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Moving the Needle Forward: Wistar Research Leads to a Coronavirus Vaccine Entering Human Trials and Additional Wistar Coronavirus Research Projects Underway

Written by The Wistar Institute on . Posted in Featured News.

While the world struggles with a growing number of people sickened with COVID-19 and health care workers engage in a tireless and heroic mission to save lives, biomedical researchers are on the front lines of a parallel and equally critical battle to develop new tools to effectively diagnose, treat and prevent a disease we are still learning about.

Scientists at The Wistar Institute’s Vaccine & Immunotherapy Center (VIC) have been working long hours and over weekends, devising new strategies to apply their expertise and technological platforms to combat SARS-Cov-2. 

So far, the work has paid off. The second COVID-19 vaccine to move into clinical testing in the U.S. is due in part to Wistar’s effort and comes from the team led by Dr. David Weiner and including Drs. Daniel Kulp, Ami Patel and Kar Muthumani, in collaboration with biotech company Inovio Pharmaceuticals, Inc.

This vaccine, based on synthetic DNA technology, was advanced in record time from computer design to preclinical testing in just under three months. Results from preclinical studies show the vaccine is effective at inducing both antibody and T cell-mediated responses soon after delivery in mice and guinea pigs, allowing researchers to unlock the next step — human testing subsequent to FDA approval.

Data from these studies are available to the scientific community while the manuscript is under consideration for publication in a high-impact journal.

Even though the vaccine will go through further testing in the lab as new tools and reagents become available, scientists have passed the baton to their pharmaceutical partner and the doctors and clinical experts working with the company to evaluate the safety of the coronavirus vaccine in people.

Announced by Inovio on Monday, April 6, the vaccine just entered a phase 1 clinical study coordinated by the University of Pennsylvania. 40 healthy adult participants in Philadelphia and Kansas City, Missouri will receive two vaccine doses four weeks apart, and initial data on immune responses and safety from this study are expected by late summer.

“I am extremely proud of all the work done by our scientists for this vaccine and the role played by Wistar as an academic engine of new technologies that are the basis for future medicines,” said Dario C. Altieri, M.D., Wistar president and CEO. “Hopefully, one day not so long from now, we will have a preventative vaccine to help curb the pandemic. It would be another enormous Wistar contribution to human health.”

In these times we need as many tools as possible to stem the pandemic. Wistar scientists are actively developing other vaccine approaches and therapeutic strategies, ranging from tricking the virus into attaching to decoy receptors to prevent it from infecting cells, to reducing inflammation that causes disease severity in those infected with the virus, to alternative ways to make and deliver protective antibodies that will neutralize the virus.

Although in early stages, most of this research has the potential to be advanced fairly quickly due to the nature of the approaches and our scientists’ previous experience with tackling other infectious agents.

“We are very excited about the potential of our COVID-19 vaccine,” said Weiner. “The preclinical results thus far motivate us to focus our efforts in additional directions and do our best to advance more approaches that can ultimately make a difference in this pandemic.”

To catalyze Wistar’s coronavirus research endeavor, the Institute recently launched the Wistar Coronavirus Discovery Fund, which will support a range of research programs and enhance the ability of our scientists to pursue innovative solutions as quickly as possible.

As the World Health Organization remarked, “Coronavirus research has accelerated at incredible speed…” because scientists, funders and international organizations have come together to solve the crisis. 

“We are all in this together and together we can all do our part,” said Weiner. 

Wistar Translational Research in Response to the COVID-19 Pandemic

Written by The Wistar Institute on . Posted in Featured News.

The Wistar Institute’s Vaccine & Immunotherapy Center (VIC) has assembled its expertise in infectious disease research, as its scientists are part of a team racing to provide a countermeasure for the ongoing coronavirus outbreak. 

A historic leader with a track record of successful vaccines that have saved millions of lives, Wistar is now leveraging synthetic DNA technology to develop a vaccine against the coronavirus. 

The laboratory of Dr. David Weiner, Wistar executive vice president, director of the VIC and the W.W. Smith Charitable Trust Professor in Cancer Research, has worked for several decades advancing the technology for generating synthetic DNA vaccines that can be used for global pandemic outbreaks. 

In December 2019, Drs. Weiner, Ami Patel, Kar Muthumani, and Dan Kulp at Wistar along with colleagues at Inovio Pharmaceuticals, Inc., Drs. Joseph Kim, Laurent Humeau and Kate Broderick, were paying particular attention to the new outbreak in Wuhan, China, caused by a virus identified as a novel coronavirus. Infections were rapidly expanding in China, and by mid-January they were starting to spill over to other countries. COVID-19, as the infection was eventually named, was not going away. The team decided to work together tackling the outbreak as soon as the opportunity to jump in arose, as they have collaborated to advance vaccines for other outbreak pathogens. 

Synthetic DNA would not need the virus itself to build vaccine candidates, as these can be modeled and developed through computer analysis of the viral sequence, using predictions based on prior experience to synthesize a prototype DNA vaccine for rapid testing. The team would use their extensive MERS coronavirus vaccine experience as a model, taking into account unique features displayed by the new coronavirus in the design. In January, as the cases increased, a consortium led by Dr. Yong-Zhen Zhang of the Shanghai Public Health Clinical Center & School of Public Health posted the first viral DNA sequences online. 

“This provided the opportunity the team was waiting for,” said Dr. Weiner. Within hours, prototype vaccines were designed and moved to development.  

The designed DNA vaccine encodes a tailored sequence as the code for the vaccine. When the vaccine is administered to a recipient, the genetic sequences are then delivered inside the cells and instruct the cells to assemble a new protein shaped like a piece of the virus. Similar to using Lego blocks, a 3-D replica of a viral antigen is built inside the body and teaches the immune system what to look out for and destroy — reproducing what would happen if the person came in contact with the true virus. 

Coronaviruses are large RNA viruses that get their name from the ‘halo’ generated by the spike protein that decorates the surface of these viruses. When a coronavirus is viewed in the laboratory using electron microscopy, the spike proteins appear to form a crown. The new strain of coronavirus has been designated SARS-CoV-2 and is the entity that causes the COVID-19 disease. 

SARS-CoV-2 is an emerging pathogen that human populations have not previously experienced although it belongs to the same family as the coronaviruses that caused Severe Acute Respiratory Syndrome (SARS), an outbreak originating in China that the world experienced in the early 2000s, and Middle East Respiratory Syndrome (MERS), an outbreak originating about a decade later in the Middle East that, while controlled, still smolders. 

The team has significant experience in developing countermeasures for a coronavirus outbreak. A synthetic DNA MERS vaccine they developed advanced into phase 2 clinical study, having achieved relevant vaccine milestones including protection of laboratory animals from infection, human safety, and immunogenicity. 

The new coronavirus vaccine effort by the Weiner team is one of a handful supported by the Coalition for Epidemic Preparedness Innovations (CEPI) for the rapid development of new vaccine approaches to the coronavirus outbreak. CEPI is a global alliance led by Norway along with several other countries with major funding from philanthropic organizations. Assembled just more than three years ago to fast-track translational vaccine approaches for emerging pandemics, the organization has been comparing vaccine technologies that could be utilized rapidly in an outbreak situation with the foresight of stemming worldwide epidemics using scientific innovations through new technology. 

That preparation is being put to the test in support of developing a vaccine response for COVID-19. In January, CEPI started to discuss funding a program for clinical vaccine development with the team. On January 23, at the World Economic Forum in Davos, CEPI announced its support for three teams based on their technologies and accomplishments showing their vaccines can be rapidly created, tested, generate consistent immunity, and can be advanced in a conceptually safe fashion to clinical trials.  

Each team funded by CEPI is comprised of industry partners and academic vaccine teams that work together to move the novel candidates through early development and into clinical study and then, if applicable, advance them to efficacy trials. This approach combines the research speed of academic investigators with the focused development and clinical production and regulatory strengths of industry leaders who are at the forefront of their technologies. 

The Initial teams were: 

  • GlaxoSmithKline (GSK) in partnership with the University of Queensland, Australia, for a recombinant protein and adjuvant approach. 
  • Moderna Therapeutics, Inc., in partnership with the National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center for a mRNA approach; and 
  • Inovio in partnership with The Wistar Institute’s VIC team. 

Five additional teams have recently been added by CEPI.

“It’s a very unique situation — it’s the first time we’re seeing a global vaccine coordinated response like this, thanks to the speed with which CEPI acted and funded the initial teams,” said Weiner. “We are honored to be able to contribute to this important effort under the advanced DNA vaccine technology program of Inovio for COVID-19.”  

The team reported immune responses to the new synthetic DNA vaccine that were induced in several animal model species after a single immunization — the first program to do so.  

CEPI’s stated initial goal was to speed advancement of the new coronavirus vaccines to phase 1 trials in four months or less. The CEPI program has made a significant difference already in mobilizing the vaccine community to advance products for COVID-19. This week, Moderna announced that they have opened their phase 1 clinical trial. Inovio announced that a phase 1 study of the synthetic DNA vaccine is preparing to open in April.  

As of March 23, just 3.5 months into this outbreak, there are approximately 372,000 reported infections with more than 16,300 deaths spread over 168 countries. In the U.S., there are over 41,000 cases which have resulted in 573 fatalities. New York has more than 12,000 cases*.  

“The Wistar Institute’s VIC works to provide new immune approaches and understanding to impact important human disease. We need countermeasures for the COVID-19 pandemic,” said Weiner. “All of us are in this together and the more tools in the toolbox, the better equipped we are to possibly protect our vulnerable populations and our first-line defenders. Rapidly advancing these tools is only the first step in this process, but it’s an important one.”


* Source: Center for Systems Science and Engineering at Johns Hopkins University

Coupling Computational Protein Engineering with Synthetic DNA Technology Enhances Nanovaccine Efficacy Allowing the Patient’s Own Body to Customize Production

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (March 11, 2020) — Scientists at The Wistar Institute reported a sophisticated technology to simplify production of nanovaccines, a novel approach to vaccination that can robustly stimulate immunity in preclinical models. The study, published online in the journal Advanced Science, is based on applying the synthetic DNA technology for in vivo delivery and assembly of computationally designed nanoparticles. This combination resulted in enhanced immune responses and may be explored for rapid development of vaccines and immunotherapies.

The use of nanotechnology for vaccine development has brought several advantages compared to traditional formulations. Nanovaccines consist of extremely small (nano) particles that are similar in size to bacteria and viruses and provide strong signals to the immune system. Nanovaccines produced in the laboratory are particularly good at driving antibody responses. However, laboratory production of nanoparticles can require complex formulations and purification steps that can increase costs and limit their development and rapid deployment.

“Computational modeling assists us in the rational design of nanovaccines that are capable of inducing potent levels of protective immunity, but large-scale production is challenging and lengthy,” said Daniel Kulp, Ph.D., associate professor in the Vaccine & Immunotherapy Center and corresponding author of the study. “We are excited to describe a new strategy that bypasses these challenges while also inducing more robust immune responses.”

In collaboration with the lab of David B. Weiner, Ph.D., Wistar executive vice president, director of the Vaccine & Immunotherapy Center, and the W.W. Smith Charitable Trust Professor in Cancer Research, and co-senior author on the study, Kulp and colleagues integrated computational design and synthetic DNA-mediated delivery, focusing on designing the nanovaccine particles to assemble themselves in vivo from a DNA template. They demonstrated that nanoparticles can be produced and assembled in vivo in bunches and elicit robust and specific immune responses in the vaccinated animals.

Using synthetic DNA technology, researchers were able to prompt the body to build and assemble in vivo optimized nanoparticles predesigned with the aid of computer modeling. An essential step in this process is the method of synthetic DNA delivery, called adaptive electroporation, which delivers a small current to the site of injection, enhancing DNA uptake and providing immune stimulation.

A nanoparticle vaccine for HIV that is currently in clinical trials was employed as a prototype for DNA delivery. The DNA-launched nanoparticles were successfully produced and correctly self-assembled both in vitro and in laboratory animals. The vaccines stimulated antibody responses comparable to the conventional protein-based nanoparticle vaccines, a gold standard in the field for the induction of antibody responses. However, the DNA-launched nanoparticles uniquely induced CD8+ T cell responses, engaging an important arm of immune system that mediates protection against viral antigens and surveillance against cancer.

The strategy was also successfully applied to induce potent responses with newly designed nanoparticle vaccines targeting the influenza virus protein hemagglutinin. Importantly, in a rigorous influenza challenge model, the DNA-launched hemagglutinin nanovaccine conferred significantly improved protection to mice than conventional formulations at a fraction of the dose.

“Our studies suggest that the confluence of synthetic DNA-mediated delivery and computational nanoparticle design could be a novel asset for vaccine development,” said Ziyang Xu, a Ph.D. student in the Weiner lab and first author on the study. “This approach demonstrated we can create new vaccines with improved potency and dose sparing to help global deployment of vaccines at times of critical need.”

Co-authors: Neethu Chokkalingam, Susanne Walker, Edgar Tello-Ruiz, Sarah T.C. Elliott, Alfredo Perales-Puchalt, Peng Xiao, Xizhou Zhu, Stacy Guzman, and Kar Muthumani from Wistar; Megan C. Wise, Paul D. Fisher, Katherine Schultheis, Eric Schade, Kate E. Broderick, and Laurent M. Humeau from Inovio Pharmaceuticals; Ruth A. Pumroy and Vera Moiseenkova-Bell from University of Pennsylvania; Sergey Menis and William R. Schief from The Scripps Research Institute; and Hanne Andersen from Bioqual Inc.

Work supported by: National Institutes of Health (NIH) grants U19 Al109646-04, R01 GM103899, R01 GM129357 and a Collaborative Influenza Vaccine Innovation Centers (CIVICs) grant;
Grants from the Bill & Melinda Gates Foundation, Inovio Pharmaceuticals, W.W. Smith Charitable Trust, and the Monica H.M. Shander Memorial Fellowship. Core support for The Wistar Institute was provided by the Cancer Center Support Grant P30CA010815.

Publication information: In vivo assembly of nanoparticles achieved through synergy of structure-based protein engineering and synthetic DNA generates enhanced adaptive immunity, Advanced Science, 2020. In press.

Wistar Joins Global Effort to Expedite Coronavirus Vaccine Development

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (Jan. 23, 2020) — The Wistar Institute announces today that they are part of a team to develop a vaccine against the recently emerged strain of coronavirus (2019-nCoV) that has infected hundreds in China and other countries, including the U.S., and resulted in numerous deaths to date. Wistar is part of a collaboration funded by the Coalition for Epidemic Preparedness Innovations (CEPI).

CEPI will fund nearly $9 million to support pre-clinical and clinical research for a vaccine advanced by Inovio Pharmaceuticals, Inc. (NASDAQ: INO), based in part on key technology generated in the lab of David B. Weiner, Ph.D., executive vice president, director of the Vaccine & Immunotherapy Center, and the W.W. Smith Endowed Chair in Cancer Research at The Wistar Institute. Wistar’s participation in this developing initiative is based on its experience and suitability of its DNA technology platform to rapidly translate a vaccine against an emerging virus with pandemic potential. Prior work by this team includes development of vaccines for Ebola, Zika and MERS, another coronavirus, during those recent outbreaks.

“Wistar feels compelled to deploy its expertise and its technological advancements to combat global emerging infectious diseases as part of its mission and is proud to be part of one of the first initiatives to approach this evolving global health threat,” said Weiner.

In addition to Wistar and Inovio, the team includes VGXI and Twist Bioscience.

The Weiner laboratory at Wistar is dedicated to accelerating vaccine and immunotherapy technologies for infectious diseases and cancer. Weiner’s research expands upon Wistar’s mission to create new treatments for the most uncompromising diseases and make lifesaving contributions to cancer biology and infectious diseases.

WISTAR’S CORONAVIRUS RESEARCH IN THE NEWS:
The Coronavirus Outbreak Is Far From Over. But Here’s How It Might End., Mar. 24
Court Radio: Coronavirus – Race Against Time: Creating a Vaccine to Fight the Spread with David Weiner, Ph.D., Mar. 8
KYW In Depth: What you need to know about coronavirus in Philadelphia, Mar. 6
Philadelphia Inquirer: Pa. is preparing for coronavirus as CDC warns spread in U.S. may be ‘inevitable’, Feb. 26
The Wall Street Journal: J&J, Sanofi, Inovio Hunt for Coronavirus Vaccines, Feb. 24
TheScientist: Newer Vaccine Technologies Deployed to Develop COVID-19 Shot, Feb. 21
FoxNews (national): Biomedical research expert on race to produce coronavirus vaccine, Feb. 17
NPR: Timetable For A Vaccine Against The New Coronavirus? Maybe This Fall, Feb. 12
Philadelphia Inquirer: Inside a Philadelphia lab, scientists race to design a coronavirus vaccine, Feb. 11
FoxNews (national) America’s Newsroom: Coronavirus vaccine to be developed from digital DNA sequencing, Jan. 30
Fox29: Philadelphia International Airport screening travelers for coronavirus, Jan. 30
KYW radio: Philadelphia scientists already at work on vaccine for coronavirus, Jan. 29
NPR: The State Of A Potential Vaccine For The New Coronavirus, Jan. 29
NBC10: Scientists at Lab in Philadelphia Work to Develop a Vaccine for Coronavirus, Jan. 29
CBS Philly: Wistar Institute In Philadelphia Part Of Team Developing Vaccine Against Deadly Coronavirus, Jan. 24
STAT: How fast can biotech come up with a vaccine for the latest outbreak?, Jan. 24
Philadelphia Inquirer: Philly-area company gets $9 million grant to develop vaccine for new Chinese coronavirus, Jan. 24
Philadelphia Inquirer: Weiner asked to comment on the coronavirus outbreak: Jan. 21

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

Digital illustration of DNA with scientific background

Synthetic DNA Technology Applied as a Novel Strategy for Delivery of Anti-HIV Antibodies

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (Nov. 8, 2019) — Scientists at The Wistar Institute applied synthetic DNA-based technology to drive in vivo production of broadly neutralizing anti-HIV antibodies in small and large-animal models, providing proof of concept for a simple and effective next generation approach to HIV prevention and therapy. These results were published online in the Journal of Clinical Investigation.

Despite exceptional advances in antiretroviral therapies, there remains a need for new preventive and therapeutic modalities to eliminate HIV infection. Researchers have isolated a number of very potent monoclonal antibodies from infected individuals that can neutralize a diverse array of HIV strains. Such monoclonal antibodies can be manufactured and administered as passive immunotherapy and represent a promising approach currently in early clinical studies.

Widespread use of recombinant monoclonal antibodies, though, remains limited by several factors related to their half-life of expression, production costs supporting high doses needed, temperature stability, formulation issues, and limitations in production of antibody combinations, among others.

“We developed the DMAb platform to allow for direct in vivo production of antibodies through synthetic DNA engineered to provide instructions to the body to make the desired antibodies,” said lead researcher David B. Weiner, Ph.D., executive vice president, director of the Vaccine & Immunotherapy Center and W.W. Smith Charitable Trust Professor in Cancer Research at Wistar. “Based on our early data, we suggest that this platform is worth further investigation as a new strategy for HIV antibody delivery.”

Weiner and collaborators engineered a panel of 16 DMAbs rederiving previously characterized broadly neutralizing antibodies into the DMAb format. These were studied in mice via injection using Cellectra adaptive electroporation to enhance the DNA uptake. Researchers observed rapid DMAb expression and sustained blood levels for several months. Furthermore, in vivo-produced DMAbs displayed strong neutralization ability, comparable to the corresponding recombinant antibodies.

Since the HIV virus is capable of mutating to escape single antibody immunity, combinations of up to four different DMAbs were tested as a strategy to overcome resistance. Total in vivo levels of antibodies produced in combination were comparable to the sum of the levels of the same antibodies administered individually, showing that this platform is flexible and suited for combination therapies with multiple antibodies. Importantly, the data supported that the combination could block more HIV viruses than the single antibodies.

Researchers next explored HIV-1 DMAb delivery in a pilot non-human primate study that is more relevant for translation to humans. Expression was detected as early as three days post-administration of one or two combined DMAbs, which displayed peak activity by 14 days. Importantly, the serum from treated animals had high antiviral activity.

“Although still in early stage of development, DMAbs have significant potential as a tool for treatment of HIV and other diseases and, if successfully translated to the clinic, will provide multiple new avenues for immunotherapy,” said Weiner. “Translational animal studies and clinical development are likely to be a very active area of research providing important information over the next few years.”

Co-authors: Megan C. Wise from Inovio Pharmaceuticals and Ziyang Xu from The Wistar Institute are co-first authors. Other co-authors include: Edgar Tello-Ruiz, Aspen Trautz, Ami Patel, Sarah T.C. Elliott, Neethu Chokkalingam, Sophie Kim, Kar Muthumani, and Daniel W. Kulp from Wistar; Jingjing Jiang, Paul Fisher, Stephany J. Ramos, Trevor R.F. Smith, Janess Mendoza, Kate E. Broderick, and Laurent Humeau from Inovio; Charles Beck, Melissa G. Kerkau, Guido Ferrari, and David C. Montefiori from Duke University.

Work supported by: National Institutes of Health grant U19 Al109646-04 (Integrated Preclinical/Clinical AIDS Vaccine Development Program), The W.W. Smith Charitable Trust and grant 2528109374 from the Martin Delaney Collaboratory: Towards an HIV Cure.

Publication information: In vivo delivery of synthetic DNA-encoded antibodies induces broad HIV-1-neutralizing activity, Journal of Clinical Investigation (2019). Advanced online publication.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

Major Grant Awarded to Wistar Supports Development of a Novel Therapeutic Approach for Antibiotic-resistant Bacteria

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (September 12, 2019) — The Wistar Institute has received a grant of approximately $4.6 million from the National Institutes of Health in support of innovative research to tackle antibiotic resistance.

Antimicrobial resistance (AMR) represents an expanding global public health concern. While antibiotic-resistant organisms are appearing at an alarming rate, there has been a 30-year hiatus in the development of novel classes of antibiotics for combatting these infections. Multidrug-resistant Pseudomonas aeruginosa is one of the top microorganisms on the list of priority AMR pathogens compiled by the World Health Organization.

A Wistar team led by David B. Weiner, Ph.D., executive vice president, director of the Vaccine & Immunotherapy Center, and the W.W. Smith Charitable Trust Professor in Cancer Research at Wistar, is advancing a novel, nontraditional approach to combat multidrug-resistant P. aeruginosa, based on a synthetic DNA technology called DNA-encoded monoclonal antibodies (DMAbs). In a recent study, Weiner and colleagues developed a targeted DMAb approach for AMR and demonstrated that these DMAbs can effectively control multidrug-resistant P. aeruginosa infection in mice.

This grant will now allow for extension of these studies by providing the researchers with $4,624,553 over four years to further implement the DMAb strategy and move it forward toward clinical development.

The Weiner lab developed DMAb technology by designing genetic sequences directly encoding monoclonal antibodies into an optimized DNA platform. These gene sequences are administered in vivo to be expressed locally at the site of injection. The recipient receives a gene-encoded blueprint instructing their cells to produce the encoded monoclonal antibody specifically targeting the bacteria. DMAbs can be developed simply and quickly and are produced directly in the patient, dramatically lowering production timeline and costs associated with manufacturing of conventional antibodies; furthermore, DMAbs do not require expensive cold chain storage and are suitable for delivery in combinations.

“Engineered synthetic DMAbs represent a transformative approach to the production of biomolecules directly in the patient,” said Weiner. “We are honored to receive this funding and feel it is an important recognition of the promise of DMAbs for the growing threat of antibiotic resistance. This support will move us closer to creating an out-of-the-box tool to fight antibiotic-resistant infections that threaten the lives of thousands every year just in the U.S.”

Co-investigators on the grant are assistant professor Farokh Dotiwala, M.B.B.S., Ph.D., associate professor Daniel Kulp, Ph.D., and research assistant professor Ami Patel, Ph.D., of Wistar’s Vaccine & Immunotherapy Center. Inovio Pharmaceuticals is a collaborator on the grant.

The multidisciplinary team will work collaboratively to enhance the existing P. aeruginosa DMAb platform and develop more potent options with improved antigen binding and receptor engagement. They will be further tested in preclinical models to support translation of this DMAb approach and ultimately move it forward to human studies.

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The Wistar Institute is an international leader in biomedical research with special cancer, immunology, infectious disease research, and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

Wistar Science is Launchpad for Creating First MERS Vaccine that Has Completed Phase 1 Human Trial

Written by The Wistar Institute on . Posted in Featured News.

Using enhanced DNA vaccine technology, Wistar scientists can speed the development of vaccines for emerging diseases creating impactful countermeasures against outbreaks.

Wistar’s Drs. Kar Muthumani, David Weiner and collaborators unlocked the R&D potential of synthetic DNA vaccines to develop the first synthetic DNA vaccine for Middle East Respiratory Syndrome (MERS) in 11 months (research published in Science Translational Medicine in 2015). The vaccine entered and completed phase 1 human trials in 2017 and results were published on July 24, 2019 in The Lancet Infectious Diseases.

In 2012, the first MERS outbreak occurred in Saudi Arabia. This virus had never been seen before. Spread through camels and bats, MERS is a highly infectious respiratory disease predominant in the Middle East. Fast forward to 2015, when an individual who had contracted MERS returned to South Korea from the Middle East. This led to a South Korean outbreak that resulted in 186 confirmed cases and 38 deaths. The outbreak affected 24 hospitals, led to the temporary closure of more than 2,000 schools, and had a significant impact on the South Korean economy.* In 2018, The World Health Organization (WHO) listed MERS as a potential public health emergency in the annual review of the Blueprint list of priority diseases.

“MERS was such a new emerging infectious disease that no research on it had been done before the 2012 outbreak,” said Muthumani. “But I knew MERS was similar to Severe Acute Respiratory Syndrome (SARS), so I gathered knowledge of the 2001/2002 SARS outbreaks in China/Asia to guide how we would create a MERS vaccine.”

Wistar’s Vaccine & Immunotherapy Center is currently leading the charge for the development of multiple synthetic DNA-based vaccines. A synthetic DNA MERS vaccine works like this: An injection of a simple DNA plasmid tells the body to generate a foreign protein derived from the pathogen, which then causes the immune system to respond and destroy the MERS virus if it were to infect the body.

Though Muthumani and his team had to start from scratch because no reagents were available to design and test vaccine efficacy, Muthumani’s knowledge of SARS — a coronavirus related to MERS — was the blueprint from which they created reagents, a pseudo-virus and developed immune responses to multiple related strains of MERS.

There are several conceptual advantages to synthetic DNA vaccines compared to other vaccine platforms. DNA vaccines possess virtually no risk of causing disease since no infectious agents are injected into the body. DNA vaccines have had an exceptional safety profile in numerous clinical trials over the last 20 years. Additionally, new technologies allow DNA vaccines to be designed and manufactured quickly and inexpensively, which makes them an ideal platform for dealing with rapidly emerging pathogens that develop in underdeveloped regions of the world.

“With how fast pandemics spread in this day and age, this technology to swiftly craft a vaccine against new threats could be revolutionary,” said Muthumani.

*Centers for Disease Control and Prevention

Why Don’t We Respect Bacteria? First Symposium on Bacterial Resistance at Wistar

Written by The Wistar Institute on . Posted in Featured News.

There is an antibiotic crunch happening globally and to address this stalemate, Wistar hosted its first gathering of top scientists working to combat antibiotic resistance. 

The recent U.K. Review on Antimicrobial Resistance outlines the growth in this problem. It predicts an increase in deaths from antimicrobial resistant (AMR) infections from 700,000 per year today, to approximately 10 million per year over the next 30 years, and that the global economic cost of AMR could reach $100 trillion dollars by 2050. 

Bacterial infections are increasingly resistant to our world collection of antibiotics, which were once our best line of defense. Many of these drugs are no longer effective for treating those same infections, and instead are leading to increasingly drug-resistant diseases, even “superbugs.” 

Wistar recently held a scientific symposium to bring experts together and share in the latest discoveries to combat AMR. The Gram-negative Bacterial Resistance Symposium, supported by Pfizer Inc., was one of the few academic-industry conferences exchanging and exploring new ideas to fighting AMR. It featured leaders from across the nation, including Wistar’s very own Drs. David Weiner, Farokh Dotiwala and Ami Patel who spoke to this “post-antibiotic” era we have entered, and provided a vision of new approaches to head off this growing concern.   

Bacteria – A Global Threat

Bacteria are classified into gram-positive and gram-negative, with gram-negative being more resistant to antibiotics due to a thicker, protective outer membrane as well as containing many internal “pump” proteins that recognize and pump out toxic drugs, allowing them to escape the effects of many current antibiotics. Of the top 10 global AMR threats, seven are gram-negative organisms. The top three most deadly threats are gram-negative infections.   

“The World Health Organization lists antibiotic resistance as one of the biggest threats to global health,” said Weiner, executive vice president, director of the Vaccine & Immunotherapy Center and W.W. Smith Charitable Trust Professor in Cancer Research at Wistar, during his opening address. “This topic is central now. For your attendance you have an assignment: We can no longer follow what has been done before, but must lead with new approaches and strategies against gram-negative pathogens!”  

Throughout the day, researchers shared challenges and solutions to better understand multidrug-resistant strains like Acinetobacter baumannii (Iraqibacter), Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli (E. coli), malaria, salmonella, shigella, and gonorrhea.

Presenters like Dotiwala, assistant professor in the Vaccine & Immunotherapy Center at Wistar, are thinking outside the box to find new approaches to getting inside gram-negative bacteria and successfully delivering a new type of drug.

Dotiwala is working on a novel class of antibiotics that would target a niche in bacterial enzymes to kill the bacteria and activate the immune system. His research will lead to highly specific antimicrobial strategies against antibiotic-resistant strains as well as promising anti-cancer immunotherapies.

Patel, a research assistant professor in Wistar’s Vaccine & Immunotherapy Center and a collaborator with the Weiner lab, is applying her research developing synthetic DNA vaccines and synthetic DNA-based monoclonal antibodies (DMAbs) to numerous infectious diseases with the hope of moving new therapies forward. 

Patel discussed how the synthetic DNA platform has the potential to prevent and improve recovery from AMR infections of Pseudomonas aeruginosa, an opportunistic organism that is a serious threat in immunocompromised people. In a hospital setting, it is easily spread and can cause pneumonia, blood infections and urinary tract infections. 

Upon closing the symposium with a panel discussion, Dr. Paul Offit, director of the Vaccine Education Center and attending physician in the Division of Infectious Diseases at Children’s Hospital of Philadelphia, said “The post antibiotic era looks like the pre-antibiotic era.” 

He then held up the 1925 book Arrowsmith by Sinclair Lewis, a fictional story about a phage discovery that cures bubonic plague and saves a South American community. Offit asked the panelists what about bacteriophages as a commercial product are holding us back, at least as a personalized approach for patients with highly intractable diseases. All the panelists agreed that the challenges are great and numerous but, as this day showcased, many promising approaches are underway. 

Dr. Sanjay Ram, professor of Medicine at the University of Massachusetts Medical School, showed promising data targeting N. Gonorrheae with designed antibodies and DNA-encoded monoclonal antibodies and suggested they may be game changing. Dr. Daniel Zurawski, chief of Pathogenesis and Virulence at Walter Reed Army Institute of Research, discussed antibody technologies that may be of particular importance for AMR as they can be combined with traditional antibiotics and tested quickly to limit resistance. Dr. Kathrin Jansen, SVP and head of Vaccine Research & Development at Pfizer Inc., commented on vaccine approaches and how researchers should think in terms of personalized treatments and how new immune tools may be very useful. 

Emily Kramer-Golinkoff made an impassioned presentation to the attending researchers that bacteria resistance constitutes the single greatest threat to the Cystic Fibrosis (CF) community. She has advanced-stage CF and is the founder of Emily’s Entourage, a nonprofit that brings together research, patient, pharmaceutical, and biotech communities to raise funds and accelerate R&D development of therapies to benefit patients who carry nonsense mutations and do not respond to current and breakthrough drugs.

“I feel the pressure of time with every single breath I take,” said Emily. “I speak on behalf of myself and every single person fighting this disease. Our lives, our futures are on your shelves, in your hands, and you are the brilliant researchers uniquely capable of developing and shepherding our life-saving therapies through the pipeline and into clinic in record speed.” 

“There is always a human cost to medical breakthroughs, and we pay the highest human cost when we don’t take on the challenges,” concluded Offit.

Symposium on Gram-Negative Bacterial Resistance
Dr. David Weiner

Synthetic DNA-encoded Antibodies Against Zika Virus Shown to be Effective in Preclinical Studies

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (Apr. 5, 2019) — A new approach for delivery of DNA-encoded monoclonal antibodies (DMAbs) has been reported by Wistar scientists and their collaborators. This new technology allows direct production of monoclonal antibody-like molecules in living animals.

In this study, published in Molecular Therapy, the researchers focused on developing novel DMAbs for protection against Zika virus (ZIKV) infection. DMAbs achieved persisting antibody expression that provided long-term protection against lethal virus challenge in both small animal and, for the first time, non-human primate preclinical models. This study provides a direct bridge to the clinic, supporting further development of the new DMAb technology towards wider application.

“We showed that the DMAb platform produces fast and transient but sustained antibody expression in the blood of small and large animal models,” said lead researcher David B. Weiner, Ph.D., executive vice president and director of Wistar’s Vaccine & Immunotherapy Center, and W.W. Smith Charitable Trust Professor in Cancer Research. “These properties, coupled with the ease of production and storage, support further development of DMAbs as a possibly ideal approach during infectious disease outbreaks to provide rapid protection to at-risk individuals and, in the case of Zika, to their offspring as well.”

Monoclonal antibodies (MAb) are a major category of therapeutic agents with potential for prevention and treatment of a host of infectious diseases. However, development and delivery of MAbs is expensive and limits its applications. The current study advances the novel DMAb technology by showing expression and protection from an infectious challenge.

ZIKV is a mosquito-borne infection endemic to several areas of the world and has become an important global public health concern, with more than two billion people at risk. No approved vaccine or treatment is currently available for ZIKV infection, which is associated with severe birth defects and neurological complications in adults. Survivors develop ZIKV-specific protective antibodies that are being studied as candidates for development of recombinant monoclonal antibodies for preventive use. However, this approach poses challenges related to development, delivery, manufacturing and storage.

The Weiner Lab engineered a synthetic plasmid DNA encoding an identified and developed potent anti-ZIKV monoclonal antibody ZK190 that binds to the virus envelope. When injected as DMAb intramuscularly in mice and non-human primates, DMAb-ZK190 resulted in antibody presence in circulating blood for several weeks to months.

Importantly, when the animals were challenged with a lethal dose of ZIKV, DMAb-ZK190 provided protection from both infection and disease.

“Our study represents the first evidence of protection with a nucleic acid-encoded antibody in a non-human primate model of infection with any infectious agent,” said Ami Patel, Ph.D., first author on the study and a research assistant professor in the Wistar Vaccine and Immunotherapy Center. “This takes us one step closer to clinical development of the DMAb platform for its deployment in the areas where it is most needed.”

Co-authors: co-first author Rianne N. Esquivel, Sagar B. Kudchodkar, Daniel H. Park, Hyeree Choi, Piyush Borole, Kanika Asija, Mamadou Bah, Shareef Shaheen, and Kar Muthumani from Wistar; Karin Stettler and Davide Corti from Humabs BioMed, SA; Jeff Allen, Janess Mendoza, Stephanie Ramos, Jing Chen, Jian Yan, Trevor R.F. Smith, Kate Broderick, Ghiabe Guibinga, and Laurent Humeau from Inovio Pharmaceuticals; Amy C. Durham from the University of Pennsylvania School of Veterinary Medicine.

Work supported by: National Institutes of Health grant T32-AI055400 and a grant from the Bill & Melinda Gates Foundation.

Publication information: In vivo delivery of a DNA-encoded monoclonal antibody (DMAb) protects non-human primates against Zika virus, Molecular Therapy (2019). Advanced online publication.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

Dr. David Weiner

Wistar’s David B. Weiner, Ph.D., Awarded Prestigious Scientific Achievement Award from Life Sciences Pennsylvania

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (Feb. 15, 2019) — David B. Weiner, Ph.D., executive vice president, director of the Vaccine & Immunotherapy Center, and the W.W. Smith Charitable Trust Professor in Cancer Research at The Wistar Institute, has been named the recipient of this year’s Scientific Achievement Award from Life Sciences Pennsylvania. The organization, with its more than 800-member companies, has a single mission to make Pennsylvania a hub of innovation by creating a business and public policy environment that fosters life sciences growth and success.

“Our Scientific Achievement Award recognizes a scientist in the Pennsylvania life sciences community who has demonstrated outstanding achievement by advancing scientific knowledge, innovation, and/or patient care,” said Christopher P. Molineaux, president & CEO of Life Sciences PA. “We can’t think of a better honoree this year than David – considered a founder of the field of synthetic DNA vaccines with more than 30 years of research contributions and scientific influence.”

At Wistar, Weiner directs a translational research laboratory in the area of novel synthetic nucleic acid technologies. His lab’s accomplishments include the first in human studies of DNA vaccines and DNA-encoded monoclonal antibodies for treating and preventing cancer and emerging infectious diseases, clinically important advances in gene expression, optimization and DNA delivery. His lab developed the first clinically efficacious DNA vaccine and has moved synthetic DNA vaccines for Middle Eastern Respiratory Syndrome (MERS), HIV, Ebola, and Zika through development into clinical studies. Weiner is igniting collaboration to also explore combination therapies for ovarian, prostate, and other cancers.

The Weiner Lab has published more than 400 papers, chapters and reviews. Weiner has received multiple awards and honors, including the National Institutes of Health Director’s Transformative Research Award, the Vaccine Industry Excellence Award for Best Academic Research Team, and his lab was named among the Top 20 Translational Research Laboratories of the Year by Nature Biotechnology. He is president of the International Society for Vaccines (ISV) and is an elected Fellow of the American Association for the Advancement of Science. He was named one of the nation’s top 40 most influential Vaccine Scientists in 2014.

“Since his arrival at Wistar, David has tremendously expanded our research enterprise in infectious diseases and cancer, bringing to clinical testing next generation technologies for vaccine and immunotherapy development,” said Dario C. Altieri, M.D., president and CEO of The Wistar Institute and director of its Cancer Center. “Working in seamless partnership with academia, industry and philanthropic foundations, David is redefining concepts of biomedical innovation and scientific preeminence that will benefit millions.”

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer, immunology, infectious disease research, and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.