There’s no underestimating the destructive power of a flu pandemic. So far, there have been only five in human history, but the worst one, the 1918 Spanish flu pandemic was so deadly. Spreading across the world, even to the Arctic and remote Pacific Islands, it infected almost a third of all the people at that time and killed between 50 million and 100 million people — at least three percent of the world’s population then.
Which is why scientists since then have been hard at work investigating molecular virology, genomics pathogenesis, epidemiology, host immune responses and other aspects of influenza research.
Thankfully, widespread fears in the mid-2000s about the world being on the brink of a global bird flu pandemic that could kill millions because of the virulence of the H5N1 bird flu virus strain never quite panned out. But health authorities and governments in most rich nations have sunk billions of dollars into research aimed to develop influenza countermeasures — diagnostic tools, therapies and vaccines.
But vaccine development remains guesswork
Yes, you read it correctly. The flu shot you take every year is a largely a product of guesswork. Well, intelligent guesswork — but the fact is, until now, doctors have tackled the flu with methods that are least 50 years old.
There are thousands of influenza strains, so every flu season, the World Health Organization predicts a few influenza strains they think will dominate and cause the most problems — and current flu vaccines are produced according to this prediction.
“They get together in January or February and look at what’s going on in the Southern Hemisphere,” says Dr. Joseph Kim, CEO of Inovio Pharmaceuticals, Inc., a rising Blue Bell, Pennsylvania biotech and vaccine developer. “They’re looking a season ahead and trying to find three strains from thousands of varieties out there. “They do their best, and they actually have a pretty good success rate.”
Then inoculation is also focused on protecting people who are most vulnerable to the virus — pregnant women, under-fives, infants and toddler, elderly or those above 50 years old, people with chronic medical conditions, health workers and caregivers.
Overall, this approach doesn’t provide widespread protection or long-term immunity.
First off, vaccines deliver a dead or weakened version of the influenza virus — a decoy meant to tell a person’s immune system what to attack. But the flu virus is a master at camouflage, cloaking itself with an outer envelope that keeps on mutating. So vaccines have to be updated each year.
And controlling the flu with current methods is like “chasing a moving target,” notes Nimalan Arinaminpathy, a postdoctoral research associate in Princeton’s Department of Ecology and Evolutionary Biology.
The consequences of this “guesswork” are dire.
While the latest pandemic — of H1N1 swine flu — wasn’t quite as disastrous as expected, it still affected as many as 89 million people and killed 8,870 and 18,300 Americans, according to the United States Centers for Disease Control and Prevention. That’s despite the billions of dollars spent worldwide and for almost a decade to prepare for an H5N1 bird flu pandemic.
“We all saw what happened in 2009 with the H1N1 outbreak,” national vaccine expert Dr. Gary Nabel at the National Institutes of Health notes. “There’s a great example of where we were all preparing for one type of seasonal flu, and something came in and it was a complete wild card.”
“We were caught flat-footed,” Dr. Nabel says. “There were deaths that could’ve been prevented if we had a universal vaccine.” He is the Vaccine Research Center director at the NIH’s National Institute of Allergy and Infectious Diseases.
“So, at the moment, vaccine programs focus on clinical protection for those receiving the vaccine,” Princeton’s Arinaminpathy says. But he says flu researchers and scientists hope to switch focus from what he calls “reactionary efforts” to “population-wide prevention” that is able “to control the virus’s spread and even its evolution.”
Arinaminpathy is part of a Princeton University-led team that has created a computational model that shows that ‘universal’ vaccines — also known as ‘cross-protective’ vaccines can protect entire populations by improving the effectivity of current vaccines — even those designed to fight specific flu strains only.
He works in the lab of co-author Bryan Grenfell, Princeton professor of ecology and evolutionary biology. The two scientists led researchers from Duke University, the U.S. Food and Drug Administration, and the NIH to develop the model using an archetype of the universal vaccine.
Universal flu shot soon?
Indeed, cross-protective vaccines — so named for being effective against several flu strains –are being developed in various labs worldwide and some are already in clinical trials. Spurred by the outbreaks of potent flu strains in recent years, developments have been good enough for experts to project that these vaccines will be available in one to five years.
Arinaminpathy and his colleagues at Princeton say the new universal vaccines would make a bout with influenza less severe by shutting down the virus’s ability to spread and mutate.
Current flu vaccines are flawed because they target the pathogen’s most adaptable components, the researchers say. In contrast, universal vaccines would target the virus’ relatively unchanging parts virus and block the virus’ infamous ability to mutate — and thus escape from a population’s growing immunity.
Ideally, the universal flu vaccine would catch all previous versions of the ever-morphing flu virus, as well as future mutations — and take the guesswork out of current vaccine development.
The NIH has funded several institutions working on the development of such universal vaccines — it granted Inovio US$3.1 and has also funded the Jupiter, California-based company, The Scripps Research Institute.
Clinical trials at Inovio are going well — so well, in fact, that government health experts expect the universal flu shots to be available in five years, at the latest.
Even if those trials fail, NIH’s Dr. Nabel still says he is confident that scientists will succeed in developing universal vaccines before the decade is out.
“If you went back five years, you would’ve said then, ‘How would we ever get there from where we are?’ Now we’re all more optimistic, whether it be Inovio or someone else that succeeds,” Dr. Nabel tells the Palm Beach Post.
Experts say that the world is closer to getting a universal flu vaccine because scientists today have a better understanding of how viruses can be neutralized. Like it has in all fields, technological advances have also helped prod along the development of this vaccine.
For decades, it’s been known that flu viruses could mutate in thousands of ways. But what cracked the puzzle for scientists — pointing the way to building this one-shot-kills-all vaccine — was being able to identify what was similar about these different strains. From there, scientists worked to find antibodies that targeted those similar parts.
“We looked at flu viruses for the last 100 years,” Inovio’s Kim says. “Because of DNA sequencing, we have a very good database of what strains have been affecting humans.”
Yes, there are thousands of viruses, but they are classified into a few families: the H1N1 swine flu family, the H5N1 or bird flu and the more familiar H2N2 and H3N2.
Researchers at Inovio used computers to crunch each family’s DNA to find what they had in common, then used that data to develop what Kim calls its “secret sauce” — a formula that replicates the common elements in a vaccine, giving people vaccinated a broader target for their immune system.
Inovio researchers have successfully tested vaccines for each family of viruses on both animals and humans. The next phase, they say, would be to combine them for a universal version. “That’s really the holy grail for vaccine discovery,” Kim says.
NIH’s Dr. Nabel is optimistic, but cautions: “You learn over time that clinical trials are the big hurdle and because you start a trial doesn’t mean it will work,” he said. “But I think it’s not unreasonable to hope.”
Meanwhile, back to the Princeton-based researchers who developed a model that revealed that the emerging class of cross-protective or “universal” vaccines improve the effectiveness of current “limited” vaccines — and by doing so, allow for better flu protection by limiting the virus’s ability to spread and mutate.
This helps achieve unprecedented control of the flu virus — both seasonally and during pandemics, the researchers say, writing in the Proceedings of the National Academy of Sciences.
In fact, running figures through their model — different proportions at which a population could be affected — the researchers found that vaccinating only 70 percent of a population with cross-protective flu vaccines brought the percentage of the population infected to zero. Or, put simply, an outbreak is prevented 100 percent when 70 percent of people in a population received the vaccines. And even when a smaller part of the population were inoculated with the new class of vaccines, a strong “herd immunity,” or a general resistance to the virus was still created.
How do the ‘universal’ flu vaccines work?
Viruses can attach to and invade host cells because of a proteins protruding from their surfaces like appendages, called hemagglutinin (HA).
These appendages are highly adaptive, and even tiny mutations in HA result in new versions of the virus that become invulnerable to the vaccine designed to destroy their former selves. This is known as “immune escape.”
But universal vaccines bypass the HA surface to target more constant proteins in the virus that are prone to evolve less, Arinaminpathy says. Because the HAs will still be active, the virus may still infect people — but it can’t be as virulent.
Right now, various universal vaccines being developed simultaneously by different labs, and they all target different viral components. But they all have the potential to slow the transmission of many strains of viruses, Arinaminpathy says.
Incorporating that dominating feature in their model vaccine, the researchers then simulated how the basic universal flu vaccine would work in two types of flu outbreak — pandemic and epidemic.
Averting a pandemic
A flu pandemic is the sudden and rapid spread of a new, highly contagious strain — and typically, it’s difficult to predict. Usually, it’s also impossible to control through vaccination alone, Arinaminpathy points out.
But because universal vaccines target parts of the virus that are relatively constant across all virus strains, they’re effective even against pandemic flu.
What’s better, using their computational model, the researchers found that even if only a small proportion of the population received vaccination, that could avert a dreaded pandemic altogether. It does this by raising “herd immunity” that allows unvaccinated individuals to be protected when a sufficient number of people around them are immunized.
Controlling yearly epidemics
But how effective are the cross-protective vaccines against those strains that cause flu epidemics every winter?
To find the answer to this, Arinaminpathy and his colleagues run their model according to the two prevailing theories of flu evolution, including a theory by a team led by Dr. Katia Koelle, a biology professor at Duke — and also part of the current research. Koelle’s team reported this theory in the journal Science in 2006.
They found that in both cases, maintaining mass immunization with the universal vaccines over a period of several years slows the evolution of the virus, or its immune escape.
Arinaminpathy and his colleagues also accounted for any potential differences the universal vaccines might have in the level of flu immunity they provide. They did this by assuming their hypothetical vaccine wouldn’t prevent infection, but would only reduce the severity of symptoms — or coughing and sneezing. But even just doing this lowers the chances of the virus being transmitted.
Overall, this led to fewer people becoming infected — and consequently, fewer people gaining immunity to the dominant flu strain.
But instead of that being a disadvantage, that becomes a plus factor. First, it would remove the advantage that any new virus strains might have, Arinaminpathy says. At the same time, lower rates of infection also means that fewer people caught the original strain — and therefore fewer could harbor mutant viruses.
“We found that by putting the brakes on flu transmission, you could also put the brakes on flu evolution,” Arinaminpathy says. “Our model illustrates how we can control the flu this way, instead of simply reacting to it every few years.
Universal vaccines need not be fully protective to control flu, Arinaminpathy concludes.
“You can close schools and administer our current crop of vaccines and antiviral drugs as much as you want, but never realistically enough to stop transmission over any extended period of time,” he points out.
“With the cross-protective vaccines, we may be able to finally throw a blanket on the transmission of all flu strains over the long term in a way that can impact the virus’s evolution.”
Motivating flu vaccine developers
“Flu control has been dogged by this problem that the virus just keeps evolving. It stays one step ahead of the traditional means of controlling it. So, with strain-specific vaccines, you’re always chasing last year’s virus,” says James Lloyd-Smith, an assistant professor of ecology and evolutionary biology at the University of California-Los Angeles. Lloyd-Smith had no role in the study, but is familiar with it.
“By using the two vaccines in conjunction, we could get more mileage out of the strain-specific vaccines before they have to be changed,” he says. “That gives us an edge in the ongoing evolutionary arms race that we’re engaged in with influenza.
“Universal vaccines won’t get rid of the flu completely, but they should take our control efforts to the next level,” he says.
The research presents a realistic and important assessment of how the universal vaccines’ ability to work against a breadth of flu strains can be wielded to benefit public health, he enthuses.
It’s the “first study that looks at the population consequences of the next generation of vaccines, both in terms of epidemiological impact and evolutionary impact on the virus,” Lloyd-Smith says.
He notes: “They combined the latest information out of these vaccine trials, and the very latest and best models of influenza virus evolution and epidemiology. They put those together and asked important and relevant questions about how this new vaccine would actually play out.”
“They give very clear insights about what the impact of these vaccines would be,” he says. “In doing so, this work provides incentive for the vaccine manufacturers to continue this research and development, and it provides some guidance for public health authorities to think about using these new vaccines once they become available, he concludes.