Bacterial infections, as we have seen, remained a cause of significant morbidity and mortality well into the first half of the twentieth century. They remain so today, although the worst culprits are now those acquired not in daily life but in hospitals and other health care facilities. But it is important to remember that neither prevention nor control of bacterial diseases became a possibility until the end of the nineteenth century. Prior to that time, infected individuals either survived—largely on the basis of their intrinsic host defense systems and good fortune—or they succumbed—an outcome that was frighteningly common, even with seemingly trivial infections.

Some bacterial infections, such as anthrax in livestock and the toxin-mediated human diseases diphtheria and tetanus, became largely preventable by the latter part of the nineteenth and early part of the twentieth centuries, respectively, with the use of effective vaccines. Others, such as typhoid and cholera, were largely banished from the developed world by a combination of improvements in hygiene and sanitation, in spite of partially effective vaccines. Still others, such as streptococcal infections, which were highly lethal prior to the late 1930s, were largely controlled by the introduction of sulfa drugs and then penicillin. These and the other newly developed antimicrobial drugs of the 1940s and 1950s appeared—temporarily as it turned out—to hold the promise that bacterial diseases would no longer threaten human health; a promise that, as we have seen, quickly went unfulfilled with the widespread development of drug resistance.

Perhaps the most common and fearsome acute bacterial disease of the early twentieth century was lobar pneumonia—a serious infection of the lungs—caused by a form of streptococcus known as the “pneumococcus.” Osler, author of the definitive textbook of medicine of the era—the book that convinced Rockefeller’s right-hand man for philanthropy, Frederick Gates, of the necessity for establishing a medical research institute in the United States—devoted nearly 400 pages of his 1000-page, first edition text—forty percent—to descriptions of known or ­suspected infectious diseases; a significant portion of these involved one entity—pneumonia.¹

The infection was neither an epidemic threat nor usually as rapidly and dramatically lethal as meningococcal meningitis. Pneumococcal disease was so highly prevalent—it accounted for nearly 77,000 deaths in the U.S. in 1890, more than half a million when adjusted for today’s population—that Osler borrowed a description used by author John Bunyan in the seventeenth century, dubbing it “captain of the men of death”—replacing tuberculosis for that distinction. Entire hospital wards were filled with these cases.

The pneumococcus was initially and independently discovered in 1881 by both Pasteur—in the course of challenging animals with saliva from victims of rabies—and George Sternberg—a military medical officer who would later become the Surgeon General of the U.S. Army, while examining his own saliva. In addition to his elegant bacteriologic studies, Sternberg left two other great legacies: he was responsible for appointing the Yellow Fever Commission, headed by Major Walter Reed, that would go on to determine the route of transmission and the cause of this dreaded disease; and he founded the Army Medical School—later to be known as Walter Reed General Hospital—a pivotal institution in the subsequent chapter of our story.² Five years after its discovery Fraenkel, in Germany, identified the pneumococcus as the major cause of acute lobar pneumonia. The name for the microbe was proposed, shortly thereafter, by Weichselbaum—the Austrian Professor of Pathological Bacteriology who one year later would be the first to identify the meningococcus in autopsy specimens from patients who had died from meningitis.

Almroth Wright, the British Army bacteriologist who had been the first to use killed typhoid vaccine on a large scale in troops deployed to India towards the end of the nineteenth century, tried a similar vaccine approach to prevent pneumococcal disease. In 1911, he vaccinated 50,000 South African gold miners—a group of otherwise healthy, young, African men who were known to be at high risk of pneumococcal disease in the overcrowded, hot, humid, germ ‘cauldron’ that they lived in for months at a time two miles below the earth’s surface—with a vaccine derived from heat-inactivated pneumococci.³ The results were disappointing; this approach to pneumococcal vaccines was subsequently abandoned.

Although microbiologically unrelated, the pneumococcus and the meningococcus share a common feature other than their prominent roles in causing sickness and death—they both reside within a polysaccharide capsule—a structure composed of a series of complex sugar molecules chemically bound together to form a layer that coats the microbe. This coating—capsule—acts as a shield that protects the bacteria from being engulfed and then degraded by specialized cells—“phagocytes”—of the immune system. Serum antibodies that usually neutralize bacteria and thus protect hosts against infection are unable to neutralize encapsulated microbes; to do so requires specific antibodies directed against the capsule. It was this concept of anticapsular antibodies that would—after a series of landmark scientific developments—initially inform the search for new forms of pneumococcal vaccines and subsequently, for meningococcal vaccines.

Although it was known since Pasteur’s time that certain bacteria produced polysaccharides, the notion that these carbohydrate compounds might be effective to induce immune responses was unlikely to have even been considered by Alphonse Dochez and Oswald Avery at the time they published their paper in 1917 describing the “specific soluble substance” elaborated by pneumococci grown in broth cultures and found in the blood and urine of patients with lobar pneumonia.⁴ Avery, a physician scientist trained in bacteriology, had joined the research staff of the Rockefeller Institute Hospital in 1913. The two scientists shared both a nearby apartment and membership on the “Pneumonia Service”—a laboratory devoted to studying the patients with pneumonia at Rockefeller—in the early years of the ­hospital.⁵ Dochez would move on to other research pursuits within infectious diseases—determining the viral etiology of the common cold and the streptococcal etiology of scarlet fever. However, Avery would spend the remaining 30 years of his active research career at Rockefeller studying the pneumococcus—specifically devoted to understanding the organism’s biochemistry and its relationship to the pathogenesis of the microbe. This research thread later led to the discovery by Avery and two colleagues—Colin MacLeod and Maclyn McCarty—that DNA, not proteins, encoded genetic ­information—a career capstone that would revolutionize biology.⁶