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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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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.