Worcester HIV Vaccine

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2020 HIV Vaccine Awareness Day

Right now, the world is focused on COVID-19, which already claimed hundreds of thousands of lives and paralyzed the economies of many countries. The low- and medium-income countries are less prepared to deal with the public health and economic challenges associated with the COVID-19 spread. Many of these countries are already struggling with diseases like malaria, tuberculosis, and HIV and will be severely impacted by the additional strain on their healthcare systems.

The pandemic of SARS-CoV-2 virus once again highlights the need to prepare for potential zoonotic infections that my spread around the world, just like HIV did 40 years ago. The worldwide response to HIV pandemic brought together scientists, doctors, advocates, and public health experts, just like COVID-19 pandemic has been met with international response. Indeed, many of the experts now working on COVID-19 have come from the HIV field. They are bringing the experience and the valuable lessons to accelerate the discovery of preventive measures and treatments for COVID-19.

In these challenging times, WHV remains committed to the development of a preventive HIV vaccine to reduce HIV infections around the world. HIV remains a major public health challenge around the world and a safe and effective vaccine is the best way to stop the virus.

WHV researchers are actively working to better understand the immune responses observed in the HVTN 124 trial, to advance our vaccine manufacturing, and to plan further clinical trials of our vaccine candidate.

WHV collaborates with UMMS to conduct preclinical vaccine studies

In preparation for further clinical testing of its PDPHV vaccine candidate, WHV is working closely with Dr. Shan Lu’s Laboratory of Nucleic Acid Vaccines (LNAV) at the University of Massachusetts Medical School to conduct immunogenicity studies of the vaccine in small animal models. The studies will test the immunogenicity of newly manufactured vaccine products for a planned Phase IIa study and help refine the design of the next clinical trials by exploring different vaccine formulation, dosing, and administration schedules.

Phase I clinical study HVTN 124 is testing safety and immunogenicity of WHV’s DNA-prime/protein-boost vaccine candidate PDPHV in healthy volunteers. The results of the trial will be available later this year, but WHV is already planning the next steps in its clinical program. Additional questions about vaccine formulation, dosing, and schedule will be answered in the follow-up clinical trials.

Testing in small animal models can be extremely helpful in down-selecting among many potential avenues of vaccine improvement. Because the PDPHV vaccine candidate has been developed at LNAV, the researchers there, including Drs. Shan Lu and Shixia Wang have extensive expertise in assessing immunogenicity of this vaccine in preclinical models. Several animal studies are being conducted to investigate immune responses to the current vaccine candidate, to help better interpret the expected results of the current HVTN 124 trial, and to bridge the findings to future clinical trials.

WHV creates DNA reference standards to facilitate future manufacturing

Working with its partner, Waisman Biomanufacturing, researchers at WHV created dedicated lots of vialed individual DNAs from its DNA vaccine to be used as reference standards in the future.

Reference standards of clinical-grade vaccine allow cross-comparison between products from different manufacturing campaigns. With their well-defined characteristics, they help ensure that the vaccine produced for a clinical trial or for commercial distribution is equivalent to the vaccine used previously to establish safety and immunogenicity.

The advances in DNA manufacturing accomplished by WHV and Waisman in their latest plasmid production resulted in substantial improvements in yield and purity of PDPHV DNA vaccine. After generating sufficient DNA final product to support its planned Phase 2a clinical trial, WHV used the remaining material to generate reference standards.

The investment in reference standards highlights WHV’s commitment to the long-term development of its PDPHV vaccine candidate. These standards will be useful in the next manufacturing campaign that will be needed to provide vaccine for the large efficacy trial, and can even be used in the future to support the licensed vaccine manufacturing.

WHV plans an ancillary study of immune responses in HVTN 124 volunteers

WHV scientists will conduct a study to better characterize the immune responses observed in volunteers in the HVTN 124 clinical study testing its PDPHV vaccine candidate.

With the completion of immunizations in all volunteers in the ongoing HVTN 124 Phase I clinical study, HIV Vaccine Trials Network recently advanced to assessing the peak immune responses observed two weeks after the last immunization. At the same time, WHV plans to supplement HVTN’s work by conducting its own investigation into the dynamics of immune responses, as well as conducting additional assay to better assess the breadth and potency of antibodies elicited by the PDPHV vaccine candidate. This proposal has been met positively by HVTN, who agreed to share the necessary samples from the HVTN124 study volunteers.

This work will be conducted in collaboration with Dr. Sha Lu’s Laboratory of Nucleic Acid Vaccines (LNAV) at the UMMS in Worcester, MA. Dr. Lu is the co-inventor of the PDPHV vaccine candidate and his laboratory has extensive expertise in assessing immune responses to the DNA/protein vaccines. Another co-inventor, Dr. Shixia Wang, will lead the studies.

In preparation for this work, LNAV recently obtained an approval for this project from UMMS’ Institutional Review Board (IRB) and is currently working with HVTN to identify and transfer the required samples for the study. The results from the study will be available later this year.

FDA provides positive feedback on WHV’s new manufacturing strategy

In preparation for IND submission, WHV requested FDA’s opinion on its approach to manufacturing protein and DNA vaccines for the planned Phase 2a clinical trial. The request included plans for improved plasmid DNA production, advancement of protein vaccine formulation, and corresponding changes to analytical assays that will be used to release the vaccine for clinical studies.

The response from FDA experts was generally positive and did not identify any major challenges to the proposed improvements in the GMP manufacturing process and testing of WHV’s vaccine components. This confirmation clears the path for advancing WHV’s vaccine candidate PDPHV to the next stage of clinical testing.

Currently, PDPHV candidate is being tested in HVTN 124, a Phase I clinical trial run by HIV Vaccine Trials Network, based in Seattle and funded by the National Institute of Allergy and Infectious Diseases. WHV recently announced its commitment to launching a Phase 2a trial to optimize the immunization approach and to further characterize the safety and immunogenicity of its vaccine candidate.

WHV completes manufacturing of DNA vaccine components

Researchers at WHV in collaboration with Waisman Biomanufacturing successfully completed manufacturing of DNA component of the PDPHV vaccine candidate.

PDPHV is WHV’s investigational vaccine, which is comprised of five DNA plasmids and four gp120 Env recombinant proteins and is being tested as a prime-boost regimen or co-administered in repeated doses, in healthy adult volunteers.

Previously, Waisman demonstrated that their proprietary plasmid manufacturing technology can be used to produce WHV’s DNA vaccine in higher yields and improved purity as compared to previous approaches. Over the past year, WHV worked with Waisman to produce all five plasmids, and now these plasmids were tested and mixed to generate the final product.

PDPHV is the first and only HIV vaccine candidate to use a multivalent approach with HIV Env proteins from the four major clades or strains of HIV.  The PDPHV vaccine is currently being tested by the HIV Vaccine Trials Network (HVTN) in a Phase I clinical trial HVTN 124. The completion of DNA manufacturing is an important step on the path to the next stage of clinical testing of the vaccine candidate.

Worcester HIV Vaccine (WHV) researchers interrogate HIV’s glycan shield

WHV researchers published new data providing detailed view of the glycan shield used by HIV-1 to protect its Envelope protein from human antibody responses. This information will be critical for characterizing recombinant Env proteins, which are important components of many HIV-1 vaccine formulations, including WHV’s PDPHV candidate.

Envelope glycoprotein (Env) of HIV-1 is an important target for the development of an HIV-1 vaccine. On the virus, Env is covered with a dense array of sugar-based glycans that comprise as much as half of its weight. These glycans form a shield protecting the virus from antibody responses, but at the same time they can serve as a target for highly potent broadly neutralizing antibodies. Thus, it is important to study recombinant Env proteins used in vaccines to characterize their glycosylation and to monitor whether it changes depending on the vaccine manufacturing process.

Working with researchers from the University of Georgia, WHV scientists compared glycosylation patterns of recombinant gp120 proteins from the four major clades of HIV (A, B, C, and AE), which was the first time in HIV vaccine research to include four Env proteins in such analysis. They compared proteins produced at small scale in laboratory conditions for research purposes to proteins produced in 50L bioreactors for clinical trials. They also tested proteins produced from two cells lines, as well as explored the lot-to-lot variability in proteins produced under identical conditions.

The researchers confirmed previous studies in the field showing high abundance of unusual oligomannose on Env proteins, with 40-50% of glycans having Man5-Man9 on all four proteins under all production conditions. Overall the differences in occupancy and glycan forms among Env from different subtypes produced under different conditions were less dramatic than anticipated and antigenicity analysis with a panel of six monoclonal antibodies showed that all four gp120s maintained their antibody-binding profiles, including antibodies that recognize glycan forms. Such findings have major implications for the production of licensed HIV vaccine including Env glycoprotein components.

The results were published as open access paper in the Journal of Virology “Glycan profiles of gp120 protein vaccines from four major HIV-1 subtypes produced from different host cell lines under non-GMP or GMP conditions”. WHV researchers will also present these results at the 2020 Keystone symposium on HIV Vaccines taking place in Keystone, CO on March 22-26.

NIAID stops vaccinations in the HVTN 702 trial

WHV commends the many researchers, donors, partners and more than 5,000 participants of the HVTN 702 trial in South Africa, which was stopped early due to lack of efficacy.

Science is incremental and with each efficacy trial the field learns what works and what does not.  It’s clear that much work needs to be done to better understand  the results of HVTN 702.    

In 2009, the RV144 trial of an HIV-1 vaccine in Thailand showed 31% efficacy in preventing HIV infections in general population. Detailed follow-up studies identified correlates of risk, suggesting which immune responses may be likely to provide protection against the virus.

Building on this success, the Pox Protein Public-Private Partnership (P5) consisting of a diverse group of stakeholders in the field, designed a similar vaccine to target subtype C HIV-1 prevalent in sub-Saharan Africa and launched the efficacy HVTN 702 trial in South Africa. Early stage clinical trials of this vaccine showed responses similar to or better than those observed in RV144.

So while the field was hopeful that the HVTN 702 trial would show some efficacy, the results are disappointing, but once again highlight the extraordinary challenge of HIV-1 vaccine development.  Now more than ever, there is a clear need to explore diverse and innovative approaches. 

Worcester HIV Vaccine remains committed to rapidly advancing its unique vaccine candidate PDPHV to further clinical testing, including an efficacy study. We will work tirelessly to make sure that a safe and effective vaccine is available to prevent HIV-1 infections around the world.

WHV Poised to Move Novel HIV Vaccine Through Clinical Development

Collaboration with UMMS Allows for Faster, More Effective Path to Advancing Clinical Trials

[DECEMBER 1, 2019]  ̶  This World AIDS Day researchers at Worcester HIV Vaccine (WHV), a biotechnology organization next to the University of Massachusetts Medical School (UMMS) announced plans to take their innovative HIV vaccine candidate through to Phase IIa clinical testing.  If proven immunogenic, this would be the first and only vaccine candidate that targets all four major HIV subtypes to advance to safety and efficacy trials in humans.

“A safe and effective HIV vaccine has the potential to shape the future course of this epidemic,” said Shan Lu, M.D., Ph.D., professor of Medicine at UMMS and the creator of WHV’s HIV vaccine. “Despite significant progress on the potential of new biomedical strategies in the global HIV response, we are still seeing more than 37 million people living with HIV around the world, and another 1.7 million newly infected each year. We know an effective vaccine to prevent HIV would be one of the biggest advances in global health.”

WHV’s investigational HIV vaccine candidate, PDPHV is in formative stages of development.  It is comprised of five DNA plasmids and four gp120 recombinant proteins and is being tested in healthy adult volunteers in a Phase I clinical trial (HVTN 124) run by the National Institute of Allergy and Infectious Diseases’ (NIAID) HIV Vaccine Trials Network (HVTN).  Immunogenicity results from the HVTN 124 trial are expected in early 2020 having just concluded all vaccinations in October.

“We are making excellent progress in preparing for the Phase IIa clinical trial of PDPHV – something that could happen as early as mid-2020, should the Phase I results show positive immunogenicity,” said Yegor Voronin, Ph.D., chief operating officer of WHV.  “We’ve done the hard work of advancing GMP manufacturing, optimizing the clinical trial design, and clarifying the regulatory pathway, all in an effort to move Phase IIa study as quickly as possible should we see a positive signal.”

Earlier this year, WHV researchers showed that they can improve the manufacturing of the DNA component of PDPHV and confirmed that its proteins continue to demonstrate an excellent stability profile, which will allow a faster and more effective path to Phase II clinical trials. 

Shan Lu and his group at UMMS have been working for more than two decades to advance a preventive HIV vaccine.  The PDPHV vaccine combines HIV DNA, which is used to prime the immune system to receive a boost of HIV protein, which signals the body to produce antibodies against HIV. This prime-boost approach activates both antibody and cell-mediated immune responses, and induces functional antibodies with better qualities and longevity than using either type of vaccine alone as shown by an earlier version of this vaccine in a single-site clinical trial conducted at UMMS.

Much of WHV’s progress in early research and development has been the result of collaborations with UMMS. In the last decade, Dr. Lu’s group at UMass Medical School received more than $30 million to oversee the development and manufacturing of PDPHV, which allowed WHV to license PDPHV from UMMS in early 2018 for its further development.  WHV has worked with Waisman Biomanufacturing (WB), a third party contracted manufacturing organization, to use  DH5a E. coli strain with WB’s proprietary technology, to manufacture DNA plasmids with purer quality and higher yields than previous cell lines. WHV is also establishing broad collaboration with academic and industry partners including the UMMS Mass Spectrometry Facility, led by Scott Shaffer, Ph.D., to develop new analytical assays to use during vaccine manufacturing.     This world AIDS Day as the global HIV community reflects upon its accomplishments, and takes stock of the challenges that lie ahead, WHV renews its commitment to rapidly and efficiently advancing a novel HIV vaccine through clinical development.  There’s no doubt that a safe and effective HIV vaccine is an essential component to ending the HIV epidemic once and for all.

HVTN to assess peak immune responses in HVTN 124

WHV’s vaccine candidate PDPHV is currently being tested in the HVTN 124 clinical trial. The trial sites recently completed all scheduled vaccinations and collected samples to assess the peak immune responses elicited by the vaccine. On November 20, 2019, WHV convened with HVTN to discuss the priorities and the timelines of conducting laboratory assays. The immediate focus was placed on the magnitude and quality of the antibody responses, including binding to Env proteins from a wide diversity of viral variants, as well as neutralization of viruses and ADCC functionality of antibodies. The results are expected in 3 months. Later this year, the volunteers will return to provide samples at 6 months after the last vaccination, which will be used to assess the durability of the responses.