DNA/MVA Vaccination of HIV-1 Infected Participants with Viral Suppression on Antiretroviral Therapy, followed by Treatment Interruption: Elicitation of Immune Responses without Control of Re-Emergent Virus

Abstract

GV-TH-01, a Phase 1 open-label trial of a DNA prime—Modified Vaccinia Ankara (MVA) boost vaccine (GOVX-B11), was undertaken in HIV infected participants on antiretroviral treatment (ART) to evaluate safety and vaccine-elicited T cell responses, and explore the ability of elicited CD8+ T cells to control viral rebound during analytical treatment interruption (TI). Nine men who began antiretroviral therapy (ART) within 18 months of seroconversion and had sustained plasma HIV-1 RNA <50 copies/mL for at least 6 months were enrolled. Median age was 38 years, median pre-ART HIV-1 RNA was 140,000 copies/ml and mean baseline CD4 count was 755/μl. Two DNA, followed by 2 MVA, inoculations were given 8 weeks apart. Eight subjects completed all vaccinations and TI. Clinical and laboratory adverse events were generally mild, with no serious or grade 4 events. Only reactogenicity events were considered related to study drug. No treatment emergent viral resistance was seen. The vaccinations did not reduce viral reservoirs and virus re-emerged in all participants during TI, with a median time to re-emergence of 4 weeks. Eight of 9 participants had CD8+ T cells that could be stimulated by vaccine-matched Gag peptides prior to vaccination. Vaccinations boosted these responses as well as eliciting previously undetected CD8+ responses. Elicited T cells did not display signs of exhaustion. During TI, temporal patterns of viral re-emergence and Gag-specific CD8+ T cell expansion suggested that vaccine-specific CD8+ T cells had been stimulated by re-emergent virus in only 2 of 8 participants. In these 2, transient decreases in viremia were associated with Gag selection in known CD8+ T cell epitopes. We hypothesize that escape mutations, already archived in the viral reservoir, plus a poor ability of CD8+ T cells to traffic to and control virus at sites of re-emergence, limited the therapeutic efficacy of the DNA/MVA vaccine.Trial Registrationclinicaltrials.gov NCT01378156

The Safety and Immunogenicity of GTU®MultiHIV DNA Vaccine Delivered by Transcutaneous and Intramuscular Injection With or Without Electroporation in HIV-1 Positive Subjects on Suppressive ART

“…Indeed, ICS analysis detected statistical differences between the TC+IM group and the EP+IM group but was underpowered to see any difference with the placebo matched control group. Future studies will be needed to determine whether DNA vaccination by either route can serve as an effective prime when combined with a boosting strategy including the use of viral vectors such as MVA (20). Additional benefit may be gained through strategies designed to refocus responses beneficial T-cell responses toward subdominant conserved regions of HIV-1 (21).…”

Cell-Mediated Immune Predictors of Vaccine Effect on Viral Load and CD4 Count in a Phase 2 Therapeutic HIV-1 Vaccine Clinical Trial

“…On the other hand, therapeutic vaccines have largely focused on the induction of cell-mediated immune responses. Immunogenicity following therapeutic vaccination has been described with reductions in viral load ( Vardas et al, 2012 ; Garcia et al, 2013 ; Pollard et al, 2014 ), as well as with no or limited effects on the rate of viral rebound or control of viral load ( Jacobson et al, 2016 ; Thompson et al, 2016 ). No immune correlates have yet been clearly defined from these generally small studies.…”

Engineering DNA vaccines against infectious diseases

“…Their studies were conducted in HIV-infected participants who were currently undergoing antiretroviral treatment. It has been demonstrated that GOVX-B11 is capable of eliciting antibodies and a T cell response against a heterologous challenge [158]. On the other hand, the PENNVAX DNA vaccines developed by Inovio Pharmaceuticals, currently in phase I, utilize the prime-boost strategy, similar to that of GOVX-B11, by combining a viral vector vaccine.…”