Development of an HIV vaccine is one of today’s critical scientific challenges. For more than 30 years, the preventive HIV vaccine field explored a number of vaccine development approaches. While much progress has been made and the field remains optimistic, past history suggests that new vaccine approaches should continue to be explored and advanced through clinical development. At WHV, we are employing novel vaccine technologies with the aim to develop a safe and effective DNA/Protein HIV vaccine that is able to protect against the many different circulating HIV strains around the world.
Early Trials in the HIV vaccine field
Recombinant protein alone approach
Between 1998 and 2003, taking cue from the classical vaccinology, two VaxGen trials tested recombinant Env protein vaccine, but found that antibodies induced by the proteins were not broadly reactive and did not protect against HIV infection (Flynn, 2005; Pitisuttithum, 2006).
Ad-5 viral vector-based approach
The next two trials, STEP and Phambili, explored the efficacy of a vaccine based on adenovirus type 5 (Ad5) vector delivering gag, pol, and nef genes of HIV-1 and eliciting T cell responses to HIV. Both trials were halted in 2007 when an interim review of STEP trial results indicated that the vaccine was not effective (Cohen, 2007). Moreover, post hoc analysis of the trials indicated that some vaccinated subgroups experienced higher HIV infection rates than placebos (Duerr, 2012).
The HVTN 505 trial tested a vaccine that delivered gag, pol, nef and env genes first using a DNA approach as a prime and then boosting with Ad5 carrying gag, pol, and env. The trial was halted in 2013 after it became clear that the regimen was not effective in preventing HIV infection or in reducing viral load in infected volunteers (Hammer, 2013).
Alvac prime-protein boost approach (non-matched Env immunogens)
In 2009, the RV144 trial was conducted in Thailand and showed 31% overall efficacy (Rerks-Ngarm, 2009). This has been the most successful preventive HIV vaccine candidate to date, and it utilized canarypox vector delivering gap, pol, and env genes that was boosted with the recombinant gp120 Env proteins used in the VaxGen trials. The trial demonstrated the promise of gene-based priming followed by the protein boost approach as most correlates of protection from the trial were antibody-based. However, it also highlighted the need to elicit stronger and more durable antibody responses because the protection in RV144 lasted for only 6 months after the final vaccination.
The HVTN 702 trial began in 2016 to further test the pox-prime/protein-boost approach that demonstrated limited efficacy in the RV144 trial. Unfortunately, in February 2020 it was announced that the trial was stopped prematurely due to observed lack of protection. While the reasons for failure require additional studies, it may be connected to the findings RV144 candidate did not induce persisting antibody responses, especially the ADCC-mediated antibody responses.
Ad-26 prime and protein boost (mosaic immunogens)
More recently, the HVTN 705 trial (Imbokodo study) assessed the vaccine efficacy of a heterologous prime/boost vaccine regimen using a mosaic Ad26.Mos4.HIV product carrying HIV gag, pol, and env antigens and an aluminum phosphate-adjuvanted clade C gp140 protein booster. Again, the study was completed prematurely after the primary analysis did not show sufficient protection against HIV infection in women in sub-saharan Africa (read more here). A similar vaccine concept is being evaluated for efficacy in the currently ongoing HVTN706 trial (Mosaiko) in a different population that is at high-risk for acquiring HIV.
WHV’s approach: Polyvalent DNA/protein HIV Vaccine (PDPHV)
DP6-001 (first generation PDPHV)
Starting in the 1990s, Dr. Shan Lu at the University of Massachusetts Medical School has been exploring the possibility of using gene delivery by DNA to elicit balanced antibody and T cell immune responses. First as a postdoctoral researcher in Harriet Robinson’s laboratory and then as the head of the Laboratory of Nucleic Acid Vaccines, he discovered that DNA is powerful at priming immune responses (both T cell and B cell) in such a way that the final antibody responses are effectively boosted with recombinant proteins. This approach, combined with the classical polyvalent vaccine approach for diverse pathogens, was used to develop the first polyvalent DNA-prime/protein-boost vaccine for HIV (PDPHV). The first generation PDPHV showed promising results in the Phase I clinical trial DP6-001. This vaccine candidate was able to induce potent and broadly reactive, gp120-specific antibodies with cross-clade neutralization and ADCC activities. This trial further demonstrated that the DNA prime – Protein boost approach is an effective method to elicit not only humoral but also cell-mediated immune responses in humans, and that a polyvalent Env formulation could generate broad immune responses against different clades of HIV-1 (Wang, 2008), paving the way for the second generation PDPHV candidate. (read more about our Clinical Trials).
Results from Dr. Lu’s laboratory including the DP6-001 trial and animal studies showed that the polyvalent DNA priming with matched protein boosts is important in eliciting higher level and more durable antibody responses than those observed in the RV144 trial where the antigens used were not matched between prime and boost.
HVTN124 (Phase 1a trial of second generation PDPHV)
The PDPHV design was further improved by selecting the most optimal Env variants based on the screening of a large panel of viruses (Wang, 2017). The GMP manufacturing process was also further optimized to produce high yield and highly purified recombinant gp120 proteins. This led to the second generation vaccine candidate PDHHV-201401 that has since been tested the a phase 1a trial HVTN124.
The second generation PDPHV vaccine showed a remarkable safety and immunogenicity profile in the HVTN124 trial. Study participants who received the polyvalent DNA/Protein prime-boost vaccine developed high breadth and high magnitude immune responses against diverse HIV subtypes. More specifically, high levels of HIV specific CD4+ T cells and antibody responses with high levels of ADCC activity as well as Tier 1A and Tier 1B neutralizing activity against HIV viral isolates from diverse subtypes were observed in all or majority of the treatment group.
WHV138 (Phase 1b trial of second generation PDPHV)
The second generation of PDPHV is currently further evaluated in the phase 1b WHV138 trial with a simplified administration schedule. Immunogenicity results will be analyzed after study completion which is anticipated to be in the early Fall of 2023.
Formation of WHV
In early 2018, the Phase Ia clinical trial HVTN 124 began to test the second generation vaccine candidate PDPHV-201401. Around the same time, Mr. Weibo Li, the head of the Glory Harvest Group in China, licensed the intellectual property for the HIV vaccine technology from UMMS and formed Worcester HIV Vaccine (WHV). The HVTN124 trial was completed in the fall of 2020 and has shown excellent safety and very promising immunogenicity results eliciting potent and broad immune responses to HIV. WHV is further advancing the second-generation polyvalent DNA-prime/protein-boost vaccine in a currently ongoing phase 1b study WHV138. Learn more about our PDPHV vaccine candidate.
