We are excited to announce that the HVTN 124 clinical trial results, published in The Lancet HIV, was selected as the paper of the month August 2024 by the International Society for Vaccine (ISV).
A recent publication in Emerging Microbes and Infections (EMI) features Worcester HIV Vaccine (WHV) as one of nine biotech companies actively contributing to the development of an HIV vaccine worldwide. Given that the HIV vaccine field is currently at a somber point – not having made real progress in the past four decades and numerous phase 2 and 3 trials failed to show effectiveness – the role of small biotech companies to advance the HIV vaccine field deserves a closer look.
Highlighting the advantages as well as challenges faced by small biotech companies, Roger Tatoud et al. explore possible support mechanisms necessary to overcome those challenges in order to support small biotech in the advancement of HIV vaccine development. Small biotech companies are in a unique position in which they can remain more agile than large pharmaceutical companies, quickly adapt to scientific advancements with a higher risk tolerance opening up new possibilities for innovation and scientific discovery. However, those opportunities also come with challenges, of which securing funding is the most significant hindering factor for initiating, sustaining, and growing a small biotech company and its product.
Financial barriers are indeed also the biggest impediment for WHV, affecting the pace at which PDPHV progresses through the development program. Despite showing extraordinary data in early-phase trials and the phase 2 vaccine supply already produced and available for clinical research, the advancement of PDPHV’s further efficacy testing has been delayed due to the large costs of conducting a phase 2 trial which requires long-term planning and funding from multiple sources. Because of the success of HIV treatment and current preventative methods other than vaccines, the value in investing in HIV vaccine development seems questionable to investors and other stakeholders for multiple reasons.
The International AIDS Society (IAS) HIV Corporate Partnership Program (CPP) Vaccine Group – established two years ago to bring together industry and non-industry partners to address the complexities of HIV vaccine research and development (R&D) – deliberated over the issues faced by small biotech companies in the HIV vaccine field and now published an outline of multiple suggestions and strategies to overcome those issues. Roger Tatoud et al. propose a multi-faceted approach that includes enhanced communication, fostering innovation, and implementing strategic funding models. The suggested recommendation to successfully support biotech’s continuous involvement in HIV vaccine R&D not only addresses the financial hurdles, but also covers issues within business development and management, intellectual property, clinical research (including regulatory affairs), policy and advocacy, and research coordination and dissemination.
Read the paper here.
The study results of phase 1 trial HVTN 124 evaluating the safety and immunogenicity of polyvalent DNA/Protein vaccine (PDPHV) were presented at the AIDS 2024 conference in Munich, Germany on July 24 during The Quest for HIV Vaccines oral abstract session.
Presenter Dr. Ian Frank, Professor of Medicine at University of Pennsylvania and HVTN 124 protocol chair, on behalf of the HVTN 124 protocol team and investigators, summarized that the vaccine candidate was safe and, particularly, the prime-boost strategy was highly immunogenic against multiple HIV clades.
The presentation highlighted study data of high response rates and magnitudes of binding antibodies to multi-clade gp120/gp140 and V1V2 antigens, as well as ADCC and CD4+ T-cell responses. Dr. Frank also stressed that PDPHV elicited binding antibody responses associated with protection from HIV acquisition- as established by previous efficacy trials – that were higher than the protective immune responses seen in those past efficacy vaccine studies.
While these are very promising findings, they need to be evaluated in larger trials with a more diverse population. WHV and their trial partners are excited to soon conduct more advanced trials to further study the efficacy of PDPHV and to hopefully help guide the HIV vaccine field in designing an effective HIV vaccine.
WHV’s single-site study WHV138, a double blind, randomized, placebo-controlled phase 1b trial was successfully completed after 3 years since study initiation. The database was recently locked and unblinded and the study participants are currently being informed of their treatment assignment. The polyvalent DNA/Protein HIV Vaccine candidate PDPHV was found to be safe and well-tolerated; no safety concerns were seen throughout the entire trial period. Immunogenicity analyses are ongoing and first results are similar to those of the HVTN124 trial, which have been published recently in The Lancet HIV.
Worcester HIV Vaccine (WHV) is pleased to announce that a novel human monoclonal antibody (mAb), HmAb64, was isolated from a trial participant who received our experimental HIV vaccine – the Polyvalent DNA/Protein HIV Vaccine (PDPHV). This result was just published by a world leading scientific journal Nature Communications.
Previously, many human mAbs were isolated from HIV infected patients and provided critical information on the interactions between the host’s immune system and the invading virus. These mAbs also revealed the key areas of the virus that a protective HIV vaccine would need to target. However, it has been very difficult to develop vaccines that can induce antibodies targeting such key areas, despite many years’ clinical studies testing a wide range of HIV vaccines candidates.
The new HmAb64 was isolated from a healthy human volunteer who received WHV’s unique DNA prime -protein boost vaccine which included antigens covering a wide range of HIV viral gene variations. The key area that HmAb64 targets is the CD4 binding site (CD4bs) – the surface of HIV interacting with human host CD4+ T cells which are important for human immunology. By entering CD4+ T cells, HIV causes a full spectrum of clinical disease after infection.
The CD4bs is a challenging target as the antigen’s conformation is very hard to produce by the traditional antigen design approach. Priming the immune system with the DNA component of WHV’s PDPHV ensures that the antigens are produced inside the body and thus mimic the virus’ antigen conformation.
Significant amounts of immunology, biochemistry, biophysics, and cry-EM analyses were carried out confirming the CD4bs specificity of HmAb64.
The real value of HmAb64 is its ability to neutralize primary HIV isolates across various subtypes – a major objective for HIV vaccine development. Several tier-2 resistant unrelated to the antigens used in the vaccines were also neutralized which further highlights the significance not only for this new mAb but also for the field of HIV vaccine development.
The final Nature Communication report is the product of collaboration among scientists from the University of Massachusetts Medical School, US NIH/NIAID’s Vaccine Research Center and Laboratory of Immune Regulation, New York University Grossman School of Medicine, Duke University and Beth Israel Deaconess Medical Center, Harvard Medical School.
WHV joins the world in commemorating HIV Vaccine Awareness Day by acknowledging the continued need to develop a globally effective vaccine against HIV infection. Today, we appreciatively reflect back on the progress WHV and collaborators have made over the last year towards that goal.
Most recently, the HVTN124 trial report was published in the Lancet HIV, in which the scientists from the HIV Vaccine Trial Network (HVTN) report immunogenicity results elicited by our vaccine candidate PDPHV (polyvalent DNA/protein HIV vaccine) that were found to be superior to many previous HIV vaccines in several ways – a very promising step forward for the whole HIV vaccine research community. Furthermore, Dr Shan Lu has been working with other renowned researchers in the field on additional immune response studies related to PDPHV, of which another paper is about to be published in a major journal soon. Overall, the development program of PDPHV is moving along well, as WHV is currently in the process of closing out the recently finished phase 1b trial WHV138 in partnership with the clinical research team at the Brigham & Women’s Hospital in Boston, MA. The trial was completed successfully after about 2.5 years, confirming further that PDPHV is safe and showing similar immunogenicity as in HVTN124 that will be explored further in the next phase 2 trial.
However, none of this progress would be possible without the numerous volunteers participating in vaccine research and our many talented partners and collaborators joining forces toward the common goal: to develop a safe and effective, preventative HIV vaccine that can eventually eliminate the threat of AIDS around the world.
We at WHV are grateful for your support and eager to continue this quest together!
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:
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.
His family wishes to share the unexpected and profound loss of our longtime friend and trusted WHV advisor Jules Mitchel on Sunday 3rd, December 2023.
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.
