Retracted HPV vaccine article – Shaw and Tomljenovic are back

Earlier this year, I wrote a post about a retracted HPV vaccine article, “Behavioral abnormalities in young female mice following administration of aluminum adjuvants and the human papillomavirus (HPV) vaccine Gardasil,” published in the one of the top journals in the field, Vaccine. This article was authored by, among others, the leading lights of the academic side of the anti-vaccine movement – Christopher Shaw,  Lucija Tomljenovic and Yehuda Schoenfeld. In particular, Shaw and Tomljenovic seem to have an obsession with the HPV vaccine.

After withering criticism across the field, especially since the article was published in a prestigious, high impact factor journal, the editors at Vaccine decided to withdraw the article:

This article has been withdrawn at the request of the Editor-in-Chief due to serious concerns regarding the scientific soundness of the article. Review by the Editor-in-Chief and evaluation by outside experts, confirmed that the methodology is seriously flawed, and the claims that the article makes are unjustified. As an international peer-reviewed journal we believe it is our duty to withdraw the article from further circulation, and to notify the community of this issue.

The paper no longer exists in chronicles of Vaccine – about the best outcome possible.

Unfortunately, despite the strong criticism of the HPV vaccine article’s methods, analysis and conclusions, another journal, Immunologic Research, published the article, with small changes, in July 2016. Nevertheless, the formerly retracted HPV vaccine article has the same issues that were discussed months ago. Nothing has changed.

Let’s take a look what the article said, what changes were made in un-retracting it, and what are still the valid criticisms.

 

All about the retracted and republished article

Because the article has been withdrawn, the Vaccine version of the abstract no longer exists on the Vaccine website and it is not indexed on PubMed. Some websites do have the original abstract. Here’s that abstract in full:

Vaccine adjuvants and vaccines may induce autoimmune and inflammatory manifestations in susceptible individuals. To date most human vaccine trials utilize aluminum (Al) adjuvants as placebos despite much evidence showing that Al in vaccine-relevant exposures can be toxic to humans and animals. We sought to evaluate the effects of Al adjuvant and the HPV vaccine Gardasil versus the true placebo on behavioral and inflammatory parameters in young female mice. Six week old C57BL/6 female micewere injected with either, Gardasil, Gardasil + pertussis toxin (Pt), Al hydroxide, or, vehicle control inamounts equivalent to human exposure. At six months of age, Gardasil and Al-injected mice spent significantly more time floating in the forced swimming test (FST) in comparison to vehicle-injected mice(Al, p = 0.009; Gardasil, p = 0.025; Gardasil + Pt, p = 0.005). The increase in floating time was already highly significant at three months of age for the Gardasil and Gardasil + Pt group (p ≤ 0.0001). No significant differences were observed in the number of stairs climbed in the staircase test nor in rotarod performance, both of which measure locomotor activity. Since rotarod also measures muscular strength, collectively these results indicate that differences observed in the FST were not due to locomotor dysfunction, but likely due to depression. Additionally, at three months of age, compared to control mice, Al-injected mice showed a significantly decreased preference for the new arm in the Y maze test (p = 0.03), indicating short-term memory impairment. Moreover, anti-HPV antibodies from the sera of Gardasil and Gardasil + Pt-injected mice showed cross-reactivity with the mouse brain protein extract. Immuno-histochemistry analysis revealed microglial activation in the CA1 area of the hippocampus of Gardasil-injected mice compared to the control. It appears that Gardasil via its Al adjuvant and HPV antigens has the ability to trigger neuroinflammation and autoimmune reactions, further leading to behavioral changes.

Let’s take a look at the Immunologic Research version:

Vaccine adjuvants and vaccines may induce autoimmune and inflammatory manifestations in susceptible individuals. To date most human vaccine trials utilize aluminum (Al) adjuvants as placebos despite much evidence showing that Al in vaccine-relevant exposures can be toxic to humans and animals. We sought to evaluate the effects of Al adjuvant and the HPV vaccine Gardasil versus the true placebo on behavioral and inflammatory parameters in female mice. Six-week-old C57BL/6 female mice were injected with either, Gardasil, Gardasil + pertussis toxin (Pt), Al hydroxide, or, vehicle control in amounts equivalent to human exposure. At 7.5 months of age, Gardasil and Al-injected mice spent significantly more time floating in the forced swimming test (FST) in comparison with vehicle-injected mice (Al, p = 0.009; Gardasil, p = 0.025; Gardasil + Pt, p = 0.005). The increase in floating time was already highly significant at 4.5 months of age for the Gardasil and Gardasil + Pt group (p ≤ 0.0001). No significant differences were observed in the number of stairs climbed in the staircase test which measures locomotor activity. These results indicate that differences observed in the FST were unlikely due to locomotor dysfunction, but rather due to depression. Moreover, anti-HPV antibodies from the sera of Gardasil and Gardasil + Pt-injected mice showed cross-reactivity with the mouse brain protein extract. Immunohistochemistry analysis revealed microglial activation in the CA1 area of the hippocampus of Gardasil-injected mice. It appears that Gardasil via its Al adjuvant and HPV antigens has the ability to trigger neuroinflammation and autoimmune reactions, further leading to behavioral changes.

There are some small differences in the wording, not important to the overall understanding of this article. Critically, he authors of the study conclude that,

It appears that Gardasil via its Al adjuvant and HPV antigens has the ability to trigger neuroinflammation and autoimmune reactions, further leading to behavioral changes.

They key conclusions are exactly the same in both versions of the article. So, nothing really new.

Predictably, the anti-vaccination crowd jumped on this article (ignoring the fact that it was withdrawn by Vaccine), claiming that,

…given the large numbers of reports of adverse reactions from people who been vaccinated with Gardasil and the other HPV vaccine, Cervarix, the mice who were injected with the vaccines showed signs and symptoms consistent with vaccine-induced damage.

According to the good folks at Retraction Watch, Shaw told them that, “much of [the] original paper that was retracted from Vaccine was revised based on the comments of the second set of reviewers for Vaccine that we found of value.” However, it appears that there really wasn’t much change in the paper, and the conclusions are exactly the same, word for word.

But it doesn’t matter that the article was republished in a peer-review journal – the same issues regarding the research and conclusions remain

Republished HPV vaccine article – point by point analysis

Here are some of the key points that should lead a reader to reading this article with a very skeptical eye:

  • Two of the authors of the article, Christopher A. Shaw and Lucija Tomljenovic of the University of British Columbia, are well-known as paid researchers of the anti-vaccine (specifically, anti-Gardasil) movement. Shaw and Tomljenovic have been compensated very well to continue to publish nonsense anti-vaccine research, generally in predatory journals. To this day, we don’t know why Vaccine originally published the article, but Shaw and Tomljenovic must have had a celebration that their bad science got into a real journal. I hope that the editors of Vaccine explain to us why they didn’t see the authors’ names and wonder if it was bad research
  • Moreover, the World Health Organization’s (WHO) Global Advisory Committee on Vaccine Safety critically examined two widely touted studies by Shaw and Tomljenovic. These studies (here and here) asserted that aluminum adjuvants in vaccines are linked to autism. Predictably, WHO’s advisory committee found their research to be “seriously flawed.” Improbably, the research was based on population level numbers (that is, compare autism rates for a large population with vaccination rates) to conclude that there is a causal association. That kind of research methodology would be laughed out of a first year epidemiology course. According to the WHO’s advisory committee, “…ecological studies cannot be used to assert a causal association because they do not link exposure to outcome in individuals, and only make correlations of exposure and outcomes on population averages.”
  • Nevertheless, animal studies do not constitute the basis of evidence for human medicine. As I have written before, claims based on very early research rarely, less than 10% of the time, ever amount to anything important.
  • In the hierarchy of medical research, animal studies rank near the bottom of the barrel. Why? See above. And primary studies based on an animal models rarely end up having applicability to science based medicine. Animal research should be treated as observations that have not been confirmed.
  • There is little biological plausibility to their hypothesis that the HPV cancer-preventing vaccine can cause behavioral issues. First, we have little (really no) evidence that the HPV antigen causes neuroinflammation or autoimmune conditions. We would see this with the virus itself (irrespective of the vaccine), yet we don’t. In addition, the fear of aluminum is overstated by too many people, and the limited amount in Gardasil (or any vaccine) would have no biological effect on humans.

Why did the original Vaccine article get “temporarily removed”? According to Retraction Watch, “the article in question has been temporarily removed as requested by Vaccine’s Editor-in-Chief Gregory Poland. In addition, Dr Poland has recommended the article be further reviewed.”

My guess is that there were a lot of proverbial raised eyebrows at the quality of research in this paper. Shaw and Tomljenovic are in the Department of Ophthalmology at the University of British Columbia, and do not have the credentials that most researchers have in publishing in Vaccine. It is also possible that the research is highly flawed–there are things in there that remind me of Séralini’s laughably designed and analyzed “GMO corn causes cancer” study.

I’m sure the next assertion made by the anti-vaccination crowd will be that the Editor-in-Chief, Dr. Poland, was pressured by Merck, Dr. Paul Offit, and the CDC to retract the article. Oh you think I’m kidding?

For those of you who don’t know Dr. Gregory Poland, he’s had it with the crowd that believe that the MMR vaccine is linked to autism. He has editorialized about this ongoing manufactroversy:

To continue pouring money into futile attempts to prove a connection to the MMR vaccine when multiple high-quality scientific studies across multiple countries and across many years have failed to show any hint of a connection, and in the face of biologic nonplausibility, is dangerous and reckless of lives, public funding, and ultimately public health.

At some point, a point I believe we have well passed, the small group of people who claim such connections, who have no new or credible data, and for which their assumptions and hypotheses have been discredited must simply be ignored by scientists and the public and, most importantly, by the media, no matter how passionate their beliefs to the contrary. Such individuals are denialists at best, and dangerous at worst.

Even though the research was republished in a lesser journal, my original analysis still stands. Gardasil causes behavioral issues in humans? No evidence whatsoever. But we do know that it does prevent many dangerous cancers.

There are huge studies, often containing millions of doses, that have not uncovered any neurodegenerative disorder of any kind in humans:

In other words, in millions of doses given to real live human beings, we’ve found no evidence of the bogus claims made by this republished article. Who are you going to believe? Researchers who did powerful research looking at neurological issues in actual humans? Or a poorly designed study in mice?

But why trust me?

Critique from the unfathomable Dr. Orac

Dr. Orac, who some anti-vaccination trolls think is me, got access to the original article (before it was scrubbed by Vaccine from the internet), and skewered it. After reading his critical review of the paper, I stand by my previous point that it smelled just like the awful GMO paper from Séralini that I mentioned before.

Go read Orac’s full review, but let me highlight the key points:

  1. The author’s hypothesis that “claims that vaccine adjuvants and vaccines can cause autoimmune disease” are generally only pushed by those who are anti-vaccine in general.
  2. The researchers used a mouse model to use as a proxy for “behavior,” by putting them through some standardized tests for mice. The problem is that the authors have provided a hypothesis, which totally lacks biological plausibility, to harm mice (because they are killed at the end of the experiment).
  3. The researchers were not “blinded” when they observed the mice go through these tests. Well, at least they didn’t mention if they were blinded.
  4. Like Séralini, the authors must have flunked basic statistics. The used a type of statistical test, called Student’s t-test,  that was meant to determine the statistical significance of two independent groups of data. The authors used it to identify differences between FOUR groups of data. It doesn’t work in those cases.

It’s bad science. No, it’s terrible science – someone might not get vaccinated against HPV which is linked to a bunch of serious cancers.

The TL;DR version

If you polish a turd and try to show it if off at an art show, it’s still a turd. If you then re-polish that turd and find another, less important, art show to show it off, it’s still a turd.

This study is just a polished turd. It does not provide us with any information with regards to the cancer preventing HPV vaccines’ safety profile. It is still a stinky turd.

Key citations

 
 
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The Original Skeptical Raptor
Chief Executive Officer at SkepticalRaptor

Lifetime lover of science, especially biomedical research. Spent years in academics, business development, research, and traveling the world shilling for Big Pharma. I love sports, mostly college basketball and football, hockey, and baseball. I enjoy great food and intelligent conversation. And a delicious morning coffee!