Heterologous prime-boost-boost immunisation of Chinese cynomolgus macaques using DNA and recombinant poxvirus vectors expressing HIV-1 virus-like particles

Virology Journal

Tom J Blanchard²  James P Stewart⁴  Michael A Skinner¹  Donald S Anson⁶  Brian Getty⁴  Stuart D Dowall³  Mike J Dennis³  Sally A Sharpe³  Simon H Bridge⁵ 

[1] Vaccine Vector Group, Dept of Virology, Imperial College London, London, UK;Consultant in Infectious Diseases & Tropical Medicine, Department for Infectious Diseases, North Manchester General Hospital, Delaunay's Road, Manchester M8 5RB, UK;Health Protection Agency, Porton Down, Salisbury, UK;Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, UK;Institute of Cellular Medicine, Newcastle University, UK;Gene Technology Unit, Department of Genetic Medicine, Women's and Children's Hospital, Adelaide, Australia

关键词: virus-like particle;    human complement protein C3d;    cholera toxin B;    fowlpox virus;    modified vaccinia virus Ankara;    recombinant poxvirus;    broadly reactive neutralising antibodies;    Prime-boost HIV vaccine;   

Others  :  1156143
DOI  :  10.1186/1743-422X-8-429

 received in 2011-08-24, accepted in 2011-09-07,  发布年份 2011

【 摘 要 】

Background

There is renewed interest in the development of poxvirus vector-based HIV vaccines due to the protective effect observed with repeated recombinant canarypox priming with gp120 boosting in the recent Thai placebo-controlled trial. This study sought to investigate whether a heterologous prime-boost-boost vaccine regimen in Chinese cynomolgus macaques with a DNA vaccine and recombinant poxviral vectors expressing HIV virus-like particles bearing envelopes derived from the most prevalent clades circulating in sub-Saharan Africa, focused the antibody response to shared neutralising epitopes.

Methods

Three Chinese cynomolgus macaques were immunised via intramuscular injections using a regimen composed of a prime with two DNA vaccines expressing clade A Env/clade B Gag followed by boosting with recombinant fowlpox virus expressing HIV-1 clade D Gag, Env and cholera toxin B subunit followed by the final boost with recombinant modified vaccinia virus Ankara expressing HIV-1 clade C Env, Gag and human complement protein C3d. We measured the macaque serum antibody responses by ELISA, enumerated T cell responses by IFN-γ ELISpot and assessed seroneutralisation of HIV-1 using the TZM-bl β-galactosidase assay with primary isolates of HIV-1.

Results

This study shows that large and complex synthetic DNA sequences can be successfully cloned in a single step into two poxvirus vectors: MVA and FPV and the recombinant poxviruses could be grown to high titres. The vaccine candidates showed appropriate expression of recombinant proteins with the formation of authentic HIV virus-like particles seen on transmission electron microscopy. In addition the b12 epitope was shown to be held in common by the vaccine candidates using confocal immunofluorescent microscopy. The vaccine candidates were safely administered to Chinese cynomolgus macaques which elicited modest T cell responses at the end of the study but only one out of the three macaques elicited an HIV-specific antibody response. However, the antibodies did not neutralise primary isolates of HIV-1 or the V3-sensitive isolate SF162 using the TZM-bl β-galactosidase assay.

Conclusions

MVA and FP9 are ideal replication-deficient viral vectors for HIV-1 vaccines due to their excellent safety profile for use in humans. This study shows this novel prime-boost-boost regimen was poorly immunogenic in Chinese cynomolgus macaques.

【 授权许可】

   
2011 Bridge et al; licensee BioMed Central Ltd.

【 图 表 】

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