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WHV is pleased to announce the publication of the HVTN 124 clinical study report in The Lancet HIV.  Study investigators led by HVTN 124 Protocol Chair Dr. Ian Frank of the Perelman School of Medicine of the University of Pennsylvania reported not only on the excellent safety profile of WHV’s polyvalent DNA/Protein HIV vaccine candidate (PDPHV), but also its unprecedented immunogenicity results in human volunteers who received PDPHV. The HVTN 124 trial was able to elicit strong and cross-reactive immune responses against several HIV subtypes by a number of immune parameters.

The randomized, placebo-controlled, double-blind phase 1a trial (ClinicalTrials.gov identifier: NCT03409276) was conducted across six US clinical sites between 2018 and 2020. The study was sponsored and managed by the HIV Vaccine Trials Network (HVTN), which is funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institute of Health (NIH).

Sixty volunteers were enrolled to test the current generation of PDPHV with two main components: a five-plasmid DNA vaccine (env A, B, C, A/E and gag C) in saline and a quadrivalent env (A, B, C, A/E) protein vaccine whose antigens are matched to the DNA vaccine and adjuvanted with GLA-SE.  Both the DNA and protein/adjuvant vaccines were delivered by intramuscular injection.

The main study consisted of two groups: one Group tested the heterologous DNA prime and protein/adjuvant boost approach, and the other group tested co-administration of the DNA and protein/adjuvant vaccine administered at the same time but injected into different arms. Both groups received five vaccinations at months 0, 1, 3, 6 and 8.

Overall, the PDPHV formulation tested in HVTN124 was well tolerated and both vaccination regimens were found to be safe. More significantly, however, was the immunogenicity of the PDPHV vaccine strategy, which was found to be superior to many previous HIV vaccines in several ways:

• The investigators observed a high response rate (90% to 100%) and high magnitude of titer (>1:10,000) of serum antibody responses among vaccinees against a panel of gp120/p140 antigens from diverse HIV-1 subtypes.
• High level and cross-subtype antibody-dependent cellular cytotoxicity (ADCC) activities were found in most vaccinees as measured by an assay in which the target cells were transfected with infectious molecular clones (IMC).  While such assay mimics a viral infection, many of the previous HIV vaccine studies did not elicit ADCC against IMC-transfected target cells. 
• Moreover, PDPHV in HVTN 124 induced neutralizing antibody activities against relatively neutralizing resistant Tier 1B viruses across different subtypes (clades B, C, AE and AG) while previous HIV vaccine studies either did not elicit such neutralizing activities or their neutralizing titers were lower than the HVTN 124 sera against the same Tier 1B virus.  
• PDPHV elicited high titer IgG responses in 67-100% of participants against gp70-V1V2 antigens from subtypes A, B, C, and AE, an established corelate of protection  against HIV infection.  The rate and magnitude of these responses exceeded those in previous HIV vaccine studies.
• Furthermore, all volunteers in the prime-boost group achieved 100% CD4+ T cell responses which has  not been universally observed in previous human HIV vaccine studies. 

Achieving such high immune responses with all of the above biomarkers in one HIV vaccine study is quite remarkable.  Given the challenge of developing an efficacious HIV vaccine, it has always been a major objective to develop a vaccine which can elicit a wide spectrum of immune responses in order to maximize the chance of preventing HIV infection.  The HVTN 124 study demonstrated that PDPHV is progress towards that objective. Advanced phase clinical trials are warranted to test the efficacy of PDPHV to prevent HIV acquisition.

Of note is that the prime-boost group in HVNT 124 seemed to consistently outperform the co-administration group with respect to response rates and/or magnitude for each immunologic outcome assayed.  More basic immunology studies are required to fully understand the true mechanisms and differences of these two approaches.  

The study team speculates that the broad and robust immune responses seen in HVTN 124 are a result of the matched prime-boost antigens and the polyvalent ENV antigen approach, a unique HIV vaccine design that originated in Dr. Shan Lu’s lab at the University of Massachusetts Chan Medical School (UMCMS). WHV licensed PDPHV IP from the UMCMS in 2018 and has been managing the product development program of this candidate vaccine.

The DNA and protein vaccines used in HVTN 124 were manufactured by Waisman Biomanufacturing, a contracted manufacturing organization, while the adjuvant was supplied by The Access to Advanced Health Institute (AAHI) who specifically formulated GLA-SE.

WHV is grateful for the HVTN 124 trial volunteers, as well as study clinicians, clinical staff, and lab scientists from all six clinical sites and the entire HVTN organization.   

At the recent HIV Vaccine Trials Network (HVTN) Conference 2023 in Seattle, WA, and the International Society for Vaccines (ISV) 2023 Annual Congress in Lausanne, Switzerland, Worcester HIV Vaccine (WHV) presented exciting data of a novel CD4 binding site specific and cross-clade neutralizing human monoclonal antibody (HmAb) elicited by the first-generation PDPHV, a collaborative effort between WHV, Dr. Peter Kwong and Dr Tongqing Zhou from the NIH Vaccine Research Center (VRC) and  Dr. Xiangpeng Kong and Dr. Kun-Wei Chan from New York University.

The research team isolated and characterized a novel CD4-binding site monoclonal antibody, HmAb64, from a DP6-001 trial volunteer who was immunized with PDPHV as a DNA prime – Protein boost regimen. On a VRC cross-clade panel of HIV-1 pseudo-virus strains, HmAb64 neutralized viruses across clades A, B, C and AE including tier-2 neutralization resistant strains. The cryo-EM structure of the antigen-binding fragment of HmAb64 indicated that the key interaction of HmAb64 is similar to the CD4-binding loop, a critical component of the CD4-binding site.

The vaccine elicitation of HIV-neutralizing antibodies with tier-2-neutralization breadth has been a challenge for several decades. Our findings represent a major step forward in the long effort to develop an effective HIV vaccine and indicates that PDPHV could be a strong vaccine candidate against HIV infection.

DP6-001 was a phase 1 trial testing the safety and immunogenicity of the first-generation PDPHV investigational product that originated from the lab of Dr. Shan Lu, Professor Emeritus at the University of Massachusetts Chan Medical School and Chief Scientific Officer at WHV. The design of this polyvalent gp120 subunit-based HIV vaccine candidate has since been improved and developed into the second-generation PDPHV, which has been tested in the phase 1a trial HVTN124 and the currently ongoing phase 1b trial WHV138. Immunogenicity studies from these trials are ongoing, including more human mAbs isolation research from HVTN124 to further investigate whether the second-generation PDPHV candidate is capable of eliciting similar or even better immune responses.

At the recent 2023 ISV Congress in Lausanne, Switzerland, a poster was presented by WHV’s trial partner highlighting the progress of WHV138, our phase 1b trial that started over two years ago and is coming to completion within the next few weeks.

WHV138 is a randomized double-blinded, placebo-controlled clinical trial exploring the safety and immunogenicity of the polyvalent DNA/Protein HIV vaccine (PDPHV), a heterologous HIV vaccine candidate with two main components: a 5-plamid env (A,B,C,A/E) gag (C) DNA vaccine and a quadrivalent gp120 (A,B,C,A/E) Protein vaccine whose antigens are matched to the DNA vaccine component – a unique approach in the HIV vaccine research field.

Under the lead of Principal Investigator Dr. Stephen Walsh, a physician in the Division of Infectious Diseases at Brigham and Women’s Hospital in Boston, MA, the clinical team enrolled 42 participants in under a year into two groups. A diverse cohort from metropolitan Boston was recruited with about half of all volunteers identifying as LGBTQI and about 1 in 5 volunteers identifying as gender non-conforming.

Both groups of WHV138 received a co-administration of PDPHV at all scheduled vaccination visits: Group 1 received the DNA vaccine in one arm and the GLA-SE adjuvanted Protein vaccine in the other arm, while Group 2 received a DNA and Protein vaccine mix without adjuvant into both arms. The vaccination schedule of Group 1 has a longer dosing internal and fewer vaccinations than Group 2 as well as the preceding multi-center phase 1a HVTN124 trial that tested the same PDPHV formulation with a DNA prime – Protein boost approach. In HVTN124, the investigational product was well tolerated with a good safety profile and great immunogenicity results that will be published soon. Similarly, WHV138 shows the vaccine regimen to be safe, well-tolerated and preliminary data suggests that PDPHV is immunogenic, including the Group 2 regimen which does not contain the GLA-SE adjuvant.

Based on these data, PDPHV seems to be a promising HIV vaccine candidate and WHV is excited to advance PDPHV’s product development program through upcoming efficacy trails.

The heterologous HIV vaccine candidate PDPHV – currently tested in phase 1b WHV138 – recently completed the stability program for both its main components, the 5-plasmid DNA vaccine and the 4-valent recombinant gp120 Protein vaccine. The DNA vaccine was manufactured in 2015 and has proven to remain stable for 8 years. The 4 separate Protein lots from HIV-1 clades A, B, C, and AE, which are mixed at bedside into a single 4-valent vaccine, recently successfully completed the final stability testing after 6.5 years since the beginning of the stability program in 2016. Both of these products were previously used for the phase 1a HVTN124 trial.  The remarkable stability profile of PDPHV is the best evidence showing WHV’s high quality GMP manufacturing and QC/QA programs.  WHV would like to thank their contracted manufacturing partner Waisman Biomanufacturing (WB) for such high quality vaccine products.

For the soon to be conducted phase 2a study, new lots of each of the components of PDPHV have already been produced at WB.  A further optimized protein vaccine vialing method was successfully implemented to allow for a simplified vaccine dispensing of the four gp120 Protein vaccine components as a single pre-mixed Drug Product (DP). It is no longer needed to mix the 4-valent protein vaccine at bedside. For the DNA vaccine component, a new lot was produced with substantial improvements in yield and purity as compared to the previously produced product. The formulations of both the DNA and the Protein vaccines did not change and after thorough consultation, the FDA provided positive feedback regarding WHV’s plans to use the newly manufactured DPs for PDPHV’s advancing product development program. The stability program of both DPs is off to a great start: The new DNA product has recently passed its third year of stability testing and the recombinant 4-valent pre-mix Protein vaccine recently passed its second year of stability testing. Both products will continue the stability program until the upcoming phase 2a in-human trial is completed.

WHV is excited to announce that we are approaching the end of our phase 1b WHV138 trial as all Group 1 participants have now completed their scheduled visits and the remaining Group 2 participants continue the study until their final 12-month follow-up visit, with the last volunteer’s last visit to be expected by December of this year.

Overall, the safety profile of the vaccine candidate PDPHV looks excellent. The trial has passed all three SMB safety reviews without any concerns. Immunogenicity studies will be performed after the trial is fully completed, but preliminary analyses look very promising and reflect the remarkable immunogenicity data from the previous HVTN124 trial – the phase 1a trial testing PDPHV under a slightly different vaccination regimen. Results from that study will be published in the near future.

The second generation PDPHV is a polyvalent HIV vaccine candidate with two main components: a 5-plasmid DNA vaccine (ENV clades A, B, C, and AE and gag-C) and a recombinant quadrivalent gp120 Protein vaccine with antigens matched to the DNA vaccine. These two components have been investigated as a DNA prime/Protein boost regimen in HVTN124 and co-administered together both with and without adjuvant in WHV138. The forthcoming phase 2a trial will further explore the best form of regimen, vaccination schedule and dosing.

WHV138 is currently the only in-human trial investigating a vaccine candidate targeting viral ENV antigens from the four major circulating HIV-1 subtypes. Based on the results from HVTN124, we believe that PDPHV has the potential to be a globally relevant HIV vaccine candidate.

Last month, the WHV team along with partners from the University of Massachusetts Chan Medical School (UMMS) presented two posters at the Keystone Symposia on HIV Vaccines.

The first poster presented data of an A32-like ADCC mediating monoclonal antibody (mAb) isolated from a donor who participated in UMMS’ phase 1 trial DP6-001 testing the safety and immunogenicity of the first generation PDPHV. The new mAb (HmAb78) has previously been shown to have cross-clade gp120 binding and potent ADCC activities comparable to A32, a potent mAb isolated from a chronically infected HIV-1 patient that serves as an ADCC benchmark for non-neutralizing mAb in the HIV field – indicating that PDPHV is capable to induce an immune response similar to that induced by HIV infection. More significantly, HmAb78 used the same germline as A32. The new data presented at this year’s Keystone HIV Vaccine meeting is a crystal structure of HmAb78 which showed that the antigen binding site was largely identical to that of A32. This work was done in collaboration with Dr. Marzena Pazgier and her postdoctoral fellow Dr. William D. Tolbert from the Department of Medicine of Uniformed Services University of the Health Sciences. Dr. Xiangpeng Kong from New York University (NYU) also played an important role in this study. These findings further confirm that WHV’s polyvalent gp120 DNA /Protein HIV vaccine targets critical viral epitopes which may be important for HIV infection. 

The second poster presented the recently determined structure and epitope of the CD4-binding site (CD4bs) human mAb HmAb64, which has also been isolated from a donor who participated in the DP6-001 trial and neutralized multiple primary HIV-1 subtypes. Through cryogenic electron microscopy, the collaborating research team at NYU (Dr. Xiangpeng Kong and Dr. Kun-Wei Chan) provided a detailed structure of HmAb64 and specifically discovered a binding mode that is distinct from known CD4bs-specific neutralizing antibodies (nAbs). These new findings can not only help with immunogen design for HIV prevention research but also provide additional evidence that PDPHV may be a strong vaccine candidate against HIV infection.

The second generation PDPHV is currently tested in phase 1b WHV138 to be concluded by the end of this year and WHV eagerly pursues to move this promising HIV vaccine candidate to more advanced in-human trials.

The WHV138 Safety Monitoring Board recently held their third periodic safety review meeting and concluded that the investigational HIV vaccine candidate PDPHV does not present any safety concerns to the trial participants. The trial can thus continue as planned without any modification.

This was the last scheduled safety review meeting for WHV’s phase 1b trial, which is already in its final stage: All active volunteers have completed their vaccination visits and are within their 12-month observation period. About a third of the Group 1 participants have already finished the trial with their final study visit. The last volunteer’s last visit is expected to take place towards the end of this year. Blood samples for immunogenicity studies are collected through the final study visit to allow for longevity analyses of the induced immune responses up until 12 months after final vaccination.

WHV’s second-generation HIV vaccine candidate PDPHV includes a 5-pladmid DNA vaccine component with a matched quadrivalent gp120 Protein vaccine component and is currently the only vaccine formulation targeting viral ENV antigens from all four major circulating HIV subtypes. With such a low-risk safety profile and promising immunogenicity results, WHV is excited to be moving PDPHV through the subsequent product development stages as the phase 1b trial WHV138 is coming to an end.

Alongside leading HIV vaccine researchers, WHV joined the quest for a safe and effective HIV vaccine in 2018, when the small biotech company was founded in Worcester, MA by licensing the intellectual property for the vaccine candidate PDPHV from Dr. Lu’s lab at the University of Massachusetts Chan Medical School. Since then, WHV has successfully undertaken a major product development campaign for the heterologous 5-plasmid DNA, quadrivalent gp120 protein vaccine and became the IND holder of the currently ongoing phase 1b trial WHV138. On HIV Vaccine Awareness Day 2023, we would like to recognize and thank the many volunteers of our trials, our clinical partners, investors, and renowned HIV experts on our team, without which the accomplishments of our vaccine development program would not be possible.

We at WHV are hopeful that PDPHV – targeting multiple subtypes of HIV-1 – can advance the HIV vaccine field towards finding a globally relevant, safe and effective HIV vaccine. Based on recent exploratory studies, WHV’s investigational product may be capable of eliciting immune responses that haven’t been seen since the RV144 trial. These remarkable preliminary immunogenicity data are resulting from the previously conducted HVTN124 trial, a phase 1a trial testing the safety and immunogenicity of PDPHV in a DNA prime – Protein boost approach. Preparations for efficacy trials to further confirm these preliminary data are in progress and will be conducted as soon as partnerships are established.

As Bill Clinton has declared over 25 years ago, “only a truly effective, preventive HIV vaccine can limit and eventually eliminate the threat of AIDS.” We at WHV are honored to participate in this mission and are eager to continue until the end of the HIV pandemic is accomplished.