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Background  Levels of non-neutralising antibodies (AB) to the C5 domain of HIV Env gp120 are inversely related to progression of HIV infection. In this phase I/II clinical study we investigated safety of Vacc-C5, a peptide-based therapeutic vaccine candidate corresponding to C5/gp41 732–744  as well as the effects on pre-existing AB levels to C5/gp41 732–744 , immune activation and T cell responses including exploratory assessments of Vacc-C5-induced T cell regulation. Our hypothesis was that exposure of the C5 peptide motif may have detrimental effects due to several of its HLA-like features and that enhancement of non-neutralising anti-C5 AB by vaccination could reduce C5 exposure and thereby chronic immune activation.    Methods  Thirty-six HIV patients on effective antiretroviral therapy were randomised to one of three dose levels of Vacc-C5 administered intramuscularly with Alhydrogel or intradermally with GM-CSF as adjuvant through initial immunisation and two booster periods over 26 weeks. Vacc-C5-specific AB were measured by ELISA and T cell responses by both IFN-γ ELISPOT and proliferative assays analysed by flow cytometry. Immune regulation was assessed by functional blockade of the two inhibitory cytokines IL-10 and TGF-β in parallel cultures. Non-parametric statistical tests were applied.    Results  Vacc-C5 was found safe and well tolerated in all patients. Only marginal changes in humoral and cellular responses were induced, without any effect on immune activation. Overall, anti-Vacc-C5 AB levels seemed to decrease compared to pre-existing levels. Whereas Vacc-C5-specific CD8 +  T cell proliferative responses increased after the first booster period ( p  = 0.020; CD4 + ,  p  = 0.057), they were reduced after the second. In contrast, Vacc-C5-induced T cell regulation increased after completed vaccination ( p  ≤ 0.027) and was lower at baseline in the few AB responders identified ( p  = 0.027).    Conclusions  The therapeutic HIV vaccine candidate Vacc-C5 safely induced only marginal immune responses, whereas Vacc-C5-induced T cell regulation markedly increased. Our data support further attention on immune regulation during therapeutic HIV vaccination studies.    Trial registration    NCT01627678 .    Electronic supplementary material  The online version of this article (doi:10.1186/s12879-017-2316-x) contains supplementary material, which is available to authorized users.

The therapeutic HIV Env C5/gp41 vaccine candidate Vacc-C5 induces specific T cell regulation in a phase I/II clinical study