Tag Archives: measles

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.

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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.

The American Public’s Response to the 2014 West African Ebola Outbreak

The American media has been extensively covering the current West African Ebola outbreak. Consequently, the American public is anxious that the epidemic might spread to the United States; a worry likely fueled by Ebola’s horrible symptoms, which can include extensive internal and external bleeding (although not the liquefying of internal organs depicted in disaster movies), and by a fatality rate that has been as high as 90% in the developing world.

Yet aside from two American medical workers, Dr. Kent Brantly and missionary Nancy Writebol, who were infected in Africa, and returned to the United States for treatment at Emory University Hospital, no other Americans have been infected with Ebola. Moreover, public health experts, speaking through the media, have repeatedly assured the American public that the chance of an Ebola epidemic here at home is extremely slight. [One reason is that Ebola is not highly contagious, as it is transmitted only by direct contact with body fluids from an infected person. Moreover, infected individuals cannot transmit Ebola to others until they begin to express symptoms themselves. For these reasons, an Ebola outbreak in the United States should be quickly contained by isolating infected individuals. What’s more, supportive care in American hospitals would dramatically decrease the likelihood of any infection being fatal.]

Consider the following facts. By August 6, the current Ebola outbreak was estimated to have killed about 1,000 persons. The largest previous Ebola outbreak, which occurred in Uganda in 2000, claimed 244 lives, and Ebola has killed a total of about 2,000 people since it first emerged in 1976. All Ebola outbreaks occurred in Africa, and no Ebola infection has ever occurred in the United States. In each of the previous Ebola outbreaks, the virus ran its destructive course and then “disappeared.”

In contrast, consider that seasonal influenza claims on average about 40,000 lives annually in the United States alone, and 500,000 lives worldwide. And, the influenza virus reappears in a somewhat different immunological guise each and every year. Yet with the exception of those occasions when a seemingly exotic new influenza strain emerged (e.g., the H1N1 swine flu of 2009), the public seems rather indifferent to influenza. Indeed, even the 1918 influenza pandemic (which claimed 196,000 American lives in the single month of October, 1918, and 50,000,000 lives worldwide) did not cause any panic. And, despite the fact that a vaccine is available to prevent the flu, all too many individuals pass up that opportunity to protect themselves.

So, how might we account for the disparity between public apprehensions regarding an Ebola outbreak in Africa, versus public complacency regarding influenza here at home? Perhaps we simply take for granted that influenza will appear every year, and afterwards we forget about it. We even confuse influenza with the much less severe common cold, saying we have the flu, when we are merely experiencing the sneezes and sniffles of a cold.

We might think that the public is more worried by newer emerging viruses (e.g., West Nile virus, the SARS virus, and Ebola), than by actually more dangerous older ones (e.g., measles and influenza), at least in part because the newer viruses are relatively unfamiliar. Also, the current spate of post-apocalyptic movies, the 24-hour news coverage on cable television, and continuous commentary on social media, have each fostered public concern over new emerging infectious agents. But, that can’t be all, since it does not explain the intense fear that polio elicited in America until the Salk and Sabin polio vaccines appeared in the mid to late 1950s; decades before cable television and social media? I was a young teenager in the early 1950s, and remember well the panic that set in every summer when the newspapers reported the first polio cases of the season. What’s more, panic increased dramatically if a neighbor or schoolmate were stricken. You were kept home from school, and couldn’t even play outside. Yet the number of poliomyelitis cases was on average “only” about 20,000 per year, which was about half the average number of influenza fatalities. [The peak year for poliomyelitis was 1952, when there were 57,879 cases.]

So, how might we account for the difference in the public’s concern for polio, versus its relative lack of concern for influenza? A possible reason for the greater fear engendered by poliomyelitis was that the paralytic disease struck mainly children, adolescents and young adults, whereas influenza threatens mainly the elderly. People are usually much more emotionally invested in their children’s well being than in their parents or even themselves.

Yet the public did worry about influenza on occasions when a novel new influenza strain appeared (e.g., the H1N1 swine flu strain that emerged in 2009). Here is another situation in which influenza caused alarm. Unusual circumstances led to flu vaccine shortages in the United States during the winter of 2004/2005. When news of the vaccine shortage first broke in October 2004, there was panic as many individuals clamored for the limited vaccine dosages then available, which, as a matter of policy were being reserved for people at highest risk (e.g., the elderly and the immunologically compromised). But, as small numbers of extra doses began to trickle in from outside sources, demand for the vaccine suddenly disappeared. Indeed, there actually was a surplus, with many doses going to waste.

The outbreak of HIV/AIDS in the early 1980s was one of the defining moments of our time, and merits a longer posting of its own. In brief, because of the association of AIDS with human sexuality in all its forms, the media of that more prudish time had difficulty speaking openly and frankly about the disease. For instance, it used the term “body fluids” to avoid mentioning “semen,” leading to misinformation regarding how the then invariably fatal disease is transmitted. Also, AIDS was associated with intravenous drug abuse. That fact, together with homophobia, resulted in infected individuals (including hemophiliacs who were infected via the contaminated blood supply) being blamed for their illness, and there was blatant discrimination against them. About 15,000 Americans still die from AIDS each year.

The above examples, taken together, point up that the public’s response to infectious disease is shaped by a variety of factors. Furthermore, we might expect that as more and more people crowd into urban areas, and also intrude into once remote areas, new exotic viruses, as well as the older familiar ones, will continue to threaten the human population.

One final point: Whereas the American media has extensively discussed the risk (or non-risk) to Americans from the West African Ebola outbreak, it has barely mentioned America’s responsibility to the West African nations attempting to deal with the outbreak there. And aside from the moral issue, it is clearly in our own self interest to address an epidemic early, at its source, rather than to allow it to spread. [Donald Trump praised Brantly and Writebol for helping out in Africa, but argued that they should not be brought back for treatment because of the risk imposed. He said, “People that go that far away to help are great but must suffer the consequences!”]

The Struggle Against Yellow Fever: Featuring Walter Reed and Max Theiler

The first part of this posting tells how a U.S. Army medical board, headed by Walter Reed, confirmed that the transmission of yellow fever requires a mosquito vector. The second part tells the story of the yellow fever vaccine developed by Max Theiler.

Bearing in mind the enormous benefit to mankind of the polio vaccines developed by Jonas Salk and Albert Sabin (1), and that Maurice Hilleman developed nearly 40 vaccines, including those for measles, mumps, and rubella (2), it would appear remarkable that Theiler was the only one of these four individuals to be recognized by the Nobel committee. In fact, Theiler’s 1951 Nobel award was the only one ever given for a vaccine! In any case, while Theiler’s vaccine was a major step forward in the fight against yellow fever, it came after a perhaps more dramatic episode in the struggle against that malady. But first, we begin with some background.

Yellow fever was another of mankind’s great scourges. Indeed, it was once the most feared infectious disease in the United States. And, while we might want to say that science has “conquered” yellow fever, that statement would not be entirely accurate. Unlike polio and measles, which have nearly been eradicated by the vaccines against them, that is not so for yellow fever. The reason is as follows. Humans are the only host for polio and measles viruses. Consequently, those viruses might be completely eradicated if a sufficient percentage of humans were to comply with vaccination regimens. In contrast, the yellow fever virus infects monkeys that range over thousands of square miles in Africa and the Amazon jungle. Thus, even with massive vaccination of humans, it would be impossible to eliminate the yellow fever virus from the world.

According to the World Health Organization’s estimates, there are still about 200,000 cases of yellow fever per year, resulting in about 30,000 deaths, about 90% of which occur in Africa. The yellow fever virus itself is the prototype virus of the flavivirus family of single-stranded RNA viruses, which also includes dengue hemorrhagic fever virus, Japanese encephalitis virus, and West Nile encephalitis virus, among others.

yellow fever map

Yellow fever is somewhat unique among the viral hemorrhagic fevers in that the liver is the major target organ. Consequently, the severe form of yellow fever infection is characterized by hemorrhage of the liver and severe jaundice. But, as in infections caused by other virulent viruses, most cases of yellow fever are mild.

Interestingly, the name “yellow fever” does not have its origin in the yellowing of the skin and eyes that is characteristic of severe disease. Instead, it has its origin in the term “yellow jack,” which refers to the yellow flag that was flown in port to warn approaching ships of the presence of infectious disease.

Yellow fever originated in Africa. It is believed to have been brought to the New World by slave ships in the year 1596. As noted above (and discussed below), yellow fever transmission, from an infected individual or primate to an uninfected one, requires a specific vector, the Aedes aegypti mosquito. The sailing ships of the day inadvertently transported the disease across oceans via the mosquito larvae in their water casks.

Before getting to our stories proper, we note a pair of intriguing instances in which yellow fever profoundly affected New World history. In the first of these, yellow fever was a key factor that led Napoleon to sell the Louisiana Territory to the United States in 1803; an act that doubled the size of the United States. It happened as follows. After Napoleon seized power in France, he reinstated slavery in the French colony of Saint Domingue (now Haiti); doing so for the benefit of the French plantation owners there. In response, the rather remarkable Toussaint Breda (later called Toussaint L’Ouverture, and sometimes the “black Napoleon”) led a slave revolt against the plantation owners. In turn, in February 1802, Napoleon dispatched an expeditionary force of about 65,000 men to Haiti to put down the revolt. The rebellious slaves, many fewer in number than the French, cleverly retreated to the hills, believing that the upcoming yellow fever season would wreak havoc on the French force. And, they were correct. By November 1803, the French lost 50,000 of the original 65,000 men to yellow fever and malaria. Thus, in 1804, Napoleon had to allow Haiti to proclaim its independence, and then become the second republic in the Western Hemisphere. Moreover, there is evidence suggesting that Napoleon’s actual purpose in dispatching the expeditionary force was to secure control of France’s North American holdings. With his expeditionary force decimated by yellow fever and malaria, that was no longer possible and, consequently, Napoleon sold France’s North American holdings (the Louisiana Purchase) to the United States.

louisiana purchaseThe Louisiana Purchase, in green.

Second, in 1882, France began its attempt to build a canal across the Isthmus of Panama. However, thousands of French workers succumbed to yellow fever, causing France to abandon the project. The United States was able to successfully take up the task in 1904; thanks to the deeds of the individuals in part I of our story, which now begins.

In May 1900, neither the cause of yellow fever, nor its mode of transmission was known. At that time, U.S. Army surgeon, Major Walter Reed, was appointed president of a U.S. Army medical board assigned to study infectious diseases in Cuba, with particular emphasis on yellow fever. Cuba was then thought to be a major source of yellow fever epidemics in the United States; a belief that was said to have been a factor in the American annexation of Cuba.

ReedMajor Walter Reed

When Reed’s board began its inquiry, a prevailing hypothesis was that yellow fever might be caused by the bacterium Bacillus icteroides. However the board was unable to find any evidence in support of that notion.

Another hypothesis, which was advanced by Cuban physician Dr. Carlos Juan Finlay, suggested that whatever the infectious yellow fever agent might be, transmission to humans requires a vector; specifically, the mosquito now known as Aedes aegypti. Reed was sympathetic to this idea because he noticed that people who ministered to yellow fever patients had no increased risk of contracting the disease, which indicated to Reed that people did not pass yellow fever directly from one to another.

Reed, as president of the medical board, is generally given major credit for unraveling the epidemiology of yellow fever. Yet there were other heroes in this story as well. Finlay, whose advice and experience were invaluable to Reed’s board, was one. He was the object of much ridicule for championing the mosquito hypothesis, at a time when there little evidence that might support it. In any case, Reed, in his journal articles and personal correspondences, gave full credit to Finlay for the mosquito hypothesis.

Acting Assistant Surgeon Major James Carroll was another hero. As a member of Reed’s board, Carroll volunteered to be bitten and, promptly, developed yellow fever. Major Jesse Lazear, also a board member, asked Private William Dean if he might be willing to be bitten. Dean consented, and he too contracted yellow fever. Fortunately, Dean and Carroll each recovered. Not so for Lazear. After allowing himself to be bitten, he died after several days of delirium.

Lazear’s contribution to gaining recognition of the mosquito hypothesis went significantly beyond his tragic martyrdom. When Reed examined Lazear’s notebook after his death, Reed found that it contained several key observations. First, Lazear had carefully documented that in order for a mosquito to be infected; it had to bite a yellow fever patient within the first three days of the patient’s illness. Second, twelve days then had to elapse before the virus could reach high enough levels in the insect’s salivary glands to be transmitted to a new victim.

The observations of the board, up to then, convinced Reed and the others that the mosquito hypothesis indeed was correct. Yet Reed knew that more extensive controlled experiments would be needed to convince the medical community. So, he directly supervised those experiments, which involved twenty-four more volunteers, each of whom may rightly be considered a hero.

Just as Reed benefited from Finlay’s insights, William C. Gorgas, Surgeon General of the U.S. Army, applied the findings of Reed’s board to develop vector control measures to combat urban yellow fever; first in Florida, then in Havana, Cuba, and next in Panama, where those measures enabled the United States to complete the canal in 1914. The last urban yellow fever outbreak in the United States occurred in New Orleans in 1905, and the last in the New World occurred in 1999 in Bolivia.

The vector control strategy works for urban yellow fever because the Aedes aegypti mosquitoes have a very short flight range and, consequently, the female mosquito does not stray far from the source of her blood meal before laying her eggs. Thus, it is only necessary to control the vector population in the immediate vicinity of human habitation. In practice, this is accomplished by draining potential mosquito breeding sites such as swamps and ditches, and destroying water-collecting objects such as discarded tires.

After Reed’s board was disbanded, he made yet another key contribution to the wiping out of yellow fever. The focus of the board had been on the means of yellow fever transmission; not with the infectious agent itself. In 1901, at the suggestion of William Welch, an eminent Johns Hopkins pathologist, Reed and James Carroll (who nearly died of yellow fever after being experimentally infected while in Cuba), asked whether yellow fever might be caused by a filterable virus. Indeed, they found that they could infect volunteers by inoculating them with filtered serum taken from yellow fever patients. What’s more, theirs was the very first demonstration of a human illness being caused by a filterable agent. That is, yellow fever was the first human illness shown to be caused by a virus. [Pasteur developed an attenuated rabies vaccine in 1885, more than a decade before the discovery of viruses. Remarkably, this most brilliant of experimentalists did not recognize that he was dealing with a previously unknown, fundamentally distinct type of infectious agent; the topic of a future posting.]

[Aside: Walter Reed spent the early years of his Army career at different posts in the American west. The Mount Vernon Barracks in Alabama, which served as a prison for captured Apache Native Americans, including Geronimo, was a particularly interesting stop for Reed. Captain Walter Reed, serving as post surgeon in the 1880s, looked after Geronimo and his followers.]

Part II of this posting concerns the development of Max Theiler’s yellow fever vaccine. But first, here is a bit more background.

Vector control measures ended yellow fever epidemics in most, but not all urban centers worldwide. Outbreaks have not occurred in the United States for more than a century. However, jungle yellow fever still persists in areas of Sub-Saharan Africa and, to a lesser extent, in tropical South America. Individuals who are infected in the jungle by wild mosquitoes can then carry the virus to densely populated urban areas, where Aedes aegypti mosquitoes can transmit the virus from one individual to another. [Vector-mediated, human-to-human transmission happens because the level of yellow fever virus in the blood of an infected person becomes high enough for the infected person to transmit the virus to a biting mosquito. In this regard, the yellow fever virus is an exception to the generalization that humans are a “dead end” host for arthropod-borne (arbo) viruses.]

Fortunately, people who live in high risk areas for yellow fever can be protected by vaccination. Indeed, the World Health Organization’s strategy for preventing yellow fever epidemics in high risk areas is, first, to mass immunize the population, and then to routinely immunize infants. [Vaccinated American or European visitors to West Africa or the Amazon need not be concerned about yellow fever. However, the risk to an unvaccinated person of acquiring yellow fever during a two-week stay at the height of the transmission season (July through October), is estimated to be 5%. Individuals wanting to enter or return from countries where yellow fever is endemic may need to show a valid certificate of vaccination. ]

Part II of our story, concerning Max Theiler and the development of the yellow fever vaccine now begins.

Even as late as the 1920s, some reputable bacteriologists remained unconvinced by the earlier findings of Reed and Carroll that yellow fever is caused by a filterable agent. Instead, they persisted in the belief that the illness is caused by a bacterium. The notion of a bacterial etiology for yellow fever was finally put to rest after A. H. Mahaffy in 1927 discovered that the yellow fever agent could be propagated and cause illness in Asian rhesus monkeys. With an experimental animal now at hand, yellow fever workers were able to prove conclusively that the disease is caused by a virus. [Mahaffy drew the virus he used in his experiments from a 28-year-old African man named Asibi, who was mildly sick with yellow fever. That isolate, referred to as the Asibi strain, will play an important role later in this anecdote.]

Regardless of the significance of the discovery that the yellow fever virus could be propagated in rhesus monkeys, Max Theiler had to contend with the fact that these monkeys were quite expensive; especially for a not yet established young investigator. [They cost the then princely sum of about $7.00 apiece.] As for mice, while they could be bred for pennies apiece, other researchers were not able infect them via the usual practice of inoculating them under the skin or in the abdomen. However, Theiler took a cue from Pasteur’s inability to propagate the rabies virus in laboratory rabbits until he put the virus directly into their brains. Thus, in 1929 Theiler attempted to do the same with yellow fever virus in mice.

TheilerlMax Theiler

Theiler’s attempts to infect the mice by intracranial injection were a success. All of the inoculated mice died within several days. Surprisingly, the dead mice did not display the liver or renal pathology characteristic of yellow fever. Instead, the mice appeared to have succumbed to inflammation of their brains. Thus, the yellow fever virus appeared to be neurotropic in mice. Also, Theiler himself contracted yellow fever from one of his inoculated mice. He was fortunate to survive.

A fortuitous result of Theiler’s perilous bout with yellow fever was that he had become immune to the virus, as revealed by the presence of antiviral antibodies in his blood. Importantly, Theiler’s acquired immunity to the virus validated the possibility of developing an attenuated yellow fever vaccine. And, in a sense, Theiler was inadvertently the first recipient of the nascent vaccine he soon would be developing.

Theiler also determined that the virus could be passed from one mouse to another. And, while the virus continued to cause encephalitis in mice, it caused yellow fever when inoculated back into monkeys; quite a unique and striking set of findings. But, and crucially significant, while continued passage of the virus in mice led to its increased virulence in those animals, the virus was concurrently losing its virulence in monkeys. [In 1930, Theiler moved from the Harvard University School of Tropical Medicine to the Rockefeller Foundation’s Division of Biological and Medical Research. The Rockefeller Foundation shared facilities with the Rockefeller Institute (now University); although it was otherwise administratively separate from it.]

Since the mouse-passed virus was becoming attenuated in monkeys, Theiler’s belief in the possibility of generating an attenuated yellow fever vaccine was bearing out. However, because the mouse-passed virus remained neurovirulent in mice, Theiler was reluctant to inoculate that virus into humans. In an attempt to solve this problem, Theiler turned from passing the virus in the brains of live mice and, instead, began passing the virus in mouse tissue cultures.

Theiler carried out seventeen different sets of trials to further attenuate the virus. In the 17th of these, Theiler used the wild Asibi strain, isolated earlier by Mahaffy. Initially, this virus was extremely virulent in monkeys, in which it caused severe liver damage. But, after passing the virus from culture to culture several hundred times, over a period of three years, a flask labeled 17D yielded the virus that was to become the famous 17D yellow fever vaccine.

Theiler never gave a satisfactory accounting for the “D” in the “17D” designation, and for what, if anything became of A, B, and C. Regardless, the genesis of 17D was as follows. Theiler initially took an Asibi sample that had been multiplying in mouse embryo tissue and continued passing it in three separate types of minced chicken embryo cultures. One of these sets contained whole minced chicken embryos, and was designated 17D (WC). A second set contained chick embryo brain only, and was designated 17D (CEB). In the third set, the brains and spinal cords were removed from the otherwise whole chick embryo tissue cultures. This set, alone among all the sets, generated an attenuated virus that did not induce encephalitis when injected directly into monkey brains. Indeed, Theiler removed the central nervous systems from the chicken tissue in this set of cultures, in the express hope of generating just such an attenuated virus. And, by hook or by crook, the virus emerging from that particular set of passages became the vaccine that is now known simply as 17D.

Field tests of Theiler’s yellow fever vaccine were underway in 1937 in Brazil, and were successfully completed by 1940. In 1951 Theiler was awarded the Nobel Prize in Physiology or Medicine for developing the vaccine.

Next, we return to a point noted above, and discussed in two earlier postings. Neither Jonas Salk nor Albert Sabin were awarded Nobel prizes for developing their polio vaccines (1). And, Maurice Hilleman was never awarded a Nobel Prize, despite having developed nearly 40 vaccines, including those for measles, mumps, and rubella (2). Indeed, Max Theiler’s Nobel Prize for the yellow fever vaccine was the only Nobel Prize ever awarded for a vaccine! Why was that so?

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. With that criterion in mind, the Nobel committee may have viewed the contributions of Salk and Sabin as derivative, requiring no additional discovery. [Hilleman’s basic discoveries regarding interferon should have been sufficient to earn him the award (2). The slight to him may have been because the Nobel committee was reluctant to give the award to an “industrial” scientist. Hilleman spent the major part of his career at Merck & Co.]

So, what was there about Theiler’s yellow fever vaccine that might be considered a discovery? Hadn’t Pasteur similarly developed an attenuated Rabies vaccine in 1885?

Perhaps the “discovery” was Theiler’s finding that passage of the Asibi strain of yellow fever virus in chick embryo cultures, which were devoid of nervous system tissue, generated attenuated yellow fever virus that was no longer neurovirulent in mice and monkeys. But, consider the following.

Theiler indeed believed that removing the brains and spinal cords from the chick embryo cultures in which 17D had been serially passed was the reason why the virus lost its neurovirulence. Nevertheless, as a serious scientist he needed to confirm this for himself. So, he repeated the long series of viral passages under the same conditions as before. But, this time, there was no loss of neurovirulence. Thus, a cause and effect relationship, between the absence of the brains and spinal cords from the tissue cultures and the emergence of non-neurovirulent virus, was not confirmed.

So, perhaps the Nobel committee merely paid lip service to the directives in Alfred Nobel’s will. In any case, Theiler’s 17D yellow fever vaccine has had a virtually unblemished safety record, and is regarded as one of the safest and most effective live-attenuated viral vaccines ever developed.

Theiler’s unshared 1951 Nobel award paid him $32,000. At the time, he resided in Hastings-on-Hudson; a village in Westchester County, NY, from which he commuted to the Rockefeller labs. Theiler’s next door neighbor in Hastings-on-Hudson was Alvin Dark, the star shortstop of the New York Giants. Nobel laureate Max Theiler was known to fellow commuters from Hastings-on-Hudson as the man who lives next door to Alvin Dark.

Virus Hunters, by Greer Williams (Alfred A, Knoff, 1960) was my major source for the material on Max Theiler.

1. Jonas Salk and Albert Sabin: One of the Great Rivalries of Medical Science. On the blog.

2. Maurice Hilleman: Unsung Giant of Vaccinology. On the blog.

 

 

 

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.