Understanding how viral innate immune evasion strategies affect adaptive immunity, and the application to vaccine development

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Vaccines are one of the best means to prevent infection and the spread of disease. Although more than 60 vaccines exist, vaccines are still needed against infections such as HIV, malaria and dengue that comprise a huge burden on global health. Contributing to this problem is our incomplete understanding of the type of immune response that provides optimal protection and how this is best evoked by vaccination. In this study vaccinia virus (VACV), the vaccine used to eradicate smallpox, will be used as a model to improve current understanding of the immune response to vaccination and this information will be used to design more potent vaccines. There are two arms that make up our immune system. The first is the 'innate' immune system, which is quick to respond to infection but is not pathogen specific. Innate immunity helps to control the infection whilst the 'adaptive' immune response develops. Adaptive immunity is specific to the invading pathogen and is required for complete pathogen clearance. Importantly, the adaptive immune response endures as a long-lived memory immunity that protects from subsequent infection. It is the development of this long-lived, pathogen-specific memory immunity that provides the basis for vaccination. The importance of the innate immune response in successful vaccination is becoming clear, although exactly how it contributes to memory immunity is not well understood. Cells in the body are able to detect the presence of invading microorganisms and respond by producing molecules such as cytokines and interferons - so named as they 'interfere' with viral infection. As well as limiting virus replication, these specialised proteins attract white blood cells (leukocytes) to the site of infection so that they can kill pathogen-infected cells and stimulate the activation of leukocytes that control the adaptive immune response. Viruses have counter-measures that limit the production and action of these anti-pathogenic and immune-activating molecules and VACV has numerous mechanisms to achieve this. Work in our laboratory has demonstrated that engineering VACV to remove the genes whose protein products act to limit the innate immune response, such as cytokines and interferons, can improve the potency of VACV as a vaccine. These data are valuable because they highlight the importance of innate immunity in shaping and influencing the memory immune response. The question we aim to answer is how does the removal of these innate immune inhibitory genes from VACV positively impact on memory immunity? By answering this question we will not only be able to improve the vaccine potential of VACV, but also enhance current understanding of how the innate immune system shapes memory immune responses, information that can be used to design better vaccines in general. VACV is a good model to answer this question as it is a well-studied virus where numerous tools are already available, it has already been used as a successful vaccine for the eradication of smallpox and there is a robust mouse model of VACV infection and vaccination. Furthermore VACV is a popular candidate as a vector for the vaccination against other diseases, such as HIV and malaria, thus the data generated by this proposed study can be directly used to improve the vaccine potential of this virus.