Influenza outbreaks work like a circle dance: People boogie with a certain virus one year, trade…

Luv Purohit / Assistant Visual Editor

Don Carter, who led a recent influenza study at Pitt, manipulates a micropipette in a laboratory atop Biomedical Research Tower 3.

Influenza outbreaks work like a circle dance: People boogie with a certain virus one year, trade it for another type and then another, and some time later the original dance partner makes a second debut.

Scientists used to think that initial exposure to a virus conferred a person with a unique protection for when it returned many years later. But thanks to researchers at Pitt, we now know that the diversity of flu dance partners in between could be equally protective and could even teach us to produce better vaccines.

Publishing their findings in July in the science and medicine journal PLOS ONE, Ted Ross, associate professor in the Department of Microbiology and Molecular Genetics at Pitt, and his research group ran a study that suggests that a lifetime of exposure to a variety of flu strains can provide immunity to a totally new strain.

And that immunity — the ability for the immune system to protect the body against infection — can be just as robust as in people with long-ago exposure to a nearly identical version of that new strain.

“When someone has seen several, they can be resistant to other, unrelated strains,” Ross said. “It takes years of infection to build up immunity.”

Past trends in viruses

These new ideas represent a response to a recent trend in virus research: The urge to make much of the relationship between the 2009 swine flu and the infamously deadly 1918 “Spanish” flu.

The trend began when scientists noticed in 2009 that elderly adults were disproportionately spared from severe infection with the swine flu, or H1N1.

The excitement accelerated when researchers in California and China found similarities between the structural building blocks of the 1918 and 2009 viruses, both H1N1, that go beyond the normal likenesses shared by seasonal H1N1 strains.

The idea then emerged that elderly people were more protected against the 2009 swine flu as a result of immunity developed early in life toward its 1918 predecessor.

But now the research group thinks that’s only part of the explanation.

The old narrative “doesn’t explain why [the 2009 flu] was so much more prevalent in the young than even middle-aged individuals,” Don Carter, lab technician and first author of the study, said in an email. “Our paper explores the idea that a diversity of infections give broader protection and helped protect against the pandemic strain because it was evolutionarily more primitive.”

The present study

In the study, the research group, led by Carter, analyzed almost 1,000 blood samples taken in 2009 from anonymous human donors participating in UPMC clinical laboratories. So that change over time could be assessed, the samples were taken from donors of a wide age range (1 month to 90 years). The blood was then spun down to isolate the intruder-targeting substance in blood: antibodies.

Antibodies work by physically attaching to foreign material invading the blood — that could mean viruses, bacteria or even debris — and then helping trigger the immune system to destroy that material.

Since the body responds to intruders by producing intruder-specific antibodies, the group could learn about the subjects’ immune system histories by exposing their antibodies to different historical viruses and seeing which antibodies attached to, or reacted with, which viruses. Applying this procedure with the 1918 and 2009 viruses and several seasonal viruses in between, the results were jolting.

Sure enough, the old narrative turned out to have some footing: Many of the antibodies that reacted with the 1918 virus also reacted with the novel 2009 virus. But that relationship was surprisingly far from perfect. According to the study, antibodies in the lion’s share of blood samples reacted either with one virus or the other, but not both.

Additionally, the samples most likely to show this “cross-reactivity” were not of the elderly, whose exposure to the 1918 virus should prime them for the 2009 strain, but of the middle-aged donors, who could have only interacted with distant relatives of the Spanish flu. On top of that, cross-reactivity was often just as great if not greater between the 2009 strain and several seasonal strains.

The findings poke holes in two contentions: that the 1918 and 2009 influenzas are functionally “identical” and that exposure to the first is required to build immune protection for the second.

The future of vaccines

But the findings do more than that.

The group’s research suggests the possibility that the immune system can prepare for the future without yet knowing it. As in the blood samples with high cross-reactivity taken from middle-aged subjects, the body looks like it can integrate decades of information about a diversity of viruses to build resistance to never-before-seen viruses.

Having found evidence for this insight in animal models, Ross assigns it wondrous potential for vaccine development.

“We could be pre-priming people for a strain that does not now exist,” he said.

What he’s talking about is a universal vaccine.

Responding to enthusiastic nodding from federal officials, this group and many other researchers across the country are hot on the trail of this holy grail of vaccines — the ability to inoculate against an unknown influenza future. Whatever the strain, the vaccine would prevent it.

“The 2009 outbreak set the U.S. government’s mind that we are not prepared for another pandemic,” Ross said. “There was a mandate from the U.S. government to try to deal with a breadth of viruses.”

Universal vaccines could transform how the government treats influenza prevention, according to Nancy Cox, director of the Influenza Division at the Center for Disease Control and Prevention.

“Public health recommendations for use of influenza vaccines would change to reflect the duration of immunity and the extent of cross protection for the ‘universal influenza vaccine’ that might be approved (licensed for use) in humans,” she said in an email.

The research group has built its “diversity-to-immunity” insight into its own vaccine prototype, dubbed “COBRA” (computationally optimized broadly reactive antigen). Using computer modeling, Ross, Carter and their colleagues are assembling the relevant pieces of viruses — i.e. the sites where antibodies have attached (antigens) — that have appeared throughout recorded history into stand-alone, synthetic vaccines.

With promising animal studies completed, the COBRA project has been picked up by Sanofi Pasteur, the largest vaccine manufacturer in the world.

The company’s optimism echoes Ross’s.

According to an emailed statement from Sanofi Pasteur spokeswoman Susan Watkins, the vaccine prototype “holds the potential to be adaptable to any delivery method. It is designed to protect against whatever strain of seasonal flu happens to be circulating, and it may be able to be produced in as little as four months … The synthetic flu shot may also be effective far longer than the traditional flu vaccine.”

As plans are hammered out for clinical trials, a vaccine could be ready in 10 to 15 years, Ross recently told the Pittsburgh Tribune-Review.

Such a vaccine could come just in time, given the unpredictable nature of influenza pandemics. After all, “It’s just a matter of time till the next one happens,” Ross said.