Neil Osterweil

June 21, 2016

BOSTON — The enticing but elusive goal of a universal vaccine against multiple strains of influenza might be within grasp, a vaccine researcher says.

"What we are trying to do is direct the human immune system toward conserved domains of the influenza virus, and thereby induce an immune response against these conserved portions of the virus," said Peter Palese, PhD, professor and chair of the Department of Microbiology at the Icahn School of Medicine at Mount Sinai in New York City.

"The big question will be whether we can induce high enough titers of this cross-protective immune response, and whether it is really long lasting," he told Medscape Medical News.

Dr Palese outlined the ambitious research during the Maurice Hilleman Award Lecture here at the American Society for Microbiology Microbe 2016.

The work is challenging, but the rewards are potentially enormous. The Centers for Disease Control and Prevention estimated that for the 2013/14 flu season, influenza vaccination prevented approximately 7.2 million illnesses (including 3.1 million medically attended illnesses) and 90,000 hospitalizations (MMWR Morb Mortal Wkly Rep. 2014;63:1151-1154).

The problem that has bedeviled public health authorities is that the influenza A virus is notoriously slippery. It is capable of infecting a large number of hosts (pigs, birds, humans, etc.) and is marked by rapid antigenic drift, which is why vaccine developers must play the odds and take their best guesses when designing vaccines for the coming flu season.

Sometimes the designers get it right, sometimes they don't. If the predominant viral strains in a given season turn out to be highly virulent, such as the killer Spanish flu strain responsible for the 1918 worldwide pandemic, the consequences can be devastating.

Dr Palese and his colleagues have explored why influenza viruses behave the way they do and why they have features not seen in other common pathogenic viruses, such as measles, mumps, and rubella.

Influenza Viruses Adapt and Evade

They previously found evidence to suggest that influenza viruses have developed a strategy that allows them to adapt rapidly and frequently to evade host defenses (Proc Natl Acad Sci U S A. 2013;110:20248-20253).

When the RNA-dependent RNA polymerases of these different viruses — mumps, measles, rubella, flu — copy genetic information, they make the same error. So why does the flu change so much but the measles does not?

"One of the thoughts we had was that the measles virus doesn't allow a spectrum of things on the surface to be changed, whereas flu can do that," Dr Palese explained.

 
We all have been infected with influenza A subtype H1 viruses, so we all have antibodies.
 

Measles virus glycoproteins and polymerases are resistant to gene insertions, so are less quick to adapt to changing circumstances in their environment. In contrast, influenza A viruses readily allow insertions in the globular "head" of the hemagglutinin proteins, but not the "stalk," indicating that genes encoding for the stalk, but not the head, are highly conserved during evolution, he explained.

Therefore, the researchers are not going after the moving target of receptors in the hemagglutinin head with their novel vaccine development strategy. Instead, they are developing chimeric antibodies that attack the stalk, which will lead, ideally, to a universal vaccine against the influenza virus.

"We all have been infected with influenza A subtype H1 viruses, so we all have antibodies," said Dr Palese. Although most of our antibodies are against the head, we have some against the stalk, he added.

Their proposal is to develop vaccines that induce an enhanced immune response to the hemagglutinin stalk by creating chimeric hemagglutinin constructs, he explained.

To date, the team has demonstrated the feasibility of this approach in mice and in ferrets. They've shown that vaccination protects against viral challenge with an H1N1 strain after hemagglutinin constructs induce protective levels of stalk-reactive antibodies. Furthermore, they have demonstrated that the protection is mediated by antibodies, and could be passively transferred from a vaccinated animal to an unvaccinated one through the serum.

They are moving toward a universal flu vaccine "by reducing the immunodominance of the hemagglutinin head and, thereby, increasing the immunogenicity of the hemagglutinin stalk and of the neuraminidase," Dr Palese pointed out.

This is a "very interesting approach," said Franz Heinz, PhD, professor of virology at the Medical University of Vienna, who is not involved in the research.

"In the immunogen of the influenza virus to which you want to raise a protective immune response, there are two parts," Dr Heinz told Medscape Medical News. "The part that is immunodominant during natural infections and after vaccination is highly variable. This is the problem of influenza vaccination in general, so there is no long-lasting immunity that is induced."

The approach Dr Palese and his colleagues are using is to raise host defense against the second part, the stalk, with chimeric hemagglutinins.

"They want to redirect the immune system toward the stalk, which then has the potential to give broadly reactive protection," Dr Heinz explained.

American Society for Microbiology (ASM) Microbe 2016. Presented June 19, 2016.

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