Programme Leader: Prof Sarah Gilbert
The aim of the Vector Engineering programme at the Jenner Institute is to improve adenoviruses and poxviruses as vaccine vectors. The basis for this is genetic manipulation of the vector genomes using BAC recombineering, which we developed first for MVA and have recently also applied to adenoviruses. We aim to use these reverse genetics systems to discover the factors responsible for disparities in the immunogenicity of different existing adenoviral and poxviral vectors, and to use these discoveries as a basis for rational enhancement.
Non-replicating recombinant viruses are a crucial technology in the quest for new vaccines. Used as vectors, they are able to deliver genes from a target pathogen and elicit potent T cell responses agains the transgenic antigen, in addition to the humoral responses induced by traditional and subunit vaccines. The most promising viral vaccine vectors are attenuated adenoviruses and poxviruses, including modified vaccinia virus Ankara (MVA). These are under intense investigation worldwide and are the principal platform used for vaccine development at the Jenner Institute.
To take two examples, the world’s two most advanced new TB vaccines (both in Phase IIB trials) are based on an adenoviral vector (Crucell) and MVA (MVA85A; Jenner Institute); and the Jenner Institute’s malaria vaccine, one of only three approaches shown to have efficacy in human challenge trials, employ heterologous prime-boost with recombinant simian adenovirus and MVA.
Despite this promise, the efficacy of viral vectors in humans is often sub-optimal, and there is a need to develop more immunogenic vectors that elicit T cell responses not only of greater magnitude, but ideally also of the right phenotype for protection against disease. Attempts to improve viral vectors based on current immunological knowledge have been partially successful. In the Grand Challenges in Global Health project, involving screening of over 100 candidate viruses, we have achieved to date significant enhancements of CD8+ T cell responses elicited by adenovectors but with only a minority of adjuvants.
In a parallel project building on published data describing modest augmentation of MVA immunogenicity by deletion of viral genes, we have generated and tested 26 MVA mutants, some lacking multiple known immune evasion factors, but observed enhancements of only twofold at best in peak CD8+ T cell responses. These findings should have clinical utility for some diseases, but also highlight how little is known about how the immune system interacts with infectious non-replicating viruses, what factors influence the nature and magnitude of responses, and therefore how viral vectors might be improved or tailored to particular applications.