stanford medicine


McCain and Obama over a sick patient

The demonization
of immunization

Shots get
the once-over

Rachel Whittle spent three nights by her daughter’s bedside, quarantined in a hot, dark hospital room in Manchester, England. When the 3-year-old Lola-Mae was admitted on a Wednesday evening last May, her temperature had already been at 104 degrees for roughly 36 hours. She had a cough like a sea lion. Her ears were so filled with fluid that she could no longer hear.

After that first night at St. Mary’s Hospital, red spots spread all over the tot’s body, and young doctors flocked to the room to see what in the United Kingdom — as well as the United States and much of the developed world — is a rare disease: the measles. “I knew it was inevitable after I found out that she had been exposed to it at a birthday party, but you pray,” says Whittle, a 34-year-old preschool teacher. “And you pray and you pray and you pray.”

Whittle had chosen not to vaccinate her daughter against the disease — a decision that haunted her as she worried whether her daughter would suffer permanent hearing loss, brain damage or even die. For two days her daughter’s bloodshot eyes were practically closed from conjunctivitis, and the girl was so sensitive to light that the curtains had to be drawn. Only following the third night, on the Saturday morning when the fever had subsided, did Lola-Mae’s dark eyes regain their spark. The mother felt a weight lift off her shoulders and let the sunlight into the room.

“I cried actually,” she says in a recent interview, recalling that moment. “To have gone through all of that, and to know that if you had given your child an injection it wouldn’t have happened.

“That was,” she adds, “one of the stupidest things I have done.”

But Whittle has plenty of company.

In June public health authorities in the United Kingdom announced that for the first time in 14 years the rate of measles, mumps and rubella immunization had dropped so low that there are now enough children susceptible to measles in England that the disease can spread continuously. While vaccination rates in the United States have fared better, health officials say that a worrisome trend is emerging. More Americans are asking for their children to be exempted on philosophical grounds from the vaccines that are required to register for school, and many state legislatures have made it easier for them to do so. One of 20 children entering school in Washington state, for instance, lacks the required vaccines, and in Ashland, Ore., it is now one of four.

Vaccines are hailed as one of the greatest advances in modern medicine. They are widely credited with leading to the eradication of smallpox worldwide and polio and diphtheria in the United States, let alone saving millions from suffering — sometimes with dire consequences — such diseases as rubella, also known as German measles; pertussis, more commonly called whooping cough; measles; and mumps. Yet in the first years of the 21st century, a seismic shift has occurred in public perceptions of vaccines. The shots are frequently perceived as being more dangerous than the diseases they prevent.

David Hughes
structures in the neck, oral cavity and cranium

What led to this reversal was the rise of a powerful movement opposed to vaccination policy, turbo-charged in the late 1990s by the hypothesis that vaccines caused an autism epidemic. Personal injury lawyers representing the parents of autistic children bankrolled research to discredit vaccines. These findings and the parents’ genuinely heart-wrenching stories became grist for best-selling books and segments on national television programs such as The Oprah Winfrey Show and Larry King Live, as well as the subject of testimony to Congress and a plethora of anti-vaccine Web sites.

Scientists have now thoroughly disproved the hypothesis that vaccines led to the spike in autism diagnoses, but the doubts persist. Health officials and vaccine supporters have upped their efforts to restore confidence in the immunization program. They aren’t just more authoritatively dismissing the criticisms — they’re also trying to fix the system that prompted them. They’re trying to get a better handle on what changed so many people’s view of vaccines from American-as-apple-pie to, in the words of one critic, “a witches’ brew of toxic materials.” Their quest to find a way to push such notions out of the mainstream is likely to determine whether there will be many more cases like Lola-Mae Whittle’s — and worse.

The pro-vaccine groups’ efforts are complicated by a virulent opposition that casts those parents who choose to vaccinate their children as either irresponsible or hoodwinked. Those who have disputed the claim of a vaccine-induced autism epidemic have on occasion been warned that they will be sued for libel or some other charge if they do not desist. They have even been subject to death threats. “A man from Seattle wrote to me that he would ‘hang me from my neck,’” says University of Pennsylvania professor Paul Offit, MD, an expert on vaccines and a vocal naysayer to notions linking them to increases in autism. He forwarded the information to the FBI. “The threat was deemed credible,” he says.

Among fully enlightened people,” an editorial in the New York Times says, “the case for vaccination is made out, and there is no longer any occasion to review the evidence.” Critics of vaccination policy, it opines, “are engaged, with perfect sincerity, in a futile attempt to head off human progress and to reopen a question about which pretty much all of the world has made up its mind.”

The editorial reflects the views of today’s medical establishment, but it appeared more than a century ago, on April 1, 1894, when public health officials in New York City were in the midst of a smallpox epidemic, according to State of Immunity: The Politics of Vaccination in 20th-Century America by James Colgrove, PhD. Indeed, as long as there have been vaccines, their proponents have had to overcome the resistance of those who decry them as too risky and unnecessary, or even as “poisons.”

Vaccines may well be victims of their own success. “Much of what is missing is the firsthand understanding of what it’s like to have one of these diseases,” says Hayley Gans, MD, assistant professor of pediatric infectious diseases at Stanford. People don’t remember the 20,000 birth defects that resulted from the rubella outbreak in 1964. “They don’t see polio,” she adds, “and see how disfiguring and deadly it can be.

“And they don’t know how to compare the risk of adverse reactions, such as neurologic complications from measles disease — about one in 1,000 cases — with the less than one in 1 million for the same complications from the MMR vaccine,” which protects against measles, mumps and rubella.

Convincing people to get vaccinated poses a unique conundrum. To begin with, vaccinations differ from other medical procedures in that they are performed on people who are healthy. What’s more, while vaccines approved for mass use are generally safe, they are not 100 percent free of risk: They may harm a small fraction of the hundreds of millions of people who receive them. And some recommended vaccines are not even intended as much for the benefit of the recipient as to prevent the spread of a disease to other, more vulnerable people — those who are too young, too old or too immune-system compromised to receive a particular vaccine. The current immunization system turns on the concept of herd immunity, which posits that the entire community will be protected from these diseases if a large enough percentage is immunized to prevent their spread.

The United States today has achieved herd immunity for measles and a host of other diseases, but it took generations to win public acceptance of vaccines. Indeed, opposition can be traced to 1721 in Massachusetts when Puritan cleric Cotton Mather persuaded a doctor to extract pus from smallpox sores and scrape it onto the skin of several people to inoculate them. It worked, but many demanded that the doctor be tried for murder, claiming the inoculations had helped to fan an epidemic. In 1809, Massachusetts became the first state in the nation to require all children to be vaccinated against smallpox before their second birthday — and in 1922 a challenge to another of its laws requiring adults to be vaccinated resulted in a landmark Supreme Court decision upholding the state’s authority to punish those who did not comply.

Colgrove, an assistant professor at Columbia University’s school of public health, chronicles how in the 20th century public health officials achieved mass immunization by using both the force of the law (including police officers rounding up people for smallpox shots) and the power of persuasion (as in the late 1920s, with one top health official saying that the diphtheria vaccine should be marketed in “almost the same manner as chewing gum, a second family car or cigarettes”). Ultimately, they not only convinced people of vaccines’ benefits, but also made them appealing. Jonas Salk was a hero for developing the polio vaccine. Elvis Presley was shown getting a shot. Although the Eisenhower administration opposed federally sponsored mass vaccination as a step toward socialized medicine, President John F. Kennedy hailed “modern vaccination achievements” in his 1962 State of the Union address and called for a national immunization program, which Congress quickly enacted. By 1981 all 50 states required that children receive certain vaccines to enroll in school.

During that period, the nation’s vaccination schedule began to grow from a single routine vaccination for smallpox in the early 1940s to shots for more than a dozen diseases today. Under the current recommendations from public health authorities and leading medical groups, a 2-year-old child will have had four doses of diphtheria, tetanus and pertussis vaccine (DTaP); three doses of polio vaccine; one dose of MMR; four doses of Haemophilus influenzae type b vaccine (Hib); three doses of hepatitis B vaccine; one dose of varicella (the chicken pox vaccine); and four doses of pneumococcal conjugate vaccine.

By and large, the public supports the program. The latest figures from the Centers for Disease Control and Prevention’s National Immunization Survey show that childhood immunization rates in 2007 remained at or near record levels, with at least 90 percent coverage for all but one of the individual vaccines in the recommended series for young children.

“The scientific community has reached a consensus that vaccines are not responsible for an autism epidemic. What matters is why these findings have been so difficult for the public to grasp.”

Still, in the last decade many state legislatures added provisions making it easier for people to opt out of vaccinations on philosophical grounds, amid mounting concerns about vaccine safety and the number of shots. The backlash can perhaps be traced to the late 1970s, when a growing number of parents charged that their children had suffered brain damage because of the diphtheria, pertussis and tetanus, or DPT, vaccine. As the number of lawsuits against the vaccine makers multiplied, the cost of a dose of DPT soared from a dime in 1981 to $3 five years later. Other vaccine prices also increased. Policymakers began to worry that mass immunization would become unaffordable. Ultimately a legislative compromise was brokered in 1986 between the parents’ group and the pharmaceutical industry. Congress waived the industry’s liability while establishing a no-fault compensation system to provide money to those determined to have suffered harm from required immunizations. Since then, a special vaccine court has considered some 6,300 cases, awarding compensation in about 2,000 of them, including some involving the DPT vaccine. That formulation was ultimately phased out in the United States in favor of a safer version, the DTaP, which uses fragments instead of whole pertussis cells.

But in recent years, the vaccine court has been overwhelmed with cases. From 2002 through 2006, it received more than 5,000 claims that vaccines induced autism — nearly five times all other claims combined during that time. The court has channeled almost all of these claims into one “omnibus” proceeding, and a panel of three judges has spent the last few years considering whether there is sufficient evidence to rule that vaccines are a plausible cause of autism. (The court did award compensation last year to a girl diagnosed with autism, though it attributed any vaccine-related harm to her having an extremely rare underlying condition, a mitochondrial disorder.)

The judges’ ruling could come down at any time, but its decision is, in some respects, beside the point. [Editor's note: The court ruled Feb. 12 in three test cases that vaccines were not responsible for causing autism, virtually eliminating any grounds for granting compensation in the roughly 5,000 remaining claims of vaccine-induced autism.] The scientific community has reached a consensus that vaccines are not responsible for an autism epidemic. What matters is why these findings have been so difficult for the public to grasp — and how so many parents of autistic children could be mistaken.

Autism’s false prophets is the term coined by the University of Pennsylvania’s Paul Offit, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia, to describe the scientists and doctors who have perpetuated the notion of a vaccine-induced autism epidemic. His book, with a title of the same name, explains how these researchers and practitioners, often on the payroll of trial lawyers, assumed such prominence. “The truth is that science doesn’t know the cause of autism,” he says in an interview. “When you have that kind of situation, historically people will stand up and say they have the answer. They offer something that medicine doesn’t: hope for a cure.”

A trailblazer in this respect was Andrew Wakefield, MD, a gastroenterologist at the Royal Free Hospital in London, who has perhaps done more than any other doctor to create the current fears about vaccines and autism. In 1998, he was the lead author of an article in the medical journal The Lancet, presenting evidence of intestinal damage in children with autism. From those findings, he posited that measles virus from the MMR vaccine irritated the gut of these kids, allowing toxins to seep out of the bowel, infect the nervous system and cause their autism. At a well-attended news conference, he presented his idea and called for use of the vaccine to be suspended.

Offit writes that the media spotlighted his claim. Over the next few years, Wakefield and his hypothesis were the subjects of some 1,500 stories, including a feature on CBS News’ 60 Minutes. What’s more, his premise seemed to vindicate the experience of many parents, who claimed that their children had been developing normally, but regressed after getting the MMR vaccine. There was one hitch: “He didn’t offer a shred of evidence,” says Offit.

It took time, however, for scientists to amass sufficient evidence that his belief was false. In the ensuing years, more than a dozen epidemiological studies found no correlation between MMR shots and autism. In a series of investigative reports starting in 2004, the Sunday Times charged that Wakefield failed to disclose a conflict of interest in his 1998 paper: An attorney representing parents of autistic children, the Times said, had supported his research with as much as $800,000. Ten of Wakefield’s 12 co-authors have since published a retraction of the hypothesis in The Lancet. In 2006, the General Medical Council, which is responsible for physician licensing in the United Kingdom, announced he faced counts of professional misconduct, and the Times recently reported new evidence that Wakefield had doctored the data in his 1998 study. (Wakefield dismisses the claim.)

Perhaps the final nail in the coffin came last September when Columbia University’s Mailman School of Public Health and the CDC concluded a six-year-long study, published in the Public Library of Science, using advanced polymerase chain reaction to look for measles virus in biopsies from children with autism. They found virtually none. The headline on Columbia’s news release about the results left no room for doubt: “Study firmly shows no connection between Measles, Mumps, Rubella (MMR) Vaccine and Autism.”

A statement was issued the next day that Andrew Wakefield “welcomed these new findings,” contending that the study, at worst, raised new questions about the connection between the MMR vaccine and autism and, at best, added credibility to his position. Wakefield had moved several years earlier to Texas, where he continues his work as executive director of an autism clinic. He is considered a hero by some, having, in the words of his biography on the clinic’s Web site, “resisted pressure to stop his research” on the link between autism and immunizations.

There are of course many other scientists who believe that there is such a link, and while some serve as expert witnesses for plaintiff lawyers, others have no such conflicts. Many of them have subscribed to a second theory of causation that emerged about a year after Wakefield’s news conference: They contend that the increase in the number of required shots had exposed children to unacceptable amounts of thimerosal, a mercury-based preservative then used in vaccines. It was discovered in 1999 that the cumulative total of the compound ethylmercury injected into children exceed by as much as 125 times the Environmental Protection Agency’s safety limits for its cousin, methylmercury. In July 1999, within weeks of the discovery, the American Academy of Pediatrics and the U.S. Public Health Service issued a joint statement calling for the phasing out of thimerosal from vaccines: While they believed its potential for harm was not substantial enough to disrupt vaccinations under way, it seemed prudent to remove it as no conclusive research had been done on the effects of this particular and distinctive mercury compound. The way it was handled led critics to charges of a cover-up, further undermining confidence in the immunization program.

In the years that followed, studies of places that had removed thimerosal from vaccines or had hardly ever used it — Denmark, Sweden, the United Kingdom and Canada — showed that it made no difference to autism: Cases increased even when children did not receive vaccines with thimerosal. Several analyses of U.S. data seemed to confirm that point. In the latest development, numbers from the California Department of Developmental Services were published in the Archives of General Psychiatry in January 2008, and the article revealed that roughly six years after the vast majority of shots were free of thimerosal, the incidence of autism in the state continued to grow. The jury is still out on whether thimerosal might cause problems for some small subset of the population, but there is a consensus that it could not be responsible for the autism epidemic.

Sadly, such scientific evidence alone may not be enough to regain public confidence. Hayley Gans, the Stanford assistant professor, describes in a recent interview how she had just seen two toddlers at Lucile Packard Children’s Hospital who had received none of their scheduled vaccines. That was the first time she had come across two in one day. One of the parents brushed aside advice about vaccination, saying that actress Jenny McCarthy had recommended not giving any shots for at least the first 18 months because young immune systems can’t handle them. “There’s no persuasive scientific evidence to support that position,” says Gans. “And there’s conclusive research showing that it’s those ages that measles and other infectious diseases are most likely to be fatal.”

Still, McCarthy has written two popular books about her success in treating her son’s autism. In them she extols the doctors who gave credence to her perception of what happened to her son after his shots. Never mind that it could simply be coincidence, as this is the period of development in which many children regress into autism with or without vaccines. Sure, it remains possible that the shots do cause autism, but such cases, if they exist, are extremely rare: Epidemiological studies show that vaccines did not cause thousands of autism cases or the increase in diagnosis.

Nonetheless, the mother with whom Gans was speaking had chosen to follow the false prophets instead of the advice from the leading medical institutions. “The big, big issue is trust,” says Gans.

Critics of vaccine policy are mistaken in linking vaccines to an autism epidemic, but that doesn’t mean that they don’t have a point.

“The bottom line is that there’s work to be done to enhance vaccine safety,” says Corry Dekker, professor of pediatrics and of infectious disease at Stanford School of Medicine and medical director of its vaccine program. As part of an effort by the National Vaccine Program Office to do just that, she spent Jan. 10 in Ashland, Ore. — where there is perhaps the nation’s largest cluster of people who have forgone vaccination — listening to some 50 citizens discuss their feelings about the vaccines. This was the second of three cities to have such meetings, and the goal was to obtain public input to the CDC’s drafting of an immunization safety agenda. “Some pediatricians might wish for the old days when they could say, ‘Johnny needs his shots’ and that would be it,” says Dekker, noting that many pediatricians are frustrated by how much time they must devote discussing vaccines with parents. “From the national policy perspective, we’re learning as a group how to deal with this information,” she adds. “We can’t just walk away from the conversation. We need to hear firsthand what these people have to say so we can act on their concerns and create effective communication strategies.”

In the wake of the criticisms of current immunization practice leveled by activists, the CDC has been trying to improve its vaccine-safety systems. In response to charges that it was compromised by conflicts of interests, for instance, it moved the responsibility for monitoring the safety of vaccines into an office separate from the division that makes recommendations for their purchase, promotion and distribution. Following its efforts to determine the effects of thimerosal, it has asked for an additional $46 million in this year’s budget to expand its data on any harm that shots may cause. Meanwhile, the National Institutes of Health in August for the first time asked for research proposals specifically on vaccine-safety issues.

“In the years that followed, studies of places that had removed thimerosal from vaccines or had hardly ever used it — Denmark, Sweden, the United Kingdom and Canada— showed that it made no difference to autism”

There may be ways, suggests Dekker, to pinpoint small subsets of the population, such as those with mitochondrial disorders, who might be more likely to have adverse reactions. People are less tolerant now of the occasional harm that is an inevitable part of a mass immunization program. Her research is already providing more specific guidance to pediatricians on how to respond to incidents that routinely arise after immunization, such as hypersensitivity reactions. She is a co-author of a study published in September in the journal Pediatrics that discusses, for instance, what to do if a patient develops hives following injections. When should the doctor refer a patient for a skin test to identify the possible causative agents? How does he or she decide whether the next vaccine in the schedule should be given? And if yes, are there specific instructions about how to proceed with that immunization?

 The current system, Dekker notes, has performed well — identifying problems that led, for instance, to the withdrawing of an early rotavirus vaccine — and research confirms that the benefits of the current regime far outweigh the risks of disease they are designed to prevent. But she adds, “To meet the demands of new and increasing numbers of vaccines and the challenge of public resistance, a new field of vaccine safety is emerging.”

There are even signs that there is starting to be a backlash to the backlash against vaccines.

Offit’s new book has galvanized supporters of vaccination to speak out in their favor. While he believes a core of anti-vaccine activists will never change their minds, many doubters will listen to the facts. The pro-vaccine advocacy group, Every Child by Two, has taken the unprecedented step of producing and distributing public service spots featuring former first lady Rosalynn Carter and actress Amanda Peet, both of whom volunteered their time. The spots underscore vaccine safety and stress that vaccines save children from illness and don’t cause autism. “We’re getting some hate mail, but most of it is positive — half is from parents of autistic kids who are thanking us,” says Amy Pisani, the group’s executive director. These parents complain that too much time and money have been spent investigating a vaccine-autism connection instead of on other promising avenues of research on autism. Pisani notes that Peet has appeared on a number of national television shows to discuss why she chose to vaccinate her child.

In this bid to turn around public opinion, public health officials have an unwanted ally: the infectious diseases that are making a comeback.

Because of her daughter’s measles, Rachel Whittle calls herself a “convert.” The child’s suffering led her to talk with the media. Images of her spotted Lola-Mae were broadcast throughout the region. “I am sure there are people who watched the interview and still haven’t vaccinated for measles,” she says. “If they had sat in a dark room with a child they thought might die, they would have thought differently.”

Physicians and health professionals such as Hayley Gans applaud Whittle’s efforts, but they wonder whether such painful stories will change people’s minds. The number of measles cases in the United States is miniscule but rising. In the first seven months of 2008, there was a record 131 cases — the vast majority were unvaccinated, including 15 victims under 10 months of age. That is twice the annual total of the previous six years. If it continues to increase at such a rate, the United States could follow in the path of England, where outbreaks of measles and mumps are becoming commonplace. Stories like Lola-Mae Whittle’s may not be enough.

“The unfortunate thing is that people will say, ‘See, the girl recovered,’” says Gans. “I just hope that we don’t have to wait until we start seeing children die.”
extras headline
movie poster frame

On the horizon More, better, faster

By Rosanne Spector

What would Edward Jenner think? It’s a safe bet that the smallpox combatant, who coined the term “vaccination” in 1796, would be startled by the vaccines that today’s researchers have in the works.

For most of the last century, vaccines have been manufactured according to well-honed practices. But now researchers are developing ways to make batches of vaccines much more quickly, in larger quantities and in easier-to-administer packages.

Stanford chemical engineering professor James Swartz, PhD, is working on a project that typifies new-era vaccines. He’s working with oncology professor Ronald Levy, MD, to speed up the production of personalized vaccines to treat a non-infectious cancer.

While the critical proteins needed for vaccines are traditionally grown in the confines of a cell — be it eggs or yeast or bacteria — Swartz is breaking down the cell walls and working directly with the cell’s protein production machinery. He essentially dumps the guts of E. coli bacteria into a test tube, creating a vaccine factory. In this cell-free environment, no resources go to waste keeping the cell alive. Even better, high quantities of vaccine, which would kill a cell, can mount in this system without harm.

Swartz’s new approach overcomes a key hurdle to the success of Levy’s vaccine: a long production time. Standard vaccine production takes several months — months during which a cancer patient’s condition can worsen. Growing the vaccine in plants, another avenue Levy has explored, speeds up the process to a few weeks [put URL for Shoot it, don’t smoke it here]. But his collaboration with Swartz could bring the time down to a few days.

Faster vaccine production would be better for old-school, protective vaccines as well. Not only would it lower costs but it would allow manufacturers to tailor vaccines to fight the dominant strain du jour. Currently, developing a vaccine for a rapidly mutating infectious agent, like the influenza virus, is a gamble. Every year, the World Health Organization makes an educated guess as to which influenza strains will be circulating the next year. Using this prediction as their guide, vaccine makers start the roughly five-month production process. The result is a pretty good vaccine — but not as good as it would be if it included strains that arose in the interim. And in the case of a pandemic like the 1918-19 Spanish flu outbreak, a quick turnaround could save millions of lives.

Stanford immunologist David Lewis, MD, is taking another tack in the vaccine production race, using a new additive that boosts a vaccine’s strength. In the United States, the usual additive of this sort — known as an adjuvant — is the chemical aluminum hydroxide, or alum for short. Lewis is testing what appears to be a more powerful adjuvant: a microscopic capsule, called a liposome, encasing strands of DNA. “Though the mechanism isn’t fully understood, the immune system appears to interpret the DNA entering into immune cells as a danger signal that a microbial intruder is lurking,” says Lewis, a scientific advisor to the company developing the compound. This seems to amp up the immune system response much higher than current adjuvants, he says.

What’s more, Lewis’s method could give vaccine makers more bang for their buck. “By reducing the amount of the disease-specific antigen required per immunization, the new adjuvant would most likely allow manufacturers to produce many more doses of flu vaccine,” says Lewis. In January, the company Juvaris BioTherapeutics announced results from a small clinical trial, reporting that a flu vaccine combined with the new adjuvant was more effective than flu vaccine alone and caused no additional side effects.

One new trend in vaccines isn’t really new at all: going for the nose. Jenner used injections to protect against smallpox in the 18th century, but healers in 16th-century China did it by blowing ground smallpox scabs up people’s noses. One big advantage of intra-nasal vaccination is its relative ease of administration. Another is it’s painless. The company MedImmune launched the intranasal vaccine FluMist in 2004 with this in mind.

“Vaccines are the ultimate prevention,” says the medical school’s senior associate dean of research Harry Greenberg, MD, who was involved in the pre-licensing phases of FluMist while on leave from Stanford. Anything that increases the number of people vaccinated is a big advance, he says.

It’s a sentiment Jenner would share.





©2009 Stanford University  |  Terms of Use  |  About Us