Human host immunology
In order to design a vaccine against a pathogen it is necessary to understand the type of immune response which can protect against infection with that pathogen and the antigen to which the response is targeted. For zoonotic infections determining this in previously infected animals may be informative. Some general principles can be used to shorten the process; looking for neutralising antibodies to external glycoproteins of viruses, or cytotoxic responses to the more highly expressed antigens of intracellular pathogens for example.
Measurement of immune responses is hampered when standardised assays are not used since it is then impossible to compare results between labs, or from different clinical studies. Ideally functional responses would be assessed, using standardised assays in immune animals which had been shown to resist infection on challenge, and the same assays would be employed to measure immune responses in vaccine trials. Functional assays may require high containment labs since the live pathogen is used. Once a correlate of protection has been defined it may be possible to develop a surrogate assay (such as neutralisation of a pseudotyped virus, or measuring total IgG if that has been shown to correlate with neutralising antibody titre) which can be used without high containment. For the measurement of T cell responses ELISpot assays are preferable since harmonisation of assays between labs can be achieved.
- Access to samples from recovered or immune people or livestock
- Access to pathogen genome sequences to predict protective antigens
- Performance of a range of immunology assays to assess T and B cell responses to the pathogen, ideally testing functional responses (e.g. in vitro bactericidal assays, neutralising antibody assays) using standardised assays
- Proposal of a correlate of immunity together with a suitable assay for use in vaccine development studies
- Access to high containment labs (labs exist, but little co-ordination of existing labs with other groups, need for studies on different pathogens, access to suitable samples, assay development expertise)
- Availability of suitable reagents (recombinant proteins, peptides for ELISpot require funding)
Greater co-ordination between groups with different facilities and expertise is required. Funding should be directed towards assisting this. Greater use should be made of livestock challenge experiments.
Development of standardised assays antibody assays could be done by NIBSC, but ideally requires the use of human serum samples which may be difficult to obtain.
Different approaches are needed in outbreak and peacetime situations. Development of validated assays (can be done by NIBSC) is time consuming, requires large quantities of reagents, and standards must be identified. This activity should be undertaken in peacetime and can then define the approach to be taken as rapidly as possible in an outbreak situation. Some materials can and should be prepared in advance, with plans to test and refine when an outbreak occurs. Phase I trials of novel vaccines can generate serum samples which may then be used to generate a reference standard for assays.
Livestock host immunology
The empirical ‘trial-and-error’ approaches to livestock vaccine design that have been successfully employed in the past have been exhausted. The development of the next generation of safe and effective vaccines is proving to be more challenging and requires detailed knowledge of both the pathogen and the host immune responses to natural and experimental infection. This is particularly true for diseases where the immune correlate of protection is not circulating antibody, but is cell-mediated immunity and/or mucosal immunity. The identification of immune correlates of infection and protection facilitates the identification of protective antigens and reduces the ‘guesswork’ in the design and delivery of prototype vaccines. These immune correlates also underpin the development of associated diagnostic tests that allow the discrimination between infected and vaccinated animals, the so-called DIVA principle. A combined DIVA vaccine/diagnostic test approach is desirable management tool for the control of many infectious diseases of livestock, such as bovine tuberculosis. The identification of immune correlates not only enhances the likelihood of success of new vaccines, but also informs on vaccine failure. This strategic approach has the potential to accelerate vaccine development and reduce animal usage in vaccine trials. The knowledge of immunology interlinks with new technologies such as reverse vaccinology and synthetic biology. The identification of immune correlates in livestock is challenging and can take months to years to achieve.
- Assays to measure humoral and cellular immune responses in infected, convalescent and vaccinated animals
- Identification of the components of the immune response that are associated with protection and discriminating these from components that are indicative of infection
- Knowledge of protective and non-protective pathogen antigens
- Ascribing function to specific individual components of complex immune responses
- Delivering antigens in a manner that elicits protective immune responses in neonates and adults
- Inducing the relevant duration of immunity by vaccination that meets the needs of the different livestock production systems
- Linking genotype to phenotype for understanding immune responses
- Inducing immunity that does not drive pathogen virulence (Marek’s)
- A relative lack of immunological reagents/assays for livestock species compared to laboratory rodents and humans, particularly for measuring cellular immune responses
- Persistent/chronic diseases where convalescent animals are rare, making it more difficult to identify and characterise protective immune responses
- Good experimental infection models
- Animal facilities to conduct vaccination and challenge experiments, particularly for high containment pathogens and exotic disease threats
- A lack of well-annotated genomes
- Understanding the impact of co-infections on vaccine efficacy in the field
- Meeting the challenge of neonatal vaccination in the face of maternal immunity
- Discriminating subdominant protective antigens from immunodominant, non-protective pathogen antigens
- Investment in the development of livestock immunological reagents/assays and associated curated databases describing their applications and availability
- Access to facilities for developing and conducting experimental challenge models
- Improved diagnostic tests for livestock diseases
- Improved knowledge of the immunity induced by vaccine delivery systems, particularly viral vaccine vectors for induction of cellular immune responses
- Technologies to create knock-out/transgenic livestock to investigate immune function (CRISPR)
- Information on all aspects of livestock vaccines is available on the BBSRC UK Veterinary Vaccinology website
- International collaboration and resource-sharing for animal disease research. Further information is available on the Global Network for Animal Disease Research website.
- Combining scientific and veterinary expertise for animal studies
- Immunological reagents for livestock
- Relative current inability to create knock-out and transgenic animals to define the function of specific immune components in livestock species
- Animal facilities