iHIVARNA phase IIa, a randomized, placebo-controlled, double-blinded trial to evaluate the safety and immunogenicity of iHIVARNA-01 in chronically HIV-infected patients under stable combined antiretroviral therapy

Springer Science and Business Media LLC - Tập 20 - Trang 1-10 - 2019
Wesley de Jong1, Joeri Aerts2, Sabine Allard3, Christian Brander4,5,6,7, Jozefien Buyze8,9, Eric Florence8,9, Eric van Gorp1, Guido Vanham8,9, Lorna Leal10,11, Beatriz Mothe4,7, Kris Thielemans2, Montse Plana10, Félipe Garcia10,11, Rob Gruters1
1Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands
2Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium
3Department of Internal Medicine and Infectious Diseases, Universitair Ziekenhuis Brussel, Brussels, Belgium
4Infectious Diseases Unit, IrsiCaixa AIDS Research Institute, Hospital Germans Trias i Pujol, Badalona, Spain
5Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
6AELIX Therapeutics, Parc Científic de Barcelona, Barcelona, Spain
7University of Vic – Central University of Catalonia (UVic-UCC), Vic, Spain
8Virology Unit, Department of Biomedical Sciences, Institute of Tropical Medicine and, Antwerp, Belgium
9Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
10Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
11Infectious Diseases Unit, Hospital Clínic, Barcelona, Spain

Tóm tắt

HIV therapeutic vaccination aims to improve the immune responses against HIV in order to control viral replication without the need for combined antiretroviral therapy (cART). iHIVARNA-01 is a novel vaccine combining mRNA delivery and T-cell immunogen (HTI) based on conserved targets of effective antiviral T-cell responses. In addition, it holds adequate stimuli required for activating antigen presenting cells (APC)s and co-activating specific T-cells (TriMix), including human CD40L, constitutively active TLR4 (caTLR4) and CD70. We propose that in-vivo targeting of dendritic cells (DCs) by direct administration of a HIV mRNA encoding these immune modulating proteins might be an attractive alternative to target DCs in vitro. This is a phase-IIa, randomized, double-blinded, placebo-controlled, multicenter study in chronically HIV-1 infected patients under stable cART. One of the three study arms is randomly allocated to subjects. Three vaccinations with either HIVACAT T-cell immunogen (HTI)-TriMix (iHIVARNA-01), TriMix or water for injection (WFI) (weeks 0, 2 and 4) are administered by intranodal injection in the inguinal region. Two weeks after the last immunization (week 6) cART is stopped for 12 weeks. The two primary endpoints are: (1) safety and tolerability of intranodal iHIVARNA-01 vaccination compared with TriMix or WFI and (2) induced immunogenicity, i.e., increase in the frequency of HIV-specific T-cell responses between baseline, week 6 and 12 weeks after treatment interruption in iHIVARNA-01-treated patients as compared to the control groups, immunized with TriMix-mRNA or WFI measured by an IFNγ ELISPOT assay. Secondary endpoints include the evaluation of time to viral rebound, plasma viral load (pVL) at w18, the proportion of patients with control of viral load, induction of T-cell responses to new HIV epitopes, polyfunctionality of HIV-specific T-cells, CD8+ T-cell in-vitro HIV suppressive capacity, the effect on viral reservoir (measured by proviral DNA and cell-associated RNA), assessment of viral immune escape by mutation and mRNA expression profiles of host immune genes. This trial aims to direct target DC in situ with mRNA encoding HTI and TriMix for co-stimulation. Intranodal injection circumvents laborious DC isolation and handling in the laboratory. The trial extends on the safety results of a phase-I dose-escalating trial. This candidate vaccine could complement or even replace cART for chronic HIV infection and could be applicable to improve the care and cost of HIV infection. EudraCT 2016-002724-83 (22 September 2016); ClinicalTrials.gov, ID: NCT02888756. Registered on 23 August 2016.

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