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A Wistar Journey Through the Past, Present, and Future of Immunization Work

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

Vaccines are a crucial public health tool in its’ arsenal against diseases. Resurgences of diseases long thought eradicated are popping up decades later in sewage waters here and abroad, and we’ve witnessed what the impact of war has on countries whose health systems have crumbled under the ravages of war—we are not as far removed as we’d like to be from diseases once prevented by vaccines. With more than half a century of basic research for vaccine development, The Wistar Institute plays an integral role in immunization around the globe.

Rubella, rabies, and rotavirus. Wistar scientists developed vaccines for these diseases that are used in immunization programs worldwide. The rubella vaccine by Wistar scientists effectively ended the pandemic in the United States, as declared by the CDC in 2005. Two rabies vaccinations developed from the Institute addresses the disease in both animals and humans. In 2006, Wistar and collaborators created a rotavirus vaccine which became part of the regular immunization schedule for U.S. babies and is used or approved in over 45 countries. And we’re just getting started.

“Immunization is possibly one of the most impactful medical interventions ever developed. Millions of lives are saved each year by vaccination, and we live healthier and longer lives due to vaccines.” states David Weiner, Ph.D., Executive Vice President, Director of Wistar’s Vaccine & Immunotherapy Center, and W.W. Smith Charitable Trust Professor in Cancer Research, in the Immunology, Microenvironment & Metastasis Program at Wistar’s Ellen and Ronald Caplan Cancer Center.

This National Immunization Awareness Month, we have shared a few snapshots of current vaccine development projects at the Institute as well as what these researchers’ hopes are for the future of immunization.

Tackling Both Infectious Disease and Cancer with Immunization

Dr. Weiner’s research takes on both infectious disease and cancer. His work encompasses developing new ways to build and deliver synthetic nucleic acid vaccines – particularly advancing a new approach that drives self-assembly of an antigen into a more potent vaccine inside a vaccinated person. This approach gives the body the genetic information to become the factory to create the vaccine. Furthermore, his lab is developing new types of cancer therapeutic vaccines with the goals of creating strong anti-cancer immunity and eradicating cancer cells.

Weiner’s collaborations with public and private institutions is centered around novel immunization technology developed from his lab called DNA-encoded monoclonal antibodies (DMAbs) against diseases such as COVID-19, Zika, and Ebola.

Regarding the future, he shares, “Together with our collaborators, we hope to move new prototype HIV vaccines into human clinical trials later this year, and continue to advance vaccines for emerging pathogens, as well as cancer immunotherapies.”

Developing DNA Vaccines

Ami Patel, Ph.D., Caspar Wistar Fellow in the Vaccine and Immunotherapy Center, focuses her scientific efforts on DNA vaccines which have potential to be more stable and economical over traditional vaccine production. “We are trying to understand how different vaccines work in the body. How do vaccines generate different types of immune responses and can we use this to understand protection against infectious diseases. We are using this information to help develop the next generation of potential vaccines.” she says.

Patel emphasizes the importance of vaccines for young children and adults by calling back to various infectious diseases like polio that are no longer very common because of immunization. “Vaccines help protect us against serious disease. Some of us remember the discomfort of chicken pox as children. There is now a vaccine.”

While she calls the COVID-19 pandemic “devastating to global health”, Patel also recognizes the pandemic’s challenges proved fertile ground for an extraordinary collaborative time for biomedical scientists. “My hope is for vaccine researchers across different disciplines to continue to work together to help us understand different infectious diseases and develop better vaccines.”

Zooming in on a Nanoscale

In collaboration with Weiner, Daniel Kulp, Ph.D., associate professor in the Vaccine and Immunotherapy Center, has embraced nanotechnology in his vaccine research. “We are developing rationally engineered nanoparticle vaccines that can elicit extremely broad coronavirus immunity providing a proof-of-concept that a pan-coronavirus vaccine is possible,” Kulp elaborates.

While the Kulp laboratory is developing several promising vaccines, he emphasizes that his goal is to assess these candidates in humans. He says, “We are working to reduce barriers for launching small experimental medicine clinical trials allowing for broader evaluation of our best vaccine concepts. Through this type of work, I have high hopes that our generation can claim credit for the eradication of SARS-CoV-2.”

Kulp expresses that “Vaccines are one of the single most effective medical technologies humans have developed saving hundreds of millions of lives. Vaccines do not work without immunizations. This message is incredibly important.”

Caspar Wistar Fellows Drs. Ami Patel, Rahul Shinde, and Daniel Claiborne post with the Briggs

Expanding the Caspar Wistar Fellows Program

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

The Caspar Wistar Fellowship is a model for recruiting the best and brightest junior scientists to Wistar where they can build scientific networks and advance their unique independent research programs.

Two years ago philanthropists Doug and Peggy Briggs established the Caspar Wistar Fellowship to attract the most talented junior scientists from across the nation and beyond, and jumpstart their scientific careers. Put at the center of a collaborative nexus of bold and distinguished scientists working in cancer and infectious disease research at Wistar, What can they achieve?

“If we can find the best and brightest junior scientists, I believe we can move their careers along much faster,” said Doug. “They have the potential, and we are giving them a leg up and hopefully more responsibility than even they think they are ready for.”

These supremely driven and curious scientists have a lot on their shoulders, but have the focus, education and courage to become our next generation of scientific leaders.

Dr. Daniel Claiborne, Wistar’s newest Caspar Wistar Fellow, joins the Fellowship from the Ragon Institute of MGH, MIT and Harvard where he is trying to better understand T cells and CAR T cells for the treatment of HIV. CAR T cells, called chimeric antigen receptor T cells, are patient-derived T cells that have been engineered to target and destroy a specific antigen on the surface of a cancer cell. They are considered “super charged” immune cells that act like a living drug, latching onto a tumor cell to terminate it. CAR T cells have been developed as an immunotherapy for cancer, but Dr. Claiborne wants to explore their potential against HIV.

“This is a huge opportunity to start my own lab so there is some trepidation, but it’s what I’ve been working towards for 13 years, so I’m also very motivated as well,” says Dr. Claiborne. “The recent publications I worked on were not the end, but the beginning in our effort to understand the hurdles in repurposing CAR T cells for HIV. We learned a lot about what these cells can and cannot do. The big question in the field is, ‘Why do CAR Ts stop working?’ It’s an open-ended question and a ton of research has already been done.”

Dr. Claiborne brings an entirely different perspective to CAR T research that will enhance our basic understanding of CAR T cells and help inform their use in oncology and immunotherapy.

“The thing we do differently is use a humanized mouse model that carries a functional human immune system,” said Dr. Claiborne. “This is a malleable small animal model with actual human cells and T cells so we can learn more about what makes our CAR T therapies fail. And that’s largely translatable to more than just HIV infection. It informs basic T cell biology and illuminates what makes T cells do their job or not in many chronic disease states. The ability to do that in a small animal model with a human immune system is powerful and one step closer to the question we all think is important: What causes T cells to lose their function.”

Dr. Ami Patel became Wistar’s second Caspar Wistar Fellow in 2020 and has lived a pretty incredible year with lots of big changes. Since the start of the pandemic, Dr. Patel has been a key leader in the SARS-CoV-2 vaccine and immunotherapy efforts at the Vaccine & Immunotherapy Center.

“In September, I became a Caspar Wistar Fellow and then a week later, I went on maternity leave,” said Dr. Patel. “I truly appreciate this opportunity and it’s exciting to pursue my own independent research. I have multiple new experiments in which to design and develop new ideas. And I’m at the early stages building my lab and getting it up and running.”

Dr. Patel was recruited to the program after shining in the lab of Wistar’s Dr. David Weiner, first as a postdoctoral fellow and associate staff scientist. She was appointed as research assistant professor in 2019.

“As a Caspar Wistar Fellow, my new independent research program is focused on understanding the cellular and immune mechanisms associated with vaccine and immunotherapy delivery and using this information to improve the next generation of vaccines against emerging pathogens that could be tomorrow’s next major outbreaks. This is a great opportunity to explore new strategies,” she says.

As she is establishing her research program, Dr. Patel is hiring her own team to manage projects that run the gamut of emerging pathogens.

“Now is the time to put my new ideas to the test and drill down on key independent experiments that will lay the foundation for my research,” Dr. Patel added.

For Dr. Rahul Shinde, Wistar’s inaugural Caspar Wistar Fellow, this stage of independence has brought a myriad of research collaborations. His work focuses on pancreatic cancer and how cancer hijacks immune cells called macrophages, which normally stimulate the immune system and destroy cancer and pathogen invaders. Dr. Shinde is trying to elucidate when and how macrophages shift their function from fighting cancer to doing cancer cells’ bidding in the tumor microenvironment. He is also interested in the gut microbiome and its connection with modulating tumor progression.

“It has been great at Wistar, and such a positive feeling setting up my lab and working to publish,” said Dr. Shinde. “I feel lucky to collaborate with Wistar principal investigators across research fields including autoimmune diseases such as lupus. I’m also exploring pancreatic cancer’s tumor microenvironment that fosters cancer growth and therapy resistance. I’ve been part of several projects making interesting observations.”

Doug Briggs believes giving strong, sharp-minded scientists a platform to launch their careers is most important.

“Bringing these early-career, star scientists along faster in their careers is helping push the biomedical research dial forward. There are big up sides — for us all — with more and faster success in science,” says Doug.

“For Doug and Peggy Briggs to stand up and create this opportunity is very motivating, especially for scientists who do high-risk and out-of-the-box research,” said Dr. Claiborne. “It’s a huge deal. Pursue your ideas and see where they take you.”

The Caspar Wistar Fellowship will continue to boost the potential in early-career scientists it brings to Wistar. With each new Fellow who calls Wistar home, Doug and Peggy’s straightforward belief becomes a more powerful engine for expanding research and pushing the Institute to succeed.

Stay tuned for the fourth Caspar Wistar Fellow to be recruited very soon!

Latest Wistar Discoveries: Fine-tuning Vaccine Delivery in Preclinical Models to Advance MERS DNA Vaccine Candidate and Discovering New Targets for Cancer Therapy

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

A team of Wistar scientists led by Dr. David Weiner, Wistar executive vice president, director of the Vaccine & Immunotherapy Center and W.W. Smith Charitable Trust Professor in Cancer Research, and Dr. Ami Patel, Caspar Wistar Fellow, and collaborators have developed a synthetic DNA vaccine candidate for Middle East respiratory syndrome coronavirus (MERS-CoV).

A vaccine candidate based on their research was shown to be safe and tolerable in a recently completed human phase 1 study with a three-dose intramuscular injection regimen and is currently in phase 1/2a trial.

Our scientists continue to expand the preclinical studies of the vaccine in support of its clinical development. They have now tested intradermal delivery using a shortened two-dose immunization schedule in non-human primates (NHP).

“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 Weiner.

In a paper published in the journal JCI Insight, he and colleagues reported that low-dose intradermal administration induces potent immunity and protects from virus challenge. The low-dose regimen with intradermal delivery was more impactful in controlling disease and symptoms than the higher dose given intramuscularly.

“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,” said Patel.

Their experience developing this MERS vaccine candidate helped the team advance a COVID-19 vaccine through clinical trials in a short time.

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 for coronaviruses and other emerging infectious diseases.

The lab of Dr. Rugang Zhang, deputy director of The Wistar Institute Cancer Center, Christopher M. Davis Professor and leader of the Immunology, Microenvironment & Metastasis Program, studies the process of cellular senescence and the changes in gene expression that accompany it.

Cellular senescence is a stable state of growth arrest in which cells stop dividing but remain viable and produce an array of inflammatory molecules collectively defined as senescence-associated secretory phenotype (SASP). These molecules account for the complex crosstalk between senescent cells and neighboring cells and the effect of cellular senescence in various physiological processes like aging and diseases like cancer.

Although senescence is regarded as a powerful barrier for tumor development, the SASP plays a role during tumor development promoting the growth of established tumors.

In a new study published in Nature Cell Biology, Zhang and colleagues pointed out a new mechanism that allows cells to turn on a set of genes encoding for the SASP molecules.

“This mechanism may potentially be targeted to stop the tumor-promoting aspect of senescence while preserving its antitumor function,” said Zhang.

The team focused on two proteins called METTL3 and METTL14 that are known for other molecular functions and found that these proteins moonlight as regulators of gene expression that help turn on SASP genes.

“Although we focused on senescence, we envision that this function of METTL3 and METTL14 may be involved in many other biological processes beyond our current study,” said Zhang. 

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.