Enhancing the Immunogenicity and Efficacy of Vectored Vaccines

Background to the Grand Challenge in Global Health Initiative
AIDS, tuberculosis (TB) 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. Malaria on its own is estimated to kill over 1 million people each year, with approximately one child dying every 30 seconds, and in addition 1 - 2 million people die from TB infection per year. The development of safe, effective and accessible vaccines is seen as the most sustainable mean 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 Challenge 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 torment 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 (www.grandchallengesgh.org) and aims to develop technologies that improve the performance of vectored vaccines by enhancing immunogenicity through the use of genetic adjuvants and by developing formulations that make vaccines resistant to heat degradation.
Genetic adjuvants are defined as molecules that when incorporated into a vaccine delivery vector they stimulate stronger immune responses. The genetic adjuvant approach of this project brings together the lead team from the University of Oxford, with collaborators from the University of Sheffield, Imaxio, Okairos, and the Wistar Institute. To develop thermostable vaccines, a collaboration with Cambridge Biostability Ltd led to the first generation of viral based vaccines that remain stable at high temperatures and can be deployed even in tropical countries without a need for refrigeration. This breakthrough could significantly help efforts to immunise more children in rural tropical countries while at the same times reducing the cost of vaccination in the developed world.
The project is funded by the GCGH initiative 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).

Project Scope
Vaccines are the most reliable and cost-effective way of combating infectious diseases. A major roadblock in combating the world’s biggest killer diseases— malaria, TB and AIDs—is the inability of the present vaccines to reliably induce protective cell-mediated immunity. New, more protective vaccines are urgently needed, and for these 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 immune defense system. Natural immune defense mechanisms employ complex molecular interplays to mount an effective anti-pathogen response, hence 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.
Building on recent advances in understanding the role of pathogen-associated molecular pattern recognition molecules and T-cell co-stimulatory pathways this project aims to identify molecules from these pathways which when incorporated into the vaccine vectors lead to enhanced immune responses. To this end, molecules belonging to Toll like signaling pathway, cytokines and costimulatory pathways are being assessed for adjuvant capacity using three delivery vectors: DNA, MVA and adenovirus. Our model antigen contains epitopes for Malaria, TB and HIV has been used for the primary discovery platform.  Another complementary approach being explored in parallel is the inactivation of inhibitory pathways utilized by viral vectors to evade the host immune response. The vision is that combining the enhancement of antigen-specific immunogenicity, through the use of genetic adjuvants, with the abolition of vector-specific immunosuppression pathways will lead to a greater enhancement of the immune response induced by virus-based vaccines.
These studies are being conducted both in vitro and in vivo with the aim of developing improved vaccines that merit testing in human clinical trials.

Research Objectives

• Studying 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.
• Exploring multimerisation of antigens through adjuvant-antigen genetic fusions to improve T cell immunogenicity.
• Generating a new range of vaccine vectors that express both antigen and signaling molecules and have the potential to substantially increase immunogenicity.
• Optimising vaccination regimes to achieve effective and long lasting immune responses.
• 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 high-throughput screening platform for an extended cDNA expression library, with a broad coverage of the mouse and mammalian genome, to identify novel candidate molecules which can be used as vaccine adjuvants.
• Progressing the most promising improved adjuvanted vaccines from animal models to human testing and conduct Phase I safety and immunogenicity trials.
• Developing thermostable formulations of live viral vectors that would enable vaccine deployment in tropical countries without the need for a refrigeration chain.

Project Partners
This project brings together three academic and three industrial partners working together as part of a collaborative network. The overall direction and coordination of the whole project takes place at the Jenner Institute, University of Oxford where Prof Adrian Hill is the Lead Investigator and Dr Migena Bregu is the Project Manager. 

University of Oxford University – the lead team
The team in Oxford is designing, constructing, and evaluating numerous adjuvanted vaccine candidates and aims to progress the most promising candidates to clinical testing. The GCGH Oxford team draws in specialist expertise in molecular biology, virology and immunology.

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 (http://www.shef.ac.uk/medicine/). Sheffield is responsible for setting up and performing high-throughput screening to identify novel activators of different aspects of T cell activation.

Imaxio
Imaxio is a French biopharmaceutical company operating in the therapeutic and diagnostic fields (http://www.avidis.fr), 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.

Okairòs
Okairòs is an Italian biopharmaceutical company dedicated to the development of chimpanzee adenovirus vectors as safe vehicles for vaccine delivery (http://www.okairos.it). GCGH work at Okairos is led by Dr Stefano Colloca and is focused on the development of adjuvanted AdCh63 vectors as vector platforms for malaria.

The 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.

Cambridge Biostability Ltd
Work at the Cambridge Biostability Ltd was directed by Dr Bruce Roser with assistance from Dr Robert Alcock. 

Collaborative Activities in the context of the Grand Challenge Initiative

1. The Walter Reed Army Institute of Research which is a key member of the project developing “A Protective Genetically Attenuated P. falciparum Sporozoite Vaccine”, also a Grand Challenge project. 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.
2. Collaboration with several members (e.g. F. Plummer, Manitoba; D. Kwiatkowski, Oxford) of two other Grand Challenge projects that aim to enhance understanding of genetic susceptibility to infection so as 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).

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