As a Malaysian, I’m surprised that Malaysia is one of the top countries whose people believe vaccines cause autism (Figure 1). Perhaps we are just not as vocal in voicing this issue, giving the illusion that vaccine hesitancy isn’t prevalent here.
The Ipsos Mori Perils of Perception Survey conducted 29,133 interviews across 38 countries in 2017. They revealed that 8–44% of people believed vaccines caused autism in children, 23–63% were unsure, and only 20–62% did not believe it. Averaging them showed nearly 6 in 10 people worldwide were unsure or believed that vaccines cause autism (Figure 1).
No wonder the World Health Organization (WHO) named vaccine hesitancy as one of the top 10 threats to public health in 2019.
Now, why do people still believe that vaccines cause autism? As a science graduate, I was under the impression that this belief has been widely debunked. But I didn’t read into the details, and perhaps there might be a reason for this belief to sustain to this day.
A backdrop on autism
Autism spectrum disorder (autism) is a life-long neurodevelopmental condition that occurs in childhood due to certain brain changes. It affects 1–2% of children worldwide, about 4-times more often in boys than girls, likely due to how different sex hormones affect brain development.
The main symptoms are impaired social communication and restricted and repetitive behaviors, which are problematic enough to impair daily activities. People with autism may also face delayed developmental skills in language, movement, cognition, and behavioral and emotional control.
It was only with the publication of the Diagnostic and Statistical Manual of Mental Disorders, third edition (DSM-III) in the early 1980s was autism professionally defined. Centuries prior to that, autism was thought of as childhood schizophrenia, mental retardation, or mere bizarre behaviors.
Although we know people with autism have distinct brain patterns than usual, we still haven‘t pinpointed which particular brain region(s) that best defines autism. Neuroscience studies have only managed to find widespread brain changes throughout the cortical areas in autism cases.
The cause of autism remains unclear. A combination of genetic, sex, maternal, childbirth, and environmental factors are known risk factors of autism, but the precise contribution of each factor is still ambiguous.
The presumed scientific basis for the autism-vaccine link
Perhaps because of the uncertain cause of autism and victims looking for a villain to blame for their child’s ailment, vaccines were put on the spot.
This anti-vaccine movement began with a 1998 scientific paper, which, though retracted in 2012, still prevails to this day as the founding proof of vaccines causing autism. Let’s see what the 1998 paper has to say.
Andrew J. Wakefield, a former physician, and colleagues had their paper, “Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children,” published in The Lancet in 1998, which was retracted as late as 2010. Wakefield was the lead investigator of the paper. And The Lancet is a highly prestigious journal to this day.
The paper was a small case series of 12 children with a history of the developmental disorder (loss of acquired skills) and intestinal symptoms (diarrhea, abdominal pain, bloating, and food intolerance). Several tests were performed, such as vaccination history, bloodwork, ileocolonoscopy, brain scans, and neuropsychiatric assessments.
A history of the MMR (mumps, measles, and rubella) vaccine was identified in eight of the children before their behavioral problems began. Five of them had an early adverse reaction to the vaccine, such as rash, fever, delirium, and convulsion). And the average time from vaccination to the occurrence of behavioral symptoms was 6.3 days (range: 1–14 days).
The MMR vaccine was thus linked to autism and other developmental conditions by either the child’s physician or parents (Figure 2).
Next, ileocolonoscopy revealed several abnormalities in the intestines, such as hyperplasia (tissue enlargement), loss of vascularity, and infiltration of inflammatory immune cells. As previous studies noted intestinal abnormalities in children with autism (which appears valid to this day), Wakefield et al. justified that their findings were not coincidental. Finally, nothing abnormal was noted in the brain scans and bloodwork.
Wakefield et al. then cited the opioid excess theory of autism first proposed in 1979, where opioid peptides produced from the metabolism of gluten and casein are leaked into the bloodstream due to a leaky gut. Such opioid peptides then act on opioid receptors of the brain, altering neurotransmission and causing autistic symptoms.
Wakefield et al. also cited Thompson et al.’s study in 1995, which reported higher rates of inflammatory bowel disease in individuals who got the live measle virus vaccine compared to those who didn’t. (Wakefield himself co-authored this study.)
Linking the two led Wakefield et al. to conclude that the MMR vaccine inflames the intestines, resulting in a leaky gut and leaked opioids, which dysregulate brain neurotransmission and cause autism.
Wakefield et al. further cited two other scientific sources pointing toward the vaccine’s causative role in autism.
The first one was the 1996 study of Herman H. Fudenberg, a former physician, titled “Dialysable lymphocyte extract (DLyE) in infantile onset autism: A pilot study,” where Fudenberg treated 40 cases of autism (20 true autistics and 20 pseudo-autistic syndromes). Most responded positively to transfer factor treatment. That was the main goal of the study. But Fudenberg also noted that 15 of the truly autistic children developed symptoms within a week after getting the MMR vaccine.
The second was a 1996 brief report by professor Sudhir Gupta, MD, Ph.D., and colleagues, titled “Dysregulated Immune System in Children with Autism: Beneficial Effects of Intravenous Immune Globulin on Autistic Characteristics.” Herein, Gupta et al. treated 25 children with autism, finding some success with long-term immunoglobulin infusion. But Gupta et al. also noted high levels of maternal (mom’s) rubella antibodies in the children. They then subtly theorized that rubella antigens introduced via MMR vaccination could complex with pre-existing maternal antibodies to cause autism.
(Vaccines like MMR introduce the pathogen’s antigen safely to train the immune system to produce antibodies that neutralize the antigen. So, when the actual pathogen infects, the antibodies are ready.)
But Wakefield et al.’s (1998) paper was full of holes, with manipulation and misrepresentation of data, breaching of ethics and human rights, and unreliable sources cited (including the opioid excess theory and papers by Thompson et al., Fudenberg, and Gupta et al.).
Was there a shred of truth in the scientific basis for the vaccine-autism link?
The crux of Wakefield et al. (1998) paper is that children with autistic also had intestinal abnormalities and developed autism within a week of MMR vaccination. Based on the opioid excess theory of autism, the MMR vaccine likely caused a leaky gut, thus leaking opioids from gluten and casein digestion into the bloodstream, which alters brain neurotransmission.
Wakefield et al.’s theory indeed sounds convincing, which is probably how The Lancet accepted this paper for publication. But further investigations into his paper revealed multiple scientific misconducts.
Brian Deer, a British investigative journalist, exposed that the children’s accounts in the 1998 paper were inconsistent with medical reports (some of which were submitted to the British general medical council) and parent interviews (Figure 3). For instance, Wakefield et al. reported a range of 1–14 days in which autism occurred after MMR vaccination. But separate interviews and reviews of medical reports revealed otherwise — some of the children had autistic symptoms before vaccination, and some developed autism as late as 6 months after the MMR vaccine. Another instance is that some children were not even diagnosed with autism.
Deer further uncovered that Wakefield filed a patent for single vaccines against measle virus (rather than the MMR, mumps, measles and rubella combination) in 1997, on the basis of a safer vaccine, which is only safer if MMR is dangerous. Wakefield also received nearly half a million pounds from lawyers to prove that vaccines cause autism. These are major financial conflicts of interest that Wakefield did not disclose.
Aside from financial gains, Deer also found that Wakefield breached ethical issues by performing invasive procedures on the children, such as anesthesia, ileocolonoscopy, lumbar puncture, and MRI brain scan without approval from the ethics committee. Some of the children were screaming and held down as the procedures were forced on them.
But even if no scientific misconduct was done, Wakefield et al.’s paper also fall apart in terms of scientific reasoning.
The opioid excess theory of autism — which forms the crux of Wakefield’s vaccine-autism link — was discredited in later years.
At least two studies from the U.K., in 2007 and 2008, found no differences in urinary opioid markers between children with and without autism. “These findings are counter to the putative mechanism of the leaky gut syndrome,” authors of the 2008 study wrote. “There is now a large body of work which refutes the theory and cannot replicate the findings.”
As follows, a 2009 systematic review of 14 studies from the U.S. did not support the use of gluten-free or casein-free diets (GFCF) in treating autism. “The data from these studies do not support the Opioid-Excess Theory,” the review authors wrote. “Until conclusive evidence is found in support of GFCF diets, restrictive diets should only be implemented in the event a food allergy or intolerance is detected.”
If the opioid excess theory of autism is invalid, the presumed mechanism of the MMR vaccine causing leaky gut and subsequent autism also becomes invalid. Now, the causative link between the MMR vaccine, inflamed and leaky gut, and autism falls apart.
Moreover, Wakefield et al.’s 1998 paper was a case series of 12 children. A case series is just a compilation of case reports, which by themselves are weak evidence. By right, case series or reports serve to generate new hypotheses for further studies in larger cohorts. After the 1998 paper was published, Wakefield refused to conduct additional studies to support his findings, despite being aware of the allegations against his paper.
What about Thompson et al.’s (1995), Fudenberg's (1996), and Gupta et al.’s (1996) papers that Wakefield et al. (1998) cited as support for the vaccine-autism link? Apparently, all of these sources are also unreliable.
First, Thompson et al. reported higher rates of inflammatory bowel disease (but not coeliac disease or peptic ulceration) in children who received the live measle virus vaccine than unvaccinated children. But other imminent scientists at that time criticized that the unvaccinated children (controls) came from a different cohort, extracted from a child-health study conducted before measles vaccines were available. Recruitment and follow-up methods, as well as baseline characteristics, were also different between the two cohorts, rendering their comparison invalid.
Second, Fudenberg (1996) described that 15 out of 20 children with autistic developed their symptoms within a week after getting the MMR vaccine. But this paper suffers the same flaw as Wakefield et al.’s (1998), which only involves case series without further verification in larger cohort studies. Fudenberg doesn't seem to be a trustworthy scientist as well. The journal Biotherapy, in which Fudenberg published his paper, was discontinued in 1998 for fringe science. Fudenberg was also a co-inventor of the autism treatments that Wakefield patented in 1997. In fact, Fudenberg’s medical license was suspended in 1995 due to “dishonorable, unethical, or unprofessional conduct,” which failed to be reinstated in 2004.
Third, Gupta et al.’s (1996) reported some success in using immunoglobulin infusion to treat children with autism, who also happened to have elevated maternal rubella antibodies. Gupta et al. then theorized that rubella antigens introduced via MMR (mumps, measles, and rubella) may interact with the pre-existing rubella antibodies to cause autism. But this was a mere hypothesis unrelated to the study findings and without plausible mechanisms of action. To this day, no data has substantiated Gupta et al.’s hypothesis. Currently, Gupta is a professor at the University of California and doesn’t seem to be involved in autism research any longer.
Overall, not even a shred of scientific accuracy was present in the infamous 1998 paper of Wakefield et al., neither the clinical data nor sources cited. In the end, this paper was retracted in 2010, and Wakefield’s medical license was stripped by the British General Medical Council.
Yes, it took 12 years, and the damage done along the way is massive and irreversible. MMR vaccine hesitancy and denial remain undeterred to this day. In 2021, nearly 40 million children were not fully vaccinated against the measles virus, a highly contagious and potentially fatal virus that still kills more than 200,000 people annually, mostly children.
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