SINGLE DOSE PROTECTION AGAINST P. berghei BY SIMIAN ADENOVIRAL VECTOR USING HUMAN CMV PROMOTER CONTAINING INTRON A

The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, U.K.; Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, 2000 Translational Research Program 125S, 31st Street Philadelphia, PA 19104-3403, U.S.A

^* To whom correspondence should be addressed. Email: saranya{at}well.ox.ac.uk.

	Abstract

Human adenovirus serotype 5 (AdH5) vectored vaccines elicit strong immune responses to the encoded antigen and have been used in various disease models. We designed AdH5 vectors expressing antigen under the control of a Human Cytomegalovirus (HCMV) immediate-early promoter containing its Intron A sequence. The transcriptional levels of antigen and immune responses to antigen in vectors with the HCMV promoter with Intron A sequence (LP) was greater than those of AdH5 vectors using HCMV promoter sequence without Intron A (SP). We compared E1E3-deleted AdH5 adenoviral vector, which affords more space for insertion of foreign sequence and showed them to be as immunogenic as E1-deleted AdH5 vector. Neutralizing antibodies to AdH5 limit the efficacy of vaccines based on AdH5 serotype and simian adenoviral vectors offer an attractive option to overcome this. We constructed E1E3-deleted human and simian adenoviral vectors encoding a pre-erythrocytic malarial antigen, P. berghei circumsporozoite protein (Pb.CSP). We compared the immunogenicity and efficacy of AdC6, a recombinant simian adenovirus serotype 6, in a murine malaria model to AdH5 and pox viral vectors, MVA and FP9. AdC6 induced sterile protection in 90% of mice in contrast to AdH5 (25%) and pox viral vectors MVA and FP9 (0%) from a single dose. Adenoviral vectors maintained potent CD8+ T cell responses for a longer period after immunization compared to pox viral vectors and mainly induced an effector memory phenotype of cells. Significantly, AdC6 was able to maintain protection in the presence of pre-existing immunity to AdH5.