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

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.

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