MRC Weatherall Institute of Molecular Medicine
DPhil research opportunities
Emeritus Professor of Molecular Immunology
Iron Metabolism and Immunology
Most of my work has been concerned with the presentation of Influenza antigens with class I molecules of the Major Histocompatibility complex. In the past we identified the major targets for T cells as the conserved nucleoprotein and matrix protein components of the virus and demonstrated that a system of cytosolic antigen presentation exists that passes peptides derived from these proteins into the ER where they bind to class I MHC molecules. With the recent pandemic this interest continues with a practical extension into the issue of whether heterotypic immunity (between pandemic strains) can be induced in man with live attenuated strains of influenza. We have developed our own design of live attenuated virus called S-FLU, that relies on mutations in the haemagglutinin signal sequence that are permissive for infection but prevent replication of the virus. The advantage of this approach is that all of the viral proteins are expressed in their appropriate context in the lung, and thus can induce a full set of local T and B cell responses. We are developing methods to deliver the vaccine virus by aerosol in collaboration with Ronan Mac Loughlin at Aerogen. Preliminary results in collaboration with Dr Kanta Subbarao (NIH) show that our vaccine viruses are capable of preventing illness caused by the most virulent forms of influenza in a murine and ferret infection model, and we are studying responses in the pig as a relevant large animal (in collaboration with Elma Tchillian, Pirbright). We are presently investigating the mechanisms of this immunity in the pig .
As part of a broader interest in the link between immunity and the evolution of seasonal influenza, we are isolating human monoclonal antibodies that neutralise the virus. We are finding that the human antibody response can often be focused on local regions of the haemagglutinin and neuraminidase molecules to such an extent that it may select point mutations and thus drive antigenic drift. In collaboration with John McCauley and Rod Daniels at the Crick Worldwide Influenza Centre we are developing sets of representative human monoclonal antibodies that select relevant mutations in the haemagglutinin and neuraminidase as reagents to monotor antigenic drift to help improve the selection of appropriate viruses for inclusion in the subunit vaccine.
An additional aim for this project is to build a library of neutralising antibodies that react with highly conserved regions of the haemagglutinin and neuraminidase that can be used as therapeutic agents. To date we have isolated very broadly inhibitory antibodies to the N1, N2 and N9 neuraminidase, and to the H1 and H5 stem regions. Crystal structures of antibodies to N1 and N9 will be used to enhance binding. This work is part of a collaboration with Prof Tao Dong and George Gao in China, and Kuan-Ying Arthur Huang in Taiwan.
In recent years our interest has extended to the isolation of potentially therapeutic antibodies to Ebola from donors receiving experimental vaccines. We have isolated 82 antibodies to date to several regions of the Ebola Glycoprotein and will be testing cocktails of these as therapies in collaboration with Miles Carroll at Porton Down.
Students will have the opportunity of working with all of our collaborators.
A haemagglutination test for rapid detection of antibodies to SARS-CoV-2
Townsend A. et al, (2021), Nature Communications, 12
The antigenic anatomy of SARS-CoV-2 receptor binding domain
Dejnirattisai W. et al, (2021), Cell, 184, 2183 - 2200.e22
A COVID-19 vaccine candidate using SpyCatcher multimerization of the SARS-CoV-2 spike protein receptor-binding domain induces potent neutralising antibody responses.
Tan TK. et al, (2021), Nature communications, 12
Hepcidin-Mediated Hypoferremia Disrupts Immune Responses to Vaccination and Infection
Frost JN. et al, (2020), Med
Lung-targeting lentiviral vector for passive immunisation against influenza
TAN TK. et al, (2020), Thorax