Date Published: January 30, 2019
Publisher: Public Library of Science
Author(s): Jürgen K. Rockstroh, David Asmuth, Giuseppe Pantaleo, Bonaventura Clotet, Daniel Podzamczer, Jan van Lunzen, Keikawus Arastéh, Ronald Mitsuyasu, Barry Peters, Nozza Silvia, Darren Jolliffe, Mats Ökvist, Kim Krogsgaard, Maja A. Sommerfelt, Alan Landay.
Vacc-4x, a therapeutic HIV vaccine candidate has previously induced a significant reduction in viral load (VL) set-point compared to placebo upon interruption of combination anti-retroviral therapy (ART) (2007/1 study). This study, (2012/1), explored the potential to maintain Vacc-4x effect by re-boosting eligible 2007/1 study participants.
Participant inclusion required 2007/1 participants to have completed all Vacc-4x immunizations and interrupted ART for up to 26 weeks. At weeks (wk)0 and 2, participants received intradermal (i.d.) Vacc-4x booster immunizations (1.2mg) on ART with GM-CSF (60μg) i.d. as a local adjuvant. ART was interrupted for up to 16 weeks (wk12-wk28). Participants were then followed on ART until wk36. VL set-point, total proviral DNA (pvDNA) and immunogenicity assessed by IFN-γ ELISPOT, T-cell proliferation and delayed type hypersensitivity (DTH) reactions were compared to participants’ values in the 2007/1 study where available.
This open, multicenter, clinical study enrolled 33 participants from 9 clinical trial sites in the US and Europe. In the per-protocol (PP) population, the VL set-point geometric mean (GM) 18162 copies/mL was not significantly changed compared to the 2007/1 study (GM VL 22035 copies/mL), (p = 0.453, n = 18). For participants with available preART VL values, the VL set-point (GM 26279 copies/mL) remained significantly lower than the preART VL set-point (GM 74048 copies/mL, p = 0.021, n = 13). A statistically significant reduction in pvDNA (49%) from baseline to wk4 was observed (p = 0.03, n = 26). DTH responses (wk4) increased significantly from baseline (p = 0.006, n = 30) and compared to the 2007/1 study (p = 0.022, n = 29) whilst the proportion of participants with ELISPOT and T-cell proliferation responses was similar between the two studies.
Vacc-4x booster immunizations safely maintained the mean VL set-point at that established following primary Vacc-4x therapeutic immunization. The reduction in pvDNA during ART supports the potential for Vacc-4x immunization to reduce HIV reservoirs and thereby contribute to combination HIV cure strategies.
Therapeutic HIV vaccination is being investigated as a prospective component of future combination strategies aimed at inducing remission of HIV infection (functional cure). Since the duration of immunity to therapeutic HIV vaccine antigens may wane over time, this study addressed the concept that periodic boosting may be required to maintain therapeutic vaccine effect and thereby contribute to sustained HIV remission.
The GM VL set-point in the PP population was not significantly lower than that obtained in the 2007/1 study (p = 0.453 n = 18). This suggests that re-boost immunizations maintained the GM VL set-point close to that obtained following primary immunization in the 2007/1 study. However, it is important to note that the treatment interruption in the 2007/1 study was 10 weeks longer than the treatment interruption in this 2012/1 study. Recently, ART-free periods in clinical studies have not generally exceeded 4 months, a margin of safety identified in the SMART study . It is not known whether the VL set-point in the 2012/1 study might have been lower or similar had the ART interruption been of the same duration as for the 2007/1 study.