Tag Archives: Andrew Wakefield

President Trump’s Advocacy of the Debunked Link Between Vaccines and Autism

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).”

References:

  1. 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.
  2.  Andrew Wakefield and the Measles Vaccine Controversy, Posted on the blog February 9, 2015.
  3. Mnookin S, How Robert F. Kennedy, Jr. Distorted Vaccine Science, Scientific American, STAT on January 11, 2017, https://www.scientificamerican.com/.../how-robert-f-kennedy-jr-distorted-vaccine-scie…
  4. 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.”

Advertisements

Norman McAlister Gregg and the Discovery of Congenital Rubella Syndrome

Our last posting (1) reviewed key facts about mumps and rubella; the other two viruses targeted by the trivalent MMR vaccine. The current posting tells how, in 1941, Australian ophthalmologist, Norman McAlister Gregg (1892-1966), discovered a link between rubella infection of a woman during pregnancy and her baby suffering from severe birth defects. Gregg’s finding was astonishing at the time because rubella, which is characterized by a rash and swollen glands, was regarded as nothing more than a mild childhood illness; a mere nuisance.

Norman Mcalister Gregg
Norman McAlister Gregg

Rubella is also known as German measles, since it was initially recognized in Germany (in 1814), and since it was at first thought to be a variant of measles. It was suspected of having a viral etiology as early as 1914, but rubella virus per se was not isolated until 1961. Norman Gregg’s story and his remarkable 1941 discovery are as follows.

Gregg received his medical degree in Australia in 1915. World War I was underway at the time, and Gregg immediately joined the British Expeditionary Force, which was then fighting in France. While Gregg was serving in France, as a captain in the Royal Army Medical Corps, he was wounded and was awarded the British Military Cross for gallantry in the field.

Gregg’s Military Cross citation read: “For conspicuous gallantry and devotion to duty during a raid. He untiringly attended to the wounded under heavy enemy fire until the last man was cleared, and showed great coolness and devotion to duty. He worked persistently throughout the raid in the open, and searched for any wounded that might have been overlooked. He behaved splendidly.” [See Aside 1]

[Aside 1: For more on the wartime experiences and heroism of several other important individuals in the history of virology see references 2, 3, and 4.]

Incidentally, Gregg was an outstanding athlete, who excelled at several sports. And, if it were not for the occurrence of World War I, he likely would have played on the Australian Davis Cup team. Note that Australian tennis players dominated international tennis tournaments until the 1960s.

When World War I ended, Gregg returned to Australia, where he served as a resident at the Royal Prince Alfred Hospital in Sydney. He then went to England in 1922 for further training in ophthalmology, and returned to Australia the following year to practice ophthalmic surgery. By 1941, Gregg established himself as senior ophthalmic surgeon at both the Royal Prince Alfred Hospital and the Royal Alexandra Hospital for Children. That very same year he published his landmark paper linking rubella infection during pregnancy to congenital birth defects.

The story of Gregg’s discovery began in 1940, during the Second World War. Australia was then in the midst of a severe rubella epidemic that began in 1939 under the crowded conditions in Australia’s wartime army camps. The illness was spread to the general population by infected soldiers, and it is very likely that some of these young soldiers transmitted the virus to their young wives; some of whom were likely pregnant. There had not been a rubella epidemic in Australia for many years prior to the 1939 outbreak.

In 1940, Gregg, in his role as an ophthalmologist in Sydney, noticed an unusually high incidence of infants born with cataracts. Gregg’s concern over the frequency of these infant cataract cases led him to write to other doctors in Australia to inquire into whether they might likewise have noticed an unusually high incidence of newborns with cataracts. After Gregg’s colleagues reported back, he knew of a total of 78 infant cataract cases, 44 of whom also had heart defects.

Several aspects of these of fetal cataract cases led the perceptive Gregg to suspect that they might be caused by an infectious agent, rather than by a solely developmental or genetic abnormality. First, from his perspective as an ophthalmologist, Gregg noted that the cataracts were atypical in that only the innermost layers of the lens, which form early in development, were affected. Second, many of the children also had heart defects and stunted development, suggesting to Gregg that a more systemic factor caused the syndrome . And, third, there was the uncommonly high frequency and widespread distribution of cases.

To determine whether these cases of congenital birth defects indeed might have a common thread, Gregg carried out a retrospective study (also called a case-control study), in which one tries to identify possibly relevant factors or conditions that existed before the outbreak of the disease. Gregg interviewed the mothers of the 78 affected infants. Remarkably, from these interrogations he learned that 68 of these mothers had contracted rubella early in their pregnancies. [Note that rubella can be so mild that some mothers, who did not report having been infected, may unknowingly have been infected.]

To inquire further into whether there might be a causal relationship between maternal rubella infection and congenital fetal deformities, Gregg next carried out a prospective study (also called a cohort study), in which one tracks a sample of the population that was exposed to the putative etiologic agent before the onset of disease. Thus, Gregg identified a cohort of pregnant women, who had experienced a rash-like illness during their current pregnancies, and then monitored those women to see if their babies displayed congenital defects. A comparison of this group of babies, with those born of mothers who had not experienced a rash-like illness, corroborated the relationship between congenital defects and maternal exposure to rubella virus.

Gregg was bold to assert that rubella during pregnancy could cause congenital malformations. First, the prevailing view at the time was that the placenta provides an impenetrable barrier to infections in utero. Second, the established belief among medical doctors was that all congenital abnormalities are inherited. Third, doctors found it difficult to accept that rubella, which was thought of as a mild disease of childhood, could be connected to severe birth defects. Fourth, there was not yet a laboratory test for rubella. Thus, Gregg’s proposition was based entirely on clinical assessments. For these reasons, Gregg’s work was initially met with skepticism by the medical community.

Nonetheless, Gregg’s findings aroused enough interest that the Australian National Health and Research Council sponsored a follow-up study by medical researcher, Charles Swan, which, when published in 1943, completely substantiated Gregg’s findings. Incidentally, it was Swan who added deafness to the symptoms of congenital rubella syndrome. Mental retardation was noted later by others.

Despite Swan’s corroborating findings, several more years would pass before Gregg’s determinations were widely accepted. [Curiously, the British medical journal The Lancet, which later published Andrew Wakefield’s discredited paper claiming a link between autism and the measles vaccine (5), stated in 1944 that Gregg had failed to prove his case.] The key that led to Gregg’s findings being finally accepted was the analysis by Oliver Lancaster, a statistician and epidemiologist at the University of Sydney, who concluded that Gregg’s data, which related severe birth defects to rubella infection during pregnancy, was statistically significant. Once accepted, Gregg’s pioneering study would greatly stimulate further research into birth defects and their causes. See Aside 2.

[Aside 2: The history of science contains many examples of correct hypotheses that were initially viewed as too radical to be accepted by the scientific community. Howard Temin’s provirus hypothesis is a particularly apt case in point (6).]

Gregg received numerous prestigious awards for his discovery from the governments and scientific societies of Australia, Canada, Great Britain, and New South Wales. But despite his many honors, Gregg is said to have remained an exceptionally humble, friendly, and caring man, who was “held in great respect and affection by all.” When he was notified that there was interest in nominating him for the 1958 Nobel Prize in physiology or medicine, he modestly stated: “I must confess that it comes as a great surprise and rather a shock that my name should even be considered . . . I feel it only fair to you to inform you that I have really no serious publications except those on Rubella as I have found very little time or inclination for writing during a very busy life.”

As noted above, rubella virus was isolated in 1961, and a live attenuated rubella vaccine was developed by 1969. The vaccine, usually given as a component of the trivalent MMR (measles, mumps, and rubella) vaccine, has vastly decreased the incidence of congenital rubella syndrome in regions where it has been used (1).

References:

(1) Andrew Wakefield and the MMR Vaccine Controversy: What about Mumps and Rubella?, Posted on the blog February 18, 2015.

(2) Max Delbruck, Lisa Meitner, Niels Bohr, and the Nazis, Posted on the blog October 30, 2014.

(3) Renato Dulbecco and the Beginnings of Quantitative Animal Virology, Posted on the blog November 19, 2014.

(4) Genealogies and a Selective History of Lysogeny: Featuring Friedrich Loeffler, Emile Roux, Andre Lwoff, Elie Wollman, and Francois Jacob, Posted on the blog January 28, 2015.

(5) Andrew Wakefield and the Measles Vaccine Controversy, Posted on the blog February 9, 2015.

(6) Howard Temin: “In from the Cold”, Posted on the blog November 25, 2014.

Andrew Wakefield and the MMR Vaccine Controversy: What about Mumps and Rubella?

Our last posting, Andrew Wakefield and the Measles Vaccine Controversy (February 9, 2015), discussed how the British journal, The Lancet, published a study by former British surgeon, Andrew Wakefield, which claimed to find a link between autism and the trivalent measles, mumps, and rubella (MMR) vaccine. Despite Wakefield’s paper being totally discredited and, consequently, being retracted by the The Lancet, as well as by ten of Wakefield’s twelve coauthors, Wakefield has stood by his claims, and is regarded as a hero by large segments of the American and British publics. What’s more, the increase in vaccine noncompliance resulting from Wakefield’s paper largely underlies the current measles outbreak in the United States (1).

Thus far, virtually all of the coverage in the media concerning Wakefield’s paper and vaccine noncompliance has been with regard to measles. But the trivalent MMR vaccine also protects against two additional well known and potentially serious viral diseases; mumps and rubella. Here are some key facts about these other two illnesses.

In pre-vaccine days, mumps was most commonly a non-life-threatening childhood infection, characterized by a painful swelling of the salivary glands and fever. Yet children still suffered from rare, but severe complications, including deafness and permanently disabling or even fatal encephalitis.

Mumps occurred mainly in children in those pre-vaccine days because mumps, like measles, is highly contagious. Consequently, an individual was unlikely to pass through childhood without having been infected.

Non-compliant parents should now be aware that one upshot of mumps vaccination regimens is that if their unvaccinated children were to be infected, it would very likely be in adolescence or adulthood. Importantly, the risk of serious mumps complications is far higher in adolescents and adults than in young children. For instance, a particularly painful orchitis (inflammation of the testis) is rare in prepubescent boys with mumps, but it occurs in more than a third of cases involving adolescents and adult men, in whom it can lead to atrophy of the affected testicle. Other glands that may be affected by mumps include the pancreas (often), ovaries, thyroid, and breast.

The introduction of a mumps vaccine in the United States in 1968 reduced the number of reported mumps cases from over 150,000 per year (there were many more unreported cases) to a few hundred cases per year. However, mumps outbreaks still occurred in the U.S., most recently in 2011-2013, when several small mumps outbreaks happened on college campuses in California, Virginia, and Maryland. A series of outbreaks also occurred in the United States in 2005-2006.

To appreciate why mumps outbreaks still occur, even in highly vaccinated populations, and why vaccine noncompliance can facilitate those outbreaks, consider the following points. First, although the mumps vaccine is highly effective, it does not prevent infection in 100% of vaccine recipients. Instead, it is estimated to protect 80% to 90% of vaccinated individuals.

Second, we need to consider again the concept of herd immunity; the immunity in the whole population that results when a sufficient 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.

What then is the percentage of individuals in a population that needs to be immune to attain herd immunity; the herd immunity threshold. It varies from one pathogen to another, depending on the virulence of the disease, the efficacy of the vaccine, and the infectiousness of the pathogen. For mumps, the herd immunity threshold is estimated to be 75%-86%. Consequently, the 10% to 20% of people who received the MMR vaccine, but who are still susceptible to mumps, may leave enough wiggle room for occasional outbreaks to still happen. Additionally, and importantly, unvaccinated individuals in the population can account for a sufficient enough discrepancy between the percentage of immune individuals in the population and the herd immunity threshold to enable outbreaks to occur. And, it is an indisputable fact that when outbreaks do occur, the vast majority of clinical cases involve unvaccinated individuals.

Particular circumstances may also facilitate an outbreak. For example, the close-contact settings of college campuses may have enabled the 2011-2013 incidents to happen. And, since routine vaccination against mumps only began in 1977, more than one-third of the mumps cases reported between1985 and 1987 occurred in adolescents, who, as a group, were inadequately vaccinated during the 1070s. And, since some of those individuals, and the ones affected in the 2011-2013 outbreaks, were post-pubescent, they were more prone to developing more serious mumps complications. Another point to note about mumps before moving on is that an individual infected with mumps can unknowingly transmit the virus for several days before the emergence of symptoms.

Rubella, also known as German measles, makes for a different, and perhaps more compelling state of affairs. Rubella, like measles and mumps, was generally known as a mild childhood illness, with most rubella cases occurring in children between 5 to 9 years of age. Clinical cases were characterized by a rash and swollen glands. However, about half of all serologically confirmed childhood rubella infections were subclinical, and many adults were unsure of whether or not they ever had that illness.

The reason most rubella infections occurred in children is because rubella, like measles and mumps, is so highly contagious. And, since rubella epidemics occurred every few years in pre-vaccine days, over 80% of individuals were immune to the virus by the time they reached adulthood.

As in the case of mumps, the advent of vaccination against rubella in 1969 brought about a change in the age distribution of rubella cases, such that outbreaks now mostly affect adolescents and young adults. Importantly, the vast majority of these cases occur in unvaccinated individuals, validating that reappearances of rubella are mainly due to vaccine noncompliance, rather than to vaccine failure.

But, since rubella is usually such an innocuous illness, why is vaccination against rubella needed at all? The key reason is that rubella poses an especially severe danger to the fetus of a susceptible pregnant woman. That is so because the rubella virus is one of only a handful of viruses able to cross the human placenta (2). Consequently, a susceptible woman, who is infected during pregnancy, runs a substantial risk that her baby will be infected in utero and, as a result, be born with severe rubella-associated birth defects (congenital rubella syndrome), which include deafness, blindness, heart disease, mental retardation, and impaired growth. One study reported that 85% of all infants born to unvaccinated women, who were infected during the first eight weeks of pregnancy, had congenital rubella syndrome! [The risks to the fetus go up dramatically if the mother is infected during the first or last trimesters of pregnancy.] Rubella infection during pregnancy can also cause a premature delivery or a still birth.

Babies born with congenital rubella syndrome are also a potential source for further rubella transmission since they shed substantial amounts of rubella virus for several months after birth. What’s more, these babies pose a particular threat to pregnant woman, either directly, or via infecting staff members in maternity wards, prenatal clinics, or doctors’ offices.

Unvaccinated women, who are already pregnant, are advised against receiving the rubella vaccine because there is a slight (1.6%) theoretical chance that the live vaccine might cause congenital rubella syndrome. Thus, any unvaccinated woman planning to become pregnant is very strongly urged to be vaccinated before conceiving. She then needs to wait at least four weeks for the vaccine to take. If a woman is not sure of her immune status, a blood test for anti-rubella antibodies can tell her whether or not she is already immune. [Accurate information on all aspects of rubella and the rubella vaccine can be found at the U.S. Centers for Disease Control website.]

Some pregnant women, for one reason or another, will remain unvaccinated. Also, since the clinical efficacy of the rubella vaccine is about 90%, an additional small percentage of women who have been vaccinated are nonetheless susceptible to rubella. However, virtually all susceptible women, and their babies, can yet be protected if enough parents comply with vaccine regimens and have their children vaccinated on schedule.

No vaccine is 100% effective. Nonetheless, the case for vaccination against rubella is compelling. Before the introduction of rubella vaccination in 1969, rubella-associated birth defects were strikingly common. Indeed, a world-wide rubella epidemic from 1964 to 1965 resulted in approximately 12.5 million rubella cases in the United States alone, including 20,000 infants who were born here with congenital rubella syndrome!

The 1964 rubella outbreak was the last such one to occur in the United States. Now, approximately 10 cases of rubella are reported each year, and congenital rubella syndrome is very rare.

The remaining few cases of rubella that still occur in the United States usually originate from infected individuals visiting from regions of the world where rubella is still endemic, or from unvaccinated U.S. residents who traveled to one of those regions and then unknowingly brought the disease back home. Importantly, rubella cases in the U.S. almost always occur in unvaccinated individuals.

A few other points to note: First, recalling that more than half of all rubella infections are clinically unapparent, individuals with asymptomatic infections nevertheless are infectious and can transmit the disease to others. What’s more, infected individuals, who will develop clinical disease, can unknowingly transmit the infection for seven days before the onset of their symptoms. [The incubation period between the time of infection and the onset of symptoms is usually 16 to 18 days.] Second, susceptible children are the major source of rubella infection. That is so because they are readily exposed to the virus in the crowded conditions existing in schools and day care centers. Third, for reasons just noted, children are the major targets for vaccination against rubella. Fourth, the herd immunity threshold for rubella is 83-85%.

Bearing in mind the crucial principle of herd immunity, and that newborns, and some children (e.g. those receiving chemotherapy or who have certain immune disorders), and pregnant women as well, cannot receive the MMR vaccine, one might presume, rightly perhaps, that receiving the vaccine is to some extent altruistic. Yet the trivalent MMR vaccine does directly protect the vaccine recipient from measles and mumps, both of which are potentially serious viral illnesses.

The MMR vaccine also protects against, rubella. But, since a major concern in that instance is to prevent infection of susceptible pregnant women, immunization against rubella may appear somewhat more altruistic. Still, vaccinated young females will be protected later in life, when they might be expectant mothers themselves. And, vaccinated young boys, as well as girls, may have the knowledge one day that they were not the cause of someone else’s tragedy. Moreover, the public at large pays the price for vaccine noncompliance, as previously eradicated diseases make their way back into the population.

In The Selfish Gene, Richard Dawkins invents a model population of birds to help explain the evolution of altruistic behaviors. Dawkins’ views in The Selfish Gene are somewhat controversial. Nonetheless, his bird model reminds me of the principle of herd immunity, and the case for human compliance with vaccine regimens. The birds are endangered by a deadly disease spread by ticks. They try cope with their situation by grooming themselves to remove their ticks. However, there is one spot they cannot reach—the tops of their heads. Evolution solves their dilemma by selecting for a behavior in which the birds work together to remove each others ticks. Importantly, some critical percentage of the birds must express this altruistic adaptation if it is to be effective. If too many of the birds were to “cheat” by having other birds remove their ticks, while not reciprocating, at least some of the population would suffer. And, if there were enough cheaters, the population would be overrun with the disease.

References:

(1) Andrew Wakefield and the Measles Vaccine Controversy, Posted on the blog February 9, 2015.

(2) Norkin, Leonard C., Virology: Molecular Biology and Pathogenesis, ASM Press, 2010. See Chapter 3 for a discussion of the placenta as a barrier to infection of the fetus.

Andrew Wakefield and the Measles Vaccine Controversy

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.

The Sunday Times report that exposed Andrew Wakefield
The Sunday Times report that exposed Andrew Wakefield

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…”

The Lancet retracts Wakefield’s paper
The Lancet retracts Wakefield’s 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 Lancet 351:637–641.

Maurice Hilleman: Unsung Giant of Vaccinology

In January 2005, more than 100 of the world’s most renowned biomedical researchers got together to pay tribute to the 85-year-old Maurice Hilleman. When it was Hilleman’s turn to address the gathering, he alluded to them as his “peers in the world of science.” Referring to Hilleman’s gracious comment, science journalist Alan Dove wrote: “By any objective measure, a gathering of Maurice Hilleman’s scientific peers would not fill a telephone booth.” (1)

Hilleman truly was a giant in the history of virology. But, if you have only a vague idea of who Hilleman was or of his achievements, you are not alone. Anthony Fauci, director of the U.S. National Institutes of Allergy and Infectious Diseases, who was present at the gathering, noted: “Very few people, even in the scientific community, are even remotely aware of the scope of what Maurice has contributed….I recently asked my post-docs whether they knew who had developed the measles, mumps, rubella, hepatitis B and chickenpox vaccines. They had no idea,” Fauci said. “When I told them that it was Maurice Hilleman, they said, ‘Oh, you mean that grumpy guy who comes to all of the AIDS meetings?’”

hillemanMaurice R. Hilleman: The greatest vaccinologist.

Consider this. Hilleman developed nine of the 14 vaccines routinely recommended in current vaccine schedules. These are the vaccines for the measles, mumps, rubella, hepatitis A, hepatitis B, and chickenpox viruses, and for meningococcal , pneumococcal, and Haemophilus influenzae bacteria. Moreover, he was the first to forecast the arrival of the 1957 Asian flu and, in response, led the development of a flu vaccine that may have saved hundreds of thousands or more lives worldwide (2). And, independently of Robert Huebner and Wallace Rowe, he discovered cold-producing adenoviruses, and developed an adenovirus vaccine. Overall, Hilleman invented nearly 40 vaccines. And, he was a discoverer of simian virus 40 (SV40). If the above accomplishments were not enough to ensure his fame, he also was the first researcher to purify interferon, and the first to demonstrate that its expression is induced by double-stranded RNA.

[Aside: I first became aware of Maurice Hilleman 44 years ago. It was in the context of his 1959 discovery of SV40, which I came across only because I was beginning my post-doctoral studies of the related murine polyomavirus. Bernice Eddy, at the U. S. National Institutes of Health (NIH), was probably the first to discover SV40, which she detected in early lots of the Salk polio vaccine (3). Hillman, then at Merck & Co, independently discovered the same virus in rhesus monkey kidney cell cultures, in which the polio vaccine was being produced. Hilleman gave SV40 its name. It was the 40th simian virus the Merck lab found in the monkey kidney cells. In 1961, both Eddy and Hilleman found that inoculating SV40 into hamsters causes tumors in the animals. Merck withdrew its polio vaccine from the market. But, by then, live SV40 had been unknowingly injected into hundreds of millions of people worldwide! More on this in a future posting.]

We begin our account of Hilleman’s achievements with his development of the mumps vaccine. In the days before the vaccine, mumps struck about 200,000 children in the United States, annually. Yet except in rare circumstances, the infection was mild, and was generally regarded as a childhood rite of passage. There is a sweetness to the story of the mumps vaccine that I hope you might enjoy.

The tale began at about 1:00 AM, on March 21, 1963, when 5-year-old Jeryl Lynn Hilleman ambled into her father’s bedroom complaining of a sore throat. Jeryl Lynn’s father felt his daughter’s swollen glands, and knew in a flash that it was mumps. And, while I suspect that many lay parents back in the day would also have recognized Jeryl Lynn’s symptoms, few would have done what her father did after first comforting his daughter. Although it was already past midnight, Maurice hopped into his car and drove the 20 minutes to his lab at Merck & Co. to pick up some cotton swabs and beef broth. Returning home, he then awakened Jeryl Lynn, gently swabbed her throat, and immersed the swabs in the nutrient broth. Next, he drove back to his lab and put the inoculated broth in a freezer.

Hilleman made the early A.M. dashes to his lab and back because he had to leave in the morning for a conference in South America, and his daughter’s infection might have cleared by the time he returned home from there. So, upon his return from South America, Hilleman, thawed the frozen sample from his daughter’s throat and inoculated it into chick embryos. Serial passage of the mumps virus in the chick embryos eventually generated attenuated mumps virus that in 1967 would serve as a live mumps vaccine.

The virus in the vaccine was dubbed the Jeryl Lynn strain, in honor of its source. Years later, an adult Jeryl Lynn Hilleman noted that her father had a need to be “of use to people, of use to humanity.” She added: “All I did was get sick at the right time, with the right virus, with the right father.”

We’ll have a bit more to say about the mumps vaccine shortly. But first, a few words about measles and rubella.

If mumps was not a major killer, measles certainly was. Before Hilleman and his colleagues introduced their measles vaccine (Rubeovax) in 1962, there were 7 to 8 million measles fatalities worldwide each year, and virtually all of the victims were children. Hilleman developed his attenuated measles vaccine from a measles strain isolated earlier by John Enders. Hilleman attenuated the Enders isolate by putting it through 80 serial passages in different cell types.

[Aside: In a previous posting, we noted that Enders, together with colleagues Thomas Weller and Frederick Robbins, shared a Nobel Prize in Physiology or Medicine for growing poliovirus in non-nervous tissue (3). Apropos the current story, bear in mind that Salk and Sabin developed polio vaccines that have nearly rid the world of this once dread virus. Nevertheless, the Nobel award to Enders, Weller, and Robbins was the only Nobel award ever given in recognition of polio research!]

Rubeovax was somewhat tainted by its side effects; mainly fever and rash. While these reactions were successfully dealt with by combining Rubeovax with a dose of gamma globulin, in 1968 Hilleman’s group developed a new, more attenuated measles strain by passage of the Rubeovax virus 40 more times through animal tissues. Hilleman dubbed the new measles strain “Moraten,” for “More Attenuated Enders.” The new measles vaccine, Attenuvax, was administered without any need for gamma globulin.

Our chronicle continues with the rubella vaccine. Rubella poses its greatest danger to fetuses of non-immune pregnant woman, particularly during the first trimester of pregnancy. In up to 85% of these women, infection will result in a miscarriage or a baby born with severe congenital abnormalities. An outbreak of rubella began in Europe in the spring of 1963, and quickly spread worldwide. In the United States, the 1963 rubella outbreak resulted in the deaths of 11,000 fetuses, and an additional 20,000 others born with birth defects (e.g., deafness, heart disease, cataracts).

Hilleman had been working on a rubella vaccine at the time of the 1963 outbreak. But, he was persuaded to drop his own vaccine and, instead, refine a vaccine (based on a Division of Biologics Standards’ rubella strain) that was at the time too toxic to inoculate into people. By 1969 Hilleman was able to attenuate the DBS strain sufficiently for the vaccine to be approved by the FDA.

Next, and importantly, Hilleman combined the mumps, measles, and rubella vaccines into the single trivalent MMR vaccine, making vaccination and, hence, compliance vastly easier. Thus, MMR was a development that should have been well received by many small children and their mothers, as well as by public health officials.

In 1978 Hilleman found that another rubella vaccine was better than the one in the trivalent vaccine. Its designer, Stanley Plotkin (then at the Wistar Institute), was said to be speechless when asked by Hilleman if his (Plotkin’s) vaccine could be used in the MMR. Merck officials may also have been speechless, considering their loss in revenues. But for Hilleman, it was simply the correct thing to do.

Like Jonas Salk and Albert Sabin before him (3), Maurice Hilleman was never awarded a Nobel Prize. There is no obvious reason for the slight in any of these three instances. In Salk’s case, it may have been because Alfred Nobel, in his will, specified that the award for Physiology or Medicine shall be for a discovery per se; not for applied research, irrespective of its benefits to humanity. But, Max Theiler received the Nobel Prize for producing a yellow fever vaccine. What’s more, the Nobel committee seemed to equivocate regarding the discovery that might have been involved in that instance. Regardless, the Nobel award to Theiler was the only Nobel Prize ever awarded for a vaccine! [A more complete accounting of the development of Theiler’s yellow fever vaccine can be found in The Struggle Against Yellow Fever: Featuring Walter Reed and Max Theiler, now on the blog.]

Sabin had done basic research that perhaps merited a Nobel Prize (3). But, the Nobel committee may have felt uneasy about giving the award to Sabin, without also recognizing Salk. Or, perhaps the continual back-and-forth carping between supporters of Salk and Sabin may have reduced enthusiasm in Stockholm for both of them.

Yet by virtually any measure, Hilleman’s achievements vastly exceeded those of Salk, Sabin, Theiler, and just about everyone else. His basic interferon work alone should have earned him the Prize. Hilleman’s group demonstrated that certain nucleic acids stimulate interferon production in many types of cells, and detailed interferon’s ability to impede or kill many viruses, and correctly predicted its efficacy in the treatment of viral infections (e.g., hepatitis B and C), cancers (e.g., certain leukemias and lymphomas), and chronic diseases (e.g., multiple sclerosis). What’s more, Hilleman developed procedures to mass-produce and purify interferon. And, regarding his unmatched achievements as a vaccinologist, he did more than merely emulate Pasteur’s procedures for developing attenuated viral vaccines. His hepatitis B vaccine was the first subunit vaccine produced in the United States. It was comprised of the hepatitis B surface antigen (HBsAg), which Hilleman purified from the blood of individuals who tended to be infected with hepatitis B virus (e.g., IV drug abusers). Subsequently, to avoid the potential danger of using human blood products in the vaccine, Hilleman developed recombinant yeast cells that produced the HBsAg. And, Hilleman’s meningococcal vaccine was the first vaccine to be based on polysaccharides, rather than on a whole pathogen or its protein subunits.

So, why then was Hilleman bypassed by the Nobel committee? John E. Calfree, in The American, wrote: “As the 80-plus-year-old Hilleman approached death, Offit and other academic scientists lobbied the Nobel committee to award Hilleman the Nobel Prize for Medicine, based partly on his vaccine work and partly on his contributions to the basic science of interferons. The committee made clear that it was not going to award the prize to an industry scientist.” (4) [Paul Offit, referred to here, is the co-developer of the rotavirus vaccine, Rotateq, and a biographer of Hilleman.]

Calfree also notes that Hilleman’s tendency towards self effacement, and his absence from the academic and public spotlight, may also have worked against him. And, unlike Salk, whose name was closely linked to his polio vaccine (3), Hilleman’s name was never associated with any of his nearly forty vaccines. [Yet in the case of Jonas Salk, his public acclaim is generally believed to have hurt him in the eyes of his colleagues and of the Nobel committee.]

Considering the enormity of Hilleman’s contributions, his anonymity was really quite remarkable. As Calfree relates: “In one of the most striking of the dozens of anecdotes told by Offit, Hilleman’s death was announced to a meeting of prominent public health officials, epidemiologists, and clinicians gathered to celebrate the 50th anniversary of the Salk polio vaccine. Not one of them recognized Hilleman’s name!”

With Hilleman’s public anonymity in mind, we conclude our account with the following anecdote. In 1998, a Dr. Andrew Wakefield became a celebrity and hero in the eyes of the public. How this happened, and its consequences are troubling for several reasons, one of which is that it brought undeserved suffering to the self-effacing and benevolent Maurice Hilleman. The Wakefield incident merits, and will have a full-length blog posting of its own. But for now, in 1998 Wakefield authored a report in the prestigious British journal The Lancet, in which he claimed that the MMR vaccine might cause autism in children. The story had a bizarre series of twists and turns, with Wakefield and co-authors eventually issuing a retraction. The immediate cause of the retraction was the disclosure that Wakefield, on behalf of parents of autistic children, had accepted funding to investigate a link between the MMR vaccine and autism. The purpose of the investigation was to determine whether a legal case against the vaccine manufacturer might have merit. In addition to the obvious conflict of interest, Wakefield’s paper had serious technical flaws as well. At any rate, a number of independent studies subsequently demonstrated that there is no causal link between the MMR vaccine and autism. And, in 2010 Wakefield was barred by the British Medical Society from the practice of medicine. But the harm had been done. Hilleman had become the recipient of hate mail and death threats. And, more important to Hilleman I expect, many worried parents, even today, prevent their children from receiving the MMR vaccine (5). Ironically, the very success of the MMR vaccine enabled people to forget just how devastating measles and rubella could be.  Maurice Hilleman succumbed to cancer on April 11, 2005.

1. Nature Medicine 11, S2 (2005)
2. Opening Pandora’s Box: Resurrecting the 1918 Influenza Pandemic Virus and Transmissible H5N1 Bird Flu  On the blog.
3. Jonas Salk and Albert Sabin: One of the Great Rivalries of Medical Science  On the blog
4. Calfree, J.E., Medicine’s Miracle Man , The American, January 23, 2009
5. Reference 4 contains a somewhat similar tale, in which a 1992 article in Rolling Stone attributed the emergence of HIV to Hillary Koprowski’s polio vaccine. It created a sensation but, as might be expected, there was no evidence to support its premise.