agency has approved Novartis's Meningitis B vaccine  and it could now be available in the UK as early as next year, if licensed here. *Novartis are currently working with the US authorities at getting it approved*

This vaccine, targeting Neisseria meningitidis group B bacteria (B subgroup causes the most problems in industrialised countries) is reported to be around 70% effective against the horrible and often deadly disease. It's roll out across the UK and Europe should save the lives and prevent the permanent damage that follows meningitis and septicemia. That's great, sure, but as scientists and people interested in public health, how the heck did they achieve this feat?

The development of this novel pharmaceutical (they call it 4CMenB) tells an inspiring story for the creation of new vaccines in the future. You can read about it here, here (free) and here (free). The Novartis team employed a strategy encompassing the realms of genomics, structural biochemistry and animal models along with the all important clinical trial system to create the vaccine that this week was approved by the EMA. 

But to begin with they had the difficult task of determining exactly what parts of the meningitis bacteria they would put into their vaccine. For one, the bacterial genome encodes two thousand proteins, all potential antigens and across the world, N. meningitidis is one diverse pathogen. So how can we make a vaccine that can elicit protective immunity across all known sequence diversity?

For the other meningitis sub types, C and A for example, we use vaccines containing their polysaccharide coat. This capsule structure that covers the bacterial cell allows the pathogen to adhere to human cells and proliferate in the body. It is also widely available - being on its surface - for your body to target. We can't do this for meningitis B as it's capsule structure looks a lot like those polysacharides of your own cells. Basically, your body won't attack it because it looks good and friendly, one of its own.

What part of this bacterium should our vaccines target?  http://wikieducator.org/images/c/c2/Bacteria_structure.png

This was the state of affairs over 40 years ago when we first realised our attempts at generating a capsular menB vaccine were failing. What's been occupying our minds for the last four decades is the discovery of antigens that allow our bodies to mount a protective immune response. This is where we encounter the other problem: the high sequence diversity of N. meningitidis strains. Strain-specific vaccines were developed but non offered a universal solution to group B meningitis. That is until now.

The Novartis group took the previous 40 years to herald a failure in our traditional vaccine development model - the old ways had failed us. So they looked to emerging technologies to provide an answer to our meningitis problem and that technology was whole-genome sequencing and bioinformatics. This allowed them to determine the entire protein - and hence antigen - coding capacity of N. meningitis and figure out which one of the two thousand proteins would be good vaccine candidates, for example: which were surface exposed and which were virulence factors. Each potential antigen was taken through lab models looking at bacterial expression, antigenicity and the capacity to generate immunity (in mice) against the diverse bacteria. Some had to be tweaked a bit to achieve cross protection but hrough this combined in silico/experimental approach they identified 3 key protective antigens that eventually made it into the vaccine that has recently been approved by the EMA, following the necessary clinical trials and now they are already applying this method to pathogenic E. coli.  Nice isn't it?

Moving ahead, how can we apply this way of thinking to specifically target other pathogens? Remember that there are many more pathogens for which no or only a poor vaccine exists than there are ones with a good vaccine. Also we are going to need a safe, protective, rapid and cost effective approach to deal with controlling infectious diseases (and non-communicable diseases) with vaccines in the future, especially with the major burden of infectious diseases in the developing world (filoviruses, respiratory syncytial virus or hand foot and mouth disease) and the ever-looming spectre of completely unknown emerging viruses from zoonotic reservoirs such as bats or birds for example. What we need is a way of rationally designing vaccines against these pathogens, not the more traditional method of labour intensively and empirically creating vaccines for each individual virus or bacteria that exists. 

Compare these two methods of creating vaccines against two viral pathogens as they represent the two sides of this vaccine debate. Which is more attractive?

: SARS coronavirus 

A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease

• Rachel L Graham,
• Michelle M Becker,
• Lance D Eckerle,
• Meagan Bolles,
• Mark R Denison
• &Ralph S Baric

Live, attenuated RNA virus vaccines are efficacious but subject to reversion to virulence. Among RNA viruses, replication fidelity is recognized as a key determinant of virulence and escape from antiviral therapy; increased fidelity is attenuating for some viruses. Coronavirus (CoV) replication fidelity is approximately 20-fold greater than that of other RNA viruses and is mediated by a 3′5′ exonuclease (ExoN) activity that probably functions in RNA proofreading. In this study we demonstrate that engineered inactivation of severe acute respiratory syndrome (SARS)-CoV ExoN activity results in a stable mutator phenotype with profoundly decreased fidelity in vivo and attenuation of pathogenesis in young, aged and immunocompromised mice. The ExoN inactivation genotype and mutator phenotype are stable and do not revert to virulence, even after serial passage or long-term persistent infection in vivo. ExoN inactivation has potential for broad applications in the stable attenuation of CoVs and, perhaps, other RNA viruses.

and Mumps virus

Identification and development of a promising novel mumps vaccine candidate strain.

Liang Y, Ma S, Liu L, Zhao H, Wang L, Jiang L, Xie Z, Dong C, Li Q.

Mumps epidemics are usually caused by airborne transmission of mumps virus (MuV) and have high morbidity in non-immunized children. Epidemiological studies in many regions of China show that the genotype F viral strain is the most prevalent. However, the genotype A strain is currently used to prepare vaccines. Regional epidemiological MuV data suggest a significant application for the development of live attenuatedmumps vaccines targeting specific genotypes. This article reports the isolation and culture of a genotype F MuV candidate strain that could be used to prepare a live attenuated mumps vaccine. This strain is shown to have good immunological efficacy and stability in neurovirulence evaluations. This work should facilitate the implementation of mumps vaccination in mainland China by targeting the most prevalent MuV genotype, genotype F.

Serruto D, Bottomley MJ, Ram S, Giuliani MM, & Rappuoli R (2012). The new multicomponent vaccine against meningococcal serogroup B, 4CMenB: immunological, functional and structural characterization of the antigens. Vaccine, 30 Suppl 2 PMID: 22607904