Zika: CD4 T cell immune correlates of Zika virus exposure
Lead Research Organisation:
Imperial College London
Department Name: UNLISTED
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
Current knowledge of T cell immunity to Zika virus is minimal. For a disease of such diverse
outcomes, from asymptomatic exposure to Guilain-Barre syndrome or neonatal
microcpephaly, there is a pressing need to characterise immunity to identify the difference
between protective and pathogenic T cell responses. In West Nile virus (WNV) infection, for
example, neuropathogenic complications are themselves attributed to effects of T cells. We
aim to supply the Zika research community with the first detailed dataset of CD4 T cell
immunity to Zika virus, establishing the immune correlates of different disease outcomes
after exposure. Our expertise and track-record in this regard is based in >12 years funding to
the Altmann/Boyton and Kwok/James teams within the consortia of the NIH Epitope
Discovery Program (IEDB). This has been a programme of high-throughput analysis to
achieve rapid characterisation of immunity in response to emerging pathogens. As such, the
teams are ready to go with precisely the toolkit required for the proposed study. Kwok/James
have led the way in characterisation of protective/pathogenic flavivirus immune correlates,
generating tetramers for multiple HLA alleles. The London and Seattle labs will here team
with Silva’s lab in Sao Paulo. Patients will be characterised, covering phenotypes from mild to
severe, and CD4 T cell immunity analysed against the protein antigens ENV, NS5, NS3, and
NS1. This will include qualitative and quantitative aspects, by ELIspot and HLA/Zika tetramer
flow cytometry, allowing immune correlates of disease outcome to be annotated. The
reagent set will subsequently be invaluable for monitoring of Zika vaccine trials.
outcomes, from asymptomatic exposure to Guilain-Barre syndrome or neonatal
microcpephaly, there is a pressing need to characterise immunity to identify the difference
between protective and pathogenic T cell responses. In West Nile virus (WNV) infection, for
example, neuropathogenic complications are themselves attributed to effects of T cells. We
aim to supply the Zika research community with the first detailed dataset of CD4 T cell
immunity to Zika virus, establishing the immune correlates of different disease outcomes
after exposure. Our expertise and track-record in this regard is based in >12 years funding to
the Altmann/Boyton and Kwok/James teams within the consortia of the NIH Epitope
Discovery Program (IEDB). This has been a programme of high-throughput analysis to
achieve rapid characterisation of immunity in response to emerging pathogens. As such, the
teams are ready to go with precisely the toolkit required for the proposed study. Kwok/James
have led the way in characterisation of protective/pathogenic flavivirus immune correlates,
generating tetramers for multiple HLA alleles. The London and Seattle labs will here team
with Silva’s lab in Sao Paulo. Patients will be characterised, covering phenotypes from mild to
severe, and CD4 T cell immunity analysed against the protein antigens ENV, NS5, NS3, and
NS1. This will include qualitative and quantitative aspects, by ELIspot and HLA/Zika tetramer
flow cytometry, allowing immune correlates of disease outcome to be annotated. The
reagent set will subsequently be invaluable for monitoring of Zika vaccine trials.
People |
ORCID iD |
Publications
Altmann DM
(2018)
Mapping innate and adaptive immune function in arbovirus infections.
in Immunology
Campbell VL
(2020)
Proteome-Wide Zika Virus CD4 T Cell Epitope and HLA Restriction Determination.
in ImmunoHorizons
Guerra-Gomes IC
(2021)
Phenotypical characterization of regulatory T cells in acute Zika infection.
in Cytokine
Keesen TSL
(2017)
Guillain-Barré syndrome and arboviral infection in Brazil.
in The Lancet. Infectious diseases
Reynolds CJ
(2018)
T cell immunity to Zika virus targets immunodominant epitopes that show cross-reactivity with other Flaviviruses.
in Scientific reports
Reynolds CJ
(2020)
Strong CD4 T Cell Responses to Zika Virus Antigens in a Cohort of Dengue Virus Immune Mothers of Congenital Zika Virus Syndrome Infants.
in Frontiers in immunology
| Description | Guillain Barre syndrome antibodies during Zika and Cikungunya vaccine trials |
| Amount | £271,764 (GBP) |
| Funding ID | 971540 |
| Organisation | Innovate UK |
| Sector | Public |
| Country | United Kingdom |
| Start | 04/2017 |
| End | 03/2018 |
| Description | NIH-NIAID. Within-scope funding extension: Comprehensive CD4 T cell epitope discovery from Zika virus. |
| Amount | $500,000 (USD) |
| Organisation | National Institute of Allergy and Infectious Diseases (NIAID) |
| Sector | Public |
| Country | United States |
| Start | 01/2017 |
| End | 12/2018 |
| Description | Guillain Barre syndrome antibodies during Zika and Cikungunya vaccine trials |
| Organisation | Imperial College London |
| Department | Imperial College Trust |
| Country | United Kingdom |
| Sector | Charity/Non Profit |
| PI Contribution | Characterisation of GBS sera |
| Collaborator Contribution | Application of glycolipid arrays to define GBS antobodies |
| Impact | None yet |
| Start Year | 2017 |
| Description | NIH-NIAID. Within-scope funding extension: Comprehensive CD4 T cell epitope discovery from Zika virus. |
| Organisation | University of Washington |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Collaborative funding following on from this MRC-Newton award; studies with David Koelle (U.WASH), Bill Kwok (Benaroya), Roque Almeida (U. Sergipe), Tatjana Keesen (U. Paraiba) to further extend our analysis of Zika CD4 T cell immunology |
| Collaborator Contribution | A large number of Zika CD4 epitopes have been characterised |
| Impact | About to write manuscripts |
| Start Year | 2017 |
| 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 |
| Description | Science Museum October Lates |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | As part of the 'October Lates' evening events at the Science Museum I gave a series of talks on the Zika crisis |
| Year(s) Of Engagement Activity | 2016 |