'SPIICA' - the Sao Paulo-Imperial College Immune Correlates in Arbovirus Infection Network
Lead Research Organisation:
Imperial College London
Department Name: Immunology and Inflammation
Abstract
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.
Technical Summary
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.
Planned Impact
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.
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.
Publications
Adrielle Dos Santos L
(2021)
Recurrent COVID-19 including evidence of reinfection and enhanced severity in thirty Brazilian healthcare workers.
in The Journal of infection
Alexander J
(2022)
COVID-19 vaccine-induced antibody and T-cell responses in immunosuppressed patients with inflammatory bowel disease after the third vaccine dose (VIP): a multicentre, prospective, case-control study
in The Lancet Gastroenterology & Hepatology
Altmann D
(2021)
Decoding the unknowns in long covid
in BMJ
Altmann DM
(2021)
SARS-CoV-2 variants: Subversion of antibody response and predicted impact on T cell recognition.
in Cell reports. Medicine
Altmann DM
(2021)
Immunity to SARS-CoV-2 variants of concern.
in Science (New York, N.Y.)
Altmann DM
(2020)
SARS-CoV-2 T cell immunity: Specificity, function, durability, and role in protection.
in Science immunology
Altmann DM
(2021)
Waning immunity to SARS-CoV-2: implications for vaccine booster strategies.
in The Lancet. Respiratory medicine
Astbury S
(2022)
HLA-DR polymorphism in SARS-CoV-2 infection and susceptibility to symptomatic COVID-19.
in Immunology
Boyton RJ
(2021)
The immunology of asymptomatic SARS-CoV-2 infection: what are the key questions?
in Nature reviews. Immunology
Captur G
(2022)
Plasma proteomic signature predicts who will get persistent symptoms following SARS-CoV-2 infection.
in EBioMedicine
Description | We have recruited extensive Chikungunya cohorts, as well as people dually infected by Chikungunya and SARS-CoV-2 in the Recife region of Brazil and are now working hard to complete immunological analysis. This is offering insights into the autoimmune repertoire triggered as a consequence of this infection |
Exploitation Route | We hope to have input into therapeutic pathways for Chikungunya associated chronic arthritis |
Sectors | Healthcare |
Description | Extensive discussion of Chikungunya infection leading to chronic autoimmune and the societal impact of this for healthcare policy in affected countries has, in terms of precedent, fed into discussions, nationally and internationally, about the necessary response to Long Covid. |
First Year Of Impact | 2021 |
Sector | Healthcare |
Description | Prof Andre Siquiera policy engagement meetings with FAPESP |
Geographic Reach | South America |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | New Chikungunya collaboration with Dr Moacyr JESUS BARRETO DE MELO REGO |
Organisation | UFPE |
Country | Brazil |
Sector | Academic/University |
PI Contribution | We have built a strong ongoing collaboration with Dr Moacyr JESUS BARRETO DE MELO REGO in Recife, a region that has suffered high prevalence of COVID-19 and Chikungunya. We are working together closely on recruitment and analysis. |
Collaborator Contribution | Cohort recruitment, biobanking, data analysis |
Impact | Manuscripts and a follow-on grants submission are in progress |
Start Year | 2021 |
Description | New collaborative award with Prof Rodrigo Stabeli on Chikungunya immune correlates |
Organisation | Faculdades Oswaldo Cruz |
Country | Brazil |
Sector | Academic/University |
PI Contribution | This award followed on directly from our initial MRC-Wellcome-Newton funds under the Zika virus response: through that collaboration we were able to build close research ties with like-minded immunologists in Brazil. This has led to several, exciting interactions, publications and research exchanges. In this specific case, it has led to a major international collaboration seeking to define immune correlates associated with arthralgia following Chikungunya infection. 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 proposed to build a joint centre of leading immunologists in England and Brazil. We 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. This will again be funded through the Newton scheme. The scheme has really been invaluable in enabling the building of new research links to address research questions that otherwise would not have been addressed, and has built real synergies between immunology in the UK and Brazil. |
Collaborator Contribution | The collaboration is a true partnership that builds on research strengths in the two countries. While the UK team will bring in their expertise in infectious disease programmes making use of wide-scale omics approaches to map the immunomes and disease correlates of emerging pathogens, the team in Brazil have established a major, multi-centre initiative, REPLICK, to decipher many clinical and genomic parameters of Chikungunya infection |
Impact | Ongoing |
Start Year | 2020 |