Close interactions with infectious diseases set University of California, Santa Cruz graduate student Ana Nuñez Castrejon and Rebecca DuBois, associate professor of biomolecular engineering, on the path to studying respiratory syncytial virus (RSV), a common and sometimes dangerous respiratory disease for which there is currently no vaccine. The two researchers recently marked an important milestone in their efforts to create an effective vaccine against the virus with the publication of their article “Structure-based design and antigenic validation of respiratory syncytial virus G immunogens” in the Journal of Virology.
For fifth-year Baskin Engineering student and lead author of the paper, Nuñez Castrejon, a bout of pneumonia that persisted for months as an undergrad sparked her interest in the study respiratory diseases. For DuBois, seeing her child go through a serious RSV infection, which can cause serious respiratory infections in infants/children and the elderly, led her to study the disease.
“We have all these wonderful childhood vaccines that eliminated so many childhood diseases, but there are still a lot of infectious diseases that are really hard on children, and RSV is one of those that causes hospitalizations in children. “, said DuBois.
Today, the team is focused on bioengineering the structure of the RSV G protein, which attaches the virus to host cells. The researchers modified the structure of the protein to eliminate its negative effects and while eliciting a protective response from the immune system in the form of antibodies that bind to the G protein.
The researcher’s 2021 paper showed that their modified G-protein was able to stimulate a stronger antibody response than native G-protein. However, it was unclear whether the modified G protein still “looked like” the native protein on the surface of the virus. The most recent study confirms that this modified G protein looks the same and is recognized by human anti-RSV antibodies.
“My paper shows that artificially mutating the protein does not disrupt the ability of antibodies to bind to it, so when used as a vaccine antigen it is possible to obtain these protective antibodies in animal models and hopefully -the, in future people will be protected from the disease,” said Nuñez Castrejon.
This article is similar to a 2017 publication crucial in the creation of the COVID-19 vaccine which described how to bioengineer the coronavirus Spike antigen to induce more and better antibodies, a strategy which was used to create to design the Moderna, Pfizer, J&J, and Spike antigens from the Novavax vaccine. Both papers use structural biology to ensure that a modified version of a virus can be recognized by the immune system to fight off the actual virus.
“It’s the same type of fundamental work that allowed scientists to design the coronavirus vaccine so quickly and allow it to look exactly like the surface of the virus, and even better,” DuBois said. “I think what people are starting to realize is that we can make vaccines that stimulate better immune responses than you get from an infection, if we can design the antigens in a way that really exposes the weaknesses of the virus.”
The research in DuBois’ lab differs from other efforts to develop an RSV vaccine in their approach to studying the proteins of the virus. Many researchers are focusing on modifying the structure of the RSV F protein, which fuses the virus and host cell membranes to get the genetic information of the virus into the cells.
But late-stage clinical trials of vaccines using this approach only show 60-70% protection against infection, which is promising but less than would be expected for a major pathogen like RSV.
In the short term, the researchers seek to further analyze the University of Georgia collaborators’ findings on how their modified protein affected disease symptoms in mice, and will continue to engineer the RSV G protein to produce stronger immune responses. Over the next five years, they hope to develop an RSV vaccine using their modified protein that is ready for clinical trials.
DuBois and Castrejon Nuñez are also collaborating with biotech company Trellis Bioscience, which is studying the use of monoclonal antibodies to treat infants with RSV infection and severe lung congestion.
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Material provided by University of California – Santa Cruz. Original written by Emily Cerf. Note: Content may be edited for style and length.