What Do We Need? Good Vaccine Design! When Do We Need It? Now!

The infectious agents that continually assault our bodies are many and diverse. Even just a few decades ago, diseases such as smallpox and typhoid were killing millions every year and some still are. Thankfully for us, at least for some diseases, this picture has changed, and the development of vaccines has played a not insignificant role in this achievement. A couple of disease have even been eradicated with the help of vaccines, namely smallpox and rinderpest (at least in nature anyway).

So, what is a vaccine?

A vaccine is defined as a biological preparation that resembles a particular disease-forming microorganism, which when administered provides acquired immunity to the disease caused by that microorganism. “On a global scale, vaccines represent one of the most successful and cost-effective health, medical and veterinary, interventions ever” commented Professor of Veterinary Clinical Microbiology, Anders Mikki Bojesen, of the Department of Veterinary and Animal Sciences at the University of Copenhagen in Denmark. “Appropriate concerns about antimicrobial resistance has sparked new life and funding into sciences aiming at preventing infections rather than dealing with them when they appear using antibiotics”.

But when looking to tackle a pathogen with a vaccination strategy, where does one begin? It may seem obvious but the key facilitator in developing an effective vaccine is having a comprehensive understanding of the pathogen, how it interacts with and evades the hosts immune system and then goes on to cause the disease. Whilst this sounds simple in principal it can be, and usually is, a far more complex undertaking. “Whilst some toxin associated diseases like tetanus and viruses like smallpox have been successfully controlled for decades by vaccines, larger organisms like bacteria and parasites are antigenically much more complex and hence have been much more difficult to handle by vaccination. Due to a deeper insight into the pathogenesis of these organisms combined with novel ways of identifying universal antigens (vaccine targets) and new knowledge about efficient immune responses, we are now at the brim of a new era where also bacterial infections may be prevented in a cost-effective manner” continued Professor Bojesen.

Choosing a type of vaccine

Once you understand your pathogen of choice (or at least think you have a vague idea) you will have to decide on the type of vaccine best suited to confer the highest levels of protection. There are a number of ways that you can modify a virulent microorganism to make it both safe for use as a vaccine and still retain the ability to induce a protective immune response to challenge. None of the methods are necessarily “better” than others and different ones may well work as efficiently for the same pathogen. However the ease of design and manufacture will ultimately determine the cost and how much the vaccine is used in reality. So, what are some of the options in this constantly developing field of science?

1. Killed/inactivated - virulent organisms that have been deactivated in some way, such as chemical or heat treatment. Examples include polio and hepatitis A.

2. Toxoid – a purified toxic component that causes the disease that has been inactivated, often chemically or via the use of heat. Tetanus and botulism vaccines are good examples.

3. Live attenuated – live organisms that have been disabled in some manor (via gene mutation or deletion – be it naturally through passaging or by genetic/chemical engineering) that makes them none pathogenic, for example yellow fever, tuberculosis (TB), MMR and Salmonella typhi.

4. Protein subunit – purified proteins of a microorganism are used to generate a productive immune response, for example some influenza vaccines. New vaccines using recombinant expression of components in Escherichia coli are currently in development.

5. DNA – insertion of DNA into vaccinated individuals that is capable of expressing a component of the infectious microorganism and inducing a productive immune response.

6. Conjugate carbohydrate – normally contains a carbohydrate expressed on the surface of a microorganism that is used to produce immunity, linked to an adjuvant like cholera toxin. Examples are the vaccines to prevent infection with Streptococcus pneumoniae.

Please be aware that transient adverse reactions like pyrexia and injection site discomfort are not necessarily bad. Indeed they are suggesting that the immune system of the vaccinated individual is responding to the vaccine and may well be generating a protective response that could prevent disease in the future. Does anyone remember the TB vaccine at school? What do you want, a pusy painful arm that your best mate decides to punch for fun or a slow, lingering death from a virtually untreatable infection with multi-drug resistant Mycobacterium tuberculosis? I know which I would choose without any hesitation.

In addition to the actual protective components, an adjuvant may be added to a vaccine formulation which helps to stimulate the appropriate immune response in the individual being vaccinated. One example of a simple adjuvant is aluminum hydroxide which can be applied to most vaccine types. However, the science behind adjuvant technology is as fast developing as vaccine design and there is a plethora of adjuvants available that stimulate the immune system in different ways to generate a productive immune response.

Whichever you chose, one of the most important current considerations in vaccinology is the ability to differentiate a vaccinated individual from a naturally infected one - so called DIVA capability. The concept was first developed by J.T. van Oirschot et al. in Holland for the prevention of pseudorabies in pigs. Generally, the concept is that the diagnostic tests that are available to diagnose the disease are not compromised by the vaccines available so that vaccines can be used in the presence of virulent pathogens without hindering their eradication. 

What should you look for in a vaccine target?

When selecting a vaccine target, there are multiple aspects that must be considered in choosing a candidate, or candidates, including coverage, efficacy, feasibility and the type of vaccine being developed. It needs to be conserved across the majority of strains in order to cover as much of the pathogen’s population (or at least the strains that cause issues) as possible, be immunogenic so you mount a response to it, stable in the population so the bugs don’t just lose it in response to immunity in the host population and seen by the immune system when it’s in its native form in the pathogen.

One final consideration is choosing the route of vaccination, i.e. intra-nasal vs subcutaneous vs intramuscular vs oral. Where a mucosal immune response is found to improve protection, vaccination may be given into a mucous membrane, such as the lip. However, it is worth bearing in mind not only which route is most effective, but also the age group or species to which the vaccine is being designed for as to what is a viable route of administration.

Is that the end?

So you have a vaccine, champagne corks pop and you save thousands of lives. In the case of some biological agents this seems to be true. One such example is the 17D vaccine developed to prevent infection with the yellow fever virus which seems to afford protection against all of the known circulating strains of virus and may provide lifelong protection. This is however not the case for influenza in many host species. “Although vaccines exist for equine influenza they need to be updated regularly because influenza viruses undergo antigenic drift [hyperlink to drift vs shift article]. This is caused by a gradual accumulation of mutations in the hemagglutinin (HA) protein which alters its appearance and so helps the virus avoid immunity acquired from previous infection or vaccination. Surveillance is needed to monitor these changes, and their effects, so that vaccine strain recommendations can be updated in a timely manner. The same is also true for human influenza vaccines” states Dr. Adam Rash, Post-doctoral Scientist in the equine influenza surveillance team based at the Animal Health Trust in Newmarket, England.

Concluding thoughts

It is an expensive an often-time-consuming process but someone has to put the work in. “Governments should fuel prevention against infections to a much larger extend as a market driven approach is likely superseded by the increasing presence of resistant bacteria with devastating potentials” concludes Professor Bojesen.