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

Abstract

BackgroundLevels 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/gp41732–744 as well as the effects on pre-existing AB levels to C5/gp41732–744, 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.MethodsThirty-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.ResultsVacc-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).ConclusionsThe 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 materialThe online version of this article (doi:10.1186/s12879-017-2316-x) contains supplementary material, which is available to authorized users.

Advances in Infectious Disease Vaccine Adjuvants

“…Brekke and colleagues combined HIV Vacc-C5, containing residues 489–511 from the HIV-1 virus C5 domain, with GM-CSF adjuvant as a peptide-based therapeutic vaccine against HIV [ 196 ]. In this Phase 1/2 clinical study, Vacc-C5 adjuvanted with GM-CSF was intramuscularly administrated to 36 participants and provided evidence for the GM-CSF-adjuvanted vaccine to be safe and well-tolerated in all patients and induce the stronger T cell immune response compared to vaccine alone (NCT01627678) [ 73 ]. A Phase 1 clinical trial in progress is assessing a vaccine containing dendritic cells loaded with S-protein from SARS-CoV-2 alongside GM-CSF as an adjuvant intramuscularly injected in 175 non-infected participants to evaluate its safety and anti-SARS-CoV-2 immunity (NCT04386252) [ 74 ].…”

A Tale of Three Recent Pandemics: Influenza, HIV and SARS-CoV-2

“…Currently, there is no vaccine for HIV-1, with many trials rendering unsatisfying results ( Tebas et al, 2012 ; Pollard et al, 2014 ; Ensoli et al, 2015 ; Dinges et al, 2016 ; Macatangay et al, 2016 ; Jacobson et al, 2016a , b ; Brekke et al, 2017 ), which is often attributed to the extensive genetic diversity that is exhibited by HIV-1. Recent work investigates the use of mRNA-based vaccines that incorporate multiple HIV subtypes, in order to cover a larger genetic diversity ( Aidsmap, 2021 ).…”

Granulocyte macrophage colony-stimulating factor has come of age: From a vaccine adjuvant to antiviral immunotherapy

“…GM-CSF has also been used as an adjuvant to combat viral infections such as HIV and COVID-19, based on its ability to enhance DC maturation, and their ability to present viral antigens [ 138 ]. Previous HIV trials employing GM-CSF as an adjuvant reported inconsistent results with various positive or negative outcomes including no effect compared to controls.…”

“…Previous HIV trials employing GM-CSF as an adjuvant reported inconsistent results with various positive or negative outcomes including no effect compared to controls. A recent HIV trial (NCT01627678) [ 139 ], used Vacc-C5 (a peptide vaccine) with GM-CSF as an adjuvant to ameliorate the vaccine’s immunogenicity and help increase T cell levels [ 138 ] reported only marginal changes. A trial in progress is assessing a vaccine composed of DC loaded with antigens from COVID-19 alongside GM-CSF as an adjuvant in non-infected participants to evaluate if it enhances anti-COVID-19 immunity (NCT04386252) [ 140 ].…”