Use of fetal tissue in vaccine development

"Some childhood vaccines, including the one against rubella -- which is part of the MMR vaccine given to millions of children worldwide for measles, mumps and rubella -- is cultured in "WI-38 human diploid lung fibroblasts," according to the U.S. Food and Drug Administration's fact sheet on the vaccine's ingredients. Merck, the vaccine's manufacturer, acknowledged that those cells were originally obtained from an electively aborted fetus. They were used to start a cell line, which is a cell multiplied over and over again to produce cells that are of a consistent genetic makeup. The WI-38 cell line is used as a culture to grow live viruses that are used in vaccines."

""Merck, as well as other vaccine manufacturers, uses two well-established human cell lines to grow the virus for selected vaccines," Merck said in a statement to ABC News. "The FDA has approved the use of these cell lines for the production of these Merck vaccines." Other common vaccines, including those for chicken pox, hepatitis and rabies, are also propagated in cells originating from legally aborted human fetuses, according to the FDA. "These abortions, which occurred decades ago, were not undertaken with the intent of producing vaccines," said a spokeswoman for the U.S. Centers Disease Control and Prevention. The original cells were obtained more than 50 years ago and have been maintained under strict federal guidelines by the American Type Culture Collection, according to Merck."

""These cell lines are now more than three generations removed from their origin, and we have not used any new tissue to produce these vaccines," the company added in its statement. To say that the vaccines contain a significant amount of human fetal tissue, as some objectors to the vaccines claim, is misleading, stressed Dr. Paul Offit, the director of the vaccine education center at the Children's Hospital of Philadelphia. "There are perhaps nanograms of DNA fragments still found in the vaccine, perhaps billionths of a gram," he said. "You would find as much if you analyzed the fruits and vegetables you eat." And to remove human fibroblast cells entirely from vaccines is out of the question, Offit explained, noting they are necessary because human viruses don't grow well in animal cells. "They have also been tested for safety and the fetal cells can go through many more divisions than most other cells before dying," he said."

"Religious organizations have sided in favor of vaccines as well, even those generally opposed to abortion. "We should always ask our physician whether the product he proposes for our use has an historical association with abortion," the National Catholic Bioethics Center states on its website, but then goes on to say "one is morally free to use the vaccine regardless of its historical association with abortion." "The reason is that the risk to public health, if one chooses not to vaccinate, outweighs the legitimate concern about the origins of the vaccine," the center's position statement continued. "This is especially important for parents, who have a moral obligation to protect the life and health of their children and those around them." Offit said he was glad the Catholic Church supports vaccination. He noted it is particularly ironic to object to the rubella vaccine using fetal cells because Cardinal Joseph Ratzinger, who later became Pope Benedict XVI, commented on the subject in 2003, saying: "Universal vaccination has resulted in a considerable fall in the incidence of congenital rubella, with a general incidence reduced to less than 5 cases per 100,000 livebirths." In other words, Offit explained, the rubella virus increases the risk of spontaneous abortion. In the U.S., vaccination prevents up to 5,000 miscarriages each year in the U.S. alone, he said."

"Fetal tissue has been used since the 1930s for vaccine development, and more recently to help advance stem cell research and treatments for degenerative diseases such as Parkinson’s disease. Researchers typically take tissue samples from a fetus that has been aborted (under conditions permitted by law) and grow cells from the tissue in Petri dishes. Many of the uses of fetal tissue – and much of the debate – are not new. “It’s just that the public is finding out about it,” said Insoo Hyun, associate professor of bioethics at Case Western Reserve University."

"Despite the long history of using fetal tissue in medicine and research, the practice could be on the way out. Even though it has led to important medical advances in the last several decades, “in the future, the need for fetal tissue will go down because of advances in stem cell [technology] that will take over,” Hyun said. One of the earliest advances with fetal tissue was to use fetal kidney cells to create the first poliovirus vaccines, which are now estimated to save 550,000 lives worldwide every year."

"In the early days of making the vaccine, researchers infected fetal kidney cells in Petri dishes to produce a large amount of virus that they could then harvest, purify and use to vaccinate people. (The virus evolves to become less deadly when it infects cells out of the body, and thus could safely be given to people to prime their immune system for the real thing.) Today manufacturers of the polio vaccine use other types of human cells, which weren’t available in the mid-1900s. They also use monkey cells, which they originally avoided for fear that making the vaccine in animal cells could put people at risk of diseases from other species."

"Many of our other common vaccines, such as chicken pox, rubella and shingles, have been produced in tissue derived from fetuses, particularly two electively terminated pregnancies from the 1960s."

"The woman was four months pregnant, but she didn’t want another child. In 1962, at a hospital in Sweden, she had a legal abortion. The fetus — female, 20 centimetres long and wrapped in a sterile green cloth — was delivered to the Karolinska Institute in northwest Stockholm. There, the lungs were dissected, packed on ice and dispatched to the airport, where they were loaded onto a trans- atlantic flight. A few days later, Leonard Hayflick, an ambitious young microbiologist at the Wistar Institute for Anatomy and Biology in Philadelphia, Pennsylvania, unpacked that box. Working with a pair of surgical scalpels, Hayflick minced the lungs — each about the size of an adult fingertip — then placed them in a flask with a mix of enzymes that fragmented them into individual cells. These he transferred into several flat-sided glass bottles, to which he added a nutrient broth. He laid the bottles on their sides in a 37 °C incubation room. The cells began to divide. So began WI-38, a strain of cells that has arguably helped to save more lives than any other created by researchers. Many of the experimental cell lines available at that time, such as the famous HeLa line, had been grown from cancers or were otherwise genetically abnormal. WI-38 cells became the first ‘normal’ human cells available in virtually unlimited quantities to scientists and to industry and, as a result, have become the most extensively described and studied normal human cells available to this day."

"Vaccines made using WI-38 cells have immunized hundreds of millions of people against rubella, rabies, adenovirus, polio, measles, chickenpox and shingles. In the 1960s and 1970s, the cells helped epidemiologists to identify viral culprits in disease outbreaks. Their normality has made them valuable control cells for comparison with diseased ones. And at the Wistar Institute, as in labs and universities around the world, they remain a leading tool for probing the secrets of cellular ageing and cancer. “Here’s a clump of cells that has had an enormous impact on human health,” says Paul Offit, chief of the division of infectious diseases at the Children’s Hospital of Philadelphia. “These cells from one fetus have no doubt saved the lives of millions of people.” Few people, however, know the troubled history of the cells — one that may offer lessons for modern researchers seeking to work with human tissues. Six years after deriving his famous strain, Hayflick made off with stocks of the cells and later started to charge for shipping them, prompting an epic legal battle with the US National Institutes of Health (NIH) in Bethesda, Maryland, about who owned the cells. That struggle nearly destroyed Hayflick’s career and raised questions about whether and how scientists should profit from their inventions."

"What’s more, the WI-38 strain has helped to generate billions of dollars for companies that produce vaccines based on the cells, yet it seems that the parents of the fetus have earned nothing. That recalls the earlier development of the HeLa cell line, named after the woman whose tumour gave rise to the cells and chronicled in Rebecca Skloot’s book The Immortal Life of Henrietta Lacks (Crown, 2010). As with HeLa, the WI-38 case highlights questions about if, and how, tissue donors should be compensated that are still urgently debated today. Last month, for example, some scientists in the United States found themselves barred from using new stem-cell lines derived from human embryos because women had been paid for the eggs used to make them (see Nature http://doi.org/mv2; 2013). The story of WI-38, unlike that of HeLa, also has its own controversial twist because it was derived from an aborted fetus. For 40 years, anti-abortion activists have protested against the use of WI-38 and vaccines developed from it. “It’s still a live issue,” says Alta Charo, a professor of law and bioethics at the University of Wisconsin Law School in Madison. “We still have people who refuse to take these vaccines because of their origins in fetal tissue."

"When Hayflick opened up that icy package from Sweden in 1962, he was working at the vanguard of virus research in the United States. At the time, the Wistar Institute was led by Hilary Koprowski, a polio-vaccine pioneer who hired Hayflick to run the centre’s cell-culture laboratory and supply cells to researchers. But Hayflick also began investigating whether some human cancers might be caused by viruses. To do so, he needed a resource that did not yet exist: verifiably normal human cells that could be reliably grown in the lab. Fetal cells, he thought, were an ideal candidate, because they were less likely to have been exposed to viruses than adult cells. Although abortions were technically illegal in Pennsylvania at the time, they were still performed when doctors said they were medically necessary. Hayflick says he was able to obtain fetuses straight from the operating room of the University of Pennsylvania Hospital across the street from Wistar. Unless the tissue was put to some use, he reasoned, “it was definitely going to end up in an incinerator”. The University of Pennsylvania says that it is unable to find records to confirm the source of fetal tissues used by Hayflick. Hayflick developed 25 different fetal-cell strains, numbered WI-1 to WI-25. But several months into the project, he began to notice something strange. Scientific orthodoxy held that cells in culture, properly treated, would replicate forever. But his oldest cell strains were beginning to replicate more slowly. Eventually, they stopped dividing altogether."

"WI-38 found a greater use in virology, where the ease of infecting the cells with a panoply of human viruses quickly made the strain an important virus-identification tool. In 1967, the cells became a workhorse in a World Health Organization survey of viruses causing lower respiratory tract infections in hospitalized children on four continents."

"Hayflick also supplied WI-38 liberally to aspiring vaccine-makers. One was Stanley Plotkin, a Wistar scientist and a physician who had seen at first hand the effects of the huge rubella epidemic that swept the United Kingdom and the United States in the early 1960s. Rubella can be devastating to fetuses whose mothers are infected: those that are not killed in utero are frequently born blind, deaf, mentally disabled or with some combination of these conditions. Working at the Wistar, Plotkin grew rubella in WI-38 at 30 °C, cooler than body temperature, creating a weakened strain that still fired up the immune system enough to protect against future infections. Trials showed that his vaccine induced better immunity against rubella than competitors. Plotkin’s vaccine was licensed in Europe in 1970 and in the United States in 1979. A version made by the pharmaceutical company Merck, based in New Jersey, is today the only rubella vaccine available in the United States, and GlaxoSmithKline uses Plotkin’s weakened virus in a rubella vaccine that it markets in Europe and Australia. The rubella vaccine was only one of many made using WI-38. In the 1960s, a WI-38-based measles vaccine was licensed in the former Soviet Union and Koprowski developed a rabies vaccine using the cells. In the early 1970s, the pharmaceutical company Wyeth (now part of Pfizer) launched an oral adenovirus vaccine developed using WI-38 and Pfizer, based in New York, used WI-38 to make a vaccine against polio. Today, the cells are also used by Merck to make vaccines against chickenpox and the painful nerve infection shingles."

"Hayflick explains that, contrary to common practice in 1962, he had not laced the cells with antibiotics at the outset because vaccine manufacturers feared allergic reactions to the drugs. Shortly before the Science article was published, Hayflick sued the NIH. He argued that the agency had violated the 1974 Privacy Act by making his name and the allegations against him available under the FOIA without including his rebuttal. He also sued for title to WI-38 and its proceeds. By then, Hayflick was also facing a criminal investigation: Stanford University had alerted local prosecutors that the case could be one of criminal theft of government property. (The prosecutors subsequently found no grounds for criminal investigation and dropped the case.) Meanwhile, some vaccine manufacturers, fearing that there would not be enough stock of WI-38 to meet future needs, switched much of their work to an alternative fetal cell strain, MRC-5."

"“Other vaccines are produced in a completely morally non-objectionable way. So why aren’t we doing this with all vaccines?” says Debi Vinnedge, the executive director of Children of God for Life, a group based in Largo, Florida, that opposes the use of WI-38 in vaccine-making. In 2003, Vinnedge wrote to the Vatican asking for an official position on whether Catholics could ethically receive vaccines made using cells from aborted fetuses. She waited two years for an answer. The letter, when it came, concluded that where no alternative exists, it is “lawful” for parents to have their children immunized with vaccines made using WI-38 and MRC-5, to avoid serious risk to their own offspring and to the population as a whole. Still, the Vatican wrote, faithful Catholics should “employ every lawful means in order to make life difficult for the pharmaceutical industries” that use such cells. Merck, a major producer of Plotkin’s rubella vaccine, has been a perennial target of abortion opponents, who have pressed the issue at Merck’s US shareholder meetings. (Merck said in a statement to Nature that “it would be exceedingly difficult, if at all possible, to develop and test an alternative”, and emphasized the vaccine’s long record of safety and effectiveness.) The irony of the protest is not lost on Plotkin. “I am fond of saying that rubella vaccine has prevented thousands more abortions than have ever been prevented by Catholic religionists,” he says."

"Profits from Merck’s rubella vaccine represent a big slice of the billions of dollars that have been made from products that have involved the use of WI-38. Among the other companies that have made money from WI-38 are Barr Laboratories (now part of Teva Pharmaceuticals, based in Petach Tikva, Israel), which today makes the adenovirus vaccine given to all US military recruits, and Sigma Aldrich in St Louis, Missouri, which charges $424 in the United States for a vial of the cells. Legal experts say it is unlikely that the parents of the fetus, or their heirs, would have any legal grounds to demand compensation for tissue collected over 50 years ago. At the time that WI-38 was derived, use of tissue without consent was routine in the United States, as it was in Sweden. Under current rules, researchers supported by US government grants are free to make use of surgically removed tissue — including aborted tissue — that has been stripped of its identifiers, without consent. However, some states have stricter rules. But, says Charo, “if we continue to debate it entirely in legal terms, it feels like we’re missing the emotional centre of the story”. It could be argued, she says, “that if somebody else is making a fortune off of this, they ought to share the wealth. It’s not a legal judgment. It’s a judgement about morality.”"

"If nothing else, the WI-38 story highlights the benefits of discussing the issues of compensation and consent with tissue donors at the outset. In the case of WI-38, suggests Charo, returning to the donor now, even with an offer of compensation, “may also be a way of re opening an experience that may for her have been painful. You have to be careful.” Hayflick argues that there are at least four stakeholders with title to WI-38 or any human cell culture: the tissue donors, the scientists whose work gave it value, the scientists’ institution and the body that funded the work. “Like me”, he adds, “hundreds of other scientists had their careers advanced using WI-38 and other human cell cultures so we all owe a moral debt to the tissue donors.”"

"Human fetal kidney cells were used to develop Genentech’s Pulmozyme, which helps clear thick mucus from the lungs of children with cystic fibrosis."

"Chaired by Representative Marsha Blackburn (R–TN), who is now helping steer President-elect Donald Trump's transition, the panel of the House Energy and Commerce Committee issued, as it exited the stage, a 413-page Final Report. Besides targeting Planned Parenthood, which receives more than $500 million annually in federal funding, much of it through the Medicaid health program for the poor, the report also takes to task research institutions, other abortion providers, and the companies that process and prepare fetal tissue for researchers. It accuses some of illegally profiting from the sale of fetal tissue, which is forbidden under the 1993 law. And it cites numerous examples to conclude that "human fetal tissue research makes a vanishingly small contribution to clinical and research efforts." But a close look at those claims reveals inaccuracies; a sampling follows: Report, p. xxxix: "In over 100 years of unrestricted clinical research, human fetal tissue has failed to provide a single medical treatment …" Fact: Several important medicines now on the market were created using fetal tissue. Amgen's Enbrel battles rheumatoid arthritis; Genentech's Pulmozyme helps children with cystic fibrosis clear the thick mucus that clogs their lungs; and Nuwiq, made by Octapharma, treats boys and men with hemophilia, a life-threatening bleeding disorder."

"Report, p. 379: "Several letters [from the Association of American Medical Colleges and others] … suggest that human fetal tissue is used for modern vaccine production. In reality, none of the nearly 75 vaccine formulations currently licensed in the United States is produced using human fetal tissue …" Fact: The WI-38 and MRC-5 cell lines, derived from two fetuses that were aborted, respectively, in 1962 in Sweden and in 1966 in the United Kingdom, are used to produce the following vaccines, all licensed and marketed in the United States: *Sanofi-Pasteur's Imovax rabies vaccine is propagated in MRC-5 cells. When they were introduced in the 1970s, human fetal cell–propagated rabies vaccines supplanted dangerous and occasionally fatal animal tissue–produced rabies vaccines. * Merck's chicken pox and shingles vaccines are propagated in MRC-5 cells; they are produced at a relatively new company plant in North Carolina. The weakened "Oka" virus used in both vaccines was initially attenuated in WI-38 cells. * Merck's rubella vaccine—the "R" component in the MMR vaccine given to U.S. infants and preschoolers—is propagated in WI-38 cells on the company's campus northwest of Philadelphia, Pennsylvania. Merck has shipped nearly 700 million doses of the rubella vaccine since its launch in 1979. Also known as German measles, rubella, like Zika virus, attacks and damages fetuses in the womb. *Hepatitis A vaccines are marketed in the United States by both Merck and GlaxoSmithKline; both companies propagate their vaccines in MRC-5 cells. *The polio component of Sanofi Pasteur's U.S.-marketed Quadracel vaccine (which also protects against diphtheria, pertussis, and tetanus) is propagated in MRC-5 cells. *The adenovirus vaccine that since 1970 has protected nearly 10 million members of the U.S. military from respiratory infections is propagated using WI-38 cells. (In seeming contradiction, the report goes on to state, one page later, that "11 [current vaccines] … are produced using historic, fetal-derived cell lines.")"

"Report, p 376: "… human fetal tissue has never been used to make the polio vaccine." Fact: Virologists at the Karolinska Institute in Sweden used fetal cells to propagate a polio vaccine in the mid-1950s; it was given to some 2000 schoolchildren. In 1967 and 1968, Yugoslavia conducted a mass polio vaccination campaign using polio virus propagated in WI-38 cells; Sweden and Switzerland had already run trials of the same vaccine. In the early 1970s, Pfizer launched a polio vaccine propagated in WI-38 cells in the United States. And the French vaccinemaker Sanofi Pasteur uses MRC-5 cells to make polio vaccine to this day."

"Senior Catholic leaders in the United States and Canada, along with other antiabortion groups, are raising ethical objections to promising COVID-19 vaccine candidates that are manufactured using cells derived from human fetuses electively aborted decades ago. They have not sought to block government funding for the vaccines, which include two candidate vaccines that the Trump administration plans to support with an investment of up to $1.7 billion, as well as a third candidate made by a Chinese company in collaboration with Canada's National Research Council (NRC). But they are urging funders and policymakers to ensure that companies develop other vaccines that do not rely on such human fetal cell lines and, in the United States, asking the government to "incentivize" firms to only make vaccines that don't rely on fetal cells. "It is critically important that Americans have access to a vaccine that is produced ethically: no American should be forced to choose between being vaccinated against this potentially deadly virus and violating his or her conscience," members of the U.S. Conference of Catholic Bishops and 20 other religious, medical, and political organizations that oppose abortion wrote to Stephen Hahn, commissioner of the U.S. Food and Drug Administration (FDA), in April. "Thankfully, other [COVID-19] vaccines … utilize cell lines not connected to unethical procedures and methods." "We urge your government to fund the development of vaccines that do not create an ethical dilemma for many Canadians," wrote Archbishop of Winnipeg Richard Gagnon, president of the Canadian Conference of Catholic Bishops, and 17 other antiabortion religious, medical, and politic groups and individuals in a 21 May letter to Prime Minister Justin Trudeau. "The … manufacture of vaccines using such ethically-tainted human cell lines demonstrates profound disrespect for the dignity of the human person.""

"Cells derived from elective abortions have been used since the 1960s to manufacture vaccines, including current vaccines against rubella, chickenpox, hepatitis A, and shingles. They have also been used to make approved drugs against diseases including hemophilia, rheumatoid arthritis, and cystic fibrosis. Now, research groups around the world are working to develop more than 130 candidate vaccines against COVID-19, according to the World Health Organization; 10 had entered human trials as of 2 June. At least five of the candidate COVID-19 vaccines use one of two human fetal cell lines: HEK-293, a kidney cell line widely used in research and industry that comes from a fetus aborted in about 1972; and PER.C6, a proprietary cell line owned by Janssen, a subsidiary of Johnson & Johnson, developed from retinal cells from an 18-week-old fetus aborted in 1985. Both cell lines were developed in the lab of molecular biologist Alex van der Eb at Leiden University. Two of the five vaccines have entered human trials (see table, below). In four of the vaccines, the human fetal cells are used as miniature "factories" to generate vast quantities of adenoviruses, disabled so that they cannot replicate, that are used as vehicles to ferry genes from the novel coronavirus that causes COVID-19. When the adenoviruses are given as a vaccine, recipients' cells begin to produce proteins from the coronavirus, hopefully triggering a protective immune response. The fifth vaccine, which has shown promise in monkeys and is headed for human trials as soon as this summer, is what is known as a protein subunit vaccine. Researchers at the University of Pittsburgh use HEK-293 cells to manufacture the coronavirus' spike protein—a vital part of its structure—which is used to trigger an immune response. The vaccine is delivered through a skin patch with 400 tiny needles. The fetal cell lines are key to producing both types of vaccine. "HEK-293 [cells] are essential for making protein subunit vaccines," says Andrea Gambotto, a vaccine scientist at the University of Pittsburgh School of Medicine and the vaccine's lead developer. Their human origin is important, he says: "Cultured [nonhuman] animal cells can produce the same proteins, but they would be decorated with different sugar molecules, which—in the case of vaccines—runs the risk of failing to evoke a robust and specific immune response." (Among the developers of the five vaccines, only Gambotto responded to a request for comment.)"

"David Prentice, vice president and research director at the Charlotte Lozier Institute, which opposes abortion, notes researchers making adenovirus vaccines have modified HEK-293 cells to be adept at packaging new genes—such as those that direct cells to assemble the coronavirus spike protein—into adenoviruses. But he adds that other technologies are available, including using cells captured from amniocentesis that are engineered to make replication-deficient adenoviruses. "The use of cells from electively aborted fetuses for vaccine production makes these five COVID-19 vaccine programs unethical, because they exploit the innocent human beings who were aborted," Prentice and a co-author—molecular biologist James Sherley, a Lozier Institute associate scholar and director of the adult stem cell company Asymmetrex—wrote in a position paper published last month."

"Arthur Caplan, a bioethicist at the New York University School of Medicine, counters: "There are better ways to win the abortion wars than telling people not to use a vaccine. These are long-over abortions. These cells are decades old, and even major religious leaders like the pope have acknowledged that for the greater good it's not worth the symbolism to put the community at risk." * The Vatican's Pontifical Academy for Life declared in 2005 and reaffirmed in 2017 that in the absence of alternatives, Catholics could, in good conscience, receive vaccines made using historical human fetal cell lines."

"A vaccine made by the Chinese company CanSino Biologics was the first COVID-19 vaccine to enter phase II human trials. It was developed using adapted HEK-293 cells that the company licensed from Canada's NRC, where the cells were developed. (NRC-developed HEK-293 cells have already been used to develop an approved Ebola vaccine.) Last month, NRC announced a collaboration with CanSino Biologics under which it is preparing to run late-stage clinical trials of the vaccine in Canada, and scale up facilities to produce the vaccine in quantity."

"One of the Warp Speed candidates, made by Janssen Research & Development, uses PER.C6 cells. The second, from University of Oxford researchers and AstraZeneca, uses HEK-293 cells. Both have received U.S. government commitments of, respectively, $456 million and $1.2 billion, if they meet milestones, through the Biomedical Advanced Research Development Authority (BARDA). Another vaccine that relies on HEK-293, being developed by two companies owned by the billionaire scientist and businessman Patrick Soon-Shiong, made an earlier, Warp Speed long list of 14 promising candidates, according to a press release from one of companies, NantKwest. Prentice says: "As they are choosing—BARDA and the Warp Speed people— what vaccines to move ahead, they should at least recognize that there is some portion of the population who would like an alternative vaccine they can take in good conscience." Caplan disagrees. "If you are going to say the government shouldn't fund things that a minority of people object to, you will have a very long list of things that won't get funded by the government, from research on weapons of war to contraceptive research.""

"The Trump administration has restricted the use of human fetal tissue from elective abortions in biomedical research. One year ago, it adopted a policy that forbids researchers at the National Institutes of Health (NIH) from using fetal tissue from elective abortions in their studies. And it imposed an extra layer of review on non-NIH scientists seeking agency funding to do research using such tissue. But the policy did not stop either group from using decades-old fetal cell lines like HEK-293 and PER.C6."