Managing Editor's note: This piece ran in January. It seemed appropriate to re-post it following the Banks v. HHS decision. Merck no longer makes the single MMR components.
By Dan Olmsted
In 1990, Merck & Co., manufacturer of the mumps-measles-rubella vaccine known as the MMR, made a significant but little-noticed change: It quadrupled the amount of mumps virus in the combination shot, from 5,000 to 20,000 units. Then in 2007 it reversed course, reducing the amount to 12,500 units. Neither the measles nor the rubella (German measles) component of the MMR was changed at all -- each remained at 1,000 units throughout.
Merck also makes the single-component mumps shot, and in 1990 it also increased the potency of that shot by the same amount, from 5,000 to 20,000 units. But unlike the MMR shot, the standalone mumps shot’s potency was not scaled back in 2007. It remains at 20,000 units.
These changes were mentioned in passing recently during an informal conversation with a Merck scientist. I started looking for an explanation for the sequence of events, but Merck did not respond to a detailed written request for comment.
Absent such an explanation, simple logic dictates the reduction had something to do with the MMR in particular rather than the mumps vaccine in isolation. But what? And what about the timing -- the increase in 1990 and the decrease in 2007?
The huge rise in autism cases began about the time the mumps component in the MMR was raised in 1990. One theory, dismissed by Merck and federal public health officials, is that viral interference between the components in the MMR could create a persistent sub-clinical measles infection in a subset of vulnerable children; and because the measles virus can cause brain damage, that could lead to autism.
A study released last week by the M.I.N.D. Institute at UC Davis reported that most of the fivefold increase in full-syndrome autism -- from 9 in 10,000 children in 1990 to 44 in 10,000 children in 2000-- is real and cannot be accounted for by broader categories or diagnostic substitution. And from 1990 to 2007, the mumps portion of the MMR was higher by roughly the same amount -- quadruple.
Merck’s decision to cut back on the increase in the mumps vaccine also is surrounded by interesting timing. The cutback, in 2007, came at the same time Merck announced it was suspending its recently introduced, much-hyped four-in-one shot, ProQuad -- the MMR with the chickenpox vaccine added to it. In suspending ProQuad, Merck cited a shortage of chickenpox vaccine; subsequently, a study showed ProQuad caused twice as many fever-induced seizures as separate MMR and chickenpox shots given at the same time, and a CDC advisory committee withdrew its preferential recommendation of the vaccine. Merck won't say when ProQuad will return to the market.
An investigation I conducted while at UPI in 2006 found two cases of regressive autism in one small city -- Olympia, Wash. -- in clinical trials leading up to approval of the vaccine. Merck said the parents originally failed to report those cases to it (though the pediatricians paid to conduct the studies for Merck certainly knew about them and would have been expected to report them); the company alerted the FDA only after my inquiry.
The Merck scientist I spoke with recently also acknowledged that viral interference can affect the potency of individual MMR ingredients; that explains why the company added a whopping dose of chickenpox vaccine to the ProQuad shot, several times more than the standalone chickenpox vaccine contains. Using the same amount of chickenpox vaccine in the MMR shot as the standalone vaccine simply wouldn’t have protected children against the disease, because more virus was needed to offset the interference from the other components.
A significant number of parents of children with regressive autism cite the MMR as the proximate cause -- they say their child was developing normally until the shot, then in many cases had a serious physical reaction within a short period of time and began losing developmental milestone and showing typical signs of the disorder. Some also developed severe gastrointestinal problems, an ailment first described in cases of regressive autism following the MMR shot by Dr. Andrew Wakefield in Britain in 1998; he named it autistic enterocolitis and found measles RNA in the children's GI tract, suggesting persistent infection.
In looking at whether the increase in mumps potency in 1990 could buttress this theory of the autism epidemic, two questions arise: Is there evidence that increasing the mumps portion of the MMR could have any impact on measles infectivity or create symptoms consistent with those described by Wakefield and parents? And, could ProQuad's higher rate of measles rash and fever-induced seizures be a warning sign that something is amiss with the MMR itself, especially beginning in 1990 when Merck tinkered with the proportions of the components?
The answers seem to be, yes and yes.
In the real world, children rarely get two viral illnesses at once -- for instance, chickenpox and rubella. But when they do, viruses tend to interact -- or interfere -- with each other in unpredictable and synergistic ways. One example: Studies in the UK and Iceland showed that when mumps AND measles epidemics hit these populations in the same year, the risk of inflammatory bowel disease spiked. That's an epidemiological argument for immune interference, and a striking fit with the observations by Wakefield, and thousand of parents, that a similar condition occurs in many children with regressive autism after they get the measles-mumps-rubella shot.
A related finding comes from a study funded by Merck. In 2005, the study reported that the four-in-one ProQuad shot -- the MMR and chickenpox -- was "generally well tolerated" and had a safety profile similar to the MMR and the chickenpox shot (also made by Merck and called Varivax) when given separately.
But there were a couple of interesting differences. First, "Measles-like rash and fever during days 5-12 were more common after the first dose of MMRV [ProQuad]" than after the MMR and Varivax given separately. The difference was substantial -- 5.9 percent who got the MMRV had the rash and 27.7 percent had fever, compared to 1.9 percent with rash and 18.7 fever after getting separate shots. While that did not alarm the researchers, it could be a foreshadowing of the doubled rate of fever-induced seizures that was spotted after ProQuad was approved.
Second, even though the new element in ProQuad was the chickenpox portion, something new and unexpected was also going on with the mumps and measles components. "Geometric mean titers to measles and mumps were significantly higher after 1 dose of MMRV than after administration" of MMR and Varivax separately, according to the study's summary. Later, the authors state: "This suggests that the measles and mumps virus replication is greater after MMRV than it is" after the MMR and Varivax given separately.
In non-scientific language, it looks like the addition of another live virus -- chickenpox -- potentiated the measles and mumps components: It kicked both viruses into higher gear and they replicated at rates higher than in the MMR. At the same time, the researchers observed a greater incidence of measles-like rash, and fever, in those who got ProQuad. Were the increased measles and mumps viruses interacting in some unexpected and potentially dangerous way?
Then, for whatever reason, sometime between February and December of last year Merck reduced the mumps component of the MMR from 20,000 units to 12,500 while leaving the standalone mumps shot as it was. During that same period, it decided to suspend production of ProQuad. In April 2007, it announced the suspension, and said no more would be available after July. Then in early 2008, Merck’s study showing the doubled risk of seizures in ProQuad was unveiled and the CDC withdrew its recommendation.
And just last month, Merck said it would stop making the individual MMR component shots including, of course, the mumps shot. That leaves the MMR as the only vaccine in town, and it means there will no longer be a mumps vaccine formulation on the market with the dose the MMR contained from 1990 to 2007.
None of this might matter if not for the fact that measles is capable of causing cause catastrophic brain damage and death; that's an argument for the measles vaccine. In medical parlance, it’s a neurotoxic virus.
"The invasion of the CNS [central nervous system] by MV [measles virus] is apparently not an uncommon event, as reflected by the finding of genomic sequences in normal autopsy cases and the widespread distribution of MV in in neurons, glial cells and vascular endothelial cells of the diseased brain," according to "Measles Virus Infections of the Central Nervous System" by Uwe G. Liebert of the University of Leipzeig, Germany, published in Intervirology in 1997. "The susceptibility of the host as well as his age and immune status at the time of infection constitutes significant factors for disease progression."
Merck acknowledges the three viruses can indeed interact to affect a child’s immune system, although in ways it says are not harmful.
A Merck scientist publicly discussed the interference issue at a CDC meeting in 2004, the year before ProQuad was approved, according to agency minutes. Dr. Florian Schodel "confirmed the possibility that the chickenpox virus component of ProQuad was causing a local immune suppression and an increase in measles virus replication. ... The current hypothesis is that the varicella and measles virus are co-infecting the same or proximate areas of the body and engaging in a specific interaction, but how that works is as yet unknown.
"He said the interference appeared to involve only the chickenpox and measles viruses – 'there is no such effect for the mumps or rubella vaccines administered locally at the same time.'"
Yet based on Merck's own 2005 study cited above, ProQuad triggers an increase in mumps virus replication, too. Live viruses in ProQuad seem to be behaving in ways "as yet unknown" that cause immune suppression, co-infection, interaction and increased replication. Even without ProQuad on the market, interaction between the MMR components and the chickenpox virus remains a possibility. The CDC started recommending the chickenpox shot in the mid-1990s at the same 12-month well-baby visit as the MMR.
That suggests the pattern highlighted by ProQuad could be at work through the increased mumps component of the MMR and the addition of chickenpox to the childhood immunization schedule in the mid-1990s. The lesson could be that combining live viruses, and then increasing them or adding new ones, is inherently dangerous, especially when invasion of the brain by one of them “is not an uncommon event.”
As Andy Wakefield told me when I was working on the series in Olympia describing the children in the ProQuad clinical trials who became ill after the vaccination and subsequently regressed into autism: "It's actually heartbreaking, listening to these parents, for more than just the immediate reasons their child has met this fate. It's that you're staring into an abyss," Wakefield said. "You're listening to stories which reflect the fundamental misconception of vaccine manufacturers of what viruses are and what they do."
Two additional points worth noting: After the increase in 1990 and decrease in 2007, there is still more than twice as much mumps virus in the MMR as there was in 1990.
The changes in the mumps virus component of the MMR serves as a potent reminder of something else: MMR is not one thing but three different exposures. And over the period 1980-2009 the MMR has changed significantly at least twice, making epidemiological studies even more difficult to interpret.
Dan Olmsted is Editor of Age of Autism.