Effect of Intranodally Administered Dendritic Cell-Based HIV Vaccine in Combination With Pegylated Interferon α-2a on Viral Control Following ART Discontinuation: A Phase 2A Randomized Clinical Trial

Abstract

Introduction: Functional cure has been proposed as an alternative to lifelong antiretroviral therapy and therapeutic vaccines represent one of the most promising approaches.

Materials and methods: We conducted a double-blind randomized placebo-controlled clinical trial to evaluate the safety, immunogenicity, and effect on viral dynamics of a therapeutic vaccine produced with monocyte-derived dendritic cells (MD-DC) loaded with a high dose of heat-inactivated autologous (HIA) HIV-1 in combination with pegylated interferon alpha 2a (IFNα-2a) in people with chronic HIV-1.

Results: Twenty-nine male individuals on successful ART and with CD4+ ≥450 cells/mm3 were randomized 1:1:1:1 to receive three ultrasound-guided inguinal intranodal immunizations, one every 2 weeks: (1) vaccine ~107 MD-DC pulsed with HIA-HIV-1 (1010 HIV RNA copies) (n = 8); (2) vaccine plus three doses of 180 mcg IFNα-2a at weeks 4-6 (n = 6); (3) placebo = saline (n = 7); and (4) placebo plus three doses of 180 mcg IFNα-2a (n = 8). Thereafter, treatment was interrupted (ATI). Vaccines, IFNα-2a, and the administration procedures were safe and well tolerated. All patients' viral load rebounded during the 12-week ATI period. According to groups, changes in viral set-point between pre-ART and during ATI were not significant. When comparing all groups, there was a tendency in changes in viral set-point between the vaccine group vs. vaccine + IFNα-2a group (>0.5log10p = 0.05). HIV-1-specific T-cell responses (IFN-ƴ Elispot) were higher at baseline in placebo than in the vaccine group (2,259 ± 535 vs. 900 ± 200 SFC/106 PBMC, p = 0.028). A significant difference in the change of specific T-cell responses was only observed at week 4 between vaccine and placebo groups (694 ± 327 vs. 1,718 ± 282 SFC/106 PBMC, p = 0.04). No effect on T-cell responses or changes in viral reservoir were observed after INFα-2a administration.

Discussion: Results from this study show that intranodally administered DC therapeutic vaccine in combination with IFNα-2a was safe and well-tolerated but had a minimal impact on viral dynamics in HIV-1 chronic infected participants.

Clinical trial registration: (www.ClinicalTrials.gov), identifier NCT02767193.

Keywords: ATI; combined strategy; dendritic cell; interferon alpha; therapeutic vaccine.

Conflict of interest statement

JG has received honoraria for speaking and advisory boards, and his institution has received research grants from ViiV, MSD, Janssen, and Gilead. As of May 1, 2018, JG is a full-time employee of ViiV Healthcare. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Leal, Couto, Sánchez-Palomino, Climent, Fernández, Miralles, Romero, González, Maleno, Paño, Pich, Nicolau, Gatell, Plana, García and the DCV3-RISVAC04 Study Group.

Figures

Figure 1

Study design.

Figure 2

Consort diagram of participants’ distribution.

Figure 3

Median VL (log10 copies/ml) during vaccination and ATI per study group.

Figure 4

ΔVL set-point [log10 mean (SE) copies/ml] for different groups of study. (A) ΔVL set-point for patients receiving vaccine, vaccine + IFN, placebo and placebo + IFN; (B) ΔVL set-point for patient receiving IFN or not, independently of being vaccinated or not.

Figure 5

VL [log10 mean (SE) copies/ml] of patients receiving or not IFN: VLs at pre-ART, weeks 6, 8, 10, 12, 14, and 16 of follow-up and set-point are represented for patients who received IFN or not, independently of being previously vaccinated.

Figure 6

Total HIV-1 specific T cell responses measured by IFN-γ ELISPOT: (A) Individual responses and mean ± SEM of SFC/106 PBMC for the different arms of the study at w0 (baseline); (B) Changes of HIV-1-specific T cell responses at w16 for the different arms of the study [Δ SFC/106 PBMC (w16-w0)]. No significant differences were observed between vaccine and placebo groups (p=0.09). No effect on HIV-1-specific T cell responses was observed with the administration of IFN.

Figure 7

Correlations between changes in VL and HIV-1-specfic T-cell responses at w16: Graphs represent the trend of inverse correlation between ΔVL and ΔHIV-1-specific T cell responses (w16-w0) (A) in vaccine group (r=-0.525, p= 0.09) (B) whereas no correlation was observed in placebo group (r=-0.275, p= 0.09).