On the influenza virus, scientists identified a new site where a broad range of influenza vaccines can target, and antibody therapies should be able to prevent a broad set of strains.
A team of scientists from the University of Chicago, Scripps, and Weill Cornell Medicine have identified an essential site on influenza viruses that future vaccines and antibodies can target to prevent infections by a broad range of influenza strains.
The results of the study were published on Dec. 23 in Nature (Guthmiller et al., 2022) The results revealed that a small subset of antibodies elicited by present and experimental influenza vaccines could target a site–hemagglutinin (HA) protein, an active site whose significance was not explored in the previous influenza antibody studies.
Results from cell culture and animal studies suggested that antibodies against this newly identified “epitope” can neutralize a wide range of influenza strains, including the strains that can cause a pandemic.
Dr. Patrick Wilson, also the senior co-author of the study, said the newly identified site would be one of the key sites we can target to develop universal influenza vaccines and antibody therapies.
Most of the experiments leading to the discovery were conducted at the University of Chicago under the leadership of Dr. Patrick Wilson, a professor of pediatrics and a scientist at Weill Cornell Medicine.
“It’s fascinating to discover a novel site of vulnerability on a virus as it shows the way for vaccine design,” said Dr. Andrew Ward, co-senior author of the study. “There are still many things to discover despite all the effort of influenza vaccine research over many years.”
Influenza virus components are studded by HA protein, the principal viral protein that antibodies can reach to neutralize the virus. However, this protein mutates over time, making one strain different from another. As a result, the neutralizing antibodies become ineffective.
Therefore, the vaccine that is designed to guard against one or two strains becomes very restricted in its effectiveness.
Over the last two decades, scientists have been exploring opportunities to find a relatively unvarying site on the HA protein where antibodies can bind and neutralize the infectivity of a broad set of strains.
In the study, the research team examined several antibodies generated in response to experimental universal influenza vaccines and seasonal influenza vaccines, and natural influenza infections.
The scientists observed that a significant proportion of the antibodies was attached to the lower portion of HA—which in influenza viruses is commonly less variable than the upper head portion.
Electron microscopy analysis revealed that some antibodies bound to a previously overlooked site at the very bottom of the HA protein structure.
Tests in mice and cell cultures showed that these anchor epitope antibodies could neutralize a wide range of influenza strains containing the common H1 subtype and cross-react with H2 and H5 strains covering a large proportion of seasonal, including pandemic-threat influenza viruses in humans.
The scientists also found that some of the humans’ antibody-making cells can produce anchor epitope antibodies—which underlines the probability of the anchor epitope as a vaccine target.
“To increase our protection against these highly mutating viruses, we need to have as many tools as possible,” said Dr. Han, the study’s co-author. “This discovery adds one more highly potent target to our repertoire.”
“The human immune system already can make antibodies to this epitope, so it’s just a matter of applying modern protein engineering methods to make a vaccine that can induce those antibodies in sufficient numbers,” Dr. Guthmiller said.
