Flu Déjà Vu

By Paul Nicolaus

March 14, 2018 | One morning, Arthur Davis began his work of digging three graves for a family of six that lived just down the road in Tennessee. That same morning a doctor sent word to handle one more, and by lunchtime he was instructed to dig yet another. Before the sun set that day, Davis was asked to create a sixth and final hole in the earth on behalf of that single household.

The reason behind all this digging was the 1918 influenza pandemic, an illness that swept across the globe and infected a third of the world’s entire population. In some communities, public gathering places like schools and churches were shut down. Libraries stopped lending books. People stopped shaking hands.

The virus battled back with a vengeance, though, turning skin blue, filling lungs with fluid, and suffocating its victims. Undertakers were flooded with a demand they couldn’t keep up with as death counts soared and bodies piled up. To limit the spread of infection, the departed were placed underground as quickly as possible. No time to build coffins, no chance to deliver eulogies.

As Arthur Davis recalled the experience of living through the pandemic and burying those who didn’t, he re-told the story of laying that entire family to rest in a single day many times over. And when he spoke of these funerals, the former lumberjack referred to them as “plantings,” as if the lives cut short by the horrific pandemic might someday grow back and bear fruit.

Learning from Tragedy

About a decade ago, microbiologist Peter Palese at Mount Sinai’s Icahn School of Medicine in New York became involved in the reconstruction of the 1918 flu virus to better understand why it was such a lethal bug—one that claimed more lives in a single year than the AIDS virus has over the course of half a century.

“At the time, there were no antibiotics,” he pointed out. Although antibiotics aren’t effective against viruses, oftentimes those with the flu also become “super-infected” with bacteria. And in the case of 1918, this was the likely cause of death behind many of the fatal cases. A lack of immunity was also a major factor in 1918 when no one had prior exposure to that particular flu strain. By now we’ve experienced descendants of that H1 virus, he said, so we all have some partial immunity.

That immunity, combined with today’s antibiotics, vaccines, and antiviral drugs means the 1918 epidemic would, in today’s environment, be a completely different story. Even though we’d be much better protected in our world of modern medicine, however, Palese cautioned that we can’t rule out the possibility that another completely different pandemic strain of the influenza virus will emerge.

According to Brad Spellberg, professor of clinical medicine at the University of Southern California, not only is another pandemic possible but it’s a sure bet considering a monster flu virus tends to rear its head every several decades. The issue that leads to a massive outbreak is a major antigenic shift, when different viruses infect the same cell, recombine, and create a “Frankenstein-like virus” much different from those that have recently circulated.

In the meantime, even when we’re not faced with one of these monstrous versions, influenza remains a challenging opponent at least in part because it is constantly evolving. There are various types of influenza viruses, and human illness is largely caused by type A and B. Influenza A viruses are divided into subtypes based on two proteins on the surface of the virus: the hemagglutinin (H) and the neuraminidase (N). So far, 18 different hemagglutinin subtypes and 11 neuraminidase subtypes have been identified.

These proteins on the surface of the virus are highly variable and change, or “drift,” in minor ways from year to year. Although seasonal vaccines are updated to match up with circulating strains every year, they are only partially effective because they target the ever-changing surfaces of the virus. The result is illness and in some cases even hospitalization or death.

While older individuals, young children, and people with other medical illnesses are the ones who are predominantly affected, the flu has the ability to kill anyone—even in our era of modern medicine. “There is nothing more terrifying than having a young, healthy person who was completely normal three days ago in your ICU on a ventilator,” Spellberg said, when “you can’t get oxygen into their system because their lungs are destroyed.”

Who’s Winning the Fight?

So who has the advantage in this ongoing battle between the human race and the flu virus a full century following the 1918 massacre? “Sometimes we have the upper hand when we make a good vaccine, and people utilize that vaccine, and we wash our hands appropriately,” said Rachael Lee with the University of Alabama at Birmingham’s Division of Infectious Diseases, and sometimes the virus does because it can quickly change and create new strains.

If 2018 is any indication, the flu seems to be winning out at the moment. While not over yet, we are in the midst of a season that is, by some measures, on par with the 2009 “swine flu” pandemic. This year’s bug has involved the H3N2 virus, a strain that tends to lead to higher numbers of doctors’ visits, hospitalizations, and deaths. To complicate matters, this season’s vaccination has been less than stellar in terms of combating this particular strain.

Each year’s shot protects against influenza A (H1N1), A (H3N2), and one or two influenza B viruses, but preliminary effectiveness for the H3N2 influenza was just 25%, according to a Feb. 26, 2018, statement from U.S. Food and Drug Administration (FDA) Commissioner Scott Gottlieb. In other words, those who received the vaccine were only 25% less likely to become sick from this strain.

The vaccines did match up better with other viruses. The overall effectiveness for H1N1 and influenza B was 67% and 42%, respectively, for all age groups combined, but there’s a clear need to better understand the reduced effectiveness of this year’s vaccines against the strain that has caused much of the illness and related fallout. The lessons learned could be used to improve the process of developing influenza vaccine in eggs, Gottlieb noted, and may also help determine whether a greater investment in alternative methods is needed, such as cell-based or recombinant DNA approaches to vaccine development.

Despite its flaws and limitations, experts tend to point out the value of the seasonal vaccine, which not only helps prevent influenza but can also lessen the severity of illness for those who come down with the bug after getting their shot. Until we come up with better methods of developing vaccinations, though, the battle between the flu virus and the human race seems destined to continue on, tit for tat.

Toward a Universal Vaccine

Today, Palese has shifted gears from studying the 1918 flu virus to pursuing the promise of a so-called “universal” flu vaccine that could, in theory, protect against most or all strains of flu, fend off public health nightmares like the kind seen a century ago, and eliminate the need for an annual vaccine.

In collaboration with teams led by Adolfo Garcia-Sastre and Florian Krammer at Mount Sinai, his group has developed an approach that zeros in on the conserved regions of the virus. Picture the influenza virus as a football, he told Bio-IT World, with many little mushrooms sitting on the surface of that ball. The heads of those mushrooms change, it turns out, whereas the stems do not. The researchers are essentially silencing those variable heads and redirecting the immune system toward the unchanging stems, which could wind up being an Achilles’ heel of sorts.

“We have been very successful in animals,” he said. “We can protect mice and ferrets and other animals against all kinds of influenza virus strains.” What remains to be seen is whether that same sort of success can be found in humans. The universal vaccine developed by Palese and colleagues is now undergoing two different Phase 1 clinical trials with support from GlaxoSmithKline and the Bill & Melinda Gates Foundation.

They are far from the only ones caught up in the pursuit of a better solution, though. The Gates Foundation is also working with CureVac, a Tübingen, Germany-based biotech company, for example, to develop an mRNA-based universal flu vaccine. The company recently announced new funding that builds upon an earlier $52 million investment made by the Gates Foundation.

Another team from the Scripps Research Institute and Janssen Research & Development (a subsidiary of Johnson & Johnson) has come up with artificial peptide molecules that neutralize a broad range of influenza virus strains. Meanwhile, a private spinoff of Oxford University’s Jenner Institute in the UK announced that it has secured $27 million from investors that will enable a clinical trial of the company’s universal flu vaccine, which uses proteins found in the core of the virus and stimulates T-cells rather than antibodies.

Yet another tactic is in the works at FluGen, a biotech spinoff that uses technology initially developed in the labs of Yoshihiro Kawaoka and Gabriele Neumann at the University of Wisconsin-Madison. The premise of the company’s RedeeFlu vaccine is that it takes a naturally occurring flu virus and modifies it by deleting a gene that is needed to reproduce more than once.

Despite progress made in recent years, there have been calls for improvements. In January, NIAID leadership made a plea for a universal vaccine in the New England Journal of Medicine, noting that a broad range of expertise and substantial resources are needed to fill existing knowledge gaps and come up with this highly sought-after solution.

A public-private partnership called the Human Vaccines Project (HVP) hopes to bring this type of wide-ranging expertise to the table through its newly created Universal Influenza Vaccine Initiative (UIVI), led by Dr. James Crowe and Dr. Clarence B. Creech with the Vanderbilt University Medical Center in Nashville, Tenn. While many are focused on actually formulating a universal vaccine, the UIVI is tackling the human immune response.

“Flu is somewhat unusual in that people are infected early in life,” Crowe explained, and then they’re repetitively infected throughout their lives. One individual might experience dozens of infections over the course of a lifetime, and past illnesses greatly influence response to vaccines or their next infection. That dynamic isn’t fully understood just yet, so UIVI is launching a series of clinical trials in diverse populations to study responses to vaccination and infection.

“We’re studying millions of single cells from individuals,” he said, and in some cases this leads to billions of genetic sequences from a single person. To deal with the enormous amounts of data generated by these lab tests, supercomputing methods are put to use. The intent is to help identify patterns of immune response that are associated with either protection or failure.

When he considers the many efforts underway to develop a flu vaccine that is more broadly protective, Crowe realizes that many want to see it happen in a three to five-year period. “That would be the goal of what everybody is pushing for,” he said. But if the history of vaccine development over the last century is taken into account, the outlook isn’t quite so rosy. After all, he noted, most new vaccine concepts take decades to develop to the point of licensure.

Even so, this big picture perspective is far from hopeless.

Historical Perspective

In 1911, not all that long before one of the most devastating outbreaks recorded in human history wreaked havoc across the globe, an undergraduate researcher named Alfred Sturtevant realized the need to map the locations of fruit fly genes whose mutations the Thomas Hunt Morgan laboratory was tracking.

To put the significance of this act into perspective within the history of genetics research, the National Institutes of Health (NIH) says Sturtevant’s gene map can be thought of as the Wright brothers’ first flight at Kitty Hawk while the Human Genome Project (HGP), whose goal was the complete mapping of all the genes of human beings, can be likened to the Apollo program lifting humanity from Earth to moon.

Progress continues as many scientists and researchers make use of techniques that grew out of the HGP to embark upon an inward voyage of discovery. The mission is no bargain, considering the genes involved are even more complex due to their combinatory powers. “There are more potential antibody genes in your body than there are stars in the galaxy,” said Crowe.

Because of this, most thought it would be impossible to ever comprehend this bodily constellation of cells, tissues, and organs that protects the human body from foreign invaders. In the last two to three years everything has sped up. The sequencing is faster, the computers are faster, and immune sequences are being catalogued by the billions. These developments are prying open a window that we’ve never had access to in the past.

And the view, according to Crowe, is both incredibly exciting and breathtakingly beautiful. “What it tells us is even though flu and a lot of other viruses can move and they’re variable and they’re sort of shape shifting,” he said, “the human immune system is even greater in its complexity and capability than these germs.”

Paul Nicolaus is a freelance writer specializing in science, technology, and health. Learn more at www.nicolauswriting.com.