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Spotlight on Wistar COVID-19 Researcher: Daniel Kulp, Ph.D., Associate Professor 

April 17, 2020

Principal investigator Dr. Daniel Kulp is one of a group of Wistar scientists undertaking coronavirus research in response to the pandemic. A protein engineering expert, his lab focuses on rational vaccine and therapeutic antibody design for a variety of priority infectious diseases. Here he explains his interesting approach and its advantages.

The immune system is highly complex and encompasses a vast amount of cell types and compartments within the human body, therefore it can be stimulated into action in many ways. Though there is no silver bullet when it comes to vaccines, researchers have explored multiple approaches to achieve protective immunity.

Most traditional vaccines are empirically designed, meaning that a whole attenuated or killed virus is used to prompt the immune response. Thanks to a deeper knowledge of the pathogen and its mechanisms, more recent, rational approaches can be utilized to engineer specific virus-derived molecules that elicit stronger, predictable and more focused immune responses and are safer and not infectious.

In my lab, we take a bottom-up engineering approach and build precise structures into our vaccines, using computer simulations to design vaccines that help steer the immune system toward protective responses against specific pathogens. This rational approach enables us to generate improved vaccines by hypothesizing and iterating new concepts.

We specialize in designing nanovaccines, which consist of extremely small (‘nano’) particles that are similar in size and shape to bacteria and viruses and are used to display multiple copies of an antigen. Such multi-valent displays within a single vaccine can significantly enhance induced immunity.

It sounds like science fiction, but it’s not a completely new concept — in fact, the first licensed nanoparticle vaccine was against hepatitis B in 1981. The early nanoparticle vaccines were limited to nanoparticles that could be found in viruses. However, we have entered into a new era where technologies built in my lab and others have enabled us to engineer synthetic nanoparticle vaccines for a variety of infectious targets. Our unique vaccine design approach in collaboration with researchers at The Scripps Research Institute has led to the development of an HIV vaccine that has entered phase 1 clinical trials.

One of the advantages of this approach is that it is amenable to rapid delivery technologies that increases the speed at which a vaccine candidate can be advanced. So, when the new coronavirus emerged, we got to work to apply this technology and our expertise to fight SARS-CoV-2 (the virus responsible for COVID-19 disease).

A critical step in developing nanovaccines is the selection and design of the antigen to display on the nanoparticles. We choose regions of the virus called epitopes, which are crucial for the virus to function, in order to stimulate a response that can block the virus from infecting our cells.

For coronaviruses to enter host cells, fusion of the virus with the cell membrane must take place. This process is regulated by a specific part of the viral Spike protein, which adorns the surface of coronaviruses. We have engineered a nanoparticle vaccine that targets this epitope and creates robust antibody responses in mice. The lab is now ready to begin testing the vaccine in large animals before translating into the clinic.

SARS-CoV-2 possesses a receptor (like many viruses) that is another vulnerable target for protective antibodies. We have demonstrated that certain regions of the receptor for influenza and HIV could be engineered onto various self-assembling nanoparticle scaffolds. We are starting to translate these concepts to SARS-CoV-2. In addition to nanoparticle vaccines, we are beginning to engineer “decoy receptors” to trick the virus and prevent infection. The big picture is that these soluble decoys can be given to patients after they get infected to boost immune defenses and help them recover with only mild symptoms. The decoy therapies will be of critical importance to give people around the world the confidence to return from quarantine.

These approaches have big potential but can require significant monetary resources to put a vaccine or therapy through preclinical testing and the clinic, so the more support we have the faster we will be able to advance our work and potentially protect billions of vulnerable individuals worldwide.