The malaria vaccine programme at Oxford is a linked pre-clinical and clinical vaccine development programme that has primarily targeted the induction of high level T cell responses against pre-erythrocytic antigens.  We undertook the first prophylactic DNA vaccine trials in Europe and showed that DNA administered by needle or by gene gun generated only moderate immunogenicity and was not protective. Following on from extensive pre-clinical studies we undertook the first clinical trials of any recombinant MVA vaccine and found a recombinant expressing the ME-TRAP insert more immunogenic than DNA, but this was not protective used alone.  However, prime-boost regimes with DNA followed by MVA were substantially more immunogenic with T cell responses reaching 1000 SFU/million.

A fowlpox (FP9)-MVA prime-boost regime was then tested in phase I/IIa clinical trials and induced good T cell immunogenicity with a higher proportion of CD8 T cells. Significant delays in time to parasitaemia were observed with both DNA-MVA and FP9-MVA regimes with an estimated 80-90% reduction in parasite load at the liver-stage. Stronger T cell responses correlated with better protection levels, but only occasional individuals showed sterile protection pointing to a need for more potent vaccines.

In all we have undertaken twelve sporozoite challenge and one blood-stage challenge study in Oxford since 2000 and these have contributed to the comparative evaluation of vaccines from our laboratory and from elsewhere (www.malaria-vaccines.org.uk).  Substitution of the circumsporozoite protein and a six antigen polyprotein insert for ME-TRAP showed a reduction in immunogenicity and efficacy.  Collaborators providing their own vaccines or devices for comparative studies include Vical, Apovia, Powderject, Pevion and GSK Biologicals. We have also enhanced the safety and informativeness of this challenge model by introducing real-time PCR monitoring during vaccine trials.

Field studies of these vectors in The Gambia and Kenya have been undertaken. These African studies have revealed lower immunogenicity than UK studies especially in areas with very high malaria transmission and there was no clear evidence of protection in two phase IIb efficacy trials.  The most promising pre-clinical data to date have been generated using adenoviral vectors, with or without an MVA boost.  To avoid the problem of anti-vector immunity to common adenoviruses in humans we have been assessing a variety of simian adenovirus vectors that are at least as immunogenic as the standard AdHu5 vector. Using the ME-TRAP insert we have observed single dose sterile protection in mice against P. berghei sporozoite challenge.  In parallel, a series of studies with the blood-stage antigen MSP-1 in the P. yoelli murine model has shown unprecedented efficacy with adenovirus and MVA vectors.  Surprisingly, this protection is mainly mediated by strong protective antibody responses which are potently induced by this vaccination regime.

We are the lead institution in a large Gates Foundation / Foundation for NIH Grand Challenges in Global Health programme that aims to identify means of adjuvanting vectored vaccines to enhance their immunogenicity and efficacy (http://www.jenner.ac.uk/vaccine_prog_gcgh.html).  We are assessing several potential adjuvants that are expressed by DNA, MVA and adenovirus vectors in parallel with expression of pathogen antigens. We aim to take the best performing adjuvant forward to a clinical trial in 2009.

The first clinical trial of any vaccine candidate based on a simian adenovirus vector was initiated in Oxford in late 2007.  This AdCh63 vector expressing ME-TRAP has been developed in a partnership with Okairos and is being assessed used alone and in a prime-boost regime with and without an MVA boost.  We have also generated blood-stage vectors expressing MSP-1 and AMA-1 inserts in the same vectors and aim to take these forward to clinical testing in the next year.  Use of the same vectors for liver-stage and blood-stage antigens should allow future development of a combination product, including a mixture of these vectors, if good efficacy is observed in phase IIa trials.