Phase I clinical trial of an intranodally administered mRNA-based therapeutic vaccine against HIV-1 infection

Abstract

Objective: The efficacy of therapeutic vaccines against HIV-1 infection has been modest. New inerts to redirect responses to vulnerable sites are urgently needed to improve these results.

Design: We performed the first-in-human clinical trial with naked mRNA (iHIVARNA) combining a dendritic cell activation strategy (TriMix:CD40L+CD70+caTLR4 RNA) with a novel HIV immunogen sequences (HTI immunogen).

Methods: A dose escalation, phase I clinical trial was performed in 21 chronic HIV-1-infected patients under ART who received three intranodal doses of mRNA (weeks 0, 2 and 4) as follow: TriMix-100 g, TriMix-300 g, TriMix-300 g with HTI-300 g, TriMix-300 g with HTI-600 g, TriMix-300 g with HTI-900 g. Primary end-point was safety and secondary-exploratory end-points were immunogenicity, changes in viral reservoir and transcriptome.

Results: Overall, the vaccine was secure and well tolerated. There were 31 grade 1/2 and 1 grade 3 adverse events, mostly unrelated to the vaccination. Patients who received the highest dose showed a moderate increase in T-cell responses spanning HTI sequence at week 8. In addition, the proportion of responders receiving any dose of HTI increased from 31% at w0 to 80% postvaccination. The intervention had no impact on caHIV-DNA levels, however, caHIV-RNA expression and usVL were transiently increased at weeks 5 and 6 in the highest dose of iHIVARNA, and these changes were positively correlated with HIV-1-specific-induced immune responses.

Conclusion: This phase I dose-escalating trial showed that iHIVARNA administration was safe and well tolerated, induced moderate HIV-specific T-cell responses and transiently increased different viral replication readouts. These data support further exploration of iHIVARNA in a phase II study. CLINICALTRIALS.

Gov identifier: NCT02413645.

Fig. 1

(a) Dose escalation flow chart. (b) Assignation of cohorts.

Fig. 2

pETheRNA mRNA vector.

Fig. 3

Changes in the magnitude of total HIV-1-specific immune responses against IN and OUT peptide pools as measured by ELISPOT (at week 0, 4, 6, 8 and 24).

Fig. 4

(a) Impact of the highest doses of iHIVARNA (Groups 4 and 5) in HIV-1 cell-associated total DNA. (b) Impact of TriMix (Groups 1 and 2) or the different doses of iHIVARNA (Groups 3–5) in HIV-1 cell-associated RNA. (c) Impact of the highest doses of iHIVARNA (Groups 4 and 5) in HIV-1 ultrasensitive plasma RNA

Fig. 4 (Continued)

(a) Impact of the highest doses of iHIVARNA (Groups 4 and 5) in HIV-1 cell-associated total DNA. (b) Impact of TriMix (Groups 1 and 2) or the different doses of iHIVARNA (Groups 3–5) in HIV-1 cell-associated RNA. (c) Impact of the highest doses of iHIVARNA (Groups 4 and 5) in HIV-1 ultrasensitive plasma RNA

Fig. 4 (Continued)

(a) Impact of the highest doses of iHIVARNA (Groups 4 and 5) in HIV-1 cell-associated total DNA. (b) Impact of TriMix (Groups 1 and 2) or the different doses of iHIVARNA (Groups 3–5) in HIV-1 cell-associated RNA. (c) Impact of the highest doses of iHIVARNA (Groups 4 and 5) in HIV-1 ultrasensitive plasma RNA

Fig. 5

Reactome gene set analysis.