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It is without a doubt that the HIV vaccine R&D community is currently facing immense challenges with an unknown future. But what the past few decades since the start of the HIV pandemic have proven is that the HIV vaccine research community is determined, resilient and innovative – all of which are not the characteristic traits of people who will easily give up. The current difficulties represent an enormous stick in the wheel for the entire HIV vaccine field, but it is especially in times of crises that people come together, build partnerships, brainstorm solutions, share resources, and join collaborative efforts to overcome those challenges. We will all tighten our belts and keep working towards our common goal: To develop a vaccine that can help prevent HIV infection around the world. Because amidst all the current unknowns, one thing is clear: The world still needs a safe and effective HIV vaccine, despite the advancements in other HIV prevention methods.

Today, on HIV Vaccine Awareness Day, WHV wants to take this opportunity to thank our partners for our joint achievements of the last few years: Not only did we successfully complete two phase 1 trials, we also published remarkable safety and immunogenicity results induced by WHV’s polyvalent DNA/Protein HIV Vaccine candidate, PDPHV. These successes drive us to continue the PDPHV product development program with our devoted partners despite the current difficulties. As we prepare for the next steps to move PDPHV through more advanced phase clinical testing, we are eager to soon start the next phase 2a trial.

A recent publication in Emerging Microbes & Infections organized by NIH supported HIV Vaccine Trial Network (HVTN) compared the immune responses observed in 13 different HIV vaccine trials, including 3 efficacy trials, and found that the polyvalent DNA prime with matched polyvalent protein/GLA-SE boost regimen of HVTN124, testing WHV’s vaccine candidate PDPHV, elicited the most robust and broad IgG and IgG3 V1V2 binding antibody and CD4+ T cell responses amongst all other regimens. In recent literature, these vaccine induced responses have been considered as “immune corelates of protection” implying that any protective HIV vaccine would need to elicit such responses. 

The paper is a large collaborative research effort among many leading HIV vaccine study experts. Of the 34 analyzed different vaccine regimens included in those 13 trials, immune responses induced by PDPHV were amongst the highest across all vaccination regimens analyzed. The DNA prime – protein boost arm of HVTN124 showed the highest median breadth scores of binding antibody responses and also 100% response rate for IgG binding antibody responses to gp70 V1V2, as well as 100% response rate and high magnitude for CD4+ T-cell responses.  More impressively, the DNA prime – protein boost in HVTN124 was the only regimen raising high level IgG3 antibody responses against gp70 V1V2 among all the regimens included in the study.  

The perhaps most significant finding is that some of these antibody responses induced by PDPHV were remarkably higher in magnitude than those seen in the Thai trial RV144, the only regimen that has demonstrated modest efficacy to date. PDPHV’s unique attribute of a polyvalent DNA prime with matched polyvalent protein boost vaccine design is also thought to have resulted in better binding and cellular immune responses than those observed in the two most recent efficacy trials HVTN 702 and 705.

These results not only confirm that the DNA prime with matched protein boost approach is a promising HIV vaccine design but also put it in a relative scale against other HIV vaccine designs of the last two decades. This very valuable comparative analysis supports to test PDPHV in more advanced clinical trials to meet the great need of an efficacious HIV vaccine for the global health.

At the HIVR4P conference in Lima, Peru held in early Oct. 2024, WHV and collaborators presented results from three different research projects related to WHV’s polyvalent DNA/Protein HIV vaccine candidate PDPHV.

As an oral presentation, Dr. Zoe Moodie presented the results from a large collaborative research effort together with colleagues from the HIV Vaccine Trials Network (HVTN), which compared the immune responses across 13 different HVTN protocols testing a variety of HIV vaccine candidates worldwide. Analyses showed the exciting results that immune responses induced by PDPHV – tested in phase 1a HVTN124 – were amongst the highest across all vaccination regimens analyzed. Not only did the DNA prime – protein boost arm of HVTN124 show the highest median breadth scores of binding antibody responses, but also 100% response rate for IgG binding antibody responses to gp70 V1V2 and 100% response rate and high magnitude for CD4+ T-cell responses. Notably, some of these antibody responses induced by PDPHV were almost three times higher in magnitude than those seen in RV144 and about two and a half times higher than the two recent efficacy trials HVTN 702 and 705. These are relevant findings that can be of great value for the entire HIV vaccine field with regards to vaccine product design and vaccination regimen.

A poster presented by Dr. Stephen Walsh and Dr. Shan Lu showed the persistence of ENV specific antibody responses elicited by PDPHV with data derived from two phase 1 clinical studies, HVTN124 and WHV138, in which the same investigational product was administered but at slightly different vaccination regimens. To study the longevity of immune responses, serum samples were collected from volunteers two weeks after each vaccination, 6 months post last vaccination in HVTN124, and both 6 months and 12 months post last vaccination in WHV138. The gp120-specific IgG responses were found to be durable over the 6-month period after the last immunization with less than one-log drop of the antibody titer. Antibody responses in WHV138 were durable over a 12-month period after last vaccination. Furthermore, serum IgG in both HVTN124 and WHV138 were cross-reactive to Env antigens from subtype A, B, C and AE. The data from both trials indicate that the vaccine-induced immune responses can be long lasting for at least a year after immunization and target multiple viral clades. These are very important features for an effective and globally relevant HIV vaccine.

Another poster, also presented by Dr. Lu, featured the isolation of HmAb64, a CD4-binding site human monoclonal antibody of a DP6-001 trial volunteer (a phase 1 trial that tested the safety and immunogenicity of first-generation PDPHV), and its ability to neutralize cross-clade tier 2 HIV strains. To learn more about this discovery, read the previously reported summary or the published paper in Nature Communications.

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.

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.