“Immunology is one of the fastest-growing disciplines with strong medical relevance to infection, cancer, and beyond. In particular, vaccinology has gained the spotlight due to the recent safe and effective COVID-19 vaccine development,” says Dr. Siyuan Ding. “I personally think understanding how vaccines work in the context of the human immune system is the most exciting field in immunology today and will pave the path for designing efficient countermeasures against microbial pathogens.”
Proposing to Design Vaccines for Diarrheal Diseases
For his proposal to design vaccines for diarrheal diseases that kill hundreds of thousands of children per year worldwide, Michelson Medical Research Foundation and the Human Immunome Project have selected Ding as a recipient of the 2023 Michelson Prizes: Next Generation Grants.
Ding, an assistant professor of molecular microbiology at Washington University in St. Louis, studies enteric viruses – those that infect the intestinal system – and how the immune system responds to them. He is currently focusing on rotavirus, which is often found in wastewater and causes severe, often fatal, diarrhea in children.
Rotavirus death rates have decreased dramatically since the 1980s thanks to two vaccines now used worldwide. But the disease still kills 200,000 children per year in regions where the virus is ever-present in the environment.
Ding says that children living in these areas are usually exposed to other diarrheal diseases, including a bacteria species called enterotoxigenic Escherichia coli (ETEC) that kills an additional 50,000 per year.
The Next Generation Grants, a $150,000 grant awarded annually to investigators 35 or younger who focus on human immunology, vaccine discovery, and immunotherapy, will allow Ding to genetically engineer new dual vaccine candidates that simultaneously target rotavirus and ETEC.
“I was drawn to biomedical science after my mother was diagnosed with nasopharyngeal carcinoma when I was a child. Seeing her going through all of that chemotherapy was pretty tough,” he says. “But I was intrigued to learn that some cancers, including nasopharyngeal carcinoma, can be caused by viruses.” As a Ph.D. student at Yale University, he studied hepatitis B and its role in liver cancer before switching to studying rotavirus as a postdoc at Stanford University.
Dr. Siyuan Ding and His Prize-Winning Rotavirus Vaccine Research
Pivoting His Virus Research Post COVID Pandemic
However, when Ding finally started his own rotavirus lab at the end of 2019, the pandemic forced him to retool immediately. “If we didn’t do Covid work, the lab would be nonexistent,” he says. “So my new lab members and I started studying how SARS-CoV-2 causes diarrhea and other gastrointestinal symptoms in about half of COVID-19 patients.” Ding’s lab was the first to find that the virus can infect and replicate in intestinal cells, causing some of the most common long-Covid symptoms.
Once the pandemic slowed down, the researchers switched back to rotavirus. Their current project involves genetically engineering the virus, turning it into a Trojan horse to carry an ETEC vaccine into the gut. “Developing an injectable vaccine against ETEC’s toxic, diarrhea-inducing protein has been challenging because antibodies in the bloodstream are limited in their capacity to make it into the gut,” says Ding. “Oral ETEC vaccines don’t work well either – enzymes in the stomach destroy the protein long before the immune system has had time to recognize it and respond.”
But rotavirus vaccines, which are fed to babies orally, deliver a live virus directly into the GI tract. The rotavirus capsid has evolved to survive acidic environments, but the vaccine still triggers an immune response within the gut.
Working with an older, discontinued rotavirus vaccine, Ding has engineered the virus to produce a version of ETEC’s toxic protein in addition to its own genome. This protects the toxin until the vaccine reaches the gut, where the immune system can start making antibodies against both.
Ding is currently assessing whether feeding this vaccine to newborn mice produces gut antibodies against the two pathogens.
He is also testing it in miniature models of the human intestine grown from human stem cells. “Eventually, we hope that this dual vaccine can be trialed in areas where both diarrheal diseases are common,” Ding says. “The Michelson grant will allow me to work in the difficult field of translational research. Having that award makes it so that I can really be committed to doing that type of work.”
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