Optimisation of cross-neutralising nanobodies to influenza haemagglutinin using in vitro molecular evolution

A 3-year full-time studentship is available at the National Institute for Biological Standards and Control, Biotherapeutics Division, in collaboration with the Division of Infection and Immunity, University College, London (UCL).

The focus of the studentship is the optimisation of cross-neutralising nanobodies to influenza haemagglutinin using in vitro molecular evolution. The studentship is expected to start on 1st October 2018.

NIBSC is a global leader in the characterisation, standardisation and control of biological medicines and has a major role in protecting and improving public health globally. NIBSC is the leading WHO International Laboratory for Biological Standardisation and is responsible for producing and distributing over 90% of all WHO International Standards introduced for the quality assurance of biological medicines. Our scientists also test products, carry out valuable research and provide advice on a routine basis and in response to emergencies. The importance of the Institute’s work is well recognised nationally and internationally.

UCL is London’s leading multidisciplinary university, with approximately 11,000 staff and 38,000 students from 150 different countries. The UCL Division of Infection & Immunity (I&I) is part of the Faculty of Medical Sciences. In the last Research Assessment Exercise (RAE 2014), the Infection and Immunology panel graded 80% of outputs from the Division as 4* (world leading) or 3* (internationally excellent). Over 60% of our PhD students carry on with their career in academia at world leading Institutions, and another 22% enter the academic medical profession.

Influenza A virus remains a persistent threat to public health resulting in 200,000-500,000 deaths worldwide every year. Vaccination is the main public health treatment option to reduce the impact of influenza, however, the rapid evolution of the virus remains a constant challenge for effective vaccine production. The pre-dominant host immune response is directed against the globular head of the main viral glycoprotein, haemagglutinin (HA), and this selective pressure drives the continuous antigenic changes of the influenza virus. The structure of the membrane proximal stem region is significantly more resistant to antigenic change and this feature has led to the discovery of stem binding human monoclonal antibodies which have broad viral neutralisation activity. The discovery of these monoclonal antibodies has led to renewed interest in passive immunotherapy as an additional treatment option to vaccination. An interesting feature of these monoclonal antibodies is that they only use their heavy chain for recognition of a conserved epitope in the HA stem, with the light chain (LC) being superfluous to requirements. This suggests that ‘heavy chain only’ may be a preferred mode of binding to the influenza HA stem suggesting naturally occurring ‘heavy chain only’ antibodies, such as as nanobodies (Nbs), may be well equipped to access similar epitopes. Our laboratories have recently described cross-neutralising Nbs which share the high selectivity, cross-reactivity and affinity of these human monoclonal antibodies, however we believe their well-documented small size, high stability, and cleft binding properties offers distinct advantages. This PhD studentship will investigate the structure/function of anti-influenza specific Nbs using state of the art molecular evolution technologies and will create improved variants with potential as a next generation immunotherapeutics against pandemic influenza.