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/

Mumps outbreaks - why here, why now? and how can we stop it?

Mumps is an acute viral disease of humans and really only humans. It is spread through the respiratory tract (probably droplets and aerosols) where the virus most likely infects the cells lining the epithelium - we don't really know this for certain. From here it spreads throughout the body, infecting organs and tissues such as the salivary glands, testes and ovaries, pancreas, and perhaps most worryingly, your central nervous system. In fact, in the pre-vaccine era, mumps was the biggest cause of aseptic meningitis across the developed world; it can also cause the more severe encephalitis.

Lucky we've got a vaccine, right?

#vaccines - can you predict how well they'll work?

 

Vaccines are great aren't they -  they offer us probably the most cost-effective means of reducing death and suffering on a worldwide scale that extends to both humans and other animals. The problem is that it's never been as easy as just dreaming up a vaccine for the latest virus to afflict us. Effective vaccines are extremely difficult to produce, even for the most well-researched pathogens and, even when you do develop one, plow billions into it's generation and testing, and get it successfully through all the necessary clinical trials it still might not work so perfectly. 

Should vaccinology embrace systems biology?

Any intelligent fool can make things bigger, more complex, and more violent. It takes a touch of genius -- and a lot of courage -- to move in the opposite direction.

E. F. Schumacher (1911-1977) British Economist

Vaccines represent one of the most cost effective methods around to prevent loss of life and disease in a whole range of animals, including the human population. Over the last 200 years or so, we've become pretty adept at producing them and so the science of vaccinology - or how to generate these complex pharmaceuticals  - has led to the eradication (and near eradication) of many viral pathogens.

This is one network in your immune response following influenza vaccination (Kokke et al 2011) as id'd through systems biology approaches. Knowledge of key mediators in these pathways may allow for the rational design of new vaccines - but is it worth it?

But, it hasn't succeeded for a number of currently killer viruses (respiratory synycitial virus and HIV to name but two) and we have begun to think that maybe the method of 'isolate, attenuate, vaccinate' or the synthesis of single virus antigen molecules isn't gonna cut it anymore. So what are we going to do?

We are wanting to rationally generate vaccines - taking a wild-type, disease-causing isolate and through some genetic engineering, make it sufficiently weak so as to generate an effective immune response in patients while not causing disease. Yet, this is harder than it looks and so some researchers are now turning to systems biology to offer a glimpse into how some of our most successful vaccines function so as we can reconstruct these processes for the numbers of viral pathogens we are yet to protect against.

*I have explored how we may attempt to do this from the viruses perspective (mumps virus versus vaccine, here), more precisely: how come the vaccine strain is less deadly than the 'wild' strains. Both are valid approaches and probably just as difficult to carry out as each other.*

Systems biology affords us a chance to more fully understand the complexity of living systems. Through the collection of reams of data (DNA sequences, gene expression changes, protein levels - and other 'omics' technologies) we are now able to adequately model what is going on in the organism/cell through now more common bioinformatic and statistical analyses. As in the quote I used above, it is not about making the study of life more complex, it is really about realizing this fact and doing something to understand it better under a broader way of thinking. This allows us to 'see' changes and functional differences that we would never have observed had we gone about such an experiment using our a priori knowledge and this global, holistic view may just be the savior that vaccinology needs now.

Example of the complex data collected during a typical 'systems' experiment - what does it all mean, and how can we find something important and worthwhile to study?

I am aware of a number of papers that are currently using this process as a primer to develop improved vaccine products (see here, here and review here of virus vaccine examples). These guys - for example: Bali Pulandran of the Emory Vaccine Centre in Atlanta, USA - are interested in comparing the immune response (humoral response, innate immunity and gene expression changes) of human subjects administered with vaccines. The response to the yellow fever virus vaccine as well as two types of influenza vaccines have been approached and through complex bioinformatic modelling they were able to pull out some significant correlates of immune response - this they hope will aid in the future testing of novel vaccines and facilitate a rational take on vaccine generation by identifying a gene(s)/protein with a functional role in the immune response. This they have begun to do in some of ther papers above - it is nice to see this kind of work being used as a basis for experimental biology.

These types of studies hail a new way of thinking about viruses, vaccines and the immune response to them; if only we can realize the power in taking a step back and looking at the diversity in each. And this type of work could be applied to any number of mechanisms such as vaccine safety or applying it to different tissues during an infection.

Saying that - this stuff isn't particularly easy, cheap or quick as you might think. But as each study generates so much data, might it not take but a few such investigations to lead us on the way of rationally attenuated and protective vaccines? So, should vaccinology embrace systems biology? I think if you have the abilities to do such a study - which from a pharma perspective definitely yes, do it as the more information we have at our disposal the better position we are in. We await further results from these groups to compare how well systems thinking goes up against human ingenuity, that has worked well in the past.

Nakaya HI, Wrammert J, Lee EK, Racioppi L, Marie-Kunze S, Haining WN, Means AR, Kasturi SP, Khan N, Li GM, McCausland M, Kanchan V, Kokko KE, Li S, Elbein R, Mehta AK, Aderem A, Subbarao K, Ahmed R, & Pulendran B (2011). Systems biology of vaccination for seasonal influenza in humans. Nature immunology, 12 (8), 786-95 PMID: 21743478

HIV & Measles - double hit pathogenesis?

Despite ongoing worldwide eradication efforts, measles infection still results in significant morbidity and mortality. Although, throughout most of the developed world measles infection has been considerably reduced there still exists massive (and deadly) outbreaks in areas such as Africa and South-East Asia. Investigation of the reasons why this disparity occurs therefore  is of major medical, political and social interest.

Many factors are likely to be behind this major difference - and all of which deserve our attention if we are ever to remove measles from the human population. There exists problems in rolling out vaccines in countries with poor infrastructure such as roads and transport facilities; disruption to what is known as the vaccine 'cold-chain' (vaccines have to be kept cold to avoid rendering them unusable) is likely to occur; general poor health of the population in these regions and possible interference of vaccination in children with high levels of passively acquired maternal antibody.

Measles vaccination efforts in Africa may not be entirely effective

Today in PLoS Pathogens, Nilsson and Chiodi highlight in a featured opinion article, another possible source: the link between co-infection with HIV-1 and Measles infection. They point out that HIV-1 infection and replication may result in impaired immune responses in both mothers and children leaving open the possibility of measles infection (no immune system, no protection). HIV-1, as I'm sure you will all know, is a potentially deadly pandemic retrovirus - particularly a major problem in sub-Saharan Africa- which infects humans where it resides in the bodies own immune system: T cells, dendritic cells and macrophages. Viral replication results in the death of these immune cells and destruction of important lymphoid tissues resulting in an individual without key immune functions.

The authors note that children born to mothers who are HIV-1 positive or are HIV-1 positive themselves develop lower levels of anti-measles antibody upon vaccination -a big deal if we're looking to protect these kids through vaccination. They show that memory B cells may be impaired and lower protection will result through failure to mount a B cell-generated antibody response. Immunity is a highly regulated system, if you remove one aspect-  in this case T cells - you will affect another pathway , in this case B cells. Thus there exists a major  problem with HIV-1 infected people and infection with other pathogens in the environment; HIV-1 infection significantly alters the host immune system weakening it to other invading pathogens such as measles which is endemic in these areas.

So how do we overcome this problem? Well, the authors suggest that on top of increasing vaccination coverage through catch-up programs it would be wise to administer anti-retroviral drugs  to mothers and children prior to vaccination to allow sufficient immune function; this should hopefully make a difference in combating both measles and HIV in the developing world, especially in an area where both cause so much pain. Hopefully, strategies such as this will aid treatment efforts for other pathogens rife in the developing world - targeting both HIV and the individual agents may be more effective.

Sadly, there exists another interaction between HIV and co-infection with other pathogens. Infection usually results in increased levels of immune cells in the blood and tissues yet these very cells are the target for HIV and if these cells increase, HIV replication will also. There exists a deadly interaction between multiple pathogens which must be broken.

Nilsson, A., & Chiodi, F. (2011). Measles Outbreak in Africa—Is There a Link to the HIV-1 Epidemic? PLoS Pathogens, 7 (2) DOI: 10.1371/journal.ppat.1001241

A mothers love declines - a measles vaccine problem?

Worldwide, measles virus infection accounts for around 200,000 deaths annually; the importance of which is emphasized given the availability of a highly effective vaccine. Vaccine effectiveness, however, is a complex matter and is subject to many problems – a major one being transfer of maternal antibodies to children during early life, a form of natural passive immunity. Although these antibodies are there for a reason and do protect offspring from infections in early life, bridging the gap until they can synthesize their own antibodies, they have been shown to inhibit the activity to certain vaccines – measles vaccine is an example (see figure below).

[caption id="" align="aligncenter" width="381" caption="Antibody concentrations in child following birth showing decline in attenuation (infection attenuation)"][/caption]

During early childhood, maternal antibody concentrations begin to wane and eventually reach such a level as to offer little protection from microbial challenge. These antibodies however are able to dampen the ability of a child to develop protective immunity following vaccination; it is this ‘window of opportunity’ that is responsible for a great number of measles virus infections and fatalities every year. The development of an effective vaccination strategy to get around this blocking effect would therefore be of great medical interest.

Recently, Kim et al (2010) publish their investigations into understanding how and why measles virus infection, in the presence of specific antibody results in the inhibition of a protective response following vaccination. Prior to this study it was unknown whether in this situation, MeV-specific B cells were being generated at all or whether they simply failed to secrete neutralizing antibody. The group used a rat model of MeV infection and simulated maternal antibody effects by passively transferring MeV specific antibodies and measuring the immunological outcomes. They demonstrated that there is a specific failure of B cells to secrete protective antibody in the presence of transferred antibody.

B cells will only secrete antibody when 3 signals are triggered:

1.     B-cell receptor/antigen interactions

2.     B – cell/ T-cell interactions

3.     Action of soluble mediators (for example: cytokines like interferon)

Kim et al hypothesized that in this model, where both signals 1 and 2 were active, inhibition of antibody secretion may be accounted for by the interference with certain soluble mediators. This idea was attractive providing the great deal of evidence showing MeV obstruction of interferon production - a pathway that normally results in the robust development of innate and adaptive immune responses. This results in two major problems involving antibody-specific inhibition of protective immune responses (maternal antibody) combined with MeV’s natural ability to inhibit the development of immunity; cases which are shared during the ‘window of opportunity’.

To this effect, the group developed a novel vaccine vector to circumvent wild-type measles interferon inhibition. Using reverse-genetics technology, they incorporated a MeV antigen gene, the haemagglutinin (HN) glycoprotein into the Newcastle Disease virus (NDV) genome as an extra gene, generating NDV-HN. NDV is an avian virus that induces high concentrations of IFNs upon infection allowing for the possibility of an effective measles vaccine in the presence of measles antibody.

The investigation confirmed the group’s predictions in that NDV-HN induced much higher levels of IFN in rat tissues when compared to MeV and that this led to development of MeV-specific neutralizing antibodies in the presence of transferred antibody. This work further verified that role that the restoration signal 3, in the form of alpha-IFN allows for B-cell secretion of antibody in in vivo and in vitro systems.

Given how medically important vaccination has been in protecting populations from often fatal and serious infectious disease and the troubles that arise when maternal antibody concentrations drop, any work developing vaccine technology to avoid these difficulties should be welcomed. Kim et al. confirmed the basis for the immunological blocks in generating MeV antibodies and began the development of a novel vector system to rationally provide protection. The results in this rat model, although not specifically applicable to the human situation, are promising in that it provides a logical framework to advance vaccine technology and prevent thousands of childhood deaths worldwide.

Kim D, Martinez-Sobrido L, Choi C, Petroff N, García-Sastre A, Niewiesk S, Carsillo T. (2011) Induction of Type I Interferon Secretion through Recombinant Newcastle Disease Virus Expressing Measles Virus Hemagglutinin Stimulates Antibody Secretion in the Presence of Maternal Antibodies. J Virol. 2011 Jan;85(1):200-7. PMID: 20962092