Vaccinated Page 16

  BRITISH COMPANIES THAT OWNED THE MINES HIRED RECRUITERS TO deliver workers—derogatorily known as kaffirs—at a fixed price per head. Some became ill on the trip from their rural homes to the city. Others, crowded into small, poorly maintained barracks, suffered severe infections. Most suffered from malnutrition. If they survived, they worked for six to nine months before returning home. The constant turnover of miners meant the continuous introduction of new men into the mining compounds. Although these men suffered from dysentery and tuberculosis, no disease was more common, more severe, or more lethal than bacterial pneumonia. And every new miner was potentially susceptible.

  In 1894, at a meeting of the Transvaal Medical Society of South Africa, doctors described an epidemic of a hundred cases of “purulent discharge from the nostrils and, in a large majority of cases, pneumonia.” Fifteen of those men died. Five years later, doctors described a similar epidemic: “One batch of ninety-three emaciated Kaffirs arrived in the beginning of July and some of these were ailing; altogether of this batch, eight died.” By the early 1900s, seven gold miners died of pneumonia every day. When doctors performed autopsies on men who had died and looked at sections of their lungs under the microscope, they found small round bacteria clustered in pairs. The name of the bacterium was Streptococcus pneumoniae, or pneumococcus. To prove that it killed the miners, researchers injected the bacteria into rabbits. Within days, all of the rabbits died.

  Once they had identified the cause of this deadly pneumonia, researchers were ready to make a vaccine to prevent it.

  THE FIRST VACCINE—EDWARD JENNER’S SMALLPOX VACCINE—PREVENTED a viral infection. Vaccines to prevent bacterial diseases like pneumococcal pneumonia lagged far behind, the first one appearing about a hundred years later; one of the reasons it took so much longer is that bacteria are much more complicated than viruses.

  Viruses and bacteria are both made of proteins that evoke protective antibodies. But viruses don’t contain many proteins; for example, measles virus contains ten proteins, and mumps virus contains nine. Bacteria are much larger; pneumococcus contains about two thousand proteins. Difficulties in determining which among these proteins evoked an immune response was among the reasons for the slower development of bacterial vaccines. Progress was also slowed by fraud.

  IRONICALLY, RESEARCHERS KNEW ABOUT BACTERIA LONG BEFORE THEY knew about viruses. Martinus Beijerinck, investigating an infection of tobacco plants, was the first to figure out what viruses were and where they reproduced. But he never saw them. Not until the 1930s, with the invention of the electron microscope, did researchers finally see the viruses they were studying. Because bacteria were so much bigger than viruses, studies of bacteria had a three-hundred-year head start. In the late 1600s, Anton van Leeuwenhoek, a Dutch dry-goods dealer, produced the first microscope. While looking through his microscope at drops of rainwater or scrapings from his teeth, he noticed tiny creatures “moving in the most delightful manner.” He called them animalcules—literally “little animals.” We now know them in part as bacteria. It wasn’t until the late 1800s that investigators found that bacteria weren’t so delightful: some caused severe, often fatal illnesses.

  The next breakthrough came when Robert Koch, a German bacteriologist, proved that specific bacteria cause specific diseases. In 1876 Koch set out to determine the cause of anthrax, a common and occasionally fatal lung disease in cattle but rarely in man. Living in the farmlands that housed his crude laboratory, Koch took pieces of spleens from cows that had died of anthrax and, using tiny wooden slivers, injected them into mice, all of which died. When he looked at the cow spleens through a microscope, they were teeming with bacteria. Koch reasoned that bacteria had killed the mice. Now he had to prove it. So he inoculated small pieces of spleens from infected cows into gelatinous fluid scooped from the center of an ox’s eye, hoping that it would provide the nutrient substances necessary for the bacteria to grow. (Many early scientific studies sound like a witch’s incantation from Macbeth.) During the next few weeks Koch watched the bacteria reproduce. He then injected his culture of anthrax bacteria into mice and found that again they all got sick; their lungs were loaded with anthrax bacteria. Koch had made an important observation. Until that time, scientists had believed that only bacteria taken from someone who was sick could make you sick. Koch proved that bacteria grown in his laboratory could also cause disease. Robert Koch was a father of the germ theory of disease.

  During the next ten years Koch found that he could grow bacteria on nutrient media made from potatoes and gelatin. He placed his media in special flat glass dishes invented by a young researcher working in his laboratory, Julius Petri. Later, Koch discovered the bacteria that cause tuberculosis and cholera. By 1900, researchers had found twenty-one different bacteria that cause diseases. “As soon as the right method was found,” said Koch, “discoveries came as easily as ripe apples from a tree.”

  Koch’s observation that bacteria could be grown in the laboratory led to a series of important discoveries and three vaccines.

  The first breakthrough occurred in the late 1800s, when two French researchers, Emile Roux and Alexandre Yersin, isolated the bacterium that causes diphtheria, then a common cause of death. Diphtheria causes a thick gray membrane to collect in the windpipe and breathing tubes, often suffocating its victims. In the United States alone, diphtheria infected two hundred thousand people every year, mostly teenagers, and killed fifteen thousand. Roux and Yersin, like Koch, found that they could reproduce the disease by injecting bacteria into experimental animals. But they also found that when they grew bacteria in liquid culture, the liquid alone caused severe and fatal disease; bacteria themselves weren’t necessary. Apparently, diphtheria bacteria were making a toxin.

  The second breakthrough resulted in the first Nobel Prize in medicine. Working in Marburg, Germany, Emil von Behring found that animals injected with diphtheria toxin made antibodies to the toxin, called antitoxin, and that antitoxin prevented disease. Scientists later extended Behring’s discovery to make antitoxins to several bacteria. Behring’s discovery was also the inspiration for the Iditarod dogsled race, which re-creates the life-saving emergency transport in 1925 of diphtheria antitoxin from Nenana to Nome, Alaska—a distance of 674 miles—during an outbreak of diphtheria. Although two children died during the outbreak, Behring’s antisera saved the lives of many others.

  Another French researcher, Gaston Ramon, made the third breakthrough in the late 1920s when he found that toxin that had been inactivated by formaldehyde could protect people against diphtheria. Now researchers no longer had to rely solely on antitoxins to fight bacterial infections. People injected with formaldehyde-treated toxin, known as toxoid, could be protected against diphtheria for the rest of their lives by making their own antibodies. This observation also led to vaccines against tetanus and, in part, whooping cough. Because of these three vaccines, the number of people killed every year in the United States by diphtheria decreased from fifteen thousand to five; by tetanus, from two hundred to fifteen; and by whooping cough, from eight thousand to ten.

  Production of new bacterial vaccines exploded in the early 1900s. Pharmaceutical companies in the United States made vaccines by growing bacteria in pure culture, killing them with chemicals, and putting dead bacteria in a tablet. They called these vaccines bacterins. Bacterins were sold to prevent strep throat, acne, gonorrhea, skin infections, pneumonia, scarlet fever, meningitis, and intestinal and bladder infections. Bacterins were easily ingested, readily available, simple to make, and highly lucrative. There was only one problem: they didn’t work. Nor did they have to. Pharmaceutical companies weren’t required to prove that their products worked until the early 1960s. Change came later, but only when prompted by disaster.

  IN 1954 CHEMISTS AT CHEMIE GRÜNENTHAL, A WEST GERMAN COMPANY, tried to make an antibiotic by heating a chemical called phthaloylisoglutamine. (Don’t try to pronounce this word in your head.) The resultant drug didn’t kill bacteria. So they tried somet
hing completely different: they tested animals to see whether the drug had an antitumor effect. Again, no luck. Finally, in a small test in people, researchers at Grünenthal found that the drug put patients into a natural, all-night sleep. On October 1, 1957, they advertised the drug as a sleeping pill and claimed that it was completely safe. They also claimed that pregnant women could use it to treat morning sickness, although they never specifically tested the drug for this use. They called the drug thalidomide. By 1960, hundreds of babies had been born with their hands and feet directly stuck to their bodies. Thalidomide damaged twenty-four thousand embryos; half died before birth. Today, about five thousand people live with birth defects caused by thalidomide.

  The thalidomide disaster caused a reevaluation of the U. S. Food, Drug, and Cosmetic Act, passed in 1938. Congress amended it in 1962 to compel pharmaceutical companies to show that their products actually worked before selling them.

  THE FIRST PERSON TO TRY TO MAKE A vaccine TO PROTECT SOUTH African gold miners from pneumococcal pneumonia was Sir Almroth Wright. In February 1911, Julius Werhner, chairman of the Central Mining Investment Corporation in London, called upon Wright, a famous British researcher. A tough, opinionated man who actively opposed women’s suffrage, Wright was the inspiration for the character of Sir Colenso Ridgeon in George Bernard Shaw’s The Doctor’s Dilemma. (The dilemma in Shaw’s play is that Ridgeon, with enough antiserum to save one person from tuberculosis, must choose between a physician colleague and a talented artist. Smitten by the artist’s wife, Ridgeon chooses the doctor, hoping that the artist will die as a consequence. Wright is said to have stormed out of an early performance of the play.) Werhner chose Wright to develop a vaccine against pneumococcus because he knew that several years earlier Wright had developed a successful vaccine against typhoid fever, caused by the bacterium Salmonella typhi. Wright had made his vaccine by growing Salmonella in pure culture and killing it with heat. Before his discovery, typhoid had been a common and fatal infection, especially among soldiers. During the Spanish-American War, about two hundred Americans died of their wounds, while typhoid killed two thousand. After Wright found that his vaccine worked, the British military gave it to all of its soldiers during the First World War. (The Second World War was the first in which more soldiers actually died in battle than of infection.)

  Wright assumed that he could make a vaccine to prevent pneumococcal infection the same way that he had made his typhoid vaccine. So he took a strain of pneumococcus, grew it in culture, and killed it with a chemical. On October 4, 1911, Almroth Wright inoculated the first of fifty thousand South African gold miners with his vaccine. In January 1914 he published his results: “The comparative statistics that have been set forth above testify in every case to a reduction in the incidence rate and death rate of pneumonia in the inoculated.” But Wright was wrong. One year later a statistician working for the South African Institute for Medical Research reanalyzed Wright’s data and found that his vaccine didn’t work at all. The reason for his failure would soon become evident.

  In 1910, one year before Wright conducted his study, German researchers had found that there were two different types of pneumococci and that immunity to one didn’t protect against infection from the other. By 1913, F. Spencer Lister, an English physician working in South Africa, had found four different types of pneumococci. More would follow. By the 1930s, researchers had identified thirty different types, and by the end of the Second World War, forty types. Today, researchers have identified at least ninety different types of pneumococci. Wright’s attempts to protect South African gold miners failed because he didn’t include enough different types of pneumococci in his vaccine. (Many of Almroth Wright’s colleagues called him “Sir Almost Right.”) Researchers had to find a way to prevent a disease that could be caused by many immunologically distinct types of the same bacterium.

  Where Wright failed, Robert Austrian, a researcher at the University of Pennsylvania, succeeded. Austrian, who grew up in a three-story, high-ceilinged brick row house on Baltimore’s Doctors’ Row, was the son of Charles Robert Austrian, physician-in-chief at Sinai Hospital and an associate professor at Johns Hopkins. “I was scared to death to go into medicine,” recalled Austrian. “My father was a hard act to follow.” A trim, well-spoken man of German Jewish ancestry, Austrian finished his internship and residency at Hopkins in 1945 and decided to pursue a career in infectious diseases. “I was told that if you wanted to learn classical bacteriology, go to Harvard or [the] Rockefeller [Institute]. But if you wanted to see the future of bacteriology, go to New York University.” At NYU Austrian met Colin MacLeod, the man who inspired his lifelong interest in pneumococcus. Austrian’s interest in a pneumococcal vaccine would soon be interrupted by a medical product first developed in Germany.

  IN 1908 A VIENNESE CHEMIST NAMED PAUL GELMO SYNTHESIZED A chemical that—because it was bright red—proved very useful in the German dye industry. The dye also stained bacteria, which made them easier to see under a microscope. Twenty-five years later, a physician named Gerhard Domagk found that if he gave this dye to mice and rabbits, he could protect them against lethal doses of bacteria. Although the dye was effective in animals, Domagk hesitated to inject it into people. But in 1935, his young daughter became very ill with a streptococcal infection of her bloodstream, an often fatal disease. The crisis forced Domagk to act. In desperation, he gave her a dose of the dye, saving her life. The dye was called sulfanilamide, and it was the first antibiotic.

  Austrian remembers the dawn of the antibiotic era: “Dr. Perrin Long [chairman of community medicine at Hopkins] was the first person to bring sulfa drugs back to the United States. The results of his treatment of several patients with streptococcal infections were so dramatic that some of his colleagues thought that he was lying. The possibilities seemed limitless.” Sulfa drugs appeared to be the magic bullet in the fight against bacterial infections. At Hopkins, Perrin Long was the keeper of the gate, the man in charge of a very limited supply of sulfa drugs. He took his charge seriously, as demonstrated by one memorable incident. A co-worker remembered a late-night phone call in 1936. “I answered it, and a woman’s voice asked for Dr. Long. He took the phone, and I heard him say, ‘You can’t fool me this time! I know you’re not Eleanor Roosevelt,’ and he hung up. Within seconds the phone rang again. This time he said meekly, ‘Yes, Mrs. Roosevelt, this is Dr. Long.’ The next day the newspapers announced that the president’s son was ill. Later, they reported that the boy had been cured by sulfanilamide, supplied by [Dr.] Long.”

  By the early 1940s, researchers had found a method to mass-produce a different antibiotic, penicillin. Now, clinicians were confident that they could eliminate pneumococcal infections. “The drop in mortality was so dramatic,” recalls Austrian, “that most people began to feel that this illness was no longer a common or serious one. And not only that: they no longer felt that it was necessary to identify pneumococci; the recognition of the organism declined. The opinion in the 1940s and 1950s was widely held that pneumococcal pneumonia had largely disappeared because of these new so-called wonder drugs.” Austrian found, however, that while antibiotics saved lives, they didn’t lessen the incidence of infection. “When I went from Hopkins to Kings County Hospital in Brooklyn, which was the third largest hospital in the United States, I was told that if I was really interested in pneumococcal pneumonia, I was probably in the wrong place because they saw so few cases every year.” Austrian set up a laboratory to determine how many people with pneumonia were infected with pneumococcus. “The place was a madhouse,” recalled Austrian. “There were four thousand beds. Beds were lined up in the corridors.” He found that about four hundred people every year were admitted to Kings County with pneumococcal pneumonia. Austrian’s colleagues remained unconvinced, believing that his findings were unique to Brooklyn. “So we got a grant from the National Institutes of Health to look at the incidence of pneumococcal pneumonia throughout the United States because, as a wag once said, ‘Brookly
n is a city opposite the United States.’ But it turned out there was just as much pneumococcal pneumonia coming into the city hospitals of Chicago, Los Angeles, and New Orleans as we had found in Brooklyn. It was very clear that the disease had not gone away. It was just a matter of seeing what you looked for.”

  After ten years of collecting data, Austrian found another surprise. He examined the death rates in three groups of patients with severe pneumococcal infections: those who had been treated with antibiotics, those treated with antiserum (made from the serum of horses injected with pneumococci), or those left untreated. Although antibiotics and antiserum clearly saved lives, they didn’t work on the most severe infections. “The death rates among those who died in the first five days were essentially the same,” said Austrian. “What this tells us is that if you are destined to die very early in illness, it won’t make a difference what treatment we give you, because we don’t understand even today [what’s causing] early death. The only alternative then to protect those at high risk of early death is to prevent them from becoming ill.” Austrian was talking about a pneumococcal vaccine.

  BETWEEN 1900 AND 1945, SCIENTISTS MADE SEVERAL IMPORTANT DISCOVERIES about pneumococcus. They found that the bacterium was surrounded by a capsule made of a complex sugar called polysaccharide, that the polysaccharide could be stripped from the bacteria, that polysaccharide injected into mice protected them against infection, and that people injected with different polysaccharides from various strains of pneumococcus developed antibodies against each of the different types. Colin MacLeod, Austrian’s mentor at NYU, made the first successful pneumococcal vaccine by taking four different types of pneumococci and stripping off their polysaccharide coats. During the Second World War, he injected either his vaccine or placebo into seventeen thousand military recruits and found that following an epidemic of pneumococcal pneumonia, his vaccine worked. E. R. Squibb made MacLeod’s vaccine in the late 1940s, using six different types of pneumococcus. Nobody bought it. Convinced that penicillin had eradicated pneumococcus, doctors weren’t interested in a pneumococcal vaccine. So Squibb stopped making it.