Vaccinated (13 page)

Now that researchers knew that Australia antigen was a protein made by hepatitis B virus, they could begin to investigate the possibility of using it to make a vaccine. Saul Krugman, the infectious diseases specialist who had fed hepatitis virus to mentally retarded children at Willowbrook, performed the controversial experiment.

Krugman was born in the Bronx, the son of Russian immigrants. His family later moved to Paterson, New Jersey, near the home of Krugman's first cousin Albert Sabin. In high school, Krugman was a lively, outgoing member of the debate team, the drama club, and the student council. After high school he attended Ohio State University until he could no longer afford it, dropping out after his junior year. He worked for a year, finally graduating from the University of Richmond and later the Medical College of Virginia. Two years later, during the Second World War, he served as a flight surgeon in the South Pacific, earning a Bronze Star. When the war ended, Krugman returned to New York and took a position at the Willard Parker Hospital as an extern (an intern without salary). From this lowly rank he made a steady climb, eventually becoming a professor of pediatrics at the New York University School of Medicine and chairman of the department of pediatrics. Krugman was a latecomer to academic medicine. He didn't publish his first scientific paper until he was thirty-nine years old. Nevertheless, by the end of his career he had published two hundred and fifty more papers and was the coauthor of a leading textbook in infectious diseases, now in its eleventh edition. Krugman's colleagues remember him as honest, thoughtful, hardworking, and highly ethical: a wonderful father, mentor, and friend. But his hepatitis B experiments, although they paved the way toward prevention of the disease, later caused many in the media and the public to see him as a monster.

Knowing the work of Blumberg and Prince, Krugman took blood from a patient with hepatitis B virus infection, let it clot, took the serum, and injected it into the veins of twenty-five mentally retarded children, again at Willowbrook. He wanted to see whether serum from people with hepatitis contained hepatitis virus. Not surprisingly, it did. Twenty-four of the twenty-five patients became sick as the virus attacked their livers. Krugman concluded that “this study indicated that serum was highly infectious for susceptible individuals.” One of the children sickened by the injection of live dangerous hepatitis B virus was still infected five years later, likely eventually to have either cirrhosis or liver cancer.

Now that Krugman had found an infectious serum that made children sick, he wanted to see if he could use it to protect them. So he took the infectious serum, diluted it in water, and heated it for one minute. Krugman hoped that by heating serum just below the boiling point he would kill hepatitis B virus but leave Australia antigen—hepatitis B surface protein—intact. He gave some children one dose of the vaccine and others two. Krugman then injected these children with untreated infectious serum, knowing that if the vaccine didn't work, virtually all would be infected with hepatitis B virus. The vaccine worked, protecting all of the children given two doses and half of the children given one dose. “It was a very, very exciting time,” remembered Krugman. “But I really wasn't trying to develop a vaccine. Actually, all we did in our little laboratory, our little kitchen, so to speak, was [to] boil hepatitis B serum and water.”

A local politician soon tempered Krugman's excitement. On January 10, 1967, Seymour Thaler, a New York state senator, took the floor of the senate chambers in Albany. Thaler said that “he had searched his soul and conscience” and that “the medical profession has presumed to act as God over the health and lives of the medically indigent.” “I have the documentary proof,” he said. “I have undergone a terrible inner conflict on whether to bring to the attention of the public that thousands of patients are being used daily as medical guinea pigs.” Jack Hammond, director of Willowbrook, stood up to disagree: “We're not using the youngsters because they are mentally retarded, but because hepatitis is a particular problem at Willowbrook. We have the consent of the parents of every child enrolled in the program.” New York State medical officials supported Hammond, pointing out that because of Saul Krugman, hepatitis had been virtually eliminated from the school. Thaler wasn't impressed. He introduced a bill banning medical research on children. Although the bill died in deliberation, the effect of the bill and its publicity on Saul Krugman didn't. “That business with Senator Thaler was very difficult,” recalled Krugman. “It happened when he ran for reelection. Politicians have to get publicity, so he invited the press to join him when he went to Willowbrook School and held a press conference and [made accusations] completely, of course, out of context. It was difficult.”

Saul Krugman's studies at Willowbrook showed that there were two different types of hepatitis virus (A and B), that gamma globulin could prevent disease, and that Australia antigen could be used as a vaccine. Humanity clearly benefited from his work. For his efforts, Krugman received many awards, including the John Howland Award, the Bristol Award, and the Lasker Award. He was also elected to the National Academy of Sciences, one of the greatest honors that a scientist can receive from his peers. And he received a special citation from parents at Willowbrook for having helped their children. But in 1972, when Krugman received an award from the American College of Physicians in Philadelphia, he needed a police escort to protect him from nearly two hundred people who came to denounce him. Protesters, sickened that he had injected retarded children with a dangerous virus, would follow Saul Krugman for the rest of his life.

 

K
RUGMAN KNEW THAT HIS EXPERIMENT AT
W
ILLOWBROOK WAS ONLY
the first step. “I don't like to call it a vaccine,” he said, “because it really wasn't a vaccine. Our finding was serendipitous. It demonstrated that a vaccine might indeed be developed. What was needed then was for the vaccine manufacturers, with their highly sophisticated technology, to follow up our lead.” Blumberg had found Australia antigen. Prince had shown that Australia antigen was hepatitis B surface protein. And Krugman had shown that antibodies to the surface protein protected children against hepatitis B virus infections. “Now all the bells were ringing,” recalled Hilleman. “Because all a vaccinologist needs is an antigen. I had to find out [first] whether or not blood from hepatitis B virus carriers had enough Australia antigen [for commercial use] and, second, whether that blood could remain safe.”

In the late 1970s, to get enough hepatitis B surface protein for his vaccine, Hilleman sought out homosexual men and drug users, groups at the highest risk of hepatitis B infection. (Many of these people lived in flophouses, stairwells, doorways, and fire escapes in the Bowery, one of the New York City's most notorious neighborhoods.) Then he began a seemingly impossible task. Hilleman took blood loaded with hepatitis B surface protein, live dangerous hepatitis B virus, large quantities of other blood proteins and—unknown to Hilleman at the time—HIV, and purified it so that only hepatitis B surface protein remained. He had no previous studies to guide him, no precedent for this kind of work.

Initially Hilleman decided, as had Krugman before him, to heat the blood. “The program went off in two different directions,” recalled Hilleman, “one of which I called Klink's Clunk. Klink was an engineer here at Merck. I told him I wanted him to build a Clunk. And that would be a continuous flow system into which we would put highly purified hepatitis B plasma, and we would pass it through a pipe with hot water, then past an ultraviolet light, and [then] into a pool of formaldehyde. That damn thing was so technical because we had to have constant flow: if we were going to put it into hot oil, everything had to be [processed very quickly]. But Klink's Clunk really hadn't significantly materialized before we developed a chemical process.”

Klink's Clunk failed, so it was on to plan B. Hilleman decided to use three different chemicals to treat the blood. He started with pepsin, an enzyme that breaks down proteins. Hilleman hoped to destroy blood proteins, such as gamma globulin, that were present in large quantities, but he didn't want to destroy the hepatitis B surface protein. It worked. “For some reason pepsin didn't destroy [Australia] antigen,” recalled Hilleman; “in fact the stuff that came out was almost totally pure.” Hilleman found that pepsin reduced the number of infectious hepatitis B virus particles in blood one hundred-thousandfold. But he knew that such a reduction might not be enough to destroy every last virus particle. So he added a second step: urea. A product of protein metabolism, urea is present in large quantities in the urine of mammals (hence its name). Like pepsin, concentrated urea also destroys proteins. Hilleman used urea because it destroyed prions, a particular group of proteins that might also be present in human blood and that were dangerous to humans.

124

In the mid-1950s a researcher named Carleton Gadjusek traveled to New Guinea to study kuru, a disease characterized by a slow but relentless decent into dementia. Gadjusek found that the disease occurred mostly in cannibals who ate human brains. At first, Gadjusek and others thought that the disease was either genetic or caused by a virus. But neither theory was correct. Kuru was caused by unusual proteins called proteinaceous infectious particles, or prions. Mad cow disease, caused by eating meat contaminated with infected brains or spinal cords, is also caused by prions. And Creutzfeldt-Jakob disease, a similar ailment, although not caused by eating contaminated meat, is also caused by prions. When Hilleman made his hepatitis B vaccine, he was afraid that blood might be contaminated with prions. “I'll tell you one thing that really worried me at the time, and that was Creutzfeldt-Jakob,” recalled Hilleman. “This disease was known to be infectious. It had been shown, quite uniquely, that urea would destroy [prions]. We used [urea] and had a pretty good reason to believe that there would be no problem.”

Hilleman wasn't finished. He wanted to add one more chemical to destroy any contaminating viruses. So he picked the one that had been used successfully by Jonas Salk to kill polio virus: formaldehyde. Polio virus, like hepatitis B virus, was difficult to destroy, but formaldehyde readily destroyed both.

Now Hilleman had his method: he would treat human blood with a combination of pepsin, urea, and formaldehyde. He knew that each of these treatments caused a one hundred-thousandfold decrease in hepatitis B virus; the combination of the three caused a quadrillionfold (1,000,000,000,000,000) decrease. Hilleman didn't know whether his method would destroy all other contaminating viruses, so he carefully tested representatives of every virus known: viruses similar or identical to rabies, polio, influenza, measles, mumps, smallpox, herpes, and the common cold. These viruses cause infections of the brain, spinal cord, liver, lungs, nose, throat, and intestines. Hilleman's chemical treatments completely destroyed every one of them. “[I thought] that if we could show that each step could kill surrogate viruses,” recalled Hilleman, “a whole bunch of different viruses, then we had a process in which viruses would be deader than deader than dead. A process that would destroy all life forms.”

As it turned out, hepatitis B surface protein was quite hardy. While the combination of chemical treatments destroyed other proteins in blood like gamma globulin, the hepatitis surface protein remained intact. Hilleman used a series of filtration steps to further purify his vaccine. In the end, Hilleman's blood-derived hepatitis B vaccine was virtually 100 percent pure hepatitis B surface protein—a technical miracle. But the road to a final product wasn't easy. “This was a precedent,” recalled Hilleman, “and it really took a lot of god-damned guts to take Merck down that trail. You can imagine the progress that we made. It was just about a damned zero data base [to start]. Shall we drop it this week, or should we wait another week? We were walking around in the dark or in the mud. This was one big gamble, I'm telling you.”

In the late 1970s Hilleman didn't test his chemical inactivation method to determine whether it killed HIV because HIV hadn't been discovered yet. Harvey Alter, a microbiologist who worked with Baruch Blumberg, remembered that “Hilleman was very careful about making the vaccine. He inactivated it in many more ways than were absolutely necessary. As it turned out, it was a great thing because then AIDS came along and scared everybody to death about taking vaccines. But he had done all the right things to kill the AIDS virus, even if he didn't know it was in there.”

Hilleman had to convince people that a vaccine made from the blood of intravenous drug users and homosexual men was safe. “You can go ahead and [take a protein],” he said, “and you can purify it, and you think you have a way of inactivating it, but you're still pretty much in the area of faith. You still don't know the potency, the safety, or the efficacy.” Hilleman had trouble getting permission from the FDA to test his new product. Then he ran headlong into the same man who had tried to torpedo Stanley Plotkin's rubella vaccine, Albert Sabin, a respected virologist whose opinions continued to influence researchers and regulators. “We had to get [permission from the FDA], and we had trouble,” recalled Hilleman. “What do you think happened? Sabin hears about it, says that [our] vaccine will not be used in any human being. Sabin said that if there was a lawsuit, he would go to court to testify against us. He would sue Krugman [his first cousin] if there were any problems with the studies. My feeling was, ‘Screw you, Albert.' We went to see John Seal [at the NIH]. He advised us against using our [blood-derived] vaccine. He said, ‘You know Albert says he's going to go public.' We had futzed around for about one year. I told Saul [Krugman] that I couldn't wait any longer, that I was going to go ahead and put this into people.”