Abstract
BackgroundThere 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.MethodsThree 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.ResultsThis 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.ConclusionsMVA 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.
Highlights
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
While numerous HIV-1 vaccine candidates have been developed, only three HIV-1 vaccine regimens have been tested in Phase III clinical trials for efficacy: VaxGen’s AIDSVAX gp120 vaccine induced non-neutralising antibodies which failed to provide protection to immunised individuals [1]; the STEP vaccine regimen comprised 3 recombinant adenovirus serotype 5 viruses expressing HIV-1 Gag, Pol and Nef, that induced CD8+ T cell responses to viral antigens but afforded no protection to vaccinees [2,3]; and the recent Thai placebo-controlled trial of repeated recombinant canarypox virus priming with recombinant gp120 boosts was designed to give antibody rather than T cell responses
A post-hoc modified analysis showed modest efficacy in preventing HIV-1 infections [4], but the placebo arm did not incorporate a poxvirus control to allow for the effects of repetitive stimulation on innate immunity, and no antibody responses capable of neutralising primary isolates of HIV-1 were demonstrated
Summary
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. Recombinant MVA (rMVA) and recombinant FPV (rFPV) have been developed as HIV-1 vaccine candidates and tested in heterologous prime-boost combinations with DNA vaccines in mice [11,12,13], macaques [14,15,16,17,18] and humans [19,20,21,22,23,24] These vaccine approaches principally elicit cytotoxic T lymphocyte (CTL) responses which are thought to be an important component of protective immunity to HIV-1 (reviewed in [25]). The design of improved Env immunogens remains a major goal to HIV-1 vaccinologists
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