Blood samples drawn at a day of vaccination were collected prior to immunisations

Blood samples drawn at a day of vaccination were collected prior to immunisations. Vacc-C5-specific antibodies in serum ELISA plates (Fisher Scientific, UK) coated with Vacc-C5 (i.e. inhibitory cytokines IL-10 and TGF- in parallel cultures. nonparametric statistical assessments 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 ( em p /em ?=?0.020; CD4+, em p /em ?=?0.057), they were reduced after the second. In contrast, Vacc-C5-induced T cell regulation increased after completed vaccination ( em p /em ??0.027) and was reduce at baseline in the few AB responders identified ( em p /em ?=?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 “type”:”clinical-trial”,”attrs”:”text”:”NCT01627678″,”term_id”:”NCT01627678″NCT01627678. Electronic supplementary material The online version of this BTRX-335140 article (doi:10.1186/s12879-017-2316-x) contains supplementary material, which is available to authorized users. strong class=”kwd-title” Keywords: HIV, Therapeutic vaccine, Immune regulation, T cell, Antibodies, Immune activation Background More than 30?years after its discovery, Human Immunodeficiency Computer virus type 1 (HIV) remains a global challenge with more than 36 million people infected worldwide [1]. Despite the achievements of effective antiretroviral therapy (ART), patients with access to ART control viremia but are not cured. Chronic immune activation is reduced, but persists [2] and is associated with non-AIDS morbidity and mortality [3, 4], an increasing concern in the long term care of HIV patients. Search for alternate treatment strategies are therefore warranted. Vacc-C5 is usually a peptide-based therapeutic vaccine candidate that aims to induce non-neutralising antibodies (AB) to the 5th constant domain (C5) of the HIV-1 envelope glycoprotein gp120 in conjunction with part of the transmembrane glycoprotein of gp41. The presence of AB towards C5 region has previously been shown to correlate with a slower disease progression [5C7]. Analysis of serum from treatment na?ve patients has demonstrated higher levels of non-neutralising anti-Vacc-C5 AB levels in HIV natural viral suppressors with moderate viral loads ( 10,000 copies/ml) than in patients with higher viral loads ( 10,000 copies/ml). Furthermore, longitudinal analysis of HIV patients BTRX-335140 has revealed an inverse correlation between anti-Vacc-C5 AB levels and disease progression [8]. The C5 domain name has sequence similarity to peptide binding sites on HLA molecules [9] and can bind both defined class II and class I restricted peptides, bindings that are blocked with anti-C5 monoclonal AB [10]. It has therefore been proposed that uncovered C5 could amplify chronic immune activation, either directly by cross-signalling via HLA-like motifs or by presentation of peptides that facilitate alloactivation-like responses [11]. Our hypothesis was that any detrimental effects of C5 explain the inverse relationship between anti-C5 AB levels and clinical progression, and that enhancement of non-neutralising anti-C5 AB by vaccination with Vacc-C5 could reduce exposure of C5. Against this background, a Proc phase I/II trial was conducted with the primary objective to evaluate security of Vacc-C5 at three dose levels administered either intradermally or intramuscularly with two different adjuvants while on effective ART. Local low dose granulocyte-macrophage colony-stimulating factor (GM-CSF) facilitates dermal dendritic cell maturation and migration to the lymph nodes for antigen presentation [12, 13] and has been used in former BTRX-335140 studies with intradermal administration of the peptide-based HIV Gag p24 vaccine Vacc-4 [14, 15] and with peptide-based malignancy vaccines [16]. Alhydrogel, the only adjuvant approved and marketed for worldwide use (e.g. pneumococcal vaccine Prevnar and HPV vaccine Gardasil), was applied in the intramuscularly administered vaccine. The secondary objectives were to explore humoral responses to Vacc-C5, HIV-associated immune activation and T cell immunogenicity. T cell responses to HIV antigens, such as C5, may be strongly regulated in chronic HIV contamination [17C19], and immune regulatory mechanisms to HIV vaccine antigens may therefore be important to consider before and during therapeutic HIV vaccination [20, 21]. We have previously assessed an exploratory parameter for vaccine antigen-induced T cell regulation, based on simultaneous blockade of the two potent, soluble cytokines downregulating HIV-specific T cell proliferation, a key feature of effector T cells [22, 23]. Our approach does not intend to differentiate the mechanistic pathways of immune system regulation, but instead measure the world wide web effect on proliferative capability of effector T cells.