Clinical assessment of a recombinant simian adenovirus ChAd63: a potent new vaccine vector.

Abstract

BACKGROUND:

Vaccine development in human Plasmodium falciparum malaria has been hampered by the exceptionally high levels of CD8(+) T cells required for efficacy. Use of potently immunogenic human adenoviruses as vaccine vectors could overcome this problem, but these are limited by preexisting immunity to human adenoviruses.

METHODS:

From 2007 to 2010, we undertook a phase I dose and route finding study of a new malaria vaccine, a replication-incompetent chimpanzee adenovirus 63 (ChAd63) encoding the preerythrocytic insert multiple epitope thrombospondin-related adhesion protein (ME-TRAP; n = 54 vaccinees) administered alone (n = 28) or with a modified vaccinia virus Ankara (MVA) ME-TRAP booster immunization 8 weeks later (n = 26). We observed an excellent safety profile. High levels of TRAP antigen-specific CD8(+) and CD4(+) T cells, as detected by interferon γ enzyme-linked immunospot assay and flow cytometry, were induced by intramuscular ChAd63 ME-TRAP immunization at doses of 5 × 10(10) viral particles and above. Subsequent administration of MVA ME-TRAP boosted responses to exceptionally high levels, and responses were maintained for up to 30 months postvaccination.

CONCLUSIONS:

The ChAd63 chimpanzee adenovirus vector appears safe and highly immunogenic, providing a viable alternative to human adenoviruses as vaccine vectors for human use.

CLINICAL TRIALS REGISTRATION:

NCT00890019.

• Authors: Geraldine A O'Hara, Christopher J A Duncan, Katie J Ewer, Katharine A Collins, Sean C Elias, Fenella D Halstead, Anna L Goodman, Nick J Edwards, Arturo Reyes-Sandoval, Prudence Bird, Rosalind Rowland, Susanne H Sheehy, Ian D Poulton, Claire Hutchings, Stephen Todryk, Laura Andrews, Antonella Folgori, Eleanor Berrie, Sarah Moyle, Alfredo Nicosia, Stefano Colloca, Riccardo Cortese, Loredana Siani, Alison M Lawrie, Sarah C Gilbert, Adrian V S Hill
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 205 Issue 5 Pg. 772-81 (Mar 01 2012) ISSN: 1537-6613 [Electronic] United States
• PMID: 22275401 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Neutralizing
• Epitopes
• Interleukin-2
• Malaria Vaccines
• Protozoan Proteins
• Tumor Necrosis Factor-alpha
• Vaccines, DNA
• thrombospondin-related adhesive protein, protozoan
• Interferon-gamma

Topics

• Adenoviruses, Simian (genetics, immunology)
• Animals
• Antibodies, Neutralizing (blood)
• CD4-Positive T-Lymphocytes (metabolism)
• CD8-Positive T-Lymphocytes (metabolism)
• Epitopes
• Flow Cytometry
• Humans
• Interferon-gamma (metabolism)
• Interleukin-2 (metabolism)
• Malaria Vaccines (administration & dosage, adverse effects, immunology)
• Malaria, Falciparum (immunology)
• Protozoan Proteins (immunology)
• Tumor Necrosis Factor-alpha (metabolism)
• Vaccines, DNA (administration & dosage, adverse effects, immunology)