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.
BACKGROUND
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.


METHODS/DESIGN
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.


DISCUSSION
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.


TRIAL REGISTRATION
EudraCT 2016-002724-83 (22 September 2016); ClinicalTrials.gov, ID: NCT02888756 . Registered on 23 August 2016.
['de Jong|Wesley|W|http://orcid.org/0000-0001-9674-2647', 'Aerts|Joeri|J|', 'Allard|Sabine|S|', 'Brander|Christian|C|', 'Buyze|Jozefien|J|', 'Florence|Eric|E|', 'van Gorp|Eric|E|', 'Vanham|Guido|G|', 'Leal|Lorna|L|', 'Mothe|Beatriz|B|', 'Thielemans|Kris|K|', 'Plana|Montse|M|', 'Garcia|Félipe|F|', 'Gruters|Rob|R|', '|||']
D016915:AIDS Vaccines D019380:Anti-HIV Agents D002908:Chronic Disease D003713:Dendritic Cells D004311:Double-Blind Method D015658:HIV Infections D006801:Humans D008213:Lymphocyte Activation D012333:RNA, Messenger D013601:T-Lymphocytes D014611:Vaccination
Therapeutic vaccine TriMix HIV-1 Reservoir Antigen-presenting cell Functional cure Immunotherapy Lymph node