Vaccines and Autism

Vaccines and Autism

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It has been a solid few months since my last article. This is due to many things: increased research load, business growth, wedding planning, and also some deep research was required for this article. So while short in length, this article was months in the making.

Let me start with acknowledging that this is a sensitive topic to many people and I get that. For many people this will cut against the grain. But that is okay. That is how it should be. Finding the truth is not always comfortable.To continue on with comfort, this article was not very comfortable to write as researching it brought me quite far outside my comfort zone: neuropsychology and immunology are not my area of expertise and I had to pull out several text books to wrap my head around some of the concepts. Yes, I literally pulled out my old textbooks to comb through them for this article to ensure I knew enough to know how little I know. I am sure you all did better things with your Friday nights than I did while brushing up for this article.

As we begin I need to make a few disclaimers: 1) As stated above, I am not an immunologist or psychologist so this piece ought to be viewed as evidence based, investigational journalism, not a hard core science piece. I have done my best to be as scientific and rigorous as possible but I don’t know what I don’t know about immunology and psychology. 2) I am human and like all of us, I have my own biases. I went into this with the idea that the evidence regarding a link between vaccines and autism was sparse, but I also went in as objective as possible. Feel free to highlight my short comings and my biases and correct any errors, that is how progress is made

The World We Live in Versus the World We Don’t.

All perspectives on a topic are shaped by one’s lived experience.

Let me begin with a vignette and paint a picture for you so I can prime your intellectual pump.

Think back to your 18th birthday.

If you are a man below the age of ~60 you probably thought of it as a big milestone. You could go down the street and buy your first cigar, vote, buy questionable magazines, and do all the things an 18 year old “man” has the new found freedom to do. Signing up for selective service probably barely crossed your mind and it seemed like a formality, like paying your taxes, but you never really thought you would have to go to war. You never lived in a world where a World War was something you thought of as an actual thing, something you would have to go fight it.

If you are a woman below the age of ~60 you probably never really fully grasped the thought of your boyfriend/fiance/husband calling you and saying, “I was drafted, I ship out to basic in 6 weeks, chances are I won’t come home”.

You can’t fully grasp what that is like (this includes me). It is, what I would guess, the same feeling you have when you become a parent. You can’t explain to someone what its like to have a child until you have one (at least this is what all my parents and child rearing friends tell me).

This matters, your perspective about events and society are shaped by the world we live in.

The world we live in today is substantially different than the world people lived in 50 years ago. The simple fact of the matter is that independent of any potential link to autism, vaccines have given you the current world you live in. A world essentially free of diseases like smallpox, polio, measles, mumps, rubella, diphtheria, and pertussis.  These images are important to contextualize this issue.

Aminu Ahmed Tudun-Wada, 47 (M), chairman of KPVTA, with two of his children at his home in Kano. Umar (R) is his only child affected by polio. Umar was born in 2003 when immunization was boycotted in the State of Kano and its surroundings; he contracted polio few months after his birth.

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Let me paint another picture, this time with with numbers. In 1920 the overall population of the United states was approximately 106 million people and 469,924 measles cases were reported, and 7575 patients died. In 1998 the overall population of the United States was ~275 million people and measles reached a provisional record low number of 89 cases with no measles-associated deaths. This means that vaccines reduced the overall burden of disease from 0.4% of the entire population to 0.00003% percent and eliminated death events completely.

When a population is generations removed from an experience it is nigh impossible for them to understand the true nature of that experience. The simple fact that we have never experienced outbreaks of disease that are preventable makes it quite difficult for us to understand the gravity of situations like this.

The Origin Story

The vaccine-autism story is one that highlights the all too human aspect of science. Science is an error correcting methodology designed to arrive at the truth. However, science done by humans, which means there are flaws, and missteps along the way. Yet, due to the self-correcting nature, the flaws are usually ironed out; such is the case in this story

The origin of the vaccine-autism link began in 1998 when a paper titled, “Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children” (cite) was published in the Lancet. The paper was a very small study of 12 children who presented with loss of acquired skill, language, and concurrent abdominal issues and diarrhea. The doctors took these 12 patients, gave them neuropsychiatric diagnosis and then essentially looked to see if there was any relation to the MMR vaccine.  Some of the data in the paper suggests there may be a link; however, even the authors of this paper made the following statements in the original paper.

“We did not prove an association between measles, mumps, and rubella vaccine and the syndrome described. Virological studies are underway that may help to resolve this issue”.

“If there is a causal link between measles, mumps, and rubella vaccine and this syndrome, a rising incidence might be anticipated after the introduction of this vaccine in the UK in 1988. Published evidence is inadequate to show whether there is a change in incidence or a link with measles, mumps, and rubella vaccine”.

In 2010 the original paper by Wakefield and his colleagues was retracted by The Lancet (1) and “Wakefield et al. were held guilty of ethical violations (they had conducted invasive investigations on the children without obtaining the necessary ethical clearances) and scientific misrepresentation (they reported that their sampling was consecutive when, in fact, it was selective” (cite). In 2011 the story appeared much more nefarious and a series of articles and editorials were published in the British Medical Journal effectively demonstrating that the most likely interpretation of the original study is that  the study was overtly fraudulent, erasing all potential credibility of the tenuous link the study reported (2, 3, 4).

We can summarize the origin story of the vaccine-autism link in a fairly succinct manner. First, the original study had substantial methodological issues (e.g. small sample size, no control group, and cross-sectional data) that prevented any robust conclusion about causation. Second, even the highly tenuous connections the hypothesis was held together buy were shown to be based on fraudulent data. The story of vaccines causing autism hits epistemological rock bottom from its very beginning.

The Deeper Dive

A hypothesis in science does not end with one experiment, scientists conduct multiple experiments to test their hypothesis from many angles. Therefore, we can not accept or dismiss the hypothesis solely based on the Wakefield study. For example, in my lab we are currently working on developing a biomarker for identifying a sub-type of people with diabetic kidney disease. Our initial work showed a positive signal for a specific protein in blood in a small group of ~135 patients (5). We are currently following this work up exploring this biomarker in larger samples with varying genetic and cultural backgrounds and at various stages of disease (the next paper shows a negative signal). The same approach applies to the vaccine and autism hypothesis. One study does not lead to robust conclusions.

On the heels of the Wakefield et al. paper there have been numerous studies studying the epidemiological data, the interventional data, and even experimental data.

Instead of going through each study paper by paper I decided to take the most relevant, peer-reviewed studies published in the last 10 years and put them in a table (see table at the end of the article, not inserted here as to keep reading flow going).

Out of the 16 epidemiology studies, 3 have shown no association and only 3 have shown an association. However, of those studies, 1 has been retracted and the author on the retracted paper is an author on the other 2 studies.

Thus on the surface it appears that the epidemiologic data, even the longitudinal data, does not support the hypothesis. This presents a substantial hurdle for anyone claiming that vaccines lead to autism to clear.
Improper Controls: A Potential Confounder

It would be very nice to wrap this article up in about 1,200 words and call it case closed; however, there is more to think about and more evidence to discuss before I can be fully satisfied that we have dug deep enough.

During my “research” for this article I reached out to several of my colleagues to get as wide a perspective on the issue as possible. Tim Sharpe does a lot of work on how potential environmental factors impact our health so I reached out to him and asked him for his insights into the issue. One of the biggest concerns he had with the research surrounding vaccine research is the problem with controls. “I find it interesting that the placebo in most vaccine trials is the exact same compound complete with adjuvants, it’s simply missing the antigen. That’s a pretty bad placebo” (Italics is my substitution of a word).

This is a valid point, very well controlled studies would require a non-vaccine control arm, an arm with vaccine with no adjuvant (e.g. aluminum or thimerosal), and vaccines containing these adjuvants. Much more controlled work ought to be done to improve our knowledge on this topic  However there has been some work done on these compounds alone, in combination of vaccines, and vaccines without thimerosal and we can begin to get some glimpses of the truth from the literature on these topics.

Thimerosal

Thimerosal is a mercury-containing organic compound. Since it is very well documented that mercury can be toxic and lead to changes in neurological function and behavior (6, 7). It has been strongly claimed that this mercury containing compound is the causal factor between vaccines (mainly the MMR vaccine) and autism. This is been studied in several large, retrospective studies of vaccination and autism rates, as well as ASD. There have also been studies that have looked at whether children with autism or ASD have higher levels of mercury or not.

In one of the more notable studies published in JAMA, there was no link between vaccination, with or without thimerosal, and autism or other autism-spectrum disorders (8). To quote directly from the paper,

autism figure 1

“The risk of autism and other autistic-spectrum disorders did not differ significantly between children vaccinated with thimerosal-containing vaccine and children vaccinated with thimerosal-free vaccine (RR, 0.85 [95% confidence interval {CI}, 0.60-1.20] for autism; RR, 1.12 [95% CI, 0.88-1.43] for other autistic-spectrum disorders). Furthermore, we found no evidence of a dose-response association (increase in RR per 25 µg of ethylmercury, 0.98 [95% CI, 0.90-1.06] for autism and 1.03 [95% CI, 0.98-1.09] for other autistic-spectrum disorders)”.

Currently, there is no compelling data to link mercury levels with autism and the clinical presentation of mercury poisoning does not quite support this idea (9). There is one study that shows that levels of mercury in the hair of children with autism is actually lower than children without autism (0.37 ppm in children with autism and 3.63 ppm in children without autism) (10) (Figures from paper are presented below). Notably, amongst the children with autism, the most severe cases had the lowest levels.

autism fig

Here is a statement by the Immunization Safety Review Committee of the Institute of Medicine (name of the organization at the time).

“Although epidemiologic evidence has not supported the hypothesis of a causal relationship between thimerosal-containing vaccines and autism, concerns continue about pediatric exposure to mercury through vaccine administration. A statement issued by the American Academy of Pediatrics and the US Public Health Service in 1999 prompted the removal of thimerosal from many vaccines. In 2004, the Immunization Safety Review Committee of the Institute of Medicine rejected the hypothesis of a causal relationship between thimerosal-containing vaccines and autism.”(11)

When we talk directly about thimerosal based adjuvants being a prime mechanisms of vaccine caused autism the data just doesn’t support that hypothesis (12,13).

More on Heavy Metal Metabolism

We can probably dive deeper into the heavy metal metabolism and autism rabbit hole and spend a good 10-20,000 words there but I think based on the data we can make some conclusions, but before I do, let me set the stage with a story.

Back in 2014 I went to the Experimental Biology conference and attended a mini symposium called, “Stem Cells for Cardiac Repair”.  I remember it very vividly and even have the program from the session that I saved because it was so memorable.

autism figure 2

There were three talks at this symposium, the first was talk was by Dr. Wu, a stem cell biologist study cardiac pathology at Stanford and he presented data on stem cells in the heart. At the end of his talk, during the question and answer session a guy who looks virtually identical to Ron Perlman stands up, walks to the microphone and states, “Sean, I don’t believe your data and I do not believe those are stem cells”.   They proceeded to go back and forth over the data quite vigorously and then questioner returned to his seat. At the end of the question and answer session they introduced the next speaker, Dr. Sussman from San Diego State, and up walks the interlocutor from the Q&A session…. “this should be interesting” I thought to myself.

He walks to the to the microphone and begins his talk by very loudly proclaiming, “This field is a quagmire”. His talk was one of the most detailed, interesting, compelling science talks I had seen at that point in my life. This guy was a good scientist, brutally honest, and called things what they were.

Why is it a quagmire? Well you have for one thing there is the previous data showing inverse associations (see above). There is the possibility of reverse causality where autism itself modifies heavy metal metabolism (14).

Much like Dr. Sussman’s interpretation of cardiac stem cell biology in early 2014, heavy metal metabolism and autism area of research is best described as a quagmire. Currently, there are so many conflicting points of data, shoddy methodology, poor conclusions being drawn, and some substantial bias present. Anyone who says there is clear data supporting this notion is either a) ignorant of the data, b) lying, c) severely confused.

One thing we can be fairly confident of is that the heavy metal based adjuvants appear to be largely ineffective and probably are not necessary, although based on the data that may be a moot point.

The Issue with Spectra

“Heterogeneity is an illusion”

One of the more troubling issues with the claims made about vaccines causing autism lies in the more recent data discussing vaccines and autism spectrum disorder. Often times when we hear things like a disease occurs on a spectrum we think, “Ahhh, good point. Not all diseases manifest the same way and to the same degree”. The issue is when one sys a disease occurs on a broad spectrum, like Autism, there is some much more fundamental beneath that saying. Something that presents an important aspect of the research to cogitate on.

The substantially diverse clinical manifestations of a condition or disease hint at separate, distinct underlying mechanisms for each unique manifestation along the spectrum. This is very well borne out in cancer biology where cancer can be thought of on a spectrum of neoplastic disorders in which each cancer has a unique underlying mechanism that makes it in and of itself its own disease and condition. We know that different cancers have different environmental triggers (e.g. smoking and asbestos result in very different types of lung cancer).

Summary

The idea that vaccines can cause autism were born out of a scientific study fraught with misconduct. It captured the publics imagination and was fueled by outrage, conspiracy theory, and an anti Big-Brother vibe. It was allowed to take root because we live in an era so removed from the devastating consequences of the destruction these viruses caused that generations of people largely do not understand their impact and importance.

Based on the current evidence there does not appear to be evidence to support the hypothesis that vaccines cause or even increase the risk of autism. The observational data does not fully support it, no mechanism has been demonstrated, and the vague clinical end-points of these investigations hamper our ability to establish a causal mechanism.  As of this moment, based on our understanding, there is overwhelming evidence that the net benefit of vaccines outweigh any potential harms on an exponential scale.