Sometimes WI-38 cells are used in basic biological discoveries that may seem esoteric but end up being relevant in ways that nonscientists can easily appreciate. A few years ago researchers at the Weizmann Institute of Science in Rehovot, Israel, used WI-38 cells to discover a key function of an enzyme called QSOX1 that is thought to have a role in helping prostate, breast, and pancreatic cancers to invade normal tissues. They found that the enzyme, which is secreted by WI-38 cells, catalyzes the formation of laminin, an important component of the thin, fibrous basement membrane that anchors many kinds of cells to the connective tissue underneath them. Cancer cells depend on laminin to spread and invade tissues. When the Israeli scientists used an antibody to block QSOX1, this shut down cancer-cell migration: lung-cancer cells that are normally mobile couldn’t move across a layer of WI-38 cells. This is the kind of far-reaching, basic discovery that appears in the esteemed journal Science, which is where the scientists published their paper.4
It’s hard to quantify the impact of fundamental findings like the Rehovot researchers’. Biology builds on itself, discovery after discovery, and apportioning credit in just the right measure to individual revelations is not terribly useful and often impossible. What’s more, findings that may at the time seem to be of only limited interest—think of Elizabeth Blackburn’s first, obscure description of the telomeres of that single-celled freshwater organism, Tetrahymena—can launch whole new fields of endeavor and lead to major discoveries and ever-deepening understandings. So can findings that are dismissed as “rash” and wrongheaded, like Hayflick’s observation that the normal cells from many different fetal organs stopped dividing after several months in lab bottles and his bold suggestion that this phenomenon might be related to human aging. It took decades for the importance of his observations and thinking to be fully appreciated. And because they were lab-based findings, far removed from patient bedsides, their impact can’t be neatly measured in terms of medicines made or lives saved.
It’s quite different with the vaccines that Hayflick enabled, not only by launching the WI-38 cells and then turning his lab into a one-stop shop for vaccine scientists and companies in search of them, but also by relentlessly fighting for their acceptance against the United States’ obdurate, ultraconservative, self-protective vaccine regulators. Few people, if any, thanked him for his efforts at the time, and by the time those efforts did come to wide public attention, it was in the worst possible way—under the damning cloud of a government investigation announced on page one of the New York Times. Certainly Hayflick brought his downfall on himself through his stubborn defiance and his inability to give an inch when he is sure he is right, which is often. But none of that takes away from the enormous impact on public health that is due to this one man’s endeavors and persistence with his beloved WI-38 cells—and to the many vaccines that resulted.
• • •
Merck’s chicken pox vaccine won FDA approval in the mid-1990s, making the company the only chicken pox vaccine maker in the world. The company makes the vaccine at a new plant in North Carolina, using MRC-5 cells—the cells launched by the British in imitation of WI-38, using Hayflick’s methods. The weakened vaccine virus itself traces its roots to its passage long ago in WI-38 cells, in the Osaka University lab of the pediatrician Michiaki Takahashi, from whose organization Merck later licensed it. The same is true of Merck’s vaccine against shingles, which was approved in 2006 for Americans over sixty and that is simply a higher-dose version of the chicken pox vaccine. Both illnesses are caused by the same virus, varicella zoster. People over sixty need a higher dose because their immune systems don’t respond as vigorously to vaccination as do young people’s.
In the first decade after 1995, when American infants began receiving a single chicken pox injection at between twelve and eighteen months of age, the incidence of disease caused by varicella zoster virus—that is, the incidence of chicken pox and shingles—and the associated number of U.S. hospitalizations and deaths declined by about 90 percent.5 In 2006 the CDC recommended that children receive a second chicken pox shot between the ages of four and six, just before school entry. The incidence of varicella-caused disease then fell another 81 percent through 2013.6 No one less than twenty years old has died of chicken pox in the United States since 2010.7
• • •
Merck finally won FDA approval for its hepatitis A vaccine in 1996, twenty years after Hilleman ordered his vaccine scientist Philip Provost to scrap his work developing the vaccine in WI-38 cells and begin again using MRC-5. The company shares the U.S. market with GlaxoSmithKline; both companies use MRC-5 cells to manufacture their vaccines. Beginning in 1996, the injection was given to infants in geographical areas with high rates of the disease, which is transmitted when people ingest food or water contaminated with the feces of an infected person. The vaccine was made part of the routine schedule for all infants in 2006.8 Between 2000 and 2013 the number of cases of hepatitis A reported to the CDC declined by 86.7 percent, from 13,397 in 2000 to 1,781 in 2013.9
• • •
The number of human deaths from rabies in the United States has declined steadily since the 1970s, thanks in part to animal control and immunization efforts that have more or less eliminated domestic dogs and cats as reservoirs of the disease—and thanks, too, to the improved human cell–propagated vaccine that arrived in 1980 courtesy of Hilary Koprowski, his colleagues, and Hayflick’s WI-38 cells. After Wyeth was forced to withdraw its vaccine in the mid-1980s, the Institut Mérieux in Lyon, France—now part of the huge vaccine-making company Sanofi Pasteur—enjoyed years dominating the U.S. market with Imovax, the rabies vaccine that is made using MRC-5 cells but that owes its existence to Koprowski and Wiktor’s tweaking of the virus in WI-38 cells half a century ago. Today, Imovax is facing stiff competition from newer vaccines that are equally effective but much cheaper to manufacture. Like Imovax, the newer vaccines are a vast improvement on the animal-nerve-tissue vaccines of the early twentieth century, which, sadly, are still used in a handful of developing countries because they are still cheaper to make.
In the United States between thirty thousand and sixty thousand people are vaccinated each year after possible exposure to rabies, with either the Sanofi human diploid cell vaccine or with a competing vaccine by Novartis, made in chick embryo cells.10 Thousands more—veterinary students, animal handlers, rabies researchers—receive preventive vaccinations.
Wild animals, particularly raccoons, bats, and skunks, are still reservoirs of the disease in the United States; the CDC receives around six thousand reports of rabid animals annually, 92 percent of them in wildlife.11 Each year several hundred domestic dogs and cats will contract rabies from wild animals because their owners have not had them vaccinated.12
In most years between one and three people die of rabies in the United States—it is a disease so rare that doctors may fail to recognize it. For people, bats are a particularly dangerous reservoir, both because they can harbor the disease without being evidently rabid and because their teeth are so tiny that people who are bitten—often while they are asleep—may not realize it.
In September 2015, a seventy-seven-year-old Wyoming woman appeared at her local hospital after five days of growing weakness and loss of balance. Her speech was slurred and she couldn’t swallow. Eight days later, her family told doctors that one month earlier she had waked with a bat on her neck. By the time they mentioned the bat, she was paralyzed, comatose, and on a breathing machine. Three days after that, she was dead. Experts at the CDC tested the woman’s saliva and skin from the nape of her neck and found rabies.
When the woman woke with the bat on her neck, her husband had examined her for a bite wound and found none, so she had not sought medical help. Her husband had reported the incident to local invasive species authorities, but they had not raised the risk of rabies.13
In 2014 a Missouri man who lived in a thickly wooded area and who had spotted a ba
t in his trailer appeared at a hospital emergency room with a sudden onset of severe neck pain and tingling in his left arm. He became fearful and began hallucinating; he communicated an aversion to water. Within three days he was on a ventilator, and nine days after that he was dead. It had taken his medical team six days to consider that he might have rabies, and confirmatory lab results weren’t returned for an additional six days. By then it was far too late for a vaccine to save him.14
In Wisconsin in 2004 a fifteen-year-old girl named Jeanna Giese became the first person known to survive rabies without being vaccinated.15 She developed neurological symptoms thirty-seven days after being bitten by a bat. Doctors put her in a chemically induced coma and administered antiviral drugs. Today she is a married college graduate.
In 2007 researchers from the Pasteur Institute in Tehran went back to the villages of northwestern Iran. There they managed to find twenty-six of the forty-five people who had been bitten by rabid animals and vaccinated thirty-one years earlier with the WI-38–propagated Koprowski vaccine. All of them still had antirabies antibodies, many at levels deemed protective by the World Health Organization.16
• • •
The U.S. rubella epidemic that was expected in the early 1970s never materialized. By 1979, ten years after the first rubella vaccine was licensed in the United States, between 75 million and 80 million children had been vaccinated in a U.S. population that numbered around 225 million. In 1969, not an epidemic year, there had been 55,549 cases of rubella reported to the CDC.17 By 1979 the number had fallen to an all-time low of 11,795.18,19 (Both the 1969 and 1979 numbers were probably gross underestimates because so many rubella infections don’t cause obvious disease.)20
Between 1969 and 1980 reports of babies born in the United States with congenital rubella declined by 36 percent to 50 infants.21 At the turn of the twenty-first century, by which time Plotkin’s RA 27/3 rubella vaccine had been immunizing American toddlers for twenty years, there were 176 reported cases of rubella in children and adults and 9 reports of babies born with congenital rubella in the United States.22 By that time more than 9 in 10 cases of congenital rubella in the United States occurred in infants born to foreign-born mothers from countries without rubella vaccination programs, or with programs only recently put in place.23
In 2005 the Centers for Disease Control and Prevention announced that endemic rubella—meaning homegrown rubella not imported with unvaccinated immigrants—had been eliminated from the United States.
In April 2015 the Pan American Health Organization reported that endemic rubella had been eliminated in the Western Hemisphere. By that time Merck had shipped more than 660 million doses of Plotkin’s WI-38–based rubella vaccine.24
Globally rubella remains a serious problem. In 2014, 28 percent of countries did not vaccinate against rubella.25 Japan, which did not begin vaccinating young boys against rubella until 1995—in the beginning, several countries vaccinated only girls because only girls go on to get pregnant—experienced a serious epidemic from 2012 to 2014, with most of the cases in adult men.26,27 Forty-five infants were born with congenital rubella.28
Sporadic imported cases of congenital rubella continue to appear in the United States. For instance, in 2012 three babies were diagnosed with the syndrome in the United States. They were born to women from African countries that do not vaccinate against the disease; each mother had been in Africa early in her pregnancy.29
Experts estimate that a hundred thousand babies are born with congenital rubella each year, most of them in developing countries.30
• • •
On a cold, crisp, sunny day in November of 2014 I visited the Merck campus at West Point, near Philadelphia—a low-lying, four-hundred-acre complex with its own trash-hauling and fire and emergency service where, since 1979, the company has made the rubella vaccine that has now been given to some 140 million U.S. preschoolers. Here, in the supersterile building 29, the company was in the midst of what is termed in the industry a “campaign” in which, over several months, it makes all of the rubella vaccine that it will produce for the coming year. (Measles and mumps vaccines, which are combined with the rubella vaccine to make the MMR injection, are made in the same facility at different times of the year to avoid cross-contamination.)
The company had been making the vaccine since September, in shifts that run daily from 8:00 a.m. to 12:30 a.m. Behind a series of gowning rooms and air locks that ensure that outside air never makes its way in, hooded technicians in white jumpsuits and steel-toed shoes with green shoelaces that mark them for sterile rooms were overseeing scores of cylindrical half-gallon plastic bottles that were rotating slowly, their sides made hazy by the WI-38 cells growing on them, the medium inside them awash with rubella virus. The cells incubate at 86 degrees Fahrenheit, the temperature that Stanley Plotkin discovered long ago would weaken the RA 27/3 vaccine virus just enough, but not too much. After several days the virus-laden medium that will become the vaccine is harvested, pooled, and filtered several times to remove the larger cellular debris of the WI-38 cells. Each batch of vaccine fills most of a sixty-six-gallon, stainless-steel tank; each will be safety-tested on a long list of parameters on which the FDA must sign off. It will then be freeze-dried, packaged with measles and mumps vaccines, labeled, and sent out, along with the sterile water to reconstitute it, to untold numbers of doctors and health workers in forty-two countries on five continents.
I met in a conference room with several key people involved with rubella vaccine production. They included Michael Lynn, a biotechnician and father of four young children. Lynn had a shaved head and bulging biceps and declared of his long hours working behind goggles, hood, and mask: “You’re helping children. To me, there’s nothing really better than that.” They also included an engineer and molecular biologist, Vic Johnston, who looked to be in his forties and who is an expert on the rubella vaccine. It was Johnston who explained to me that it was 2008 when Merck last retrieved a single sterile ampule of WI-38 cells from the scores of vaccine-ready ampules held at the American Type Culture Collection. Before that the company hadn’t needed one since 1995.
Johnston said that when on these occasions the tiny, decades-old ampule arrives at Merck from the ATCC, it contains about three million cells. The company expands these cells to create a working bank of cells—dozens of ampules—with population doubling levels in the low twenties; these it freezes. They will last eight or ten or thirteen years. Each year, during its annual campaign, the company will draw on the cells from this bank. It will begin with about 120 million such cells; by the end of the campaign, some 37 billion infected WI-38 cells will have been conscripted to produce the vaccine virus. By this point the cell populations will have reached a doubling level in the low thirties. While these cells aren’t killed by the virus, they will become “sort of exhausted” after producing vast quantities of it, Johnston said. So there, clinging to the plastic sides of the glass roller bottles, they will end a long journey—a mostly deeply frozen trip that took their progenitors from deep in Mrs. X’s womb to a Swedish hospital to the Karolinska Institute to the Wistar Institute to Stanford University to the American Type Culture Collection and finally to West Point, Pennsylvania.
“Do you ever lose sleep,” I asked Johnston, “worrying about running out of WI-38?”
He hesitated for a beat. Then he said that if the company could begin each rubella campaign with somewhat older WI-38 cells than it starts with now—a change that would require FDA approval—“that would essentially make the supply infinite.”*
• • •
Nanobits of the cells used to make them are present in all viral vaccines, whether or not they are made with fetal cells. These bits of protein and DNA are so small that they pass through the filters that catch larger cell remnants. In the case of the WI-38 cells used to make rubella vaccine, the minuscule DNA snippets that are present in one dose of vaccine weigh in the neighborhood of
180 nanograms, which is about 0.6 millionths of an ounce. (The blood circulating in the vessels of a twenty-two-pound toddler weighs about five billion times as much.) These WI-38 remnants are considered so safe, because of the cells’ normalcy—the fact that they never turn cancerous—and because of the decades-long safety records of the vaccines made in them, that neither the Food and Drug Administration nor the World Health Organization sets an upper limit on the levels of WI-38 DNA allowed to be present in the rubella vaccine.*31,32
I am moved by the intimate interaction between the WI-38 cells and the hundreds of millions of people who have benefited from the rubella and adenovirus vaccines made using them. When they are vaccinated, they are literally, physically connected to Mrs. X’s fetus. Taking this idea further, to the level of infinitesimal bits of WI-38, one could argue that this physical relationship extends to every adult and child vaccinated against shingles and chicken pox with the Merck vaccine that once passed through WI-38 cells, and to everyone who has been saved from a horrifying death by Sanofi Pasteur’s rabies vaccine, created by Koprowski and his colleagues at the Wistar half a century ago, using WI-38. Admittedly, at so many removes the notion of a physical link between these vaccinees and the WI-38 fetus is almost completely symbolic—it’s a single drop in the Pacific Ocean, perhaps. But “philosophically” it is true, says Alan Shaw, who developed the shingles and chicken pox vaccines for Merck.33
• • •
Mrs. X has never been compensated for the use of her fetus. But the institutions and companies that market the WI-38 cells as research tools and turn them into vaccines have made a lot of money. In the spring of 2016, scientists ordering a tiny ampule of WI-38 cells from a cell bank paid as much as $467. In the mid-1980s, when the WI-38–based rabies and rubella vaccines were still under patent, the Wistar Institute collected more than $3 million in royalties annually; some 15 percent of these were shared by the inventors: Plotkin, Koprowski, Fernandes, and Wiktor, before he passed away in 1986.34 The money in vaccine making today is orders of magnitude bigger. Teva, the company that uses WI-38 cells to make adenovirus vaccine for the Pentagon, earned about $30 million from sales of that vaccine in 2012.35 (The company declined to provide a more recent figure.) Merck’s sales of its rubella- and chicken pox–containing vaccines in 2015 grew 10 percent to $1.5 billion.
The Vaccine Race Page 45