Flu: An old, but unconquered enemy

From the Winter 2019 edition of Vanderbilt Medicine Magazine

Illustrations by Sam Kerr

One hundred years ago, multiple “waves” of a deadly flu swept across the world. Ultimately, the 1918 flu, which lingered into 1919, infected most of the world’s population and killed 50 million people. At the time, the cause of the flu outbreak was not understood, and there were no antibacterial medicines, ventilators or intensive care units to care for patients suffering from influenza’s leading complication, bacterial pneumonia.

We now know the molecular features of influenza viruses and can produce vaccines to protect against infection. But influenza is a wily foe. Its genetic makeup drifts over time, and the annual flu vaccine relies on prediction about the viruses that will be circulating and infecting humans. The virus can also make sudden shifts in its genetics, changing entire molecules that stud its surface — the hemagglutinin (HA or H) and neuraminidase (NA or N) molecules that we use to name flu viruses (the 1918 flu was an H1N1-type virus) — and other molecules as well.

Influenza viruses also infect other animals, and while bird or pig viruses don’t usually infect humans, genetic shifts can happen that allow a virus to jump species. Pigs, which are susceptible to infection by both bird and human influenza viruses, can become mixing vessels where flu genes intermingle to produce new viruses.

Vanderbilt University School of Medicine has a long history of excellence in vaccine-related research, from basic science studies to clinical translational research to evaluation of the impact of vaccines on the population. Vanderbilt Medicine talked to three infectious disease and vaccine experts about the 1918 flu and our preparation for future pandemics.

James Crowe Jr., MD, Ann Scott Carell Professor of Pediatrics and Pathology, Microbiology and Immunology, directs the Vanderbilt Vaccine Center and conducts research on viral immunology and antibody production.

Kathryn Edwards, MD, Sarah H. Sell and Cornelius Vanderbilt Professor of Pediatrics, is the scientific director of the Vanderbilt Vaccine Research program and evaluates the safety and effectiveness of vaccines.

William Schaffner, MD, professor of Health Policy and Medicine, has worked extensively on the effective use of vaccines and has helped establish national vaccine policies.

Their comments were edited for clarity.



How was the 1918 flu unique?

WS: There isn’t any doubt that it was the most severe influenza pandemic in recorded history. Over two seasons, it infected an extraordinary proportion of the entire global population and caused extraordinary amounts of illness and death. The descriptions of some of those illnesses are chillingly vivid because people became ill in the morning and by the afternoon were blue because they were cyanotic and air hungry, and they were dead by the evening.

KE: There were a number of interesting things that were happening at the same time. Certainly, there was the influence of the war and the transport of young men across the Atlantic. During the summer of 1918, we were shipping 10,000 young men a day to Europe. And there was close contact in crowded barracks in the military training camps in the United States. There was also a push to make sure that the whole country was behind the war effort, so people were moving from rural areas to cities and were living in crowded conditions in the big cities. We know that close contact breeds transmission of both viruses and bacteria.

There was also a public health denial about what was happening. Particularly with the second wave in the fall of 1918, public health officials said this is just flu as usual. There was no acknowledgement that there was a problem and no prohibition initially on mass gatherings.

WS: The 1918 flu had distinctive epidemiologic features. In conventional influenza outbreaks — the kind that we have every year — the most severely affected people are the very young and the very old. If we look at hospitalization rates or deaths by age, in your mind you see a U-shaped curve. The youngest and the oldest are at the high points on the ends of the curve, and older children, adolescents and young adults are the bottom of the U — their hospitalization rates and death rates are lower. However, in the 1918 epidemic, we have a W-shaped curve. So young adults, 20- to 40-year-olds, also were stricken with the most severe kind of influenza that resulted in hospitalizations and deaths. And that still is, as far as I know, inexplicable.


Was there something different about the virus that caused the 1918 flu pandemic?

JC: It was more deadly than other flu viruses that have caused pandemics, and at the molecular level, there’s no simple answer for why that is. There are a handful of changes in the virus that individually may not be sufficient to catapult it to such lethality, but as a constellation they do, and we don’t really understand why they interact in that way.

The evidence now is that the 1918 virus was a bird flu virus that went directly to humans. The government has funded a lot of bird research recently, where scientists are collecting wild bird feces, and there are a lot of scary flus out in bird feces right now, all over the world.


Scary how?

JC: We can look at the genetic sequences of the viruses and tell that they have the features of flus that we know kill people very effectively, like the 1918 virus.


So, a pandemic flu like the 1918 flu could happen again?

KE: No question. We are a global community, and a potential pandemic virus is an airplane ride away.

JC: It could happen any day. It’s like a ticking time bomb. In 1918 it happened in a population that was really susceptible to that type of flu, and it just sort of swept across the world. I don’t see any reason it wouldn’t happen again in exactly the same way.

WS: It’s interesting. If you talk to the average person on the street about flu, they say, ‘Flu comes every year, it’s kind of a pain in the neck, they’re trying to sell us this influenza vaccine that’s not so great, blah, blah, blah.’ Familiarity breeds, if not contempt, at least disdain.

But if you talk to infectious disease doctors or public health doctors, the single infection, bar none, that they fear the most is influenza, because they realize its capacity for creating pandemics, for creating a new virus for which basically the whole world’s population is susceptible. And as that virus works its way around the globe, it has the potential for creating degrees of illness and complications, hospitalizations and deaths that’s second to no other infectious disease. So, although flu is an old enemy, flu is not a conquered enemy by any stretch of the imagination.


What have we done to prepare for a future pandemic?

WS: The World Health Organization has set up a surveillance network around the world that works 365 days a year with sampling sites, getting specimens from individuals who have respiratory infections. The viruses are isolated and can now have their genetic sequences done very, very quickly. That information is all brought together in the World Health Organization’s computers and is sent to the influenza mavens around the world to watch the turbulence of all these recombinant influenza viruses and how they’re spreading. There are all the time swine and bird viruses that are coming up; they can cause small clusters of infection in humans, but they don’t appear to have the genetic capacity to spread readily from person to person, and they tend to die out.

We have antiviral treatments; we have antibacterial treatments for the complications of pneumonia; we have the capacity, still not optimal, to make influenza vaccines. Putting all that together along with our intensive care capacity, we can blunt the impact of new influenza pandemics in ways that you couldn’t even dream of back in 1918.

JC:  I think it’s an open question whether we would deal with it much better — if a virus of that virulence crossed over from birds into humans. We had a little bit of a dry run in 2009 with the pandemic H1N1 flu virus. That virus went all over the world; we didn’t stop it. We got lucky because it didn’t kill as many people as 1918 on a per infection basis.

Once you get a person-to-person spread of a highly lethal virus, that’s when the fire will burn. There won’t be enough medicines or vaccines or treatments or ventilators; none of that will be sufficient. The trick will be, can we contain it with public health measures, just like was done in 1918, like keeping people out of school and work and public places, and even things like hand-washing. Those will be the principal things that we’ll use during a major pandemic.

Researchers like me, we’re all aspiring to make vaccines and antibodies and treatments. I mean, that’s what we’re all about, a universal flu vaccine. But I still think we are not ready for a large-scale pandemic, and we’ll just use regular public health measures against one.


Tell us about the universal flu vaccine efforts.

JC: We and many other research groups have been picking apart the immune responses of individual people. And when we sort through hundreds or thousands of immune molecules, we see that some people make amazing molecules that would kill all flus. Now we know that the flu virus does have sites of vulnerability; it can’t change everything on the virus surface, or it would blow itself up. We’re starting to discover the sites of vulnerability that don’t change, and we know if we could focus the vaccine response on those, then we would have a very effective vaccine. There’s a lot of optimism around vaccines that would be broader, and even universal against all flus.


What are the challenges to getting a universal flu vaccine?

JC: Vaccines are a very difficult area for development because there’s a very, very high safety bar. You want a vaccine that prevents all flus, which is a very shape-shifting sort of bug, without hurting anybody.

KE: And how would we test a universal flu vaccine? How do we test another vaccine if we’re already getting the annual seasonal flu vaccine? Is it ethical to not give somebody a vaccine that’s recommended and study another one? No, not really. Do you study it in countries that don’t recommend vaccines? Do you study it during off seasons? Do you look at it first in adults, and how do you study it in little kids? These are not trivial matters.

JC: There’s also a question of economics: how much will people pay for a great flu vaccine? We’re talking about some of the most advanced technology ever developed, and people are spending decades of work and billions of government and commercial dollars to get to a universal flu vaccine. But there’s this sort of expectation that you should be able to get a flu vaccine for $10, or even free. There are relatively few manufacturers of flu vaccine because it just doesn’t make much money. Are we as a society committed to making a universal flu vaccine?


What should the public be doing?

KE: We have a problem with communicating about influenza to the public. There’s a distrust that the public has about flu vaccine, and about vaccines in general. Anti-vaccination sentiment is growing.

The last night I was a pediatric resident, I stood by the bed of a child who died of Haemophilus influenzae meningitis. She was this beautiful curly red-headed little girl who came walking in, and by the end of the day she was dead from a bacterial meningitis. Today we vaccinate against it. Nobody sees it anymore; the residents don’t even know about it. So, when parents say, “I don’t want this vaccine,” I want to say “I wish you could have stood there with me.”

During the last flu season, 183 children in the United States died because of influenza. The majority of these children were unvaccinated, and half of them were previously healthy. Flu is a serious disease. People think it’s just a cold, but it isn’t.

JC: I think the public doesn’t understand how amazing vaccines are; vaccines should be touted as the most successful technology in human history. For some reason our society has tagged vaccines, and actually flu vaccines in particular, with some kind of weird aura that people have some hesitancy about them. It’s crazy. People would rather become infected with wild type flu, which we know kills tens of thousands of people every year, than they would take a vaccine which might make 5 to 10 percent of peoples’ arms hurt for a day. That does not make sense.

People really ought to be knocking on their Congressman’s door saying, when am I going to get my universal flu vaccine? Honestly, the NIH budget is pretty small compared to other allocations of funds we make. We’re at risk for a virus that demonstrably can kill 50 million people; wow, you might want to be prepared for such a thing.

WS: We should all, every one of us older than 6 months of age, get vaccinated against influenza each and every year. Without a doubt, the current vaccine we have is the best way to prevent influenza. It’s an imperfect vaccine, but year in and year out, it completely prevents many, many cases of influenza. And even if you get the vaccine and consequently still get influenza, you’re very likely to have a milder, less serious infection; you’re less likely to get pneumonia, have to go to the hospital, be admitted into the intensive care unit; and you’re less likely to die. We ought to give the vaccine more credit. I like to paraphrase the old French philosopher Voltaire, who reminded us that waiting for perfection is the great enemy of the current good. And what we have today is a pretty good vaccine; it happens to be the best that medical science can produce today. We ought to use the best we have to do a lot of good each year.

In the meantime, we need even more attention and more financial support to advance influenza diagnosis, treatment and vaccine creation. That would have collateral advances for the prevention of many other diseases at the same time. That continues to be a profoundly sound investment on the part of our society.