Abstract\nBackground: Levels of non-neutralising antibodies (AB) to the C5 domain of HIV Env gp120 are inversely related\nto progression of HIV infection. In this phase I/II clinical study we investigated safety of Vacc-C5, a peptide-based\ntherapeutic vaccine candidate corresponding to C5/gp41732ââ?¬â??744 as well as the effects on pre-existing AB levels to\nC5/gp41732ââ?¬â??744, immune activation and T cell responses including exploratory assessments of Vacc-C5-induced T\ncell regulation. Our hypothesis was that exposure of the C5 peptide motif may have detrimental effects due to\nseveral of its HLA-like features and that enhancement of non-neutralising anti-C5 AB by vaccination could reduce\nC5 exposure and thereby chronic immune activation.\nMethods: Thirty-six HIV patients on effective antiretroviral therapy were randomised to one of three dose levels of\nVacc-C5 administered intramuscularly with Alhydrogel or intradermally with GM-CSF as adjuvant through initial\nimmunisation and two booster periods over 26 weeks. Vacc-C5-specific AB were measured by ELISA and T cell\nresponses by both IFN-Ã?³ ELISPOT and proliferative assays analysed by flow cytometry. Immune regulation was\nassessed by functional blockade of the two inhibitory cytokines IL-10 and TGF-Ã?² in parallel cultures. Non-parametric\nstatistical tests were applied.\nResults: Vacc-C5 was found safe and well tolerated in all patients. Only marginal changes in humoral and cellular\nresponses were induced, without any effect on immune activation. Overall, anti-Vacc-C5 AB levels seemed to decrease\ncompared to pre-existing levels. Whereas Vacc-C5-specific CD8+ T cell proliferative responses increased after the first\nbooster period (p = 0.020; CD4+, p = 0.057), they were reduced after the second. In contrast, Vacc-C5-induced T cell\nregulation increased after completed vaccination (p ââ?°Â¤ 0.027) and was lower at baseline in the few AB responders\nidentified (p = 0.027).\nConclusions: The therapeutic HIV vaccine candidate Vacc-C5 safely induced only marginal immune responses,\nwhereas Vacc-C5-induced T cell regulation markedly increased. Our data support further attention on immune\nregulation during therapeutic HIV vaccination studies.
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