Karen Weintraub Contributor GEN

New Candidate Fights Back against the Flu’s Efforts to Undermine the Human Immune System

Researchers have inched closer to a universal flu vaccine, using a genetically modified live virus to safely protect a small number of mice and ferrets against influenza.

The flu can make people sick despite repeated vaccinations—in part because the strain(s) selected for the vaccine may not be matched well to the strain that is circulating that year—but also because the virus has a mechanism for evading the body’s immune system.

A new universal flu vaccine candidate, developed by scientists from the University of California Los Angeles and elsewhere, gets around this viral mechanism.

Called hyper–interferon-sensitive or HIS, the vaccine uses a live virus containing genes that have been mutated in eight locations. The mutations make the virus less dangerous and reduce its ability to evade interferons, the front line of our body’s built-in immune response, said Yushen Du, M.D., Ph.D., who led the research as a Ph.D. student in the Department of Molecular and Medical Pharmacology at UCLA. The findings were published on January 18, 2018 in Science.

Think of interferon as the body’s “radar alert system” for incoming viruses, suggested Marcel Curlin, M.D., an associate professor of medicine at Oregon Health & Science University, in Portland. As it infects us, the flu virus knocks out this radar system, allowing metaphoric enemy planes to advance. The new vaccine is designed to eliminate the pathogen’s radar detection capacity, leaving intact the vaccine recipient’s ability to find and fight off incoming planes.

Dr. Curlin praised the HIS approach as “a really clever way to weaken a virus.” Theoretically, the same strategy should also work against other infections, such as hepatitis C, malaria, and herpes, which haven’t been good targets for vaccination to date, he said.

The HIS vaccine is a live influenza virus, which means it could theoretically cause the disease it is aimed at preventing. The eight mutations were designed to weaken or attenuate the virus. A virus, because it evolves so rapidly, might be able to restore a few mutations, but it is unlikely to be able to recover from that many hits, Dr. Curlin said.

There are always more risks with live viruses than dead ones, though, noted Dr. Curlin. The virus might not be weakened enough—so it could still be dangerous to some recipients. Or, it could be weakened so much that it’s ineffective. For the flu, he said, which can be deadly but isn’t as dangerous as, say, HIV, the research team’s methodology makes sense.

Dr. Du said she and her colleagues have shown their candidate vaccine to be safe and effective in two animal species, but will need to at least test it in many more ferrets and other animals before moving into people. She said she expects it will take about three more years of preclinical work before the vaccine could be ready to try in people.

What remains unclear, Dr. Curlin said, is whether any one approach will be enough to make a vaccine truly universal against all strains of the flu, or other dangerous pathogens.

Dr. Curlin said his “educated guess” is that the HIS strategy will need to be combined with an antibody approach.

HIS focuses on the body’s own cells, which have been hijacked by the pathogen to reproduce itself.

Most successful vaccines work by stimulating the production of antibodies, or “proteins that circulate and coat the surface of foreign invaders and tag them for elimination,” as Dr. Curlin describes them. Once we have been exposed to a particular pathogen, the body produces antibodies designed to recognize it. The antibody approach hasn’t worked against complex pathogens like influenza, malaria and HIV, though, because they can mutate to evade antibodies.

The HIS work, Dr. Curlin said, “really does open the door to trying new things.”

John Shiver, Ph.D., head of Global Research and Development for Sanofi Pasteur, which has also been working on an anti-body approach to a universal flu vaccine, praised the new research.

“The work presented by Du et al. is quite elegant,” he wrote in an email. But of course, he added, the vaccine candidate needs to be further tested. The “…‘true’ performance of any such candidate can only be determined through clinical evaluation,” he emphasized. And there are likely to be industrial and regulatory challenges to this approach, he said, though he did not elaborate on those potential challenges in his statement.

Speaking from Zhejiang University, in Hangzhou, China, where she is on medical rotations in oncology, Dr. Du said every day in her clinic reminds her of the importance of her research. “A broad-protection vaccine is urgently needed,” she said. “I’m in clinic right now, and there are tons of flu-infected people here.”

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