All of our preventive vaccination trials in humans have been conducted by the HVTN, a network that is funded and supported by the NIH. The HVTN is the largest worldwide clinical trials network focused on the development and testing of HIV/AIDS vaccines. Our Phase 1 trials have tested safety, dosing regimens and immunogenicity. The results of a two group Phase 1 trial (designated HVTN 045) testing the safety of DNA inoculations is published in AIDS Research and Human Retroviruses 22:678 (2006). A four group trial (HVTN 065) testing different DNA priming and MVA boosting regimens is published in the Journal of Infectious Diseases 203:610 (2011). A three group trial (HVTN 094) testing the effect of co-expressing GM-CSF in the DNA prime is published in PLoS ONE 12(7): e0179597. https://doi.org/10.1371/journal.pone.0179597). An ongoing fourth Phase 1 trial (HVTN 114) is testing the effects of late boosts with MVA, gp120 protein or MVA+gp120 protein on our Phase 2a trial.
Phase 1 Human Clinical Trials. In our first Phase 1 clinical trial, HVTN 045, our DNA vaccine was tested without MVA boosting to document the safety of the DNA. Our second Phase 1 clinical trial, HVTN 065, was designed to test the combined use of DNA and MVA and consisted of a dose escalation as well as regimen studies. The low dose consisted of 0.3 mg of DNA and 1x107 tissue culture infectious doses (TCID50) of MVA. Once safety was demonstrated for the low dose in 10 participants, the full dose (3 mg of DNA and 1x108 TCID50 of MVA) was administered to 30 participants in a regimen that used two DNA primes and two MVA boosts, all spaced at two-month intervals (DDMM). A single dose of DNA at time 0 followed by MVA at weeks 8 and 24, a DMM regimen, and three doses of MVA administered at weeks 0, 8 and 24, an MMM regimen, were also tested in 30 participants each. Participants were followed for 12 months to assess vaccine safety and to measure vaccine-induced immune responses.
Data from the HVTN 065 trial again documented the safety of the vaccine products but also showed that the DDMM and MMM regimens induced different patterns of immune responses. The full dose DDMM regimen induced higher CD4+ (77%) and CD8+ (42%) T cell response rates than the MMM regimen (43% CD4+ and 17% CD8+ response rates). In contrast, the highest response rates and highest titers of antibodies to the HIV Env protein were induced in the group that received only the MVA using the MMM regimen. Antibody response rates were documented to be higher for the MMM group using three different assays designed to measure total binding antibody levels for an immune dominant portion of the Env protein (27% for DDMM and 75% for MMM), binding of antibodies to the gp120 subunit of the envelope glycoprotein (81% for DDMM and 86% for MMM) and neutralizing antibodies (7% for DDMM and 30% for MMM). The 1/10th dose DDMM regimen induced overall similar T-cell responses but reduced antibody responses while the response rates were intermediate in the DMM group.
The HVTN also sponsored and conducted a Phase 1 clinical trial in humans (HVTN 094) of an adjuvanted form of our vaccine, which co-expressed GM-CSF in the DNA priming vaccine. This trial also tested the value of adding a 3rd MVA boost at 4 months after the 2nd MVA boost (DDMM_¬M regimen). The results of HVTN 094 did not show a significant benefit from adding the GM-CSF adjuvant to the vaccine; but, did show the 3rd-spaced MVA boost enhancing Ab responses. Therefore, the 3rd-spaced MVA boost, but not the GM-CSF adjuvant, is being advanced in clinical trials.
The HVTN 114 trial was initiated by the HVTN in January 2017 to test the 5 year durability of immune responses elicited by GOVX-B11 and the effect of additional administrations of antigens (“late boosts”) on the Ab responses elicited in the Phase 2a trial, HVTN 205 (see below). Three late boosts are being tested: (1) AIDSVAX B/E, a bivalent gp120 protein that was left over from the partially successful RV144 trial in Thailand, (2) AIDSVAX B/E +MVA62B, and (3) MVA62B. While HVTN 114 is ongoing, newer gp120 proteins are being cGMP manufactured and safety tested with the goal of advancing GOVX-B11 in the presence and absence of protein boosts.
Phase 2 Human Clinical Trials. Based on the safety and immunogenicity results in the HVTN 045 and HVTN 065 trials, the full dose DNA/MVA and MVA-only regimens were selected for testing by the HVTN in a Phase 2a trial (designated HVTN 205) which was completed in 2012 and is published in the Journal of Infectious Diseases 210:99-110 (2014). HVTN 205 was designed to evaluate the safety and immunogenicity of the GeoVax vaccines in healthy, HIV-uninfected adults. In HVTN 205, 299 participants were randomly assigned to three study arms: 149 participants received two injections of the DNA vaccine followed by two injections of the MVA vaccine (DDMM arm), 75 participants received three MVA injections and one placebo injection (MMPM arm), and 75 participants received four injections of placebo. After the final vaccination, antibody responses against the HIV Envelope protein (Env), the target for protective antibody, were detected in 93.2% of the DDMM arm. At six months after final vaccination (the latest time point tested), gp140 IgG antibody response titers in the DDMM and MMM arms had declined by less than 3-fold indicating good durability of the antibody response. Additionally, the antibody responses after vaccination had high affinity binding, a characteristic which has been associated with prevention of HIV infection in preclinical models. HVTN 205 also showed low response rates for serum IgA, a desirable characteristic because serum IgA competed with serum IgG for reducing the risk of infection in the partially protective RV144 AIDS vaccine trial in Thailand. Response rates for serum IgG3, an isotype associated with activating innate methods of protection such as complement (C')-mediated lysis and antibody-dependent cellular cytotoxicity were excellent (91%). Based on the results of HVTN 205 and HVTN 094 as well as preclinical challenge studies testing the protective efficacy of simian prototypes of the GOVX-B11 vaccine, the DDMM_M regimen is undergoing further advancement. More information on HVTN 205 and the comparison of the immune responses elicited in the trial compared to those elicited in RV144 can be found in the White Paper, GOVX-B11, a Clade B HIV Vaccine.