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Drs. David Weiner and Ami Patel working at a hood in the lab

Low-dose Administration of MERS DNA Vaccine Candidate Induces Potent Immunity and Protects From Virus Challenge in Preclinical Models

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

PHILADELPHIA — (April 22, 2021) — A synthetic DNA vaccine candidate for Middle East respiratory syndrome coronavirus (MERS-CoV) developed at The Wistar Institute induced potent immune responses and afforded protective efficacy in non-human primate (NHP) models when given intradermally in abbreviated, low-dose immunization regimen. A similar vaccine candidate was previously shown to be safe and tolerable with a three-dose intramuscular injection regimen in a recently completed human phase 1 study and is currently in expanded studies of phase 1/2a trial. New results were published today in JCI Insight.

“While several vaccine products are being advanced against MERS and other coronaviruses, low-dose delivery and shortened regimes are crucial to rapidly induce protective immunity, particularly during emerging outbreaks, as the current SARS-CoV-2 pandemic has emphasized,” said David B. Weiner, Ph.D., Wistar executive vice president, director of the Vaccine & Immunotherapy Center (VIC) and W.W. Smith Charitable Trust Professor in Cancer Research, who led the study.

Researchers evaluated the immunogenicity and protective efficacy of their MERS synthetic vaccine when delivered intradermally using a shortened two-dose immunization schedule compared with intramuscular delivery of higher doses in NHP.

“Given that human efficacy trials for MERS vaccines may be challenging due to the low number of yearly cases, animal models such as our NHP model are valuable as a bridge with human data coming from early-phase clinical trials,” said Weiner.

In this study, Weiner and team report robust antibody neutralizing antibodies and cellular immune responses in all conditions tested. A rigorous virus challenge experiment showed that all vaccination groups were protected against MERS-CoV compared to unvaccinated control animals. However, the low-dose regimen with intradermal delivery was more impactful in controlling disease and symptoms than the higher dose delivered intramuscularly in NHP models.

“To our knowledge, this is the first demonstration of protection with an intradermally delivered coronavirus vaccine,” said Ami Patel, Ph.D., Caspar Wistar Fellow at the Vaccine & Immunotherapy Center and one of the lead authors of the paper. “Intradermal delivery of synthetic DNA vaccines has significant advantages for rapid clinical development. It can be dose sparing and has higher tolerability in people compared with intramuscular injection. The positive results of this study are important not only for the advancement of this MERS vaccine but also for development of other vaccines.”

“Our team is also advancing a COVID-19 vaccine through clinical trials, and we were able to do so in a very short time thanks to our previous experience developing the MERS vaccine,” added Weiner.

Importantly, no evidence of adverse effects on the lungs was observed in any of the dosing groups compared to unimmunized control animals. Through the assessment of a large panel of blood cytokines, researchers showed significant decrease in all mediators of inflammation, which further suggests the vaccine prevents the destructive inflammation induced by coronaviruses.

“In the past twenty years, three new coronaviruses have emerged and caused human outbreaks. The current SARS-CoV-2 pandemic has further emphasized the importance of rapid infection control for coronaviruses and other emerging infectious diseases,” said Emma L. Reuschel, Ph.D., a staff scientist in the Weiner lab and co-first author on the study. “Vaccine candidates that are simple to deliver, well tolerated, and can be readily deployed in resource-limited settings will be important to achieve control of infection.”

Co-authors: Ziyang Xu, Faraz I. Zaidi, Kevin Y. Kim, Regina Stoltz, and Kar Muthumani from The Wistar Institute; Dana P. Scott, Friederike Feldmann, Tina Thomas, Rebecca Rosenke, Dan Long, Jamie Lovaglio, Patrick W. Hanley, and Greg Saturday from National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT; Janess Mendoza, Stephanie Ramos, Laurent Humeau, and Kate E. Broderick from INOVIO Pharmaceuticals, Inc.

Work supported by: Funding from the Intramural Research Program, National Institutes of Allergy and Infectious Diseases, and the Coalition for Epidemic Preparedness Innovations (CEPI).

Publication information: Intradermal delivery of a synthetic DNA vaccine protects macaques from Middle East respiratory syndrome coronavirus, JCI Insight (2021). 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.

Coronavirus COVID-19 SARS-CoV-2 Concept Image.

DARPA and JPEO-CBRND Award $37.6M to The Wistar Institute and Collaborators at INOVIO, AstraZeneca, Penn, & Indiana University to Develop Innovative COVID-19 Treatment

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

PHILADELPHIA — (Dec. 15, 2020) — A team of scientists from The Wistar Institute, INOVIO, AstraZeneca, the Perelman School of Medicine at the University of Pennsylvania, and Indiana University has received a $37.6 million award over two years from the Defense Advanced Research Projects Agency (DARPA) and the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND) for rapid preclinical development and translational studies of DNA-encoded monoclonal antibodies (DMAbs) as countermeasures for COVID-19.

DMAbs, unlike conventional therapeutic antibodies, are administered as genetic blueprints that instruct the patient’s body to build its own highly specific antibodies against pathogens, such as bacteria and viruses, and as immunotherapeutics for cancer. Conceptually DMAbs have advantages over traditional monoclonal antibodies in scale-up and delivery, which would rapidly benefit large populations.

Worldwide, more than 72 million people are infected with SARS-CoV-2 and more than 1.6 million have died. The U.S. outbreak alone has resulted in the hospitalization of over 110,000 people. Sixteen million Americans have been infected, and more than 300,000 have died of COVID-19 since the outbreak began.*

Wistar scientists and their collaborators pioneered the development of DMAb technology as a unique asset to combat the COVID-19 pandemic. In addition to their high specificity for the target, DMAbs have important advantages of rapid manufacturing, low cost of production, and temperature-stable storage and distribution.

The concept of synthetic DMAb technology was originated in the laboratory 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. The technology involves the design and delivery of genetic sequences that encode monoclonal antibodies into an optimized DNA platform. This genetic blueprint is then administered to a person so that their own body becomes the production site of highly specific antibodies which, in the case of SARS-CoV-2, target essential parts of the virus. In animal studies, DMAbs have been applied to prevent infection as well as to treat infection.

“We are thrilled that DARPA and JPEO-CBRND have chosen Wistar to assemble this exceptional team to focus on advancing potential DMAb countermeasures for the SARS-CoV-2 crisis,” said Weiner. “Our team combines many different strengths to advance this approach from the bench to the bedside at lightening speed. We have a strong track record of working together to advance DNA-based solutions into the clinic and look forward to advancing these first-in-human studies as a possible risk mitigation approach for COVID-19.”

This paradigm-shifting award supports a unique public-private collaboration, which includes world-class capabilities in synthetic DNA therapeutics and monoclonal antibody technology. Together, with the support of exceptional clinical and translational teams and a global pharmaceutical company, this multidisciplinary approach is uniquely suited to address the unprecedented global health crisis brought about by COVID-19.

The program goal will be to rapidly design, enhance and scale SARS-CoV-2-specific DMAbs, and move them into laboratory and animal model studies. If successful, this will provide the foundation for rigorous, first-in-human clinical trials.

“This partnership broadens the scope and application of our DNA medicines platform across the spectrum of needed COVID-19 treatment modalities and opens the door for faster, more cost effective, and scalable production of monoclonal antibody products for other infectious diseases, cancers and other unmet medical needs,” said J. Joseph Kim, Ph.D., president and CEO of INOVIO. “Working with our partners, we are excited about the potential this offers both for situations requiring immediate clinical response and benefit.”

Mark Esser, VP and Head of Microbial Sciences, AstraZeneca, said, “We are excited to combine capabilities with Wistar and this world-class team to evaluate the potential of these DNA-delivered antibodies to impact the way we can respond to prevent and treat infection.”

“This COVID-19 pandemic presents a unique and immediate challenge to the world, one in which DNA treatments have the potential to move us to a future where COVID-19 is much more manageable,” said Pablo Tebas, M.D., a professor of Infectious Diseases at the Perelman School of Medicine at the University of Pennsylvania. “We are eager to build upon previous DMAb research and put it to the test against COVID-19.”

“We are very excited and honored to be part of this extraordinary team,” said Jesper Pallesen, Ph.D., assistant professor of molecular and cellular biochemistry at Indiana University. “The promise of DMAb technology is huge, and its implementation into our global anti-COVID-19 efforts will leave a resonating and lasting footprint. We are delighted to bring structural biology expertise to the team and to provide atomic-detail evaluation of DMAb technology efficacy mechanisms.”

Wistar, INOVIO, and the University of Pennsylvania with the Department of Defense and the Coalition for Epidemic Preparedness Innovations (CEPI) are in late-stage studies of a synthetic DNA vaccine for COVID-19. Through the collaboration with JPEO-CBRND, this work is supported by the Office of the Assistant Secretary of Defense for Health Affairs with funding from the Defense Health Agency.

Grant information: Synthetic DNA-encoded monoclonal antibodies (DMAbs) targeting COVID-19, 2020-2022.

*Data from the Johns Hopkins Coronavirus Research Center and The COVID Tracking Project at The Atlantic.

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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.

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A tick on a blade of grass

Wistar Creates a New Synthetic DNA Vaccine Against Powassan Virus

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

PHILADELPHIA — (Oct. 29, 2020) — Scientists at The Wistar Institute have designed and tested the first-of-its-kind synthetic DNA vaccine against Powassan virus (POWV), targeting portions of the virus envelope protein. A rapidly reemerging tick-borne disease, POWV has been reported to be fatal in 10% of infected people with detrimental neurological consequences including encephalitis and meningitis. This new POWV vaccine candidate, described in a paper published today in PLOS Neglected Infectious Diseases, is one of many emerging infectious disease DNA vaccine discoveries being advanced by the Vaccine and Immunotherapy Center at The Wistar Institute.

Unlike the widely recognized Lyme disease, POWV causes a little known, potentially deadly infectious disease that is transmitted through tick bites during fall and spring seasons. POWV is an RNA virus belonging to the flavivirus family, the same as Zika virus, but passed to people by ticks instead of mosquitoes.

Transmission can occur rapidly and symptoms including flu-like fever, body aches, skin rash, and headaches can present anytime during the 1-4 week incubation period. Although still considered relatively rare, in recent years the number of reported cases of people sick from Powassan virus has been increasing in North America, including infecting former U.S. Senator Kay Hagan who contracted Powassan virus and died from the disease. There are no vaccines or therapies available to treat or prevent this emerging infection.

Kar Muthumani, Ph.D., former associate professor and director of the Laboratory of Emerging Infectious Diseases at The Wistar Institute,* and senior author on the study, collaborated with the laboratory of David B. Weiner, Ph.D., executive vice president and director of Wistar’s Vaccine and Immunotherapy Center, to design and test this synthetic DNA vaccine.

The effectiveness of this vaccine was evaluated in preclinical studies that showed a single immunization elicited broad T and B cell immune responses in mice similar to those induced naturally in POWV-infected individuals, and that vaccine-induced immunity provided protection in a POWV challenge animal model.

“The significant protection in mice demonstrated by our vaccine is highly encouraging and strongly supports the importance of this vaccine approach for further study,” said Muthumani.

Residents of and visitors in POWV-endemic areas are considered at risk of infection, especially during outdoor work and recreational activities. In the U.S., cases of POWV disease have been reported in Northeastern states and the Great Lakes region.

“Given the risk of serious complications from POWV and the 300% increase in incidence of POWV infection over the past 16 years, we will continue efforts to advance this urgently needed emerging infectious disease vaccine candidate towards the clinic,” said Weiner.

Co-authors: Hyeree Choi1, Michelle Ho1, Sagar B. Kudchodkar1, Emma L. Reuschel1, Kenneth Ugen5, Erin Reynolds2, Pablo Tebas3, J.Joseph Kim4, Mohamed Abdel-Mohsen1, Saravanan Thangamani2, David B. Weiner1, Kar Muthumani1
1Vaccine & Immunotherapy Center, The Wistar Institute, Philadelphia, PA; 2Department of Microbiology and Immunology, SUNY Center for Environmental Health and Medicine, SUNY Upstate Medical University, Syracuse NY 13210. 3Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 4Inovio Pharmaceuticals, Plymouth Meeting, PA., 5University of South Florida, Tampa, FL.

*Current address: K. Muthumani, CSO, GeneOne Life Sciences, Inc., Blue Bell, PA

Work supported by: INOVIO Pharmaceuticals, Inc.

Publication information: A novel synthetic DNA vaccine elicits protective immune responses against
Powassan virus, PLOS Neglected Tropical Diseases (2020). 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’s Business Development team is dedicated to advancing Wistar Science and Technology Development through creative collaborations. wistar.org.

Scientists Engineer DNA-based Nanotechnology to Stimulate Potent Antitumor Immune Responses in Preclinical Models

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

PHILADELPHIA — (Sept. 10, 2020) — Combining their expertise in protein engineering and synthetic DNA technology, scientists at The Wistar Institute successfully delivered nanoparticle antitumor vaccines that stimulated robust CD8 T cell immunity and controlled melanoma growth in preclinical models. Study results were published online in Cancer Immunology Research, a journal of the American Association for Cancer Research, and support exploration of this immunotherapy approach for additional cancer types.

Nanovaccines consist of extremely small (nano) particles — similar in size to bacteria and viruses — used to display multiple copies of an antigen and able to elicit strong immune responses. The team previously reported on using DNA instructions to launch in vivo production of nanoparticle vaccines (DLnano-vaccines).

DLnano-vaccines assembled in the body produced stronger immune responses than protein based nanoparticle vaccines in an infectious disease setting, especially inducing CD8 T cell responses.

“We wanted to test DLnano-vaccines for cancer immunotherapy and obtain proof of concept that this platform could be successfully applied in the cancer field, thanks to its effectiveness at prompting CD8 T cells responses,” said Daniel Kulp, Ph.D., associate professor in Wistar’s Vaccine & Immunotherapy Center and co-corresponding author of the study, who specializes in nanotechnology and protein engineering for vaccine development.

Due to their ability to specifically kill malignant cells, CD8 T cells play a pivotal role in anticancer immunity, therefore engagement of these cells represents a necessary step for the success of anticancer vaccine approaches, although this type of immune response is typically difficult to achieve by vaccination with proteins or inactivated virus.

Researchers designed DLnano-vaccines displaying 60 copies of protein parts derived from the melanoma-specific antigens Trp2 and Gp100 and tested these in mouse models of melanoma, observing prolonged survival that depended on CD8 T cell activation both in therapeutic and prophylactic settings.

“One of the advantages of synthetic DNA technologies over other methods is the versatility of the platforms,” said Ziyang Xu, Ph.D., a recent doctoral graduate working at Wistar and the first author of the study. “DLnano-vaccines may be designed for various cancer targets and our study shows this is a promising strategy for cancer immunotherapy that may warrant further testing.”

To elucidate the mechanism through which DLnano-vaccines activate CD8 T cells, the team studied the effects of the DNA-launched version of a previously described HIV nanoparticle vaccine (eOD-GT8-60mer). They observed that DLnano-vaccines administered via electroporation resulted in transient muscle cell apoptosis that attracted macrophage infiltration at the injection site, which in turn was instrumental to activate CD8 T cells.

DLnano-vaccines were developed using synthetic DNA technology 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 also a co-senior author on the study.

Co-authors: Neethu Chokkalingam, Edgar Tello-Ruiz, Mamadou A. Bah, Susanne Walker, and Nicholas J. Tursi from Wistar; Megan C. Wise, Paul D. Fisher, Katherine Schultheis, Kate E. Broderick, and Laurent Humeau from Inovio Pharmaceuticals, Inc.

Work supported by: National Institutes of Health (NIH) grants U19 Al109646 and Collaborative Influenza Vaccine Innovation Centers (CIVICs) contract 75N93019C00051; additional support was provided by Inovio Pharmaceuticals, Inc., a grant from the W.W. Smith Charitable Trust, and the Monica H.M. Shander Memorial Fellowship.

Publication information: A DNA-launched nanoparticle vaccine elicits CD8+ T-cell immunity to promote in vivo tumor control, Cancer Immunology Research, 2020. Online publication.

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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’s Business Development team is dedicated to accelerating the translation of Wistar discoveries into innovative medicines and healthcare solutions through licensing, start-ups and creative collaborations. wistar.org.

The Wistar Institute & Allevi Inc. Collaborate on 3D Bioprinting Project to Advance COVID-19 Research

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

PHILADELPHIA — (June 25th, 2020) — The Wistar Institute, a biomedical research leader in cancer, immunology and infectious diseases, and Allevi, Inc. a Philadelphia based startup pioneering innovative 3D biofabrication technologies, announce a collaboration to use 3D bioprinting to help combat COVID-19.

In a time where the coronavirus pandemic has led to nearly 8 million infections and more than 437,000 deaths worldwide1, scientific research is more important than ever. Allevi will apply its patented 3D bioprinting platform to create three-dimensional lung models that Wistar scientists will use to study SARS-CoV-2, the virus that causes COVID-19. The goal will be to investigate the mechanisms deployed by this pathogen to infect humans and identify potential ways in which it may be blocked.

Wistar expertise in immunology and virology and its state-of-the-art biosafety level 3 capabilities to safely study pathogens combined with Allevi’s platform technology will be essential to the success of this collaboration.

“We are accompanying the spectacular work from our peers in the scientific community and have identified tremendous potential for our platform to enable COVID-19 research in a much faster, yet physiologically relevant manner,” said Taciana Pereira, Allevi Vice President of Life Sciences and a co-principal investigator on the project. “We believe that scientists from all areas need to unite now to solve this crisis, so we are ecstatic to work with Wistar and Dr. David Weiner.”

The collaboration will be led by David B. Weiner, Ph.D., Executive Vice President, director of the Vaccine & Immunotherapy Center (VIC) and W.W. Smith Charitable Trust Professor in Cancer Research. “We have been advancing scientific investigations aimed at the treatment and prevention of COVID-19, and we believe that Allevi’s innovative approach is an exciting modality to gain unique insights into the inner workings of the novel coronavirus,” stated Weiner, also a co-principal investigator on the project.

“This project has the potential to be a significant asset in the fight against COVID-19, and the scientific community will benefit greatly from this endeavor,” said Robert Langer, Sc.D., David H. Koch Institute Professor at the Massachusetts Institute of Technology (MIT) and Allevi Scientific Advisory Board member.

1Data from the Johns Hopkins University Center for Systems Science and Engineering (Updated June 16, 2020)

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Founded in 2014, Allevi’s mission is to make it easy to design and engineer 3D tissues using desktop 3D bioprinters that are versatile, powerful, and easy-to-use. Allevi’s 3D bioprinters and bioinks are trusted by leading researchers and industry giants in hundreds of labs globally in the fields of tissue engineering, organ-on-a-chip research, pharmaceutical validation, biomaterial development, and regenerative medicine. allevi3d.com

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’s Business Development team is dedicated to advancing Wistar Science and Technology Development through creative collaborations. wistar.org.

Positive Results from Preclinical Testing Support Clinical Development of COVID-19 DNA Vaccine

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

PHILADELPHIA — (May 20, 2020) — The Wistar Institute, an international biomedical research leader in cancer, immunology and infectious disease, announces a study reporting initial immunogenicity of a synthetic DNA vaccine for SARS-CoV-2 developed in collaboration with Inovio Pharmaceutical, Inc., and other scientists. Published in Nature Communications, the report focuses on immune studies in animals, which show induction of functional antibody responses and T-cell responses following immunization. The vaccine, INO-4800, was advanced to phase 1 clinical testing in 10 weeks (clinicaltrials.gov NCT04336410).

The SARS-CoV-2 coronavirus emerged in December 2019 in the city of Wuhan, China. Infection causes the viral pneumonia disease COVID-19 that has spread quickly around the world. On March 11, 2020, the World Health Organization declared COVID-19 a global pandemic. Currently in the U.S., there are 1.5 million confirmed infections and more than 90,000 deaths occurring in just months, making COVID-19 infection the leading cause of death in the country.

No vaccines or major therapies are available to prevent infection or control the disease and the U.S. government has made development of a vaccine for COVID-19 a top priority. The viral genome became available on January 11, 2020, and the Wistar-Inovio team immediately began working to design and develop a new vaccine, based largely on their previous experience creating a synthetic DNA vaccine against the related coronavirus that causes Middle East respiratory syndrome (MERS).

Working with Inovio, a group led by David B. Weiner, Ph.D., Wistar executive vice president, director of the Vaccine & Immunotherapy Center (VIC) and W.W. Smith Charitable Trust Professor in Cancer Research, focused on rapid development of a synthetic DNA-based vaccine targeting the major surface antigen Spike protein (S) of SARS-CoV-2 into preclinical studies.

“We focused on both assay development and vaccination studies to test if immune responses induced by the vaccine in laboratory animals were functional against the virus. Our focus was the induction of immune responses that could in concept make it difficult for SARS-CoV-2 to have a home in the human body,” said Weiner, co-senior author of the publication. “The vaccine was designed leveraging our synthetic DNA technology, which has a set of conceptual advantages including accelerated clinical development built on a conceptually safe, non-live, simple platform that has scalable manufacturing and temperature stability. The vaccine-induced antibodies in vaccinated animals were of sufficient quantity and quality to block interaction of the virus with its receptor, which is its doorway into infecting the body, and were present in the lungs, a place where immunity is very important. The vaccine also induced T-cell function, which is critical for clearing viral infections from the body. These are indications that the immunity it induced might provide no escape for the SARS-CoV-2 virus. We are looking forward to additional studies and examining data from the ongoing clinical trial.”

The team includes Wistar VIC investigators Daniel Kulp, Ph.D., Kar Muthumani, Ph.D., and Ami Patel, Ph.D., who is a shared first author in the paper.

DNA vaccines work by delivering the genetic information required to make a certain viral protein in the recipient’s body, which stimulates the immune system to recognize that protein as foreign and build a response against it, thus targeting the virus and providing protection from infection.

Expressed in vitro, INO-4800 induced robust expression of the S protein. Within days following a single immunization of mice and guinea pigs, the vaccine induced antigen-specific T cell responses and functional antibodies that neutralize the virus, blocking the ability of the SARS-CoV-2 S protein to bind to the angiotensin-converting enzyme 2 (ACE2) host receptor on human cells.

Importantly, SARS-CoV-2-specific antibodies were detected in the lungs of immunized animals, suggesting they might protect against upper and lower respiratory disease that is associated with severe cases of COVID-19.

“While this candidate continues its journey as a potential vaccine against COVID-19, we are continuing our work in the lab to gather more information on the vaccine’s performance in small and larger animals,” said Patel, who is a research assistant professor at Wistar. “We will further characterize antibody functionality, cellular responses, and the ability of INO-4800 to mediate protection of animals against viral challenge.”

Co-authors: Trevor R.F. Smith and Stephanie Ramos from Inovio co-first authors. Other co-authors include Xizhou Zhu, Ebony N. Gary, Susanne N. Walker, Mansi Purwar, Ziyang Xu, Pratik Bhojnagarwala, Neethu Chokkalingam, Elizabeth Parzych, Emma L. Reuschel, Nicholas Tursi, Jihae Choi, Edgar Tello-Ruiz, Mamadou A. Bah, Yuanhan Wu, Daniel Park, Yaya Dia, Ali Raza Ali, Faraz I. Zaidi, Kevin Y. Kim, Sophia Reeder, Makan Khoshnejad, Jacqueline Chu, Kar Muthumani, and Daniel W. Kulp from Wistar; Dustin Elwood, Jian Yan, Katherine Schultheis, Jewell Walters, Maria Yang, Patrick Pezzoli, Arthur Doan, Miguel Vasquez, Igor Maricic, Dinah Amante, Alison Generotti, Timothy A. Herring, Ami Shah Brown, J Joseph Kim, Jean Boyer, Laurent M.P.F. Humeau, and Kate E. Broderick (corresponding author) from Inovio Pharmaceuticals; Nianshuang Wang, Daniel Wrapp, and Jason S McLellan from University of Texas at Austin; and B Wang from Fudan University, China.

Work supported by: Funding from the Coalition for Epidemic Preparedness Innovations (CEPI).

Publication information: Immunogenicity of a DNA vaccine candidate for COVID-19, Nature Communications (2020). 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.

Philanthropy Powering Science: $1.6M in New Funding for Wistar Coronavirus Research

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

In mere weeks, philanthropic support of Wistar’s Coronavirus Discovery Fund has exceeded $1.6M in new funding thanks to an extraordinary response from individuals, foundations, and corporate sponsors. As our scientists focused their research to advance vaccines, drugs, and diagnostics targeting the novel coronavirus, SARS-CoV-2, Wistar donors moved with the same speed, committing to put our discovery science into action in a variety of important ways. This pace of investment in research now underway at Wistar will allow us to accelerate and potentiate progress against SARS-CoV-2 and future viral threats the world may confront.

Under the leadership of Dr. David Weiner, executive vice president, director of the Vaccine & Immunotherapy Center (VIC), and W.W. Smith Charitable Trust Professor in Cancer Research, our team continues to carry out pivotal laboratory testing of its synthetic DNA vaccine. Funding support has enabled us to expand that research through the purchase of critical equipment that allows for real-time, high-throughput assays required for vaccine development, and will hasten the Institute’s ability to respond to future pandemic threats as they arise.

Dr. Daniel Kulp, associate professor in the VIC, is engineering nanoparticle-based immunotherapies that target SARs-CoV-2. He and his team use extremely small (nano) particles to display multiple copies of critical parts of the virus in order to stimulate immunity against COVID-19.  Donor support for his project is allowing the lab to design molecular simulations of the SARS-CoV-2 spike protein — the surface protein that lets the virus invade healthy cells.

Not only did individual donors make a strong commitment to Wistar Science; so did foundations, including The G. Harold and Leila Y. Mathers Charitable Foundation. Dr. Hildegund Ertl, vaccine expert and a professor in the VIC, is creating a SARS-CoV-2 vaccine based on safe viral delivery technologies. Genetically modified adenoviruses are great delivery vehicles for vaccines because they induce neutralizing antibodies and killer T-cell responses. Dr. Ertl’s goal is to apply innovative technologies created in her lab to develop a vaccine that will produce strong and sustained protection to COVID-19. The Mathers Foundation and steadfast Wistar supporters quickly mobilized to provide critical support for this project.

This is not Wistar’s first pandemic. We are uniquely prepared for this moment by a near-century’s worth of Wistar achievement in developing vaccines that have saved countless lives. Wistar’s community of supporters has provided the resources and tools our scientists need to work efficiently and effectively to address this pandemic. For that, we thank you deeply. We’re all in this for science. Because Wistar Science saves lives.

If you would like to play a role in advancing Wistar’s research fighting COVID-19, your donation will keep the momentum going and inspire our scientists to continue tackling the world’s biggest threats. 

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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.