On March 28, 2014, more than a year before Donald Trump announced his candidacy for the Presidency of the United States, he tweeted: “Healthy young child goes to doctor, gets pumped with massive shot of many vaccines, doesn’t feel good and changes – AUTISM. Many such cases!”
Although Trump’s anti-vaccine sentiment has not been a secret, he nonetheless took the medical community by surprise when, on January 10, 2017, just days before he was sworn in as the 45th President of the United States, he met with anti-vaccine activist, Robert Kennedy Jr., at Trump Tower in Manhattan, where, per Kennedy, Trump asked him to head a new government commission on vaccine safety (1).
Kennedy claimed that representatives of Trump’s transition team approached him before the meeting to ask whether he would be interested in participating in a vaccine inquiry. Moreover, he stated that Trump’s chief strategist, Stephen K. Bannon; Trump’s counselor, Kellyanne Conway; and then Vice President-elect Mike Pence also attended the meeting. A few hours later, a spokesperson for Trump confirmed that Trump was “exploring the possibility of forming a committee on autism,” but added that no final decisions had been made (1).
The “possibility” that Trump might form a committee on vaccines and autism (irrespective of who heads it) raises fears in the medical community that, by doing so, Trump would give a sense of legitimacy to the discredited anti-vaccine point of view, which, in turn, would give many parents misinformation regarding the crucial need to get their children vaccinated. Vaccines are safe and effective. What’s more, they have prevented more human (especially childhood) suffering and death than any other measure in history! If Kennedy’s panel (or any other action by Trump, which reflected his “alternative” view of vaccines) led to even a small decrease in vaccination rates, the result would be the otherwise preventable deaths of children, including infants too young to be vaccinated (2), as well as the elderly.
The idea that vaccines might cause autism first gained widespread attention in 1998 after the British medical journal, The Lancet, published a study involving only 12 children, by former British surgeon, Andrew Wakefield, which claimed to find a link between the measles vaccine and autism. However, an investigation by the British Medical Council later found that data in The Lancet paper was fraudulent. Moreover, Wakefield’s study received financial support from lawyers representing parents of autistic children; a conflict of interest that Wakefield did not disclose. The British Medical Journal took the extraordinary step of publishing a report in which it concluded that Wakefield’s study was not simply bad science, but a deliberate and elaborate fraud. The Lancet paper was retracted and Wakefield was stripped of his medical license. A subsequent large scale study by the U.S. Institute of Medicine, involving more than a half million children, found no evidence whatsoever of any connection between vaccines and autism (2).
Some individuals, including Kennedy, believe that thimerosal (a mercury compound once added to some vaccines as a preservative) is the link between vaccines and autism. However, thimerosal was added only to killed vaccines (e.g., the vaccines against diphtheria, whooping cough, and tetanus), whereas the MMR vaccine—the original source of the vaccine controversy—is a live vaccine. What’s more, all vaccinations in the United States have been thimerosal-free since 2001, while new cases of childhood autism have not abated since then. Furthermore, extensive studies by the US Centers for Disease Control (CDC), and by the US Institute of Medicine, could not find any connection between thimerosal and autism (2). At first, Kennedy completely ignored these studies, but later asserted that these government agencies were participating in a major cover-up (3).
Considering: 1) the overwhelming scientific evidence against the anti-vaccine point of view, 2) the extensive expert advice available to Trump from physicians and biomedical scientists both within and outside the government and, 3) the unceasing federal oversight of vaccine safety (by the both the CDC and the FDA), why would Trump reopen this issue at all, especially via a panel headed by a layperson, when doing so under any conditions will undermine public health? Is it to distract the public’s attention from more politically troubling issues, or is it merely a play to his base, or does Trump actually believe what he says?
Ben Carson, a physician and former presidential aspirant, and now Trump’s pick to head the Department of Housing and Urban Development, framed the vaccine issue as a matter of government infringement on the peoples’ liberties; a point of view that resonates with the political right (see Aside 1.), as does Trump’s bizarre view, as tweeted in 2012, that: “The concept of global warming was created by and for the Chinese in order to make U.S. manufacturing noncompetitive.”
[Aside 1: Carson, a physician by background, ignores the crucial concept of herd immunity. People who cannot get vaccinated (e.g., young infants, pregnant women, children suffering from leukemia or other immune deficiencies) are yet protected from measles by herd immunity; that is, the immunity in the entire population that results when a high enough percentage of individuals has been vaccinated. When that level of compliance is attained, there are not enough susceptible individuals in the population to sustain the chain of transmission. Thus, vulnerable individuals, who cannot be vaccinated, pay the price for vaccine noncompliance by those who opt out.]
What might Trump’s position on vaccines portend for those biomedical scientists and physicians who would publicly oppose his anti-vaccine sentiments? For a hint, this past December Trump’s transition team asked the DOE for a list of its employees who worked on climate change, or who had attended climate change meetings, thereby raising the specter of repercussions against those who do not adhere to Trump’s stance on the climate change issue. Would the prospect of such repercussions undermine the willingness of physicians and scientists to speak out against Trump’s stance on vaccines?
This past week, Tom Price, Trump’s pick to head the US Department of Health and Human Services (HHS), rejected the claim that vaccines are linked to autism. He did so during his confirmation hearing before the Senate Finance Committee, thus offering some hope that the Trump White House might not pursue its debunked stance on vaccines. Nonetheless, bearing in mind Trump’s unpredictability, and his alternative view of reality regarding other issues, scientific and otherwise, scientists must remain vigilant, and be willing to speak out against policy decisions based on ideological political agendas or “alternative” views of reality, rather than sound scientific evidence.
“Scientists, medics and commentators who have fought vaccine disinformation in the past must take a deep breath and return to the fray. There is no need to wait for this commission to be announced officially. There is no need to wait until it issues its findings. There is no cause to be surprised if it shows little regard for science — or even if it targets scientists who speak out in favor of vaccination… Lives are at stake (4).”
Shear MD, Haberman M, and Belluck P, Anti-Vaccine Activist Says Trump Wants Him to Lead Panel on Immunization Safety. NY Times January 11, 2017.
Andrew Wakefield and the Measles Vaccine Controversy, Posted on the blog February 9, 2015.
4. Trump’s vaccine-commission idea is biased and dangerous. Nature 541:259, 2017. doi:10.1038/541259a
Addendum: The following is from the January 11, 2017 NY Times report (1).
Both Mr. Trump and Mr. Kennedy have described themselves as “pro-vaccine.” But they have repeatedly expressed concerns about what they claim is a link between vaccines and the development of autism. At a Republican presidential debate in September 2015, Mr. Trump described knowing people personally who had seen a cause and effect.
“Autism has become an epidemic,” Mr. Trump said in the debate. “Twenty-five years ago, 35 years ago, you look at the statistics, not even close. It has gotten totally out of control.”
“I am totally in favor of vaccines,” he added. “But I want smaller doses over a longer period of time. Same exact amount, but you take this little beautiful baby, and you pump — I mean, it looks just like it’s meant for a horse, not for a child, and we’ve had so many instances, people that work for me.”
Mr. Trump has also repeatedly used Twitter to spread his concerns about the safety of vaccines. In particular, he has often raised doubts about giving children vaccines in a single large dose rather than several smaller ones… Mr. Kennedy said Mr. Trump “believes in those anecdotal stories” about the dangers of vaccines. He said the president-elect “says if you have enough anecdotal stories saying the exact same thing, that you can’t dismiss the validity.”
John Enders (1897- 1985) was one of the subjects of a recent posting, Vaccine Research Using Children (1). In the 1950s, Enders used severely handicapped children at the Walter E. Fernald State School in Massachusetts to test his measles vaccine—a vaccine that may have saved well over 100 million lives. Irrespective of the ethical issues raised by the incident at the Fernald School, Nobel laureate John Enders was one of the most highly renowned of virologists, and there is much more to his story, some of which is told here.
Enders grew up in West Hartford, Connecticut. His father, who was CEO of the Hartford National Bank, left the Enders family a fortune of $19 million when he passed away. Thus, John Enders became financially independent, which may help to account for his rather atypical path to a career in biomedical research.
Enders was under no pressure to decide on a vocation, and had no particular objective in mind when he enrolled at Yale University in 1915. In 1917 (during the First World War) he interrupted his Yale studies to enlist in the Naval Reserve. He became a Navy pilot and then a flight instructor. After three years of naval service, Enders returned to Yale to complete his undergraduate studies.
After Enders graduated from Yale he tried his hand at selling real estate in Hartford. However, selling real estate troubled him, in part because he believed that people ought to know whether or not they wanted to buy a house, rather than needing to be sold (2, 3). Thus, Enders considered other callings, finally deciding to prepare for a career teaching English literature.
What might have motivated that particular choice? Here is one possibility. During the years when Enders was growing up in West Hartford, his father handled the financial affairs of several celebrated New England writers, including Mark Twain. [The young Enders always admired Twain’s immaculate white suits whenever he visited the Enders home (3).] So, perhaps Enders’ early exposure to eminent writers among his father’s clients planted the seed for his interest in literature. In any case, Enders enrolled at Harvard to pursue graduate studies in preparation for his new calling.
Enders received his M.A. degree in English Literature from Harvard in 1922. Moreover, he was making substantial progress towards his Ph.D., when his career took yet another rather dramatic turn; one reminiscent of that taken later by Harold Varmus, who likewise did graduate studies in English literature at Harvard, with the intent of becoming an English teacher (4).
The changes in the career plans of both Enders and Varmus—from teaching English literature to biomedical research—were prompted by the friends each had who were at Harvard Medical School. Varmus’ friends were his former classmates from Amherst College. Enders first met his friends from among his fellow boarders at his Brookline rooming house.
Dr. Hugh Ward, an instructor in Harvard’s Department of Bacteriology and Immunology, was one of the friends Enders met at his rooming house. Enders wrote, “We soon became friends, and thus I fell into the habit of going to the laboratory with him in the evening and watching him work (5).” Enders was singularly impressed by Ward’s enthusiasm for his research (5).
During one of the trips that Ward and Enders made to the laboratory, Ward introduced Enders to Hans Zinsser, Head of Harvard’s Department of Bacteriology and Immunology. Zinsser was an eminent microbiologist, best known for isolating the typhus bacterium and for developing a vaccine against it.
Enders soon became fascinated by the research in Zinsser’s lab. So, at 30-years-of-age, and on the verge of completing his Ph.D. in English Literature, Enders changed career plans once again; this time to begin studies toward a doctorate in bacteriology and immunology, under Zinsser’s mentorship.
Zinsser, a distinguished microbiologist, was also a sufficiently accomplished poet to have some of his verses published in The Atlantic Monthly. That aspect of Zinsser likely impressed the literate Enders, who described his mentor as: “A man of superlative energy. Literature, politics, history, and science-all he discussed with spontaneity and without self-consciousness. Everything was illuminated by an apt allusion drawn from the most diverse sources, or by a witty tale. Voltaire seemed just around the corner, and Laurence Sterne upon the stair. . . . Under such influences, the laboratory became much more than a place just to work and teach; it became a way of life (3).”
Enders was awarded his Ph.D. in Bacteriology and Immunology in 1930. Afterwards, he remained at Harvard, as a member of the teaching staff, until 1946, when he established his own laboratory at the Children’s Medical Center in Boston.
Why might Enders have been satisfied staying so long at Harvard, for the most part as Zinsser’s underling? Perhaps that too might be explained by his financial independence. In any case, in 1939, while Enders was still at Harvard, he initiated the singularly significant course of research for which he is best remembered.
In 1939, in collaboration with Dr. Alto Feller and Thomas Weller (then a senior medical student), Enders began to develop procedures to propagate vaccinia virus in cell culture. After achieving that goal, the Enders team applied their cell culture procedures to propagate other viruses, including influenza and mumps viruses.
Enders and his coworkers were not the first researchers to grow viruses in cell culture. However, they were the first to do so consistently and routinely. Thus, the Enders lab launched the “modern” era of virus research in vitro. Virology could now advance much more quickly than before, since most virologists would no longer need to grow, or study their viruses only in live animals.
A recurrent theme on the blog is that key scientific discoveries may well be serendipitous. The case in point here was the unforeseen 1949 discovery by Enders and his young collaborators, Tom Weller and Frederick Robbins, that poliovirus could be grown in cultured cells. That crucial discovery made it possible for Jonas Salk and Albert Sabin to generate a virtually unlimited amount of poliovirus and, thus, to create their polio vaccines. Importantly, the discovery happened at a time when polio researchers believed that poliovirus could grow only in nerve cells. Their dilemma was that nerve cells could not be cultured in the laboratory.
Enders, Weller, and Robbins were not working on polio, nor did they have any immediate intention of working on polio when they made their finding. In fact, when the thirty-year-old Robbins (see Aside 1) came to work with Enders, he proclaimed that he wanted to work on any virus, except polio (6).
[Aside 1: Weller was one year older than Robbins. Both had been Army bacteriologists during the Second World War, and they were classmates and roommates at Harvard Medical School when they came to Enders for research experience. Robbins’ father-in-law, John Northrop, shared the 1946 Nobel Prize in chemistry with James Sumner and Wendell Stanley (7). In 1954, Robbins joined his father-in-law as a Nobel laureate (see below).]
The Enders team was trying to grow varicella (the chicken pox virus) when, on a whim; they made their critical discovery. It happened as follows. While attempting to propagate varicella virus in a mixed culture of human embryonic skin and muscle cells, they happened to have some extra flasks of the cell cultures at hand. And, since they also had a sample of poliovirus nearby in their lab storage cabinet; they just happened to inoculate the extra cell cultures with polio virus.
The poliovirus-infected cultures were incubated for twenty days, with three changes of media. Then, Enders, Weller, and Robbins asked whether highly diluted extracts of the cultures might induce paralysis in their test mice. When those highly diluted extracts indeed caused paralysis in the mice, they knew that poliovirus had grown in the cultures. See Aside 2.
[Aside 2: Whereas Enders, Weller, and Robbins did not have pressing plans to test whether poliovirus might grow in non-neuronal cells, they probably were aware of already available evidence that poliovirus might not be strictly neurotropic. For instance, large amounts of poliovirus had been found in the gastrointestinal tract.]
Despite the exceptional significance of their discovery, Robbins said, “It was all very simple (6).” Weller referred to the discovery as a “fortuitous circumstance (6).” Enders said, “I guess we were foolish (6)”—rather modest words from a scholar of language and literature. See Aside 3.
[Aside 3: Current researchers and students might note that Enders’ entire research budget amounted to a grand total of two hundred dollars per year! The lab did not have a technician, and Weller and Robbins spent much of their time preparing cells, media, and reagents, as well as washing, plugging, and sterilizing their glassware.]
In 1954, Enders, Weller, and Robbins were awarded the Nobel Prize for Physiology or Medicine for their polio discovery. Interestingly, they were the only polio researchers to receive the Nobel award. The more famous Salk and Sabin never received that honor (8).
If Enders were so inclined, might he have produced a polio vaccine before Salk and Sabin? Weller and Robbins wanted to pursue the vaccine project, and Enders agreed that they had the means to do so. In fact, Weller actually had generated attenuated poliovirus strains by long-term propagation of the virus in culture; a first step in the development of a vaccine (3). Yet for reasons that are not clear, Enders counseled his enthusiastic young colleagues to resist the temptation (6). See Aside 4.
[Aside 4: Enders may have spared Weller and Robbins the sort of anguish that Salk experienced when some of his killed vaccine lots, which contained incompletely inactivated poliovirus, caused paralytic poliomyelitis in some 260 children (8).]
The Enders poliovirus group began to disperse, beginning in 1952 when Robbins became a professor of pediatrics at Western Reserve. Weller left in 1954 to become chairman of the Department of Tropical Public Health at Harvard.
Regardless of whether Enders might have regretted not pursuing the polio vaccine, he soon would play a hands-on role in the development of the measles vaccine. The first critical step in that project occurred in1954, at the time when the Salk polio vaccine was undergoing field trials. It was then that Enders and a new young coworker, pediatric resident Thomas Peebles (Aside 5), succeeded in cultivating measles virus in cell culture for the first time.
[Aside 5: Enders was known for nurturing bright young investigators. His latest protégé, Tom Peebles, spent four years in the Navy, as a pilot, before enrolling at Harvard Medical School. Peebles graduated from medical school in 1951, and then did an internship at Mass General, before coming to the Enders lab to do research on infectious diseases in children. When Enders suggested to Peebles that he might try working on measles, Peebles eagerly accepted.]
Here is a piece of the measles vaccine story that happened before Peebles’ success growing the virus in cell culture. At the very start of the vaccine project, Enders and Peebles were stymied in their attempts to get hold of a sample of measles virus to work with. Their quest for the virus began with Peebles searching the Enders laboratory freezers for a sample. Finding none there, Peebles next inquired at Boston area health centers; still without success. After several more months of fruitless searching, Peebles received an unexpected phone call from the school physician at the Fay School (a private boarding school for Boys in a Boston suburb), telling him about a measles outbreak at the school. Peebles immediately rushed to the school, where he took throat swabs, as well as blood and stool samples from several of the school’s young patients. He then rushed back to the Enders laboratory, where he immediately inoculated human infant kidney cells with his samples. [Enders obtained the cells from a pediatric neurosurgeon colleague, who treated hydrocephalus in infants by excising a kidney, and shunting cerebrospinal fluid directly to the urethra.]
Peebles monitored the inoculated kidney cell cultures for the next several weeks, hoping for a sign of a virus replicating in them. Seeing no such indication of a virus in the cultures, Peebles made a second trip to the Fay School, which, like the first trip, was unproductive.
On a third trip to the school, Peebles obtained a sample from an 11-year-old boy, David Edmonston. The sample from young Edmonston indeed seemed to affect the kidney cell cultures. Still, Peebles needed to carry out several additional experiments before he could convince a skeptical Enders and Weller—first, that a virus had replicated in the cultures and, second, that it was measles. Peebles convinced the two doubters by demonstrating that serum from each of twelve convalescing measles patients prevented the virus from causing cytopathic effects in the inoculated cell cultures. That is, the convalescent serum neutralized the virus. The measles virus growing in those cultures was named for its source. It is the now famous Edmonston strain.
Enders, in collaboration with Drs.Milan Milovanovic and Anna Mitus, next showed that the Edmonston strain could be propagated in chick embryos (3). Then, working with Dr. Samuel Katz (1), Enders showed that the egg-adapted virus could be propagated in chicken cell cultures.
By 1958, Enders, Katz, and Dr. Donald Medearis showed that the Edmonston measles virus could be attenuated by propagating it in chicken cells. Moreover, the attenuated virus produced immunity in monkeys, while not causing disease (3). Thus, the attenuated Edmonston strain became the first measles vaccine. [Tests of the vaccine in humans led to the episode at the Fernald School (1).]
The Enders measles vaccine was attenuated further by Maurice Hilleman at Merck (9). In 1971 it was incorporated into the Merck MMR combination vaccine against measles, mumps, and rubella (9, 10).
The MMR vaccine has had a remarkable safety record, and it was widely accepted until 1997; the time when the now discredited claim that the vaccine is linked to autism first emerged (10). However, even prior to the MMR/autism controversy, vaccine non-compliance was already a problem. But, in that earlier time, parents were declining to have their children vaccinated, not because of safety issues, but rather because they questioned the severity of measles. Ironically, that was why David Edmonston refused to have his own son receive the vaccine.
Despite receiving the Nobel Prize for his polio work, Enders maintained that developing the measles vaccine was more personally satisfying to him and more socially significant (3).
Vaccine Research Using Children, Posted on the blog July 7, 2016.
John F. Enders-Biographical, The Nobel Prize in Physiology or Medicine 1954. From Nobel Lectures, Physiology or Medicine 1942-1962, Elsevier Publishing Company, Amsterdam, 1964.
Children have been used in vaccine research since its very beginning, usually said to have been in 1796, when Edward Jenner inoculated 8-year-old James Phipps with cowpox, and then challenged young James with actual smallpox (1). However, earlier, in 1789, Jenner inoculated his own 10-month-old son, Edward Jr., with swinepox. Edward Jr. then came down with a pox disease, which he fortunately recovered from. His father then challenged him with smallpox.
Edward Jr. survived his exposure to smallpox. But, since Edward Sr. wanted to determine the duration of young Edward’s protection, he again challenged his son with smallpox in 1791, when the boy was two. Edward Sr. inoculated his son yet again with smallpox when the boy was three. Fortunately, young Edward was resistant to each of the smallpox challenges his father subjected him to.
Jenner used several other young children in his experiments, including his second son, Robert, who was 11-months-old at the time. One of the children in Jenner’s experiments died from a fever; possibly caused by a microbial contaminant in an inoculum. [Microbes were not known in the late 18th century.]
We have no record of how Jenner (or his wife) felt about his use of his own children. However, there is reason to believe that Jenner felt some remorse over his use of James Phipps, who he referred to as “poor James.” Jenner looked after Phipps in later years, eventually building a cottage for him; even planting flowers in front of it himself.
By the 20th century, some of the most esteemed medical researchers were using children—in institutions for the mentally deficient—to test new drugs, vaccines, and even surgical procedures. These institutions were typically underfunded and understaffed. Several of them were cited for neglecting and abusing their residents. Moreover, their young patients were usually from poor families, or were orphans, or were abandoned. Thus, many of the children had no one to look out for their interests. In addition, research at these institutions was hidden from the public. [The goings-on at these institutions were, in general, hidden from the public, and most of the public likely preferred it that way.] Federal regulations that might have protected the children were not yet in existence, and federal approval was not even required to test vaccines and drugs.
In the early 1940s, Werner Henle, of the University of Pennsylvania, used children at Pennhurst—a Pennsylvania facility for the mentally deficient—in his research to develop an influenza vaccine. [Pennhurst was eventually infamous for its inadequate staffing, and for neglecting and abusing its patients (2). It was closed in 1987, after two decades of federal legal actions.] Henle would inoculate his subjects with the vaccine, and then expose them to influenza, using an oxygen mask fitted to their faces.
Henle’s vaccine did not protect all of his subjects. Moreover, it frequently caused side effects. Additionally, Henle maintained (correctly?) that a proper test of a vaccine must include a control group (i.e., a group exposed to the virus, but not to the vaccine). Thus, he deliberately exposed unvaccinated children to influenza. Children who contracted influenza had fevers as high as 104o F, as well as typical flu-like aches and pains.
Despite Henle’s investigations at Pennhuerst, he was a highly renowned virologist, best known for his later research on Epstein Barr virus. See Aside 1.
[Aside 1: While Henle was researching his influenza vaccine at Pennhurst, Jonas Salk concurrently worked on an influenza vaccine, using adult residents (ranging in age from 20 to 70 years) at the Ypsilanti State School in Michigan.]
Next, consider Hilary Koprowski, an early competitor of Jonas Salk and Albert Sabin in the race to develop a polio vaccine (3). By 1950, Koprowski was ready to test his live polio vaccine in people. [That was four years before Sabin would be ready to do the same with his live polio vaccine.] Koprowski had already found that his vaccine protected chimpanzees against polio virus. And, he also tested his vaccine on himself. Since neither he nor the chimpanzees suffered any ill effects, Koprowski proceeded to test his vaccine on 20 children at Letchworth Village for mentally disabled children, in Rockland County, NY. [Like Pennhurst, Letchworth Village too was cited for inadequately caring for its residents.] Seventeen of Koprowski’s inoculated children developed antibodies to the virus, and none developed complications.
Koprowski did not initiate his association with Letchworth. Actually, Letchworth administrators, fearing an outbreak of polio at the facility, approached Koprowski, requesting that he vaccinate the children. Koprowski gave each child “a tablespoon of infectious material” in half a glass of chocolate milk (4). Koprowski never deliberately infected the Letchworth children with virulent virus.
Koprowski reported the results of his Letchworth studies at a 1951 conference of major polio researchers, attended by both Salk and Sabin. When Koprowski announced that he actually had tested a live vaccine in children, many conferees were stunned, even horrified. Sabin shouted out: “Why did you do it? Why? Why (4)?” See Aside 2.
[Aside 2: In the 1930s, Canadian scientist Maurice Brodie tested a killed polio vaccine in twelve children, who supposedly had been “volunteered by their parents (4).” For a short time Brodie was hailed as a hero. However, too little was known at the time for Brodie to ensure that his formaldehyde treatment had sufficiently inactivated the live polio virus. Consequently, Brodie’s vaccine actually caused polio in several of the children. After this incident, most polio researchers could not conceive of ever again testing a polio vaccine, much less a live one, in children.]
Neither Koprowski nor Letchworth Village administrators notified New York State officials about the tests. Approval from the state would seem to have been required, since Koprowski later admitted that he was certain he would have been turned down. And, it is not clear whether Koprowski or the school ever got consent from the parents to use their children. However, recall there were not yet any federal regulations that required them to do so.
Koprowski was untroubled by the uproar over his use of the Letchworth children, arguing that his experiments were necessary. Yet he later acknowledged: “if we did such a thing now we’d be put on jail…” But, he added, “If Jenner or Pasteur or Theiler (see Aside 2) or myself had to repeat and test our discoveries [today], there would be no smallpox vaccine, no rabies vaccine, no yellow fever vaccine, and no live oral polio vaccine.” Moreover, he maintained that, secret or not, his use of the Letchworth children fit well within the boundaries of accepted scientific practice.
[Aside 2: Nobel laureate Max Theiler developed a vaccine against yellow fever in 1937; the first successful live vaccine of any kind (5). Theiler formulated a test for the efficacy of his vaccine, which did not involve exposing humans to virulent virus. Sera from vaccinated human subjects were injected into mice, which were then challenged with the Yellow Fever virus.]
Koprowski referred to the Letchworth children as “volunteers (6).” This prompted the British journal The Lancet to write: “One of the reasons for the richness of the English language is that the meaning of some words is continually changing. Such a word is “volunteer.” We may yet read in a scientific journal that an experiment was carried out with twenty volunteer mice, and that twenty other mice volunteered as controls.” See Aside 3.
[Aside 3: Koprowski was a relatively unknown scientist when he carried out his polio research at Letchworth. He later became a renowned virologist, having overseen the development of a rabies vaccine that is still used today, and having pioneered the use of therapeutic monoclonal antibodies. Yet, he is best remembered for developing the world’s first effective polio vaccine; several years before Salk and Sabin brought out their vaccines.
Most readers of the blog are aware that the Salk and Sabin vaccines are credited with having made the world virtually polio-free. What then became of Koprowski’s vaccine? Although it was used on four continents, it was never licensed in the United States. A small field trial of Koprowski’s vaccine in 1956, in Belfast, showed that its attenuated virus could revert to a virulent form after inoculation into humans. Yet a 1958 test, in nearly a quarter million people in the Belgian Congo, showed that the vaccine was safe and effective. Regardless, the vaccine’s fate was sealed in 1960, when the U.S. Surgeon General rejected it on safety grounds, while approving the safer Sabin vaccine. Personalities and politics may well have played a role in that decision (3, 4).
Interestingly, Sabin developed his vaccine from a partially attenuated polio virus stock that he received from Koprowski. It happened as follows. In the early 1950s, when Koprowski’s polio research was further along than Sabin’s, Sabin approached Koprowski with the suggestion that they might exchange virus samples. Koprowski generously sent Sabin his samples, but Sabin never reciprocated.
Koprowski liked to say: “I introduce myself as the developer of the Sabin poliomyelitis vaccine (7).” He and Sabin had a sometimes heated adversarial relationship during the time when their vaccines were in competition. But they later became friends.]
Sabin was at last ready to test his polio vaccine in people during the winter of 1954-1955. Thirty adult prisoners, at a federal prison in Chillicothe, Ohio, were the subjects for that first test in humans. [The use of prisoners also raises ethical concerns.]
Recall Sabin’s public outcry in 1951 when Koprowski announced that he used institutionalized children to test his polio vaccine. In 1954, Sabin sought permission to do the very same himself; asserting to New York state officials: “Mentally defective children, who are under constant observation in an institution over long periods of time, offer the best opportunity for the careful and prolonged follow-up studies…”
Although Sabin had already tested his attenuated viruses in adult humans (prisoners), as well as in monkeys and chimpanzees, the National Foundation for Infantile Paralysis, which funded polio research in the pre-NIH days of the 1950s, blocked his proposal to use institutionalized children. Thus, Sabin again used adult prisoners at the federal prison in Ohio. With the concurrence of prison officials, virtually every inmate over 21 years-old “volunteered,” in exchange for $25 each, and a possible reduction in sentence. None of the prisoners in the study became ill, while all developed antibodies against polio virus.
Testing in children was still a necessary step before a polio vaccine could be administered to children on a widespread basis. But, Sabin’s vaccine could not be tested in children in the United States. Millions of American children had already received the killed Salk vaccine, and the National Foundation for Infantile Paralysis was not about to support another massive field trial of a vaccine, in children, in the United States (3).
Then, in 1959, after a succession of improbable events, 10 million children in the Soviet Union were vaccinated with Sabin’s vaccine (3). The Soviets were so pleased with the results of that massive trial that they next vaccinated all seventy-seven million Soviet citizens under 20 years-of-age with the Sabin vaccine. That figure vastly exceeded the number of individuals in the United States, who were vaccinated with the rival Salk vaccine during its field trials.
Next up, we have Nobel laureate John Enders who, in the 1950’s, oversaw the development of the first measles vaccine. Enders and co-workers carried out several trials of their attenuated measles vaccine; first in monkeys and then in themselves. Since the vaccine induced an increase in measles antibody titers, while causing no ill effects, they next tested it in severely handicapped children at the Walter E. Fernald State School near Waltham, Massachusetts.
Enders seemed somewhat more sensitive than either Henle or Koprowski to the ethics of using institutionalized children. Samuel L. Katz, the physician on Enders’ team, personally explained the trial to every Fernald parent, and no child was given the vaccine without written parental consent. [Federal guidelines requiring that step still did not exist.] Also, no child was deliberately infected with virulent measles virus.
Katz personally examined each of the inoculated Fernald children every day. None of these children produced measles virus, while all of them developed elevated levels of anti-measles antibodies. Also, the Fernald School had been experiencing severe measles outbreaks before the Enders team vaccinated any of its children. But, when the next measles outbreak struck the school, all of the vaccinated children were totally protected.
In 1963, the Enders vaccine became the first measles vaccine to be licensed in the United States. Several years later it was further attenuated by Maurice Hilleman (8) and colleagues at Merck. In 1971, it was incorporated into the Merck MMR (measles, mumps, and rubella) vaccine. See Aside 4.
[Aside 4: Before Enders carried out his measles investigations he pioneered the growth of viruses in tissue culture. In 1949, Enders, and collaborators Thomas Weller and Frederick Robbins, showed that poliovirus could be cultivated in the laboratory. This development was crucial, allowing Salk and Sabin to grow a virtually unlimited amount of polio virus and, consequently, to develop their polio vaccines. In 1954, Enders, Weller, and Robbins were awarded the Nobel Prize for Physiology or Medicine for their polio virus work.]
It may surprise some readers that before the mid 1960s the so-called Nuremburg Code of 1947 comprised the only internationally recognized ethical guidelines for experimentation on human subjects. The Nuremburg Code was drawn up by an American military tribunal during the trial of 23 Nazi physicians and scientists for atrocities they committed while carrying out so-called “medical” experiments during World War II. [Sixteen of the 23 Nazis on trial at Nuremburg were convicted, and 7 of these were executed (see Note 1)].
The Nuremberg Code’s Directives for Human Experimentation contained strongly stated guidelines. Its tenets included the need to obtain informed consent (interpreted by some to prohibit research using children), the need to minimize the risks to human subjects, and the need to insure that any risks are offset by potential benefits to society.
But, despite the well-articulated principles of the Nuremberg Code, it had little effect on research conduct in the United States. Federal rules, with the authority to regulate research conduct, would be needed for that. So, how did our current federal oversight of research come to be?
A 1996 paper in the The New England Journal of Medicine, “Ethics and Clinical Research,” by physician Henry Beecher, brought to the fore the need for rules to protect human subjects in biomedical research (9). Beecher was roused to write the paper in part by the early 1960s experiments of Saul Krugman, an infectious disease expert at NYU. Krugman used mentally deficient children at the Willowbrook State School in Staten Island, New York, to show that hepatitis A and hepatitis B are distinct diseases (9). Also, before a hepatitis vaccine was available, Krugman inoculated the children with serum from convalescing individuals, to ask whether that serum might protect the children against hepatitis. Krugman exposed the children to live virus either by injection, or via milkshakes seeded with feces from children with hepatitis.
Krugman found that convalescent sera indeed conferred passive immunity to hepatitis. Next, he discovered that by infecting passively protected patients with live hepatitis virus he could produce active immunity. Krugman had, in fact, developed the world’s first vaccine against hepatitis B virus (HBV) (see Aside 4). [Although Krugman used mentally deficient institutionalized children in his experiments, his investigations were nonetheless funded in part by a federal agency; the Armed Forces Epidemiology Section of the U.S. Surgeon General’s Office.]
[Aside 4: The first hepatitis B vaccine licensed for widespread use was developed at Merck, based on principles put forward by Nobel Laureate Baruch Blumberg, (10).]
Beecher was particularly troubled by two aspects of Krugman’s experiments. First, Krugman infected healthy children with live virulent virus. Beecher maintained that it is morally unacceptable to deliberately infect any individual with an infectious agent, irrespective of the potential benefits to society. [See reference 11 for an alternative view. “The ethical issue is the harm done by the infection, not the mere fact of infection itself.”]
Second, Beecher charged that the Willowbrook School’s administrators coerced parents into allowing their children to be used in Krugman’s research. The circumstances were as follows. Because of overcrowding at the school, Willowbrook administrators closed admission via the usual route. However, space was still available in a separate hepatitis research building, thereby enabling admission of additional children who might be used in the research.
Were the Willowbrook parents coerced into allowing their children to be used in the research there? Consider that the parents were poor and in desperate need of a means of providing care for their mentally impaired children. Making admission of the children contingent on allowing them to be used in the research might well be viewed as coercion. Yet even today, with federal guidelines now in place to protect human subjects, institutions such as the NIH Clinical Center admit patients who agree to participate in research programs. Is that coercion?
Beecher’s 1966 paper cited a total of 22 instances of medical research that Beecher claimed were unethical (9). Four examples involved research using children. Krugman’s work at Willowbrook was the only one of these four examples that involved vaccine research. Beecher’s other examples involved research using pregnant women, fetuses, and prisoners. But it was Beecher’s condemnation of Krugman’s hepatitis research at Willowbrook that is mainly credited with stirring debate over the ethics of using children in research.
Did Krugman deserve Beecher’s condemnation? Before Krugman began his investigations at Willowbrook, he plainly laid out his intentions in a 1958 paper in the New England Journal of Medicine (12). Importantly, Krugman listed a number of ethical considerations, which show that he did not undertake his Willowbrook investigations lightly. In fact, Krugman’s ethical considerations, together with his plans to minimize risks to the children, were not unlike the assurances one might now submit to an institutional review board (11).
Many (but not all) knowledgeable biomedical researchers claimed that Beecher misunderstood Krugman’s research and, thus, unjustly vilified him. Krugman was never officially censored for his Willowbrook investigations. Moreover, condemnation of Krugman did not prevent his election in 1972 to the presidency of the American Pediatric Society, or to his 1983 Lasker Public Service Award.
To Beecher’s credit, his 1966 paper was instrumental in raising awareness of the need to regulate research using human subjects. Beecher was especially concerned with the protection of children and, apropos that, the nature of informed consent.
In 1974, the National Research Act was signed into law, creating the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The basic ethical principles identified by the Commission are summarized in its so-called Belmont Report, issued in 1978. Its tenets include minimizing harm to all patients, and the need to especially protect those with “diminished autonomy” or who are incapable of “self-determination.” In addition, federal guidelines now require universities and other research institutions to have Institutional Review Boards to protect human subjects of biomedical research. [Reference 13 (available on line) contains a detailed history of the establishment of these policies.] See Aside 6.
[Aside 6: The infamous U.S. Public Health Service Tuskegee syphilis research program, conducted between 1932 and 1972, in which several hundred impoverished black men were improperly advised and never given appropriate treatment for their syphilis, also raised public awareness of the need to protect human subjects. More recently, research involving embryonic stem cells and fetuses has stoked an ongoing and heated public debate. Policies regarding this research are still not settled, with stem-cell research being legal in some states, and a crime in others. Other recent technological advances, such as DNA identification and shared databases, have been raising new concerns, such as the need to protect patient privacy. In response to these new developments, in June 2016, the US National Academies of Sciences,Engineering and Medicine released a report proposing new rules (indeed a complete overhaul of the 1978 Belmont Report) to deal with these circumstances. The Academy’s report has stirred debate in the biomedical community]
Note 1: The use of children in medical research makes many of us profoundly uneasy. We may be particularly troubled by accounts of the exploitation of institutionalized children, who comprised a uniquely defenseless part of society. Indeed, it was the very vulnerability of those children that made it possible for them to be exploited by researchers. Consequently, some readers may well be asking whether the activities of vaccine researchers Krugman, Koprowski, Sabin, Henle and others might have been comparable to that of the Nazis on trial at Nuremberg. So, I offer this cautionary interjection. While in no way condoning the vaccine researchers using institutionalized children, their work was carried out for the sole purpose of saving human lives. As Koprowski suggested above, if not for that work, we might not have vaccines against smallpox, rabies, yellow fever, and polio. Now, consider Josef Mengele, a Nazi medical officer at Auschwitz, and the most infamous of the Nazi physicians. [Mengele was discussed several times at Nuremberg, but was never actually tried. Allied forces were convinced at the time that he was dead, but he had escaped to South America.] At Auschwitz, Mengele conducted germ warfare “research” in which he would infect one twin with a disease such as typhus, and then transfuse that twin’s blood into the other twin. The first twin would be allowed to die, while the second twin would be killed so that the organs of the two children might then be compared. Mengele reputedly killed fourteen twin children in a single night via a chloroform injection to the heart. Moreover, he unnecessarily amputated limbs and he experimented on pregnant women before sending them to the Auschwitz gas chambers.
Edward Jenner and the Smallpox Vaccine, Posted on the blog September 16, 2014.
Pennhurst Asylum: The Shame of Pennsylvania, weirnj.com/stories/pennhurst-asylum/
Jonas Salk and Albert Sabin: One of the Great Rivalries of Medical Science, Posed on the blog March 27, 2014.
Oshinsky D, Polio: An American Story, Oxford University Press, 2005.
The Struggle Against Yellow Fever: Featuring Walter Reed and Max Theiler, Posted on the blog May 13, 2014.
Koprowski H, Jervis GA, and Norton TW. Immune response in human volunteers upon oral administration of a rodent-adapted strain of poliomyelitis virus. American Journal of Hygiene, 1952, 55:108-126.
Fox M, Hilary Koprowski, Who Developed First Live-Virus Polio Vaccine Dies at 96, N.Y. Times, April 20, 2013.
Controversy over the measles vaccine, and the spate of vaccine noncompliance that underlies the current measles outbreak in the United States, stem mostly from a totally debunked 1998 study by former British surgeon, Andrew Wakefield. In Wakefield’s now infamous report, he and co-authors claimed to find a link between the measles vaccine and autism. Here are some essential facts concerning measles, the measles vaccine, and Wakefield’s paper.
We begin with the crucial concept of herd immunity. People who cannot get vaccinated (e.g., young infants, pregnant women, children suffering from leukemia or other immune deficiencies) are nonetheless protected from measles by herd immunity; the immunity in the whole population that results when a high enough percentage of individuals in the population has been vaccinated. When herd immunity is attained, there are not enough susceptible individuals in the population to sustain the chain of transmission.
But, if enough parents opt out of having their children vaccinated, then herd immunity is lost, and outbreaks might then occur, as is happening now. Herd immunity against measles requires vaccination rates as high as 95 percent. That is so because measles is one of the most contagious of all viruses. Yet, all too many parents are now opting out of vaccinating their children; in many cases for fear that the measles vaccine might cause autism.
The measles incubation period is another important issue. The elapsed time, between initial infection and onset of illness, averages 10–12 days (rash may not appear until 18 days). Moreover, infected individuals can transmit the virus for several days before becoming ill. These points, together with the exceptionally high rate of measles transmission, mean that keeping sick children home from school or play group, is not an effective means for containing spread of the disease.
Next, consider the severity of measles, which all too many people, including some medical professionals, do not appreciate. [I heard one medical doctor on TV say measles is like the common cold.] Before the introduction of the first measles vaccine in 1963, and the WHO-sponsored global eradication program, death rates from measles ran as high as 7 to 8 million children, worldwide, annually. And, despite the current availability of effective measles vaccines, there still are more than 30 million measles cases per year worldwide, of which more than 1 million are fatal. As you might expect, the vast majority of fatal measles cases occur in unvaccinated populations in the developing world. In fact, in some unprotected groups, measles is the major cause of death in children less than five-years-old. [Reliable information on all aspects of measles can be found on line at “Measles – Centers for Disease Control and Prevention,” http://www.cdc.gov/…/meas.]
The above data unmistakably support the case for vaccination against measles. Ever since the first measles vaccine was introduced in 1963, the incidence of measles has been dramatically reduced in all regions of the world where vaccination programs were put in place. In the United States, the number of measles cases declined from about 500,000 per year before 1963, to no endemic cases whatsoever in 2000!
But, since measles persisted elsewhere in the world, and, since the measles virus is so highly contagious, it returned to the United States in the years between 1989 and 1991, when vaccination rates fell below the critical level needed to maintain herd immunity. In that earlier 1989 outbreak, poor compliance with vaccine programs was, ironically, due to the success of the vaccine program. Because measles was no longer existent in the United States, it was not in the public’s consciousness, resulting in public complacency towards vaccination.
At present, segments of the public are opting out of vaccinating their children largely because of Wakefield’s discredited 1998 paper in The Lancet, which asserted that the trivalent measles, mumps, and rubella (MMR) vaccine might cause autism. Here is the story of how and why Wakefield’s 1998 paper fell into disrepute.
The validity of Wakefield’s 1998 findings first came under question in 2004 when an article in the Sunday Times of London reported that Wakefield had not disclosed a conflict of interest that might have compromised his objectivity. The newspaper revealed that Wakefield accepted £55,000 ($103,000) to support his study, from lawyers representing parents of autistic children. The purpose of the financial support was to validate the parents’ legal claims against the vaccine manufacturer. Astonishingly, some of the families in Wakefield’s study actually were selected by these lawyers. Next, in 2006, the Sunday Times reported that the lawyers had paid Wakefield personally more than £400,000, none of which was ever reported.
Irrespective of Wakefield’s conflict of interest, the 1998 study was exceptionally weak on several counts. First, its conclusions were based on a sample size of only twelve children. What’s more (and virtually unbelievably), the association between the vaccine and autism was concluded merely from interviewing the children’s parents; people who were not likely to be the most objective of observers, since at least some were looking for someone or something to blame for their children’s condition.
The credibility of Wakefield’s already weak paper took a major hit when it was revealed in 2009 that he had manipulated patients’ data. Wakefield’s paper claimed that the families of eight of the twelve children attributed their children’s autism to the MMR vaccine and that the children’s problems emerged within days after their vaccinations. The Wakefield paper also reported the discovery of a new inflammatory bowel disease it associated with the vaccine, and it proposed that the new disease also might be connected to autism. However, an investigation by the British Medical Council (BMC) found that in most cases the data in The Lancet was not in accord with the children’s medical records. In only one case was there any suggestion that there was any problem within days of the vaccination. In fact, in many of the cases, the parents expressed concerns about autism before their children’s’ vaccinations. And, a November 2011 paper in the British Medical Journal reported that an investigation of Wakefield’s raw data revealed that none of the twelve children in his study had signs of inflammatory bowel disease.
The BMC’s investigating panel ruled that Wakefield had “failed in his duties as a responsible consultant”, acted both against the interests of his patients, and “dishonestly and irresponsibly” in his published research. What’s more, the British Medical Journal took the extraordinary step of publishing a report in which it concluded that Wakefield’s study was not simply bad science, but a deliberate and elaborate fraud. Shortly afterwards, Wakefield was removed from the United Kingdom’s Medical Register and barred from practicing medicine in the UK.
In a large scale study, involving more than a half million children, the U.S. Institute of Medicine (IOM), a respected independent arbiter, found no evidence whatsoever of any connection between vaccines and autism. Other large and well designed studies likewise found no such connection.
In 2010, The Lancet responded to the above revelations by retracting Wakefield’s 1998 paper. Moreover, ten of Wakefield’s twelve co-authors issued a retraction, which included the following: “We wish to make it clear that in this paper no causal link was established between (the) vaccine and autism, as the data were insufficient. However the possibility of such a link was raised and consequent events have had major implications for public health. In view of this, we consider now is the appropriate time that we should together formally retract the interpretation placed upon these findings in the paper…”
Despite these developments, Wakefield has stood by his claims, and many still regard him as a hero. What’s more, Wakefield’s claims continue to influence many parents, and they are a major reason for the sharp decline in vaccination rates in the United Kingdom and in the United States.
Why might The Lancet have published Wakefield’s 1998 paper in the first place? As explained by Richard Horton, Editor-in-Chief of The Lancet, the journal was interested in the new gastrointestinal disorder described in the paper, rather than in the parents’ testimony regarding a possible link between the MMR vaccine and autism. Horton states: “The central thrust of the paper was this new syndrome. This is not an uncommon kind of report. If you read any text book of epidemiology, the very first description of any new syndrome often comes with either a case report or a case series.” [Note the rather inconspicuous title of Wakefield’s highly flawed but influential paper: “Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children”]
Horton also noted that the journal was well aware that the Wakefield paper might have an adverse public health impact, which it sought to avoid by including in the paper the disclaimer that there was no proof of causation or association between the MMR vaccine and autism, and also by identifying the paper as an “early” report. But the media and the public could hardly be expected to disregard the sensational story behind the disclaimers.
We conclude with a few related items.
Doubts about Wakefield’s scientific credibility might have been raised before he ever turned his attention to the measles vaccine and autism. In 1993 he published reports concluding that the measles virus might cause Crohn’s disease, and two years after that he published a paper (in The Lancet) suggesting a link between the measles vaccine and Crohn’s disease. Neither of these claims could be verified by a number of subsequent peer-reviewed studies.
Some individuals believe that thimerosal (a mercury compound once added to some vaccines as a preservative) is the link between vaccines and autism. Regarding the possibility that thimerosal in the MMR vaccine might be responsible for autism, the MMR vaccine is a live vaccine, and thimerosol was added only to killed vaccines (e.g., the vaccines against diphtheria, whooping cough, and tetanus). What’s more, all routine vaccinations in the United States have been thimerosol-free since 2001.
One might presume that the way to convince vaccine skeptics of the safety of vaccines, and of their importance for the good of all, is for public health experts and medical practitioners to confront the deniers with the data and the facts. Yet the result of those efforts is usually quite the opposite of what is intended. When confronted with the facts, the deniers dig their heels in even deeper to hold on to their anti-vaccine position. And, we scientists don’t reassure the public by always qualifying our pronouncements with statements such as “to the best of our knowledge” or “as far as we know.” [I am by no means suggesting that we ought to abandon our inclination to not speak in absolutes.]
The state of affairs was not helped when some 2016 presidential aspirants (one of whom is a medical doctor) not only equivocated over the pubic health aspects of the vaccine controversy, but also framed it as an issue of government infringement on the peoples’ liberties. As expected, the latter position has more political potency among conservative voters. However, the debate does not break cleanly between liberals and conservatives, or along income or education demographics. In fact, the movement to forgo vaccinations has become popular in some more liberal and affluent communities; the organic grocery demographic. [Somehow it is better to expose a child to a dangerous disease, so that the child might have “natural” immunity to the disease, rather than have the child receive a safe vaccine that prevents the dangerous disease in the first place.] Even veterinarians are running up against the anti-vaccine movement, as more and more pet owners are foregoing vaccines against distemper and other pet ailments.
Because government enforcement of vaccine regimens might be viewed by many as an intrusion on individual liberty, all but two states (Mississippi and West Virginia) allow exemptions based on religious beliefs. In addition, nineteen states allow exemptions based on personal (whatever that may mean) beliefs. All states do allow medical exemptions, since some children (e.g. those receiving chemotherapy or who have certain immune disorders) cannot receive vaccines. Nevertheless, despite the fact that states in which it is easier to obtain non-medical exemptions have higher rates of vaccine-preventable disease, moves are afoot in several states (including Mississippi and West Virginia) to make it easier still to obtain personal belief exemptions.
Reference: Wakefield, A. J., S. H. Murch, A. Anthony, J. Linnell, D. M. Casson, M. Malik, M. Berelowitz, A. P. Dhillon, M. A. Thomson, P. Harvey, A. Valentine, S. E. Davies, and J. A. Walker-Smith. 1998. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. The Lancet351:637–641.