A universal flu vaccine that protects against all strains of the virus is often hailed as the holy grail of influenza research, but it’s still out of reach. Now antibodies isolated from a flu patient have provided new clues for what scientists believe could be the development of a broadly protective antiviral drug, as well as a universal flu vaccine.
Antibodies collected from the individual, who was hospitalized with flu, saved mice from all 12 strains of flu viruses tested, according to new research published in Science by the Icahn School of Medicine at Mount Sinai, the Washington University School of Medicine and Scripps Research.
The researchers discovered that the antibodies worked by interfering with neuraminidase, the same protein targeted by Roche’s popular flu drug Tamiflu (oseltamivir). Neuraminidase is one of two proteins that help newly formed viruses exit host cells and move to infect new cells. The other is hemagglutinin, which is the primary target of seasonal flu vaccines.
After examining three seemingly non-hemagglutinin-targeting antibodies from the patient, study co-senior author Florian Krammer, Ph.D., a professor at Mount Sinai, found that one blocked all known neuraminidase types in flu viruses, including those in both influenza A and B viruses.
“The breadth of the antibodies really came as a surprise to us,” Krammer said in a statement. “Typically, anti-neuraminidase antibodies can be broad within a subtype, like H1N1, but an antibody with potent activity across subtypes was unheard of.”
The researchers then tested the antibodies in mice that were challenged with a lethal dose of influenza virus. All three showed efficacy against multiple strains. One antibody, dubbed 1G01, protected the mice from all 12 strains, which included three groups of human flu virus, as well as avian and swine subtypes.
By studying the antibodies’ structures, the scientists found that they each had a loop that was inserted in the conserved active site of neuraminidase, effectively preventing the protein from releasing new virus from the surface of cells. That could explain why the antibodies provide such broad protection across different strains, they argued.
Because there are so many flu strains, scientists have to develop vaccines for the upcoming season according to the most prevalent strains, and sometimes a mismatch renders the products ineffective. Ideally, a universal vaccine would cover all strains, but developing one has not been not easy. GlaxoSmithKline recently abandoned such a vaccine candidate, GSK3816302A, which combines Mount Sinai’s chimeric hemagglutinin technology and GSK’s AS03 adjuvant, after lackluster interim phase 1 data.
As influenza viruses mutate, some develop resistance to existing neuraminidase inhibitors such as Tamiflu. So better drugs that can offer broader protection are urgently needed, as well.
Researchers at the Emory University's Institute of Drug Development recently discovered a compound dubbed EIDD-2801. The drug blocks RNA polymerase, an enzyme that’s essential in the ability of the influenza virus to replicate its genome. The idea is that when the virus can’t copy its genome properly, it can become nonfunctional, blocking replication.
In ferrets—the most commonly used animal model for influenza research—EIDD-2801 inhibited replication of various strains of influenza, including seasonal and pandemic viruses and the H1N1 swine flu virus responsible for the 2009 pandemic. The study was published in Science Translational Medicine by scientists from Emory and the Institute for Biomedical Sciences at Georgia State University.
With help from the University of Washington, the team demonstrated that the compound had a very high barrier to resistance. “We have not identified specific resistance mutations yet and are confident to say that the genetic barrier against viral resistance is high,” said the study’s senior author, Richard Plemper, Ph.D., a professor at Georgia State, in a statement.
EIDD-2801 is now in preclinical testing, and human testing is expected to begin next year.
As for the antibody 1G01, the Mount Sinai-led team that discovered it suggested it might be useful for treating flu patients who end up intensive care after it's too late to use Tamiflu. That's because all the mice survived, even if they were given the antibody 72 hours after infection.
Over the long term, the researchers believe the discovery of 1G01 will provide a picture of what a broadly protective antibody to neuraminidase looks like. That could guide the development of a universal flu vaccine that induces similar antibodies, they said.