"Grand Challenges in Global Health" Project

Project Leader: Prof Adrian Hill

Background

AIDs, Tuberculosis and Malaria are among the world’s biggest health challenges as they account for nearly six million deaths a year. TB and Malaria are fully curable and yet they remain a huge health and economic burden in the developing world. Preventive measures through the development of safe, effective, and accessible vaccines are seen as the most sustainable means to win the fight against these global diseases.

In 2005, the Gates Foundation, in partnership with the Foundation for the National Institute of Health, the Wellcome Trust and the Canadian Institute of Health Research, set up the Grand Challenges in Global Health (GCGH) initiative with the ambition to boost international efforts in the fight against infectious diseases that severely affect the developing world.

The overarching goal of the GCGH initiative is to address the scientific challenges needed to eradicate infectious diseases that affect the developing world. $450 million in grants were awarded in 2005 to fund 43 projects worldwide working to tackle 14 Grand Challenges covering prophylactic measures, therapeutics, limiting drug resistance, improving nutrition and accurate measures of health status.

Enhancing the immunogenicity and efficacy of vectored vaccines

This project addresses Grand Challenge #5: Solve how to design antigens for effective, protective immunity and aims to develop a new generation of vectored vaccines which have improved immunogenicity imparted by a ‘genetic adjuvant’ approach and improved thermal stability using a novel ‘sugar glass’ formulation. Genetic adjuvants are defined as molecules that when encoded by the vaccine delivery vector, stimulate stronger immune responses. The project is funded for $10 million with a start date of 15 August 2005. The grant is managed by the Foundation for the National Institutes of Health (FNIH) and the lead investigator is Professor Adrian Hill.

Project scope

A major roadblock in combating Malaria, TB and AIDs is the inability of the present vaccine candidates to reliably induce protective cell-mediated immunity. For the new generation of vaccines to be effective, they must stimulate greater immune responses than those achieved so far. This project aims to enhance the immunogenicity and the protective efficacy induced by vectored vaccines by pairing the antigen with immunoactivating molecules belonging to the host immune system. Natural immune defense mechanisms employ complex molecular interplays to mount an effective anti-pathogen response. The approach of this project is based on the rationale that by incorporating genes that form part of the innate and adaptive immune system into the vaccine vectors the immune responses to the vaccine can be significantly improved.

Molecules belonging to Toll like signaling pathway, cytokines, and costimulatory pathways have been screened for adjuvant capacity when expressed from three delivery vectors: DNA, MVA and adenovirus. Multimerisation of the antigen through genetic fusions to multimerising molecular tags is another strategy investigated for adjuvant capacity. Another complementary approach being explored in parallel is the deletion of immunoinhibitory genes from MVA vectors. The abolition of vector induced immunosuppression pathways is a route to greater enhancement of the immune response induced by MVA vaccination.

These studies are being conducted both in vitro and in vivo and the goal is to identify a potent adjuvant that merits testing in human clinical trials.
This programme of work has brought together the lead team from the University of Oxford, with collaborators from the University of Sheffield, Okairos, and the Wistar Institute.

A collaboration with Cambridge Biostability Ltd led to thermal stabilization of MVA and adenovirus vaccines showing great promise for fridge-free vaccine deployment in tropical countries.

Research objectives

Screening pathogen-recognition, co-stimulatory receptor pathways and proinflammatory cytokines to determine which molecular components are able to enhance immunogenicity when expressed by plasmid DNA, pox, or adenoviral vectored vaccines.

• Generating a new range of vaccine vectors that express both antigen and signaling molecules and have the potential to substantially increase immunogenicity.
• Developing adjuvant-antigen genetic fusions, which assemble in heptameric proteins when expressed from vectored vaccines.
• Optimising vaccination regimes to achieve effective and long lasting immune responses with adjuvanted vectored vaccines.
• Exploring the effect of removing negative immunomodulators from viral vectors in order to evoke effective and long-lived immune responses after vaccination.
• Setting up a screening platform for an extended cDNA expression library, with a broad coverage of the mouse and mammalian genome to identify molecules able to activate proinflammatory gene expression in vitro and test these activators for adjuvant capacity in vivo.
• Testing improved adjuvanted vectors with antigens in animal models, beginning with malaria, and conducting Phase I safety and immunogenicity trials with the most promising candidate vaccine.
• Developing thermostable formulations of live viral vectors that would enable vaccine deployment in tropical countries without the need for a refrigeration chain.

Project Partners

University of Oxford

The direction and coordination of the project takes place at the University of Oxford where Prof Adrian Hill is Lead Investigator and Dr Migena Bregu is Project Manager. Oxford is designing, constructing, and evaluating numerous adjuvanted vaccine candidates and aims to progress the most promising candidates to clinical testing.

University of Sheffield

Work at the University of Sheffield is directed by Prof Steven Dower and Dr Endre Kiss-Toth with the assistance of Ms Karen Holland. Sheffield is responsible for setting up and performing high-throughput screening to identify novel activators of different aspects of T cell activation.

Wistar Institute

Work at the Wistar Institute is directed by Prof Hildegund Ertl. Wistar is assessing adjuvants for the enhancement of mucosal immunity with particular relevance to HIV vaccination.

Okairòs

Okairòs is a biopharmaceutical company dedicated to the development of chimpanzee adenovirus vectors as safe vehicles for vaccine delivery. GCGH work at Okairòs is focused on the development of adjuvanted AdCh63 vectors, which is led by Dr Stefano Colloca with the assistance of Fabiana Grazioli.

Imaxio

Imaxio is a French biopharmaceutical company operating in the therapeutic and diagnostic fields collaborating with the Jenner Institute as part of this GCGH project to develop adjuvants that confer structural modifications on the antigen to enhance vaccine immunogenicity. GCGH work at Imaxio is led by Dr Fergal Hill.

Cambridge Biostability Ltd

Work at the Cambridge Biostability Ltd was directed by Dr Bruce Roser with assistance from Dr Robert Alcock. Nova Laboratories has now acquired Cambridge Biostability's technology.

Collaborations

The group collaborates with The Walter Reed Army Institute of Research which is a key member of another Grand Challenge project developing “A Protective Genetically Attenuated P. falciparum Sporozoite Vaccine”. The Walter Reed and the Oxford team are the two major sites globally undertaking sporozoite challenge studies. Collaboration with Dr Heppner on standardization of the malaria human challenge model has happened in the past and will continue.

There is also a collaboration with several members (e.g. F. Plummer, Manitoba; D. Kwiatkowski, Oxford) of two other Grand Challenge projects that aim to increase understanding of genetic susceptibility to infection to inform vaccine design: “Comprehensive Studies of Mechanisms of HIV Resistance in Highly Exposed Uninfected Women” and “Learning From the Human Genome How Protective Immunity Against Malaria Works”.

Further information

For further information about our programme of work or if you are interested in collaborating with us please contact Dr Migena Bregu (migena.bregu@ndm.ox.ac.uk)

Group members

Prof Adrian Hill, Project Leader
Dr Matt Cottingham, Postdoc
Dr Alex Spencer, Postdoc
Dr Migena Bregu, Project Manager