Groundwork for COVID-19 Vaccine Laid at Dartmouth

Discoveries originating in a basic science lab at Geisel School of Medicine’s Department of Biochemistry and Cell Biology are being used in the newly approved COVID-19 vaccine from the Pfizer/BioNTech partnership.

Beginning in 2016, structural biologist Jason McLellan, PhD, and his colleagues at Geisel and two other prominent labs, conducted groundbreaking research on the coronavirus spike protein, the major surface protein that this type of virus uses to bind to human cells and invade them.

McLellan and his team designed a special form of the spike protein that makes it more likely to be effective as a vaccine antigen, a part of the virus that can be used to stimulate antibody production in advance, and thus help the body fight off infection.

Jason McLellan, PhD

“It is exciting to see the huge impact of this novel research by Jason and his colleagues,” says Duane Compton, PhD, dean of the Geisel School of Medicine. “It is a good reminder of the importance of basic science research and its ability to save lives around the world.”

Four years ago, McLellan and his team made their first major breakthrough at Dartmouth working with a human coronavirus known as HKU1, one of the causes of the common cold and closely related to more potent and deadly coronaviruses such as SARS (Severe Acute Respiratory Syndrome)-CoV and MERS (Middle East Respiratory Syndrome)-CoV.

“Our goal was to determine the first three-dimensional structure of a coronavirus spike protein,” recalls McLellan, now an associate professor of molecular biosciences at the University of Texas at Austin. “We wanted this information so we could do more structure-based vaccine design. This involved using these structures to do protein engineering and identify substitutions or mutations we could make in the proteins that would cause the spikes to be more stable.”

Stability is important, he says, because it makes the antigen a better target for antibodies, molecules the body makes to fight infection. Vaccines work by training the immune system to make antibodies that can recognize and bind to the antigen, blocking its entry into host cells.

Prefusion-stabilized spike protein from SARS-CoV-2

Mapping the structure of the HKU1 spike protein enabled the researchers to then design their antigen, while they were working on creating a coronavirus vaccine antigen for MERS. The stabilized antigen proved effective, not only for MERS but also many of the most dangerous and deadly coronaviruses, including now SARS-CoV-2 (the virus that causes COVID-19).

“It’s hard to attribute the high efficacy rates seen so far in the vaccine just to the stabilizing mutations we added—the companies have also developed some excellent platforms—but we think the stabilizing mutations have helped,” says McLellan. “And I think the success of the prior research has allowed Pfizer/BioNTech to have the confidence to rapidly choose their antigen and move quickly into manufacturing large quantities for clinical trials.”

“It is very gratifying to see fundamental discoveries from the McLellan research team translated into a leading COVID-19 vaccine,” says Charles Barlowe, PhD, chair of biochemistry and cell biology at Geisel. “Jason’s contributions to vaccine development are also a wonderful testament to his insightful and collaborative approach to science.”

Vice Provost for Research Dean Madden, PhD, notes that Dartmouth excels at research that answers fundamental scientific questions while simultaneously laying the groundwork for important real-world applications. “Dartmouth ranked #20 in the world and top of the Ivy League in the 2017 Nature Innovation Index, which measures the per-capita contributions of published research to technological innovations worldwide. Jason’s research is a brilliant example of the value of this approach.”

Founded in 1797, the Geisel School of Medicine at Dartmouth strives to improve the lives of the communities it serves through excellence in learning, discovery, and healing. The Geisel School of Medicine is renowned for its leadership in medical education, healthcare policy and delivery science, biomedical research, global health, and in creating innovations that improve lives worldwide. As one of America’s leading medical schools, Dartmouth’s Geisel School of Medicine is committed to training new generations of diverse leaders who will help solve our most vexing challenges in healthcare.