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

Abstract

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.

Keywords: Antigen-presenting cell; Functional cure; HIV-1; Immunotherapy; Lymph node; Reservoir; Therapeutic vaccine; TriMix.

Conflict of interest statement

CB and BM are co-inventors of the HTI immunogen sequence. CB is CSO of, and receives compensation from, AELIX Therapeutics, a Barcelona biotech company developing HTI in the context of different vaccine vectors. BM is a consultant for AELIX Therapeutics. KT is the founder and SCO of eTheRNA and receives compensation from eTheRNA, a Brussels immunotherapy spin-off company of Vrije Universiteit Brussel. All other authors declare that they have no competing interests.

Figures

Fig. 1

Overview of the study period, interventions and assessments

Fig. 2

Screening, assessments and interventions schedule for iHIVARNA phase IIa. 1 screening at most 8 weeks prior to enrollment at W0. Interval of 4 to 2 weeks is advised and optional consideration period of up to 2 weeks is offered. 2F full visit, L laboratory alone, P phone call. 3 full physical examination vs. vitals/lymph nodes alone. A full physical examination must be performed during follow-up when clinically indicated. 4 applicable to female subjects (reproductive age and not anatomically sterilized). Intranodal injection and treatment interruption is only allowed after a negative pregnancy test. 5 laboratory tests for safety includes hemoglobin, hematocrit, leucocytes, antibodies. Neutrophil count, thrombocytes, creatinine, aspartate aminotransferase (ASAT), alanine transaminase (ALAT), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total bilirubin, amylase (or lipase), creatine kinase (CK, known as creatine phosphokinase), glucose, CD4+ and CD8+ cells and HIV viral load. 6 follow-up of vital signs (RR/pulse) at 5 min and 60 min after injection. 7 cART treatment interruption (ATI) starting from week 6 up to week 18. When there is an undetectable viral load at week 18, ATI is continued until week 30. Schedule according to template available from SPIRIT Statement,© 2013 Chan et al. [12]