Recipe Revealed for Even More Powerful COVID-19 Vaccines – Better Protection Against Coronavirus Variants

NEIDL, Broad Institute scientists say next-generation vaccines could boost a different arm of the immune system, better protecting them against variants of the coronavirus.

A new study looking at how human cells activate the immune system in response to SARS-CoV-2 infection could open the door to even more effective and potent vaccines against the coronavirus and its rapidly emerging variants, helping the global pandemic continues to smolder.

Researchers from Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL) and the Broad Institute of MIT and Harvard say it’s the first real look at what kinds of “red flags” the human body uses to get help from T cells – killers sent out by the immune system to destroy infected cells. Until now, COVID vaccines have focused on activating another type of immune cell, B cells, which are responsible for making antibodies. Developing vaccines to activate the other arm of the immune system – the T cells – could dramatically increase immunity against the coronavirus, and more importantly, its variants.

In their findings, published in Cell, the researchers say current vaccines may be missing some key bits of viral material that can trigger a holistic immune response in the human body. Based on the new information, “companies should re-evaluate their vaccine designs,” said Mohsan Saeed, a NEIDL virologist and the paper’s co-corresponding author.

When Broad Institute researchers sought help investigating the molecular effects of coronavirus infection, Mohsan Saeed (center) and members of his NEIDL lab, Da-Yuan Chen (left) and Hasahn Conway (right), were ready to spring into action. She had already created human cell lines that could easily be infected with SARS-CoV-2. Credit: Photo courtesy of Saeed lab

Saeed, an assistant professor of biochemistry at the BU School of Medicine, conducted experiments on human cells infected with the coronavirus. He isolated and identified those missing pieces of SARS-CoV-2 proteins in one of NEIDL’s Biosafety Level 3 (BSL-3) labs. “This was a major undertaking because many research techniques are difficult to adapt for high containment levels [such as BSL-3]Said says. “The overall coronavirus research pipeline we have created at the NEIDL, and the support from our entire NEIDL team, has helped us on our way.”

Saeed became involved after being approached by genetic sequencing experts at the Broad Institute, computational geneticists Pardis Sabeti and Shira Weingarten-Gabbay. They hoped to identify fragments of SARS-CoV-2 that activate the immune system’s T cells.

Mohsan Saeed, BU NEIDL virologist, says the new findings could be a game changer for coronavirus vaccine design. Credit: Photo Courtesy of Mohsan Saeed

“The emergence of viral variants, an active area of ​​research in my lab, is a major concern for vaccine development,” said Sabeti, a leader in the Broad Institute’s Infectious Disease and Microbiome Program. She is also a professor of systems biology, organic and evolutionary biology, immunology and infectious diseases at Harvard University, and an investigator at the Howard Hughes Medical Institute.

“We immediately jumped into action because my lab… [already] generated human cell lines that can be easily infected with SARS-CoV-2,” says Saeed. The group’s efforts were led by two members of the Saeed lab: Da-Yuan Chen, a postdoctoral associate, and Hasahn Conway, a lab technician.

From the onset of the COVID pandemic in early 2020, scientists around the world knew the identity of 29 proteins produced by the SARS-CoV-2 virus in infected cells — viral fragments that now make up the spike protein in some coronavirus vaccines, such as the Moderna, Pfizer-BioNTech, and Johnson & Johnson Vaccines. Later, scientists discovered another 23 proteins hidden in the virus’ genetic sequence; however, the function of these additional proteins has been a mystery until now. The new findings from Saeed and his collaborators reveal — unexpectedly and critically — that 25 percent of the viral protein fragments that prompt the human immune system to attack a virus come from these hidden viral proteins.

How exactly does the immune system detect these fragments? Human cells contain molecular “scissors” — called proteases — that, when invaded, chop off bits of viral proteins produced during infection. Those pieces, which contain internal proteins exposed by the chopping process — such as the way the core of an apple is exposed when the fruit is segmented — are then transported to the cell membrane and pushed through special doorways. There they stay outside the cell, acting almost like a hitchhiker, swinging down the aid of passing T cells. Once T cells notice that these viral flags are poking through infected cells, they launch an attack and attempt to clear those cells from the body. And this T-cell response is not unimportant – Saeed says there are links between the strength of this response and whether or not people develop serious illness in people infected with the coronavirus.

“It’s quite remarkable that such a strong immune signature of the virus comes from regions [of the virus’ genetic sequence] which we were blind to,” said Weingarten-Gabby, lead author of the paper and postdoctoral researcher in the Sabeti lab. “This is a striking reminder that curiosity-driven research is at the root of discoveries that could transform the development of vaccines and therapies.”

“Our discovery… could help develop new vaccines that will more closely mimic our immune system’s response to the virus,” says Sabeti.

T cells not only destroy infected cells but also remember the virus flag so that the next time the same or a different variant of the virus appears, they can launch an attack stronger and faster. That’s a critical benefit, as Saeed and his collaborators say the coronavirus appears to slow the cell’s ability to call in immune help.

“This virus wants to go undetected by the immune system for as long as possible,” says Saeed. “Once it’s noticed by the immune system, it’s going to be eliminated, and it doesn’t want to.”

Based on their findings, Saeed says, a new vaccine recipe, which incorporates some of the newly discovered internal proteins of the SARS-CoV-2 virus, could be effective at stimulating an immune response capable of producing a large number of new address emerging coronavirus variants. . And given the rate at which these variants continue to appear around the world, a vaccine that can protect against all of these variants would be a game-changer.

Reference: “Profiling SARS-CoV-2 HLA-I peptidome reveals T-cell epitopes of ORFs outside the frame” by Shira Weingarten-Gabbay, Susan Klaeger, Siranush Sarkizova, Leah R. Pearlman, Da-Yuan Chen, Kathleen ME Gallagher, Matthew R. Bauer, Hannah B. Taylor, W. Augustine Dunn, Christina Tarr, John Sidney, Suzanna Rachimi, Hasahn L. Conway,
Katelin Katsis, Yuntong Wang, Del Leistritz-Edwards, Melissa R. Durkin, Christopher H. Tomkins-Tinch, Yaara Finkel, Aharon Nachshon, Matteo Gentili, Keith D. Rivera, Isabel P. Carulli, Vipheaviny A. Chea, Abishek Chandrashekar, Cansu Cimen Bozkus, Mary Carrington, MGH COVID-19 Collection & Processing Team, Nina Bhardwaj, Dan H. Barouch, Alessandro Sette, Marcela V. Maus, Charles M. Rice, Karl R. Clauser, Derin B. Keskin, Daniel C. Pregibon, Nir Hacohen, Steven A. Carr, Jennifer G. Abelin, Mohsan Saeed, Pardis C. Sabeti, accepted May 27, 2021, cell.
DOI: 10.116/j.cell.2021.05.046

This research was supported by the National Institute of Health, the National Institute of Allergy and Infectious Diseases, the National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium, a Human Frontier Science Program Fellowship, a Gruss-Lipper Postdoctoral Fellowship, a Zuckerman STEM Leadership Program Fellowship, a Rothschild Postdoctoral Fellowship, the Cancer Research Institute/Hearst Foundation, a National Science Foundation Graduate Research Fellowship, EMBO Long-Term Fellowships, a Cancer Research Institute/Bristol-Myers Squibb Fellowship, the Parker Institute for Cancer Immunotherapy, the Emerson Collective, the G. Harold and Leila Y. Mathers Charitable Foundation, the Bawd Foundation, Boston University startup funds, the Mark and Lisa Schwartz Foundation, the Massachusetts Consortium for Pathogen Readiness, the Ragon Institute of MGH, MIT and Harvard, and the Frederick National Laboratory for Cancer Research.