The Vaccine Race

by Meredith Wadman

  The group of experts convened by the WHO concluded in a written report that human diploid cells were promising for helping researchers to diagnose viral diseases—an important use for an organization whose job was to track infectious diseases worldwide.48 Using the cells, disease detectives could take, for instance, a sputum sample from a patient with a respiratory infection and, based on the damage it did to the cells in a dish, identify the viral culprit. By this time scientists had cataloged nearly one hundred human viruses that infected the cells. The cells’ huge “virus spectrum” set them apart from other lab-based cells, which were not so hospitable to a broad array of viruses.49

  In the context of vaccine making, the WHO group wrote, the cells’ apparent freedom from contaminating microbes and cancer-causing properties “are of particular importance.” Yes, they might possibly harbor unrecognized infections or cancer-causing capabilities that current tools simply couldn’t detect. Nonetheless, the scientists concluded, compared with the alternatives, human diploid cells “represent at the present time the nearest approach to an acceptable system” for manufacturing vaccines.50

  They urged the WHO’s director general to develop manufacturing standards for vaccines made using the cells, “as it may be anticipated that [they] will increasingly be used in vaccine production.”51

  • • •

  In Sweden, Switzerland, and Croatia they were already in use. Late in 1961 Hayflick had produced more of Koprowski’s live polio vaccine, this time using his recently launched WI-26 cells as microscopic vaccine factories. The resulting vials he handed to Koprowski, who promptly sent them on to two European colleagues: Margareta Böttiger, the polio-trial point woman in Sven Gard’s Stockholm lab; and a short, thin, intense pediatrician named Fritz Buser, in Bern.

  A few months later Hayflick would make still more Koprowski polio vaccine, this time using his brand-new WI-38 cells. This he sent to another Koprowski collaborator: a tall, extremely laconic Croatian named Drago Ikić (pronounced EEK-ich), who tended to utter his rare words with a slight smile.

  Ikić, a physician/scientist who ran the prominent Institute of Immunology in Zagreb, had just left a job as the country’s top vaccine regulator and retained close ties to that office. He would become a major proponent of human diploid cell vaccines. In 1967 and 1968, due to his influence, Yugoslavia would become the first country to license WI-38–propagated vaccines, against polio and measles.

  The three European physicians—Ikić, Buser, and Böttiger—set to work running vaccine trials in infants and children with Hayflick’s new human cell–produced polio vaccines. They had a big stage when they were ready to announce their results: in September 1963 ninety-six delegates from eighteen countries met in the Croatian seaside resort town of Opatija for a conference on the study and uses of human diploid cells. By then the trio had vaccinated nearly six thousand infants, preschoolers, and schoolchildren.

  They were enthusiastic about what they had found. The vaccine generated antibodies just as well as monkey cell–based vaccine, Böttiger reported after feeding the vaccine, in juice, to 125 elementary school children in Uppsala.52

  “We did not observe any untoward reactions in vaccinated individuals, neither virus associated ones, nor any side effects,” proclaimed Buser, who had fed the vaccine to eight hundred Swiss infants and children.53

  “One of the most important objects of our observations was infectious hepatitis,” Ikić said after vaccinating five thousand Croatian preschoolers and schoolchildren in the spring of 1963. (He first tested the vaccine on 179 staffers at the Institute of Immunology.) “It can be concluded on the basis of the information collected that human diploid cell strains (Wi-38)[sic] are free of infectious hepatitis virus.”54

  Perhaps with these results buoying his inveterate optimism, Koprowski huddled in his office with Hayflick and Plotkin in December 1963 to compose a letter to his fellow Polish expatriate C. Mackowiak—“Macko”—the director of the French vaccine-licensing agency. There the Institut Mérieux, a vaccine maker based in Lyon, was inquiring about making a Koprowski polio vaccine using WI-38 cells.

  “Dear Macko,” wrote Koprowski, “WI-38 has met all the requirements for a human diploid cell strain to be used for vaccine production.” American companies weren’t using it, he added, only because the vaccine-regulating Division of Biologics Standards “has chosen to ignore” the deficiencies of monkey kidney cells. “We are firmly of the opinion that if a vaccine manufacturer [using WI-38 to make polio vaccine] were to apply to [the DBS] for a license, it would be impossible for Dr. Murray to refuse.”55

  Back in Bethesda the taciturn Murray was giving no indication that this was the case. And U.S. vaccine makers weren’t about to bet that he would change his mind.

  PART TWO

  Rubella

  CHAPTER NINE

  An Emerging Enemy

  Australia, 1941

  London, England, 1962–63

  Although one was struck with the unusual appearance of the cataracts in the first few cases, it was only when other similar cases continued to appear that serious thought was given to their causation.

  —Norman McAlister Gregg, Australian ophthalmologist, 19411

  Early in 1941 a tall, athletic eye surgeon with a thriving practice in Sydney, Australia, noticed an alarming uptick in the number of blind babies being sent to his office.

  Norman McAlister Gregg had a mind as sharp as his impressive abilities in cricket, golf, and tennis. He had finished with first-class honors in his medical class at the University of Sydney in 1915 before departing for World War I, where in France he served as a captain in the Royal Army Medical Corps. He was decorated for “conspicuous gallantry” after searching out and tending to the wounded while under heavy enemy fire.

  After the war Gregg completed a residency in ophthalmology in the United Kingdom. He then returned to Sydney, where he launched a successful private practice. He was a man with little tolerance for slackers or fools, but he was kind and compassionate to patients and had a habit of listening deeply to their stories. He was also infectiously enthusiastic, with a curious, penetrating mind.2

  By early 1941 Gregg, balding and bespectacled at age forty-nine, had become the senior eye surgeon at the Royal Alexandra Hospital for Children in Sydney. In the first half of that year, the blind babies began turning up, one after another. By June he had seen thirteen of them—an unusually high number in a city of around one million residents.

  All the babies had cataracts: milky white opacities in what should have been the transparent lenses of their eyes. (The lens is an elliptically shaped, bloodless, nerveless structure that measures about one centimeter in diameter in adults. It sits behind the pupil, shape-shifting to help the eye focus on near or distant objects.) The white opacities, usually in both eyes, had been present from birth, their parents said. They made what should have been black pupils appear as if they were white.

  When Gregg put drops in the babies’ eyes to expand their pupils, the pupils responded weakly and sluggishly to light. The older babies—those more than three months old—also displayed coarse, jerky, purposeless eye movements. “It was a searching movement of the eyeballs and indicated the absence of any development of [focus],” Gregg would write.

  But it was the extent of the cataracts themselves, which were unlike any congenital cataracts that he had seen, that caught Gregg’s attention as he examined baby after baby. The opacity was densely white in the dead center of the lens, but toward the periphery its density lessened, changing to a cloudier, smoky appearance: a “whitish haze.” Finally, there was an unaffected zone at the very edge of the lens.

  Gregg knew that during embryonic development the center of the lens grows first and that its peripheral layers are laid down later in pregnancy, like the outer layers of an onion. Whatever had caused the cataracts must have done so during early embryonic life.

  The babies’ e
yes weren’t their only problem. They tended to be small and poorly nourished. They had difficulty breast-feeding, a problem often seen in newborns with heart defects. Gregg asked a pediatrician colleague, Margaret Harper, to examine eight of the babies. She heard a harsh murmur along the breastbone in every one of them. It would ultimately emerge that twelve of the thirteen had been born with heart anomalies. Gregg was disturbed, and suspicious that what he was seeing wasn’t a mere coincidence. The received wisdom held that all birth defects were inherited, transmitted from parent to child in the genes. To suggest that environmental factors might play a role was considered patently unscientific. But this sudden “epidemic” of cataracts in newborns, the similarity of the babies’ unusual cataracts, and the co-occurrence of the babies’ eye and heart problems led Gregg to suspect a common, possibly environmental cause.

  One day two mothers of babies with cataracts were sitting in Gregg’s waiting room talking about their babies. One mentioned to the other that she had had German measles while she was pregnant. She was worried that it had affected her baby. The other mother said that she too had had German measles while she was expecting. During her baby’s appointment, each woman mentioned this fact to Gregg and asked him if the disease might be to blame.3

  Gregg had been searching for a clue, and this one all but shouted at him. He took careful histories from the two mothers and began contacting the mothers of the other eleven babies to ask if they had suffered from German measles while they were pregnant. He also contacted close colleagues—fellow Sydney-based ophthalmologists—and asked them how many cases of congenital cataracts they had seen recently. Could they ask the mothers whether they had had German measles while pregnant? He put the same questions to ophthalmologists around the rest of eastern Australia from Melbourne to Brisbane.

  The medical name for German measles is rubella. It comes from the Latin and means “little red.” Rubella is generally a mild disease that is transmitted by droplets coughed, sneezed, or otherwise expelled from the mouth or nose of an infected person. It is characterized by fever, swollen glands, and a rash. It owes its popular nickname to the fact that it was first described by a German, Friedrich Hoffmann, in 1740.4 (The first English description was penned by British physician William Maton in 1815.)5

  A Scotsman, Henry Veale, serving with the Royal Artillery in India, coined the term “rubella” in 1866, after carefully documenting the course of an outbreak in a Bombay boarding school. His study also distinguished the disease from classical measles, a distinctly different malady, which was present in the school at the same time.6

  Before Veale’s paper was published, and for most of a century afterward, rubella was viewed by doctors as an annoyance—a sort of “bastard measles”—although thanks to the work of Veale and others, it was formally recognized as a distinct entity by an international medical congress in 1881. It was a trivial disease, they thought, an irritant that could confuse the diagnosis of other, more dangerous rash-inducing diseases, particularly classical measles and scarlet fever, which killed children with regularity.

  In fact, rubella is so mild that up to two-thirds of infected people aren’t even aware they have it.7 Those who do have symptoms may experience a low-grade fever and swollen glands where the jaw meets the neck and at the hairline on the back of the neck—symptoms that set in twelve to twenty-three days after they are first infected with the virus. In some people, especially young women, rubella can cause aching joints, or even an arthritis that makes joints red, hot, stiff, and swollen and that can continue or recur for months. In about one in five thousand cases, and typically in adults rather than children, rubella causes encephalitis, an inflammation of the brain that is fatal in one of five cases.8

  Rubella’s hallmark is a pink or red rash that starts about two weeks after exposure. It often begins on the face and travels down to the trunk and limbs. It’s composed of flat pink or red patches and can have small, raised bumps. Occasionally it is itchy. It lasts about three days.

  Rubella is not as wildly contagious as classical measles. But it definitely spreads. While people are at their most contagious when the rash is new, they can pass on the virus for a week before and a week after the rash appears. If they don’t have a rash or other symptoms, they can spread the virus anyway.

  When Gregg began seeing the blind babies, Australia had been at war since September 1939, with large numbers of young men living in closely packed military camps in preparation for shipping out to Europe and Africa. Infectious diseases circulated easily in the crowded barracks.

  In 1940 Australia experienced a widespread rubella epidemic. Unusually, it was a severe rubella that knocked down fully grown adults. Many had throbbing wrists and ankles and raw, sore throats. Others were simply laid low. In the new infectious disease unit at Sydney’s Prince Henry Hospital, the average rubella patient stayed eight days.9

  Medical experts have hypothesized that conditions were ripe for the Australian outbreak not only because of the crowded military camps but also because many of the recruits in wartime Australia came to large cities from rural areas where they had likely never been exposed to the disease. They therefore hadn’t developed antibodies against the virus, making them a prime breeding ground for an epidemic. As the war went on, the continuing influx of recruits to the cities provided a constantly replenished source of nonimmune soldiers.10 They then went home on leave, taking the disease back to their families, wives, and girlfriends. The situation may have been aggravated by the employment of young women in munitions factories, offices, and the armed services.

  After his two patients first asked if their babies might have been damaged by rubella, Gregg checked the records of rubella admissions to the infectious-disease unit at the huge Prince Henry Hospital. What he found confirmed his suspicion: the peak period of rubella admissions had occurred between mid-June and August of 1940, seven to nine months before the bulk of the unlucky babies were born in March, April, and May of 1941.

  When Gregg interviewed the mothers of his eleven other infant patients with cataracts, only one of them said that she had not had German measles while she was pregnant. She also told him that she was kept so busy looking after her ten children that she couldn’t remember any details of her pregnancy, except that she was ill at about the sixth week.11

  The answers that came in from his ophthalmologist colleagues in Sydney and the rest of eastern Australia were as close to definitive as Gregg could have hoped. His colleagues had diagnosed sixty-five babies with cataracts. This brought the total, including the babies that Gregg had seen, to seventy-eight. Of these, the mothers of sixty-eight reported having had German measles while pregnant. Among the remaining ten, five said they didn’t know, or hadn’t had rubella. In a couple of cases the ophthalmologists didn’t get around to asking the question. In another the mother reported “kidney trouble” while pregnant.

  Of the sixty-eight women who were sure they’d had rubella, the vast majority had been ill during the first or second month of pregnancy. For most of these that meant July or August of 1940.

  For Gregg the case was clinched. In October of 1941 he stood before the Ophthalmological Society of Australia and reported on his cases, stating plainly that rubella during pregnancy had caused not only the cataracts but also the heart defects. By that time fifteen of the babies were dead. Their autopsies had revealed a number of heart defects, most commonly the failed closure of a fetal blood vessel connecting two major arteries near the heart, a condition called “patent ductus arteriosus” (PDA).

  Gregg published his findings that same year in Transactions of the Ophthalmological Society of Australia, in a now-classic paper entitled “Congenital Cataract Following German Measles in the Mother.”12

  While his discovery was taken seriously and quickly followed up and confirmed in Australia, elsewhere Gregg’s findings were slow to be picked up, in part because people were distracted by the war. He also took his share of di
sdain for bucking the received wisdom of the day by suggesting an infectious cause for a set of congenital defects. One editorial in the British journal the Lancet in 1944 noted that the study was retrospective and had relied on women’s word-of-mouth accounts of having had rubella. Gregg, it intoned, “cannot yet be said to have proved his case.” The editorial writer went on to assail the lack of statistical rigor in a key 1943 follow-up study by other Australians, which linked maternal rubella during pregnancy to cataracts, deafness, heart disease, and microcephaly—an abnormally small head, which is frequently accompanied by intellectual disability.13 The Lancet writer concluded that, if rubella was a real problem in pregnancy, it would likely have been noticed long ago: “The lay public have always held that congenital malformations have an extrinsic explanation—from being frightened by a dog to falling down stairs—and it will be strange if the influence of a mild illness in the first months of pregnancy, accompanied by a rash, has escaped attention.”14

  In 1946 an editorial in the Journal of the American Medical Association fully accepted Gregg’s findings and their serious implications but conjectured that the particular rubella virus that caused the severe epidemic in Australia in 1940 might have had unique abilities to affect the fetus and might be responsible, through travelers, for cases that had since been reported in the United States and England.15 American women were paying attention, and many decided to take no chances. One study followed 104 women in New York City who between 1949 and 1955 were diagnosed with rubella during the first three months of their pregnancies. Forty-five chose to have abortions because of their infections.16