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.

Additional Metadata
Persistent URL dx.doi.org/10.1097/QAD.0000000000002026, hdl.handle.net/1765/111842
Journal AIDS (London, England)
Rights no subscription
Citation
Leal, L. (Lorna), Guardo, A.C. (Alberto C.), Morón-López, S. (Sara), Salgado, M. (Maria), Mothe, B. (Beatriz), Heirman, C, … García, F. (Felipe). (2018). Phase I clinical trial of an intranodally administered mRNA-based therapeutic vaccine against HIV-1 infection. AIDS (London, England), 32(17), 2533–2545. doi:10.1097/QAD.0000000000002026