New study could lead to more effective, potent COVID-19 vaccines

A new study on 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, maintaining the smoldering global pandemic.

Researchers at Boston University’s National Emerging Infectious Diseases Laboratories (NEIDL) and the Broad Institute at MIT and Harvard say this is the first real insight into the types of “red flags” the human body uses to get help from T cells – killers sent by the immune system to destroy infected cells. So far, COVID vaccines have focused on activating a different type of immune cell, B cells, which are responsible for creating antibodies. Developing vaccines to activate the other arm of the immune system – T cells – could dramatically increase immunity against the coronavirus and, most importantly, its variants.

In their conclusions, published in Cell, researchers say current vaccines may lack some important pieces of viral material capable of triggering a holistic immune response in the human body. Based on the new information, “companies should re-evaluate their vaccine designs,” says Mohsan Saeed, NEIDL virologist and co-author of the article.

Saeed, assistant professor of biochemistry at the BU School of Medicine, performed experiments on human cells infected with the coronavirus. He isolated and identified these missing pieces of SARS-CoV-2 protein in one of NEIDL’s biosafety level 3 laboratories (BSL-3). “It was a big undertaking because many research techniques are difficult to adapt for high containment levels [such as BSL-3]”Saeed said.” The global coronavirus research pipeline that we have created at NEIDL and the support of our entire NEIDL team has helped us along the way. “

Saeed got involved after being contacted 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 T cells of the immune system.

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

“We took action right away because my laboratory had [already] generated human cell lines that could easily be infected with SARS-CoV-2, ”says Saeed. The group’s efforts were led by two members of the Saeed lab: Da-Yuan Chen, 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 are now the spike protein in certain coronavirus vaccines, such as Moderna Vaccines, Pfizer-BioNTech and Johnson & Johnson. Scientists later discovered 23 other proteins hidden in the genetic sequence of the virus; however, the function of these additional proteins has been a mystery until now. The new findings from Saeed and colleagues reveal – unexpectedly and critically – that 25% of the viral protein fragments that trigger 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 – which, when cells are invaded, cut off pieces of viral proteins produced during infection. These pieces, containing internal proteins exposed by the chopping process – like how the core of an apple is exposed when the fruit is segmented – are then transported to the cell membrane and pushed through special doors. There they stay outside the cell, acting almost like a hitchhiker, stirring the help of passing T cells. Once the T cells notice these viral signals entering the infected cells, they launch an attack and attempt to eliminate these cells from the body. And this T-cell response is not insignificant – Saeed says there are links between the strength of this response and whether or not people infected with the coronavirus develop serious illness.

“It is quite remarkable that such a strong immune signature of the virus comes from the regions [of the virus’ genetic sequence] we were blind to, ”says Weingarten-Gabby, lead author of the article and postdoctoral researcher at the Sabeti laboratory. . “

“Our discovery (…) may aid in the development of new vaccines that will more precisely mimic the response of our immune system to the virus,” Sabeti said.

T cells not only destroy infected cells, but also memorize the flags of the virus so that they can launch an attack, stronger and faster, the next time the same or a different variant of the virus appears. This is a crucial benefit, as Saeed and colleagues say the coronavirus appears to delay the cell’s ability to call for immune assistance.

“This virus wants to go unnoticed 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, according to Saeed, a new vaccine recipe, incorporating some of the newly discovered internal proteins that make up the SARS-CoV-2 virus, would be effective in stimulating an immune response capable of attacking a wide range of Newly emerging coronavirus variants. . And given the speed at which these variants continue to appear around the world, a vaccine that can provide protection against all of them would be a game-changer.

About Hector Hedgepeth

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