Merck's mumps vaccine is good. But not good enough.

It came out this week that two former employees are suing Merck (here's the document), the pharmaceutical company/giant, over what they say was a deliberate attempt to con the US government - and by extension many other countries - into buying a mumps vaccine in the form of their combination MMR-II vaccine that was not as effective as they had previously stated. 


As documented here this has been jumped on by a number of anti-vaccinationists but if you really look at the data from the "real world", you'll quickly see how all parties have really jumped the gun a bit on this issue and that clearly the vaccine is - and has been - working well. But it could be better.

Do we really need a new measles vaccine?

Measles, that deadly childhood infectious disease is almost a distant memory to most people nowadays, that is except for a few isolated outbreaks across the US and Europe. This is all because of a really amazing preventative therapy: the vaccine.

Vaccines are great. They are by far the most effective means that we have to control - and hopefully eradicate - infectious diseases from a range of species. Measles is one of these diseases that, over the last half a decade or so, we have backed into a corner across the world. Before the introduction of global immunisation the measles virus caused around 2.6 million deaths, most of which were children. To show just how great the vaccine is: 2008 saw only 164,000 deaths (see the WHO data here). A big number still but a 97% decrease in associated fatalities is pretty impressive, so why then - in an editorial piece in the esteemed journal Vaccine, are they calling for researchers to develop a new vaccine?

Are microbes evolving to escape vaccination?

What if all those vaccines - those ones that work really well - all stopped working? Imagine if the viruses and bacteria from which they are trying to protect you against, evolved and adapted to life in a largely immune population? Those robust antibody and T cell responses generated within a person following vaccination supply the perfect breeding ground for the selection of resistant mutants where anibodies can no longer recognise and neutralize their targets and where T cells fail to eliminate infected cells. So, is it possible and is it happening?

Well, we already know this kind of phenomenon from influenza, right? Every year we have to change the strains that are put into your flu jab to match those viruses predicted to be circulating come winter. This is based on generating an antigenic match of vaccine to wild virus; specifically, their surface HA proteins must look the same. This is why there has been such a push to develop universal influenza vaccines capable of immunizing people against all flu strains. For viruses like measles and mumps however, we have our universal vaccine, or at least we thought we did.

Influenza may change through antigenic drift and shift forcing us to develop new vaccines each year, but do other viruses evolve through antigenic drift and force us to generate improved vaccines for them? http://news.bbc.co.uk/

Will viruses eventually hail our destruction?

#SciDoom The summer of 1918 heralded the arrival of the now infamous strain of influenza virus known from here on as the 'spanish flu' in which 6% of the world's human population succumbed to its deadly form of pneumonia. That particular virus outbreak swept across the world and did it's damage over a single year before abruptly ending it's reign of terror just as quickly as it started. 

In the heat of the 'swine 'flu' epidemic. Will a virus wipe us out or can we stop it before it does it?  http://news.bbc.co.uk/

The same thing may well have happened across either in Asia or Africa when the smallpox virus first emerged into the human population, only to end up killing 500 million people in the 20th century alone. And to show that this is not some strange quirk of the past - just google virus outbreak and you'll be bombarded with the recent problems with Hendra virus outbreaks in Western Australia. Viruses have had - and always will have - the ability to cause serious damage and with that comes the power to cause some serious fear. 

(For the more curious reader, see: HIV, SARs, Nipah, ebola, marburg).

Nothing, I don't think, will ever change that.

Ebola - virus from the forest. http://en.ird.fr/

The real question then comes down to - are we doomed when it comes to these viruses? Will a virus eventually appear that will kill off the entire human race? How likely is it that some as yet unknown virus will emerge from a tropical rainforest somewhere and end up wiping us out? 

What I think the answer to this is that we just don't know and we cannot say yet BUT we are in a better position nowadays than we have ever been and this in itself is cause to be optimistic. 

3 reasons why I believe what I believe:

1. We understand a lot more about viruses than we did 50 or 100 years ago - just look at the sheer amount of work that has been published in the last decade (even if all of it isn't worldclass, ground-breaking stuff). Researchers have discovered the many mechanisms that viruses employ to enter our bodies and gain access to our cells; we know how they spread within the body and we are constantly investigating how they cause disease and illness. This is all with a goal of eventually preventing it through the exploitation of our new-found knowledge. Decades ago, people were not able to do the kind of research we are now carrying out daily in the lab and I predict that this will even get better in next couple of years
2. Many new vaccines are being developed and tested in a clinical setting every year with an aim to eradicate or at least seriously reduce the number of those particular viral infections. Just look at what has happened with HPV vaccine, chickenpox, parainfluenza viruses and even consider the historical prowess of the measles, mumps and rubella vaccine. We have also officially wiped out rinderpest virus - a major killer of cattle worldwide. These viruses will definitely not starve us. On top of the developments in vaccine generation -  lot of research is throwing back very positive results concerning new antiviral molecules that may show great potential.
3. We are even trying to outsmart the viruses at their own game of emergence by attempting to detect them early on and hopefully prevent them from spreading any further than that small focal point of infection. Groups like that led by Nathan Wolfe (and others - see the Emerging Infectious Diseases Journal) have been spending years in sub-Saharan Africa, in the rainforests of the Congo Basin, trying to see what viruses lurk in the animals living there. We do not want another HIV, ebola or indeed Hendra/nipah occurring again without us knowing about it first. 

But sadly, its not all great in the world of virology research. Each one of the above points has a number of disclaimers or nasty examples where we haven't really made all that much progress:

We may know a lot about the molecular biology of these viruses - but what is that actually worth in terms of new vaccines/antivirals? See mumps virus SH protein distribution (cyan) within a cell. P Duprex.

• Clearly the last 50 years of molecular virology hasn't yet really proved it's worth, as it is pretty difficult to effectively convert that kind of knowledge into a clinical setting. Not every standard university research group has the ability - or the money - to fund a large clinical trial against their particular candidate drug target.

• A number of viruses we have completely sucked at developing any vaccines at all for. And even when we do develop them, the make things even worse.

• No matter how many people you have looking for viruses out there, I can assure you there are more viruses than people so we all know who is gonna win that one.

But, as I said before, we are in a hell of a better position than we were in 1918 when that spanish flu struck the world. Look at what happened with the SARS outbreak or avian/swine-influenza - we have developed a great global protection system that can prevent these viruses.

So, are we doomed? 

I cannot say and I don't think anybody really can either - that is with reference to viruses.

 

Improving global immunisation with more heat tolerant vaccines

During the last century, mass vaccination campaigns were rolled out across much of the industrialised world. And, with much success, we have near eradicated most common virus infections from these populations.   Despite the more recent efforts to bring the developing world into this fold, major setbacks have been uncovered, one being: how exactly are we to stably transport  delicate vaccine stocks from their place of production to the regions that need it most.

   Many of these vaccines, known as 'live attenuated vaccines' - or LAVs-are generally unstable in the environment outside of our cells and bodies. For example, the measles virus has an outer lipid membrane that is highly delicate and damage to this removes any chance of this vaccine working. Basically, these LAVs, which rely upon a weaker infection, cannot successfully complete their replication cycle without an envelope. Generally, the ability of a vaccine to provide protection is intrinsically linked to its overall structure; you destroy the structure, you destroy protection.

Unstable measles virus particles

  The more difficult places to transport vaccines to  happen to be more tropical regions, like sub-Saharan Africa, South America and South-East Asia. These places are very warm and humid which goes against what our vaccines like. With temperatures up to 40 degrees Celsius and the fact that freezing also destroys the vaccine, the only way forward is the implementation of a cold chain. If we keep the vaccine stock 'chilled' from manufacture (see Merck or the Serum Institute of India) all the way to administration, then we have a chance to prevent its degradation. But this is not as easy as it may sound as it is economically and logistically difficult to achieve this in developing countries. To overcome this, the produced vaccine stock is freeze-dried to remove any water that may contribute to its instability and when this prep reaches the clinic it is then reconstituted through the addition of a solvent preparation, which has then all got to be kept cool.

With measles virus vaccines however, even upon reconstitution, there are still major losses to immunogenicity and this problem is compounded with the use of multi-dose vials of vaccines. A single vaccine stock, prepared in the morning may now sit in the clinic unrefrigerated until the end of clinic hours. If we were then to get immunized at 5:00 pm, what are the chances of that being successful? It is thus not much of a surprise to hear that many virus outbreaks have been attributed to breaks in the cold chain like this. Our ability to eradicate many diseases in these countries and hence worldwide, is blocked by difficulties in the cold chain.

   Being so, Bill and Melinda Gates identified "Vaccines That Do Not Require Refrigeration" as one of their funded 14 Grand Challenges in Global Health and the results of one potential solution to this problem have just been published in the journal Vaccine (read it here). This work aimed at identifying novel reconstitution liquids that would increase the thermostability of the prepared vaccine and therefore increase its 'shelf-life' in these more difficult environments. Using a recombinant measles vaccine virus that expresses green fluorescent protein (GFP) upon infection, the group were able to assess the level of infectivity of a range of vaccine stocks reconstituted in varied solutions.

Counting measles virus infected (GFP positive) cells

   Indeed, they tested >11,000 formulations (myriad combinations of buffers, stabilizers, solubilizers, preservatives, pH and tonicifiers - whatever they are?) using their recently developed high-throughput system in which they were able to automate the whole process. These results were validated and confirmed with another virus, this time an adenovirus expressing GFP; results were the same. The group identified a formulation that caused the vaccine to "suffer <1.0 log loss after 8 h at 40 ◦ C in the liquid state", a major improvement on a previous loss of" 1 log of potency after 8 h at 37 ◦ C in the reconstituted (liquid) form". In conclusion, they identified a novel vaccine formulation that substantially increased the stability of two viruses, which can be used in immunization campaigns worldwide. As I've alluded to before, the use of high-throughput screens has much potential in the world of virus research.

Log loss of infectivity of vaccines

   How is this result likely to change vaccine implementation in the real world then? Well, the evidence presented here indicates the ability of creating more stable vaccines that would transfer to better vaccine coverage yet the real problem appears to be whether current vaccine manufacturers would accommodate such a significant change to production, especially given their inherent unwillingness to invest in the developing world.

   The cost associated with this may be offset by the savings made through reduction in vaccine wastage and loss of cold chain implementation but we must realise that only when such an improvement looks attractive to the market will change come. The future of vaccination looks to be bright, especially with the combination of newer technologies and the backing of large philanthropic organisations.

Schlehuber LD, McFadyen IJ, Shu Y, Carignan J, Duprex WP, Forsyth WR, Ho JH, Kitsos CM, Lee GY, Levinson DA, Lucier SC, Moore CB, Nguyen NT, Ramos J, Weinstock BA, Zhang J, Monagle JA, Gardner CR, & Alvarez JC (2011). Towards ambient temperature-stable vaccines: The identification of thermally stabilizing liquid formulations for measles virus using an innovative high-throughput infectivity assay. Vaccine PMID: 21616113

Why should we support WHO Immunisation week?

Currently, children find themselves vaccinated against the harmful effects of myriad different bacterial and viral pathogens: Corynebacterium diphtheriae (diptheria), Clostridium tetani (tetanus), bordatella pertussis (pertussis/whooping cough), polio (poliovirus), hepatitis (hepatitis A and B virus), Haemophilus influenzae, measles, mumps and rubella viruses, pneumonia (Streptococcus pneumoniae), tuberculososis (Mycobacterium tuberculosis) and chickenpox/shingles (varicella zoster virus). Add to these: cholera, human papilloma virus, influenza, meningitis and rotavirus and what you have is a recipe for the improvement of global health.

As many of us in more developed regions of the world rarely come across such things (although it is hard to forget the continuing presence of measles, mumps and influenza across North America and Europe), you may not consider many of these diseases important, yet imagine the effect these pathogens have across the developing world. Think of the young lives lost to these common respiratory pathogens and think of what effect chronic illnesses such as paralytic polio and hepatitis have on not just individuals but communities and families. And, what  must also be remembered is the reason why, we in the developed world, may not come across these terrible diseases - the reason is vaccination. Moreover, the continuing force of rapid and easy global air travel requires us to develop a truly global immunisation effort to prevent the transmission of these pathogens.

 
This week marks the World Health Organisation's (WHO) Immunisation week which has been set up to focus attention on the continuing importance of protecting our children from common yet serious vaccine-preventable diseases. With 180 countries and territories participating worldwide and specifically holding their own weeks in support of this, teams will aim to extend vaccination coverage and support into areas not easily accessible to immunisation campaigns and importantly begin mass-coverage schemes for the likes of measles and polio. But, what is really important here is that this is not just about vaccination, it is about increasing child survival in a broader sense in already under-developed regions and to this effect, vitamin supplements and other medicines are also being distributed.

WHO immunisation week sets out to:

Engaging communities for immunization

Immunization week is led by WHO to:

• vaccinate vulnerable populations, for example those living in border areas and urban fringes;
• raise awareness on the importance of immunization in protecting people against life-threatening illnesses;
• expand the culture of disease prevention and control though vaccination;
• ensure continuing political commitment for immunization

The upkeep of global immunisation requires that the worldwide human population is continuously protected via vaccination, remembering that many of those diseases mentioned above still cause significant illness and deaths in across the developed world. Amazingly, it is not as if we need to develop new vaccines to protect from these diseases; we have them already. Vaccination has proved to be a safe and cost-effective means at reducing the effects of these diseases on the global population so support WHO immunisation week and help raise awareness of just how essential a global strategy to vaccination is.