'SPIICA' - the Sao Paulo-Imperial College Immune Correlates in Arbovirus Infection Network

The Aedes egypti mosquito can spread a number of different viruses. In regions of Brazil, these include the different types of Dengue virus, as well as Zika virus, Yellow fever virus and Chikungunya virus. Of these, perhaps the least is understood about Chikungunya. It is believed to be rather underdiagnosed. The symptoms can include headache, fever and rash. However, the key concern is that a proportion of patients will go on to develop a devastating arthritis-like, chronic disease which can continue for years. In some cases, disease is fatal. This is thus a disease which causes great misery to those infected and also, a great financial healthcare burden in caring for chronic disease. There is an urgent need to unravel why it is that some people experience mild disease, while others develop severe, chronic disease. It is believed that the chronic, joint disease is mediated not by the virus itself, but by the immune response to it. For this reason, there is an urgent need to understand the detailed aspects of protective host immunity, so reducing the risk that any future vaccines may inadvertently induce rather than prevent joint disease. To address this question, we here propose to build a joint centre of leading immunologists in England and Brazil. We have called the joint centre 'SPIICA', an astronomical allusion to two separate stars that appear as one. We will work closely together, including joint workshops and staff training. Central to the plan is to recruit a Chikungunya patient cohort, 90 patients in each of four groups, across three seasons at 6 clinical centres in Brazil. Each patient will be carefully evaluated clinically for Chikungunya symptoms and followed longitudinally, giving periodic blood samples. These blood samples will be evaluated using a large array of state-of-the art technologies, allowing correlations to be drawn between the immune response and the disease features. The approaches include characterisation of the antibody response to the virus, of the response by subsets of white blood cells including T lymphocytes and natural killer cells, and of immune mediators in the blood termed cytokines. Our aim is that, by the end of this study, we will have a much-improved rationale to explain the different outcomes following infection. This should help explain how to build vaccines that can promote protection without causing harm and also, how to predict who might be the patients who will develop the chronic disease, treating them before symptoms develop.

We here build on successful links between infection and immunity researchers in Sao Paulo and Imperial College, established under previous Newton funding. Our aim is to extend this grouping into a Joint Centre Partnership, seeking to establish the immune correlates governing differential disease outcome after exposure to Chikungunya virus (CHIKV). Among arboviruses, CHIKV is of concern for its ability to cause chronic, arthritis-like joint disease, which can persist for years. From murine models, it is believed the polyarthralgia is driven by immunopathology rather than virus per se. This emphasises the need for a clearer understanding of the immune correlates in human patients. This understanding is a prerequisite both for ensuring that any vaccine strategy promotes protection rather than immunopathology and also that we have a toolkit to map the effects of any vaccine trial. We will recruit a CHIKV patient cohort, 90 patients in each of four groups, across 3 seasons at 6 clinical centres in Brazil. Each patient will be evaluated clinically and followed longitudinally, giving sequential blood samples. Samples will be evaluated using an arsenal of analyses, across labs in the two countries. We will conduct detailed studies of serological correlates, mapped at the level of CHIKV antigens and antibody isotype, also encompassing generation of and characterisation of exemplar human neutralizing monoclonal antibodies. We will undertake multi-parameter flow cytometry of innate and adaptive immune subsets. The response of each patient group will be characterised at the level of cytokine arrays and RNAseq transcriptomic biosignature. We will conduct T cell epitope mapping using CHIKV peptide libraries. We will also investigate metabolic consequences of CHIKV infection across the patient groups. We aim to build an improved rationale explaining the different outcomes following infection thus favouring vaccines offering protection without immunopathogenesis.

1. Our aim is that the work of this Joint Centre Partnership should have impact at an academic, clinical, societal and economic level.
2. We have indicated in our Communications plan how we will take all possible steps to communicate our findings about CHIKV immune correlates to the academic community, to clinicians, to healthcare decision-makers and politicians, to vaccinologists and to members of the public.
3. Improved understanding of CHIKV would have direct impact on researchers investigating immunology of arboviral infection, including implications for safe, protective vaccines.
4. Improved understanding of CHIKV serology will have impacts on improved serodiagnostics and seroepidemiology. This has implications both for regional and national healthcare provision planning, and for the commercial development of improved diagnostic reagents for the often difficult problem of differential diagnosis between superficially similar acute infections such as Dengue, Zika and Chikungunya.
5. Improved knowledge of CHIKV immunopathogenesis and dissemination of this knowledge to the public in at-risk areas will have benefits for understanding of disease risks and minimisation of exposure.