The Great Influenza: The Epic Story of the Deadliest Plague in History

by John M. Barry

In camp after camp, bacteriologists fell into line. Bacteriologists at Camp MacArthur in Texas were not alone in their determination “to obtain the highest possible incidence of B. influenzae,” and they found it in 88 percent of lungs.

sometimes B. influenzae was still not being found at all. Investigators were especially failing to find it in the lungs of victims who died quickly. In at least three camps—Fremont in California and Gordon and Wheeler in Georgia—the

In early 1919, Park and Williams reversed their position. They stated, “This evidence of multiple strains seems to be absolutely against the influenza bacillus being the cause of the pandemic. It appears to us impossible that we should miss the epidemic strain in so many cases while obtaining some other strain so abundantly. The influenza bacilli, like the streptococci and pneumococci, are in all probability merely very important secondary invaders.”

Only one researcher in the world was reporting success in transmitting the disease with a filtrate: Charles Nicolle of the Pasteur Institute. But Nicolle’s entire series of experiments involved fewer than a dozen

people and monkeys. He tried four separate methods of transmitting the disease and claimed success for three of them. First he dripped filtrate into the nasal passages of monkeys and reported they got influenza. This was possible, although monkeys almost never get human influenza. He injected a filtrate into the mucosal membranes around the eyes of monkeys and reported they got influenza. This was theoretically possible, but even less likely. He also claimed to have given two human volunteers influenza by filtering the blood from an ill monkey and injecting the filtrate subcutaneously—under the men’s skin. Both of the men may have gotten influenza. Neither of them could have gotten it by the method Nicolle claimed. Nicolle was brilliant. In 1928 he won the Nobel Prize. But these experiments were wrong.

lacking other candidates, many scientists remained convinced Pfeiffer’s did cause the disease, including most of th...

(Fleming never did see penicillin as an antibiotic. A decade later Howard Florey and Ernst Chain, funded by the Rockefeller Foundation, did, and they developed Fleming’s observation into the first wonder drug. It was so scarce and so powerful that in World War II, U.S. Army teams recovered it from the urine of men who had been treated with it, so it could be reused. In 1945, Florey, Chain, and Fleming shared the Nobel Prize.)

In 1931, Pfeiffer himself still argued that, of all organisms yet described, the pathogen he had called Bacillus influenzae and that informally bore his name had “the best claim to serious consideration as the primary etiologic agent, and its only competition is an unidentified filterable virus.”

Avery continued to work on the influenza bacillus for several years after the pandemic. As his protégé René Dubos said, “His scientific problems were almost forced on him by his social environment.” By that he meant that the Rockefeller Institute influenced his choice of problems. If something mattered to Flexner and Cole, Avery worked on it.

Pneumonia had done the killing. It remained the captain of the men of death. Pneumonia was the target. He returned to his work on the pneumococcus full-time. He would study it for the rest of his scientific life.

Griffith’s report seemed to make meaningless years of Avery’s work—and life. The immune system was based on specificity. Avery believed that the capsule was key to that specificity. But if the pneumococcus could change, that seemed to undermine everything Avery believed and thought he had proved. For months he dismissed Griffith’s work as unsound. But Avery’s despair seemed overwhelming. He left the laboratory for six months, suffering from Graves’ disease, a disease likely related to stress.

His work now turned in a different direction. He had to understand how one kind of pneumococcus was transformed into another. He was now almost sixty years old. Thomas Huxley said, “A man of science past sixty does more harm than good.” But now, more than ever, Avery focused on his task.

Avery had found that the substance that transformed a pneumococcus from one without a capsule to one with a capsule was DNA. Once the pneumococcus changed, its progeny inherited the change. He had demonstrated that DNA carried genetic information, that genes lay within DNA.

Among historians of science, there has been some controversy over how much immediate impact Avery’s paper had, largely because one geneticist, Gunther Stent, wrote that it “had little influence on thought about the mechanisms of heredity for the next eight years.” And Avery’s conclusions were not immediately accepted as true by the broad scientific community. But they were accepted as true by the scientists who mattered.

Prior to Avery’s discovery—and proof—that DNA carried the genetic code, he was being seriously considered for the Nobel Prize for his lifetime of contributions to knowledge of immunochemistry. But then came his revolutionary paper. Instead of guaranteeing him the prize, the Nobel Committee found it too revolutionary, too startling. A prize would endorse his findings and the committee would take no such risk, not until others confirmed them.

James Watson, with Francis Crick the codiscoverer of the structure of DNA, wrote in his classic The Double Helix that “there was general acceptance that genes were special types of protein molecules” until “Avery showed that hereditary traits could be transmitted from one bacterial cell to another by purified DNA molecules.

Peter Medawar observed, “The dark ages of DNA came to an end in 1944 with” Avery. Medawar called

The case fatality rate is high because both viruses bind only to cells deep in the lung, so the starting point for the disease is, in effect, viral pneumonia. Deaths have occurred in places as far apart as Azerbaijan, Egypt, and China.

Since the original publication of this book, scientists have found evidence (the question is not settled) that seven of the eight segments of the 1918 virus are of avian origin, and the virus jumped species to humans probably after a reassortment (see 112) with another virus in which it acquired a human hemagglutinin gene—the gene which allows the virus to bind to and thus infect cells. And even that eighth segment had recent avian roots. This reassortment would have occurred when the avian virus infected a mammal—human, horse, pig, whatever—that was simultaneously infected by another influenza virus carrying that gene.

Before addressing those questions, we need to understand the commonalities of the few pandemics we have information about: 1889, 1918, 1957, 1968, and 2009. First, all five came in waves. (A few scientists argue that the difference in lethality between 1918’s first and second waves mean that these were caused by different viruses, but evidence showing otherwise seems overwhelming. For one thing, exposure to the first wave provided as high as 94 percent protection against the second wave, far better protection than the best modern vaccine affords, and that’s just one piece of the evidence that the same virus caused both waves.)

We also know that every wave of every pandemic has been at least a little different. In 1918, of course, that difference was dramatic, but 1968 may be more puzzling. In the United States, 70 percent of pandemic deaths occurred in the 1968–69 influenza season, with the rest in 1969–70. Europe and Asia were the opposite, with few deaths in 1968–69 and the overwhelming majority in 1969–70—even though a vaccine was available by then. Incidentally, the 1968 pandemic gave us the H3N2 virus, which has continued to cause the most severe disease of several circulating influenza viruses ever since.

“When you’ve seen one influenza season, you’ve seen one influenza season.”

There is one answer to all this: a universal vaccine, i.e., a vaccine that works against all influenza viruses.