FIGHTING THE FLU
SARA LAUX | APRIL 19, 2018
Up to 100 million people died in the 1918 Spanish flu pandemic. 100 years later, the search for a universal flu vaccine starts in an egg at McMaster.
Picture a beachball studded with lollipops.
Or an orange covered with broccoli stalks.
Or a globe with mushrooms growing out of it.
Describing the flu virus is relatively easy. Treating it, on the other hand, has historically been a little more challenging.
2018 marks the 100th anniversary of the so-called Spanish Flu, a global pandemic with three distinct waves that broke across the world from Tahiti to the Arctic and almost everywhere in between.
Over the waning months of the First World War in 1918 and the beginning of 1919, fully one-third of the world’s total population — about 500 million people — is estimated to have become sick. The death count is reckoned to be somewhere between 50 million and 100 million people, almost half of them between the ages of 20 and 40.
For comparison, the First World War killed approximately 40 million soldiers and civilians over the span of four years of bloody, brutal fighting.
And while the 1918 influenza pandemic is far from the deadliest disease outbreak in history in terms of the proportion of cases to fatalities — the recent Ebola epidemic and the Black Death were far deadlier to those who fell ill — the sheer number of dead globally prompted one historian in 1971 to call it “the greatest medical holocaust in history.”
One hundred years later, the world is a different place. And while we’ve developed some important weapons in the fight against both influenza A, which has caused all the global flu pandemics to date, and influenza B, the war is still on — and there’s no clear winner yet.
Fighting the flu is like doing battle with an enemy that never attacks the same way twice. While some strains might only be armed with sticks and rocks, a pandemic strain like the 1918 flu is a full-out nuclear blast.
That’s because the virus is constantly mutating — experiencing minor alterations from year to year called “drifts,” then, every so often, changing into something almost wholly unrecognizable in a full-out “shift.”
Seasonal flu — the kind we deal with every year, the kind that we vaccinate against with varying degrees of success — is caused by viruses that have drifted. Our immune systems generally recognize seasonal strains — not enough to stop us from getting sick, but enough that, unless we’re very young, very old or otherwise immunologically compromised, we aren’t likely to experience severe illness or death.
In an average flu year in Canada, about 12,000 people are hospitalized, and 3,500 die, with most of those deaths caused by secondary bacterial infections like pneumonia. Worldwide, seasonal flu causes between 250,000 and 500,000 deaths out of an estimated one billion cases.
Influenza pandemics, on the other hand — like the one in 1918, as well as later outbreaks in 1957, 1968 and 2009 — are usually caused by new strains of influenza A that arise when multiple strains mix their genetic materials. Often, these have existed previously in animals like birds and pigs. The danger in pandemic strains lies in the fact that an unrecognizable strain of flu can cause a far more severe illness as the immune system scrambles to defend itself against a weapon it’s never seen, overwhelming the body with an inflammatory response (called a “cytokine storm”) that can lead to respiratory distress even without a secondary infection.
Of course, a high death rate doesn’t work in the virus’ favour, so pandemic strains will generally mutate into a less virulent form, becoming the seasonal form of the illness after a year or two.
By definition, pandemics are unpredictable — and while antibiotics and antiviral medications provide treatment options for those who become ill, they’re not ideal. Antibiotics only work on bacterial infections, so they’ll treat secondary bacterial pneumonia, but won’t do anything to the flu itself.
And while antivirals like Tamiflu have been shown to reduce illness by a day or two in normally healthy people, no one knows for sure whether they’re particularly effective against severe illness.
There’s also the matter of antibiotic and antiviral resistance — eventually, bacteria and viruses become resistant to the drugs designed to knock them out. One class of drug currently approved by Health Canada — used in conjunction with other antivirals to treat severe flu — turned out to be almost wholly ineffective against certain strains over the space of a single flu season.
At a more fundamental level, there’s still much that remains unknown about flu. Why it’s seasonal, for example. Or its distribution and circulation patterns in countries around the world, especially in Africa. We’re also not good at predicting what strains will be circulating in any given season, making the creation of seasonal vaccines a hit-or-miss proposition.
All this uncertainty means that every year, the flu continues to make large numbers of people sick. In some cases, it kills them. Every few years, it kills more people than usual and makes many more sick.
There’s got to be a better way.
“Despite how far medicine has come in the 100 years since 1918, our ability to deal with a flu pandemic has progressed insignificantly.”
Matthew Miller, an assistant professor in the Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences and a member of the McMaster Immunology Research Centre, is very aware that what we don’t know about flu could kill us.
“In regard to our pandemic preparedness, despite how far medicine has come in the 100 years since 1918, our ability to deal with a flu pandemic has progressed insignificantly,” he explains. “We can’t predict pandemics, and therefore the seasonal flu vaccines are by definition mismatched with whatever a new pandemic strain would be.”
Miller’s solution to the problems created by flu’s perpetual shifts and drifts?
Stop focusing on trying to predict and prevent illness from changing seasonal strains with yearly vaccines, and start looking at developing a universal flu vaccine: one that wouldn’t have to change, that could be administered far less often. One that could target both seasonal illness and guard against pandemics.
One that could stop people from dying, from getting severely ill — or even sick at all.
Easier said than done.
The flu virus is mostly round, like a beach ball. On its surface, though, are two proteins: hemagglutinin (“H”) and neuraminidase (“N”). These proteins give influenza A viruses their letter-number combo names: H1N1, strains of which caused both the 1918 pandemic and the most recent pandemic in 2009. H2N2, which caused the so-called “Asian flu” pandemic of 1957. H3N2, which was responsible for the “Hong Kong” flu of 1968.
There are 18 subtypes of hemagglutinin, only three of which have infected humans on a global scale — and it’s this protein that researchers see as the key to developing a consistent, universal vaccine.
Hemagglutinin is shaped like a lollipop, poking up from the surface of the virus, candy part first. It’s this candy part that keeps changing its flavour each year, so to speak — mutations pile up on hemagglutinin’s head, changing it from season to season. And, of course, more than one virus can be circulating in a single flu season — meaning there may be several different flavours floating around.
In developing seasonal vaccines, researchers try to predict what flavour hemagglutinin’s lollipop head will be and grow those strains in a lab, often using eggs as a growth medium. An inactive form of the virus is injected as a vaccine, causing the body to develop antibodies that then help the body fight off an infection with the same strain.
But predicting what strains will be circulating in any given season is hard, making the seasonal vaccines vary in effectiveness. This year, for example, the seasonal vaccine demonstrated “poor effectiveness” against a particularly severe strain of H3N2 that has been circulating in both the southern and northern hemispheres.
There’s no question that vaccines help stop the spread of flu. Dr. Mark Loeb ’96, a professor of pathology and molecular medicine in McMaster’s Faculty of Health Sciences, has done extensive work looking at the role of seasonal vaccines in providing protection to isolated Hutterite communities in Alberta and Saskatchewan — and demonstrated that simply vaccinating the children in the colony was sufficient to provide partial protection to the rest of the population.
“We found that just by vaccinating the children, the indirect protection was about 60 per cent [for the rest of the population] — which was the same level as the children who had gotten the shot in the arm,” he explains. “Those who didn’t get a flu shot were protected to the same level as the children who got vaccinated, because of this ‘herd’ effect.”
While Miller echoes the importance of getting the seasonal vaccine each year, his long-term goal is more proactive approach — and he’s getting closer and closer to realizing that ambition.
Mindful of flu’s changeable nature, researchers are working to develop a universal vaccine that will produce antibodies that recognize the hemagglutinin’s stick, rather than the head — which, as is the case with lollipops, doesn’t change. This means that no matter how often a flu virus mutates, those antibodies will still provide protection.
Miller is now working on a vaccine with researchers at the Icahn School of Medicine at Mount Sinai in New York that will introduce a number of novel inactive virus strains with similar sticks, essentially “training” the immune system to focus on fighting the stalk, rather than chasing after the ever-changing heads. Their vaccine is currently in stage 1/2 clinical trials — which means it’s being tested in healthy adults, although it’s still too early to tell whether it works well in protecting humans against infection.
Miller’s is one of dozens of labs across the world currently working on a universal flu vaccine — but he says the competition is a good thing.
“None of these vaccines may be perfect the first time around,” he told CBC Radio’s White Coat, Black Art recently.
“Exploring a lot of promising options simultaneously generates the greatest hope that one of these, or a combination of them, will be ready for distribution at the earliest possible time.”
MARRYING MEDICINE WITH MATH
Understanding the 1918 flu pandemic isn’t just an interesting historical exercise — it can be instrumental in understanding future pandemics as well.
Just ask David Earn, a professor of mathematics at McMaster who specializes in creating mathematical models that explain how infectious diseases spread in human populations.
At the most basic level, Earn creates a visualization of data — weekly confirmed cases of influenza in Alberta during the 2009 H1N1 pandemic, for example — and compares the observed pattern of cases with patterns predicted by various models.
In Alberta, the observed data showed that flu cases trailed off in June and peaked again in September. Why? Well, models that include reduced transmission when schools are closed for the summer also show this same pattern. Further modelling showed that weather also affected flu cases in Alberta, but to a much smaller degree than school closures.
Mathematical models can help researchers predict how many people might get sick during an epidemic or pandemic, or what methods work best for preventing the spread of disease.
According to Earn, building models that explain data from the 1918 pandemic is key to confirming that those models are useful for understanding other flu epidemics.
“If mechanistic models that we build appear to explain the patterns of cases and deaths during the 1918 flu pandemic, that gives us more confidence in using those models in the future as tools to forecast what’s likely to happen when the next pandemic hits.”
HUNTING THE HISTORY OF FLU IN HAMILTON
While some researchers are concerned with the future of flu, Ann Herring is more interested in its past — specifically, what flu and other infectious diseases reveal about a society at a particular period.
That’s quite a lot, as it turns out.
“Epidemics reveal all the fractures in society, all the tensions, the haves and have nots,” says the professor emerita, now retired from McMaster’s Department of Anthropology. “They tell you how political organizations behave. Any kind of crisis opens up things that are percolating beneath the surface.”
As an anthropologist, Herring says her role is to understand the impact of an epidemic on everyday life, and how local circumstances may have created different experiences of the same global phenomenon.
For several years, students in Herring’s fourth-year honours seminar class learned these lessons first-hand. Rather than writing traditional final papers, classes created eight anthologies of original articles exploring the experience of epidemics in Hamilton. Two of them, Anatomy of a Pandemic (2006) and Recurrence and Resilience (2010) dealt with the impact of the 1918 pandemic on Hamilton.
Using original sources and working closely with city archivists and historians, the students researched and wrote scholarly articles that painted a vivid picture of a city caught in the waves of the flu epidemic.
“I wanted to create a situation where, instead of being consumers of knowledge, students were the producers,” Herring explains. “I told them that Hamilton had supported their university career, and now it was time to return something to the people of Hamilton.”
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