Pathogen Biology
A rate-limiting step in developing effective vaccines, and controlling outbreaks of disease, is lack of knowledge of the basic biological properties of the causative agent
This is overwhelmingly clear for new or rapidly emerging diseases where the most fundamental questions require urgent attention: Is the pathogen viral, bacterial, parasitic? Is it related to something that has been seen previously? Is it cultivable in the lab? Does it induce a potent and protective immune response in the target host? Will antigen identification be straightforward? Is vaccine development the most appropriate way to deal with this disease?
Knowledge of basic biology is also a major consideration when attempting to develop vaccines for known diseases, though some of the key questions may be different: Is the pathogen highly variable? Does it have a high recombination rate? What is the host range? Can it persist in the environment, the host or the population? What is the mode of transmission? Is the epidemiology complex or poorly understood? Is the mechanism of immunity understood? Are there leading vaccine antigens available? What is the best way to improve efficacy, longevity, delivery, of vaccines?
The UKVN decision guide may assist vaccine developers in identifying knowledge gaps in basic pathogen biology.
Isolating the pathogen from an outbreak and correctly identifying it are crucial first steps. It is important to be sure that the isolated agent is responsible for causing the observed disease. This may include formal demonstration of Koch’s postulates (infection of a model host with the purified agent and observation of disease pathology). Where this is not possible, for example, if there is no good animal model for a human disease, or where urgency prevails, then indirect parameters can be evaluated; these may include isolation of the same agent from a number of symptomatic individuals, observation of acute phase immune responses that are specific for the agent, and comparison of symptoms/courses of infection with previous outbreaks.
Once a causative agent is identified, the next critical steps will vary depending on the type of pathogen and what is already known about it or about closely related pathogens.
If the agent is known, or related to a previously circulating pathogen, the pathway towards a vaccine (or other method for control) will benefit from extant biological knowledge. This previous experience should make it possible to predict whether vaccine development is feasible and likely to be effective, as well as help decide what type of vaccine to make (live attenuated, killed, subunit, or live vectored). This in turn will dictate the next critical steps, for example whether it is essential to grow large quantities of the agent (for attenuation, or for preparation of killed antigen) or generate detailed genomic/transcriptomic data (for molecular cloning of antigens for recombinant subunit or vector vaccines). If it is clear at this stage that vaccine development is not a feasible first- line option, for example if the pathogen is known to evade host immune responses, or if there is no clue about which part of a complex pathogen is essential for its survival (and/or for induction of immunity), then priorities for biological research will need to focus on these very basic questions.
If the agent is not previously known it will be necessary to determine whether infected hosts are able to develop protective immunity, and preferable to understand the type of host immune response that is responsible for this protection and the antigens in the pathogen that are targeted. To do this it will be critical to generate whole genomic/transcriptomic data from the agent, which will help to understand its origins and aid prediction of potential vaccine antigens for molecular cloning (essential for some types of vaccine). It will be necessary to determine the best method for growing the pathogen so that ample stocks can be obtained for setting up serological assays and diagnostics tests as well as for vaccine development and other essential biological characterisations including the testing of host range, virulence and pathogenicity. At this point it should be clear whether vaccine development is a feasible option and decisions can be made about what type of vaccination approach to pursue.
In all cases, the decision 'tree' about whether to go ahead with vaccine development will be profoundly influenced by the nature of the pathogen. The 'simpler'; the agent, the higher the chances are that an effective vaccine can be made.
The large body of existing knowledge on the biology of viruses means that for these agents there should normally be a good chance of success although there are exceptions that remain totally refractory to vaccine development, Other problems that can be encountered include the capacity of some viruses to mutate rapidly and/or undergo genetic recombination which can result in them 'escaping'; the immune protection induced by the vaccine.
There is also a good body of knowledge on how to make effective bacterial vaccines; these have been remarkably successful in controlling some life-threatening diseases of humans, mostly through the use of killed subunit or inactivated 'toxoids';, although there are also some live-attenuated vaccines. However there are many bacterial pathogens for which there are no current vaccines, often because of their complex pathogenesis and a lack of identifiable vaccine targets as well as some specific complications such as type-specific immunity or expression of superantigens. Other problems include short-lived immunity meaning that frequent re-vaccination is needed, and in some cases highly variable levels of protection.
When it comes to parasitic diseases, which are a major burden for both humans and livestock in many parts of the world, there are few vaccines and to date these are restricted to veterinary pathogens there is a variable amount of basic biological knowledge on parasites available; for some including Plasmodium species there continues to be huge global research efforts focused on vaccine development but the vast majority of parasitic disease remains neglected. The most potent barriers to advancement relate to difficulties in culturing parasites, their complex pathologies and developmental growth cycles, their abilities to evade or subvert host immune responses and their relatively large genome sizes.
- Ability to grow pathogens outside of the host. Mostly a problem for parasites, but also for some viruses
- Understanding of host-pathogen interactions leading to identification of antigenic components of the pathogen that induce immunoprotection. Mostly a problem for parasites but also some bacteria and viruses.
- Understanding of the most potent immunoprotective responses in the host and how to induce these by vaccination
- Generation of multi-omics tools for complex pathogens, particularly with large or difficult genomes, to assist in predictive biology, especially to identify pathogen essential genes and antigen targets
- Need to explore multiple vaccination platforms to improve the delivery of pathogen antigens to the host and thereby improve both potency and longevity of immunoprotective responses
- Need to understand how specific pathogens survive in the population and environment as this influences disease transmission, rate of spread, opportunities for recombination and general pathogen ‘fitness’
- Targeted funding for development of in vitro or ex vivo cultivation for the most important refractory pathogens
- Support for research in the most appropriate host species – preferably the real target species. Where this is not possible invest in models that most closely replicate disease in the real host.
- Increase support for applied immunology/vaccinology within UK research establishments
- Prioritise sequencing and bioinformatics resources for more complex pathogens
- Targeted funding for higher-risk vaccine platform exploration
- Investment in One Health approaches to epidemiology and modelling
There is a lack of centres that have critical mass for work on host-pathogen interactions and very few centres that have a genuine ‘One Health’ strategy underpinning their work on human and/or animal diseases. A number of disciplines are poorly resourced such as livestock (including avian and fish) immunology, parasitology, entomology and molecular bacteriology.