Tag: Weiner

PHILADELPHIA — (Feb. 4, 2022) — Nearly four decades after its discovery, HIV has killed 36.3 million people, with no vaccine in sight. However, a new study by researchers at The Wistar Institute, an international biomedical research leader in cancer, immunology, infectious disease, and vaccine development, takes a promising step in the direction of developing an HIV vaccine.

The findings, published in Nature Communications, demonstrate the promise of using a unique native-like trimer to develop Tier-2 neutralizing antibodies—the kind that matter for combatting HIV—in mice for the first time.

Previously, eliciting these types of antibodies using candidate vaccines required long and expensive experiments in large animal models creating a significant bottleneck on HIV-1 vaccine development. “With our new finding, we have opened the door to rapid, iterative vaccinology in a model that can produce Tier-2 neutralizing antibodies, enabling development of more advanced HIV vaccine concepts,” said Daniel Kulp, Ph.D., associate professor in the Vaccine & Immunotherapy Center at The Wistar Institute and corresponding author on the paper.

The researchers encoded the native-like trimer into DNA for delivery into the mice. This has the practical advantage of turning the host bodies into “antigen factories” instead of requiring what would otherwise be a complex vaccine manufacturing process. The researchers then compared the results from the mice who received the DNA-encoded native-like trimer to results from mice who received a standard protein immunization. Only those mice that received the DNA-encoded native-like trimer developed Tier-2 neutralizing antibodies.

“We were able to generate strong immune responses with both platforms, but the DNA platform uniquely drove this neutralizing response,” said Kulp.

Once they’d verified their immunization regime was producing Tier-2 antibodies, Kulp and his colleagues isolated monoclonal antibodies from the mice and used cryo-electron microscopy to determine the atomic structure of one Tier-2 neutralizing monoclonal antibody. They found that the antibody binds to an epitope (a segment of a protein that sticks out of the antigen, which prompts an immune response) called C3V5. In the gold standard HIV vaccine model (non-human primates), prior research has shown that antibodies binding to C3V5 protect animals from a SHIV infection, which is a close relative of HIV that infects non-human primates.

“The structure gives us incredible insight into how this antibody is able to neutralize the virus,” said Kulp. “For the first time, we can strategize about how to design new vaccines that can generate broadly neutralizing antibody responses to the C3V5 epitope.”

Coauthor David B. Weiner, Ph.D., executive vice president and director of the Vaccine & Immunotherapy Center and the W.W. Smith Charitable Trust Professor in Cancer Research at The Wistar Institute, emphasized the utility of their findings.

“What we’ve done is enable direct in vivo self-assembly of structurally designed immunogens, which are engineered and delivered using nucleic acid technology, inside the vaccinated animal. Our data demonstrating induction of autologous Tier 2 neutralization illustrate the value of this approach as a tool to create surgically tailored immunity against a difficult pathogen’s vulnerable sites, in this case for HIV.”

Co-authors: Ziyang Xu, Susanne Walker, Neethu Chokkalingam, Mansi Purwar, Edgar Tello-Ruiz, Yuanhan Wu, Sonali Majumdar, Kylie M. Konrath, Abhijeet Kulkarni, Nicholas J. Tursi, Faraz I. Zaidi, Emma L. Reuschel, Ishaan Patel, April Obeirne, David B. Weiner, and Daniel W. Kulp from The Wistar Institute; Megan C. Wise, Katherine Schultheis, Lauren Gites, Trevor Smith, Janess Mendoza, Kate E. Broderick, and Laurent Humeau from Inovio Pharmaceuticals; Alan Moore, Jianqiu Du, and Jesper Pallesen from Indiana University.

Work supported by: National Health Institutes (NIH) IPCAVD Grant U19 Al109646-04; W. W. Smith Charitable Trust; and Wistar Monica H.M. Shander Memorial Fellowship.

Publication information: Induction of Tier-2 Neutralizing Antibodies in Mice with a DNA-encoded HIV Envelope Native Like Trimer, Nature Communications, 2022. Online publication.

###

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.

PHILADELPHIA — (Feb. 1, 2022) — The first generation of COVID-19 vaccines have been highly effective, but also have limitations: their efficacy can wane without a booster shot, and they may be less effective against some variants. Now scientists at The Wistar Institute have developed a more targeted vaccine that, in animal studies, shows stronger, broader, and more durable protection in a single, low dose.

The vaccine combines three technologies – immune focusing, self-assembling nanoparticles, and DNA delivery – into a single platform for the first time. In addition to its other advantages, the vaccine could be stored at room temperature, making it potentially easier to transport to remote or developing locations than existing mRNA vaccines, which require specialized cold storage.

“This is among the first next-generation vaccines that will have more advanced features and broader protection,” said Daniel Kulp, Ph.D., associate professor in the Vaccine & Immunotherapy Center at The Wistar Institute and corresponding author of the study.

The paper, “Nucleic acid delivery of immune-focused SARS-CoV-2 nanoparticles drive rapid and potent immunogenicity capable of single-dose protection,” was published in the journal Cell Reports.

Existing vaccines include an unmodifided receptor binding domain of SARS-CoV-2 spike protein. The new vaccine includes a rationally engineered receptor binding domain using computational and structure-based design methodologies. The engineered receptor binding domain blocks ‘immune distracting’ sites and can therefore elicit stronger levels of protective, neutralizing antibodies.

Researchers then used naturally self-assembling proteins to form nanoparticles which display these highly engineered immunogens. By arranging themselves into structures that resemble an actual virus, the nanoparticles are more easily recognized by the immune system and transported to the germinal centers, where they activate B cells which produce protective antibodies.

Using nucleic acid vaccine delivery technology similar to mRNA, the nanoparticle vaccine is encoded in DNA and delivered into cells thereby giving genetic instructions for the body to build the immunogen internally. This is an advance over traditional vaccines that must be manufactured in specialized factories through complex vaccine production processes. In contrast to other vaccines, Dr. Kulp noted that one advantage of the DNA platform is that it doesn’t require refrigeration and it can also be quickly reformulated to target new variants.

In animal models, researchers found that the DNA delivered immune-focused nanoparticle vaccine produced much higher levels of neutralizing antibodies than the vaccine that wasn’t immune-focused.

“A difficulty with current vaccines is that neutralizing antibodies decline over time,” Kulp said. The nanoparticle vaccine produced durable responses after a single immunization out to six months in mice, unlike what we are seeing with current SARS-CoV-2 vaccines in people.

The ultimate test for SARS-CoV-2 vaccine candidates is protection from death in SARS-CoV-2 challenge experiments. The researchers found that in a lethal challenge model 100% of mice who received the immune-focused nanoparticle vaccine were protected from death with a single low dose. Most mice who received the standard, non-immune focused vaccine died within 10 days of challenge.

The vaccine assessment was conducted in both wild-type mice and mice that were genetically engineered to mimic human immune systems, he noted.

Even without being updated, the immune-focused vaccine showed a comparable level of antibody production to Delta, and other variants, Kulp said. That’s partly because of the immune focusing approach itself, he noted; in blocking parts of the receptive binding domain for the purpose of inhibiting non-neutralizing antibodies, it also blocks many of the areas affected by spike protein mutations. Studies on the Omicron variant are underway.

Researchers are seeking funding to begin human trials of the vaccine.

Co-author 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, said the vaccine could provide a needed step forward to improve protection against COVID-19.

“Current vaccine effects on reducing transmission of SARS-CoV-2 variants of concern including Delta and Omicron could be improved for their breadth of protection as well as their immune potency,” Weiner said. “This study demonstrates that using a nucleic acid approach combined with in vivo structural assembly of a glycan immune-focused nanoparticle drives single protection and neutralization against diverse variants of concern in a dose-sparing formulation. Additional studies of this vaccine approach for SARS-CoV-2 appear timely and important.”

Co-authors: Kylie M. Konrath, Kevin Liaw, Yuanhan Wu, Xizhou Zhu, Susanne N. Walker, Ziyang Xu, Neethu Chokkalingam, Nicholas J. Tursi, Mansi Purwar, Emma Reuschel, Drew Frase, Benjamin Fry, and Ami Patel from Wistar; Katherine Schultheis, Igor Maricic, Viviane M. Andrade, Kate E. Broderick, Laurent M.P.F. Humeau, and Trevor R.F. Smith from Inovio Pharmaceuticals; Himanshi Chawla and Max Crispin from the University of Southhampton; Jianqiu Du and Alan Moore from Indiana University; Jared Adolf-Bryfogle and Jesper Pallesen from the Institute for Protein Innovation; Matthew Sullivan from the University of Pennsylvania; and Christel Iffland from Ligand Pharmaceuticals.

Work supported by: Wistar Coronavirus Discovery Fund, CURE/PA Department of Health grant SAP# 4100083104, COVID/PA Department of Human Services grant SAP# 4100089371, NIH/NIAID CIVICs grant 75N93019C00051, Wistar SRA 16-4 / Inovio Pharmaceuticals, Indiana University.

Publication information: Nucleic acid delivery of immune-focused SARS-CoV-2 nanoparticles drive rapid and potent immunogenicity capable of single-dose protection, Cell Reports, 2022.

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.

###

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.