HPV vaccine safety – European Medicines Agency update

As I’ve written on a number of occasions, HPV vaccines, Gardasil, Cervarix and Silgard, are powerful anti-cancer vaccines. They prevent infection by up to 9 different types of genital and oral human papillomavirus (HPV), the most common sexually transmitted infection (STI) in the USA. HPV is generally transmitted from personal contact during vaginal, anal or oral sex.

HPV is believed to cause nearly 5% of all new cancers across the world, making it almost as dangerous with regards to cancer as tobacco. According to the CDC, roughly 79 million Americans are infected with HPV–approximately 14 million Americans contract HPV every year. Most individuals don’t even know they have the infection until the onset of cancer. About 27,000 HPV-related cancers are diagnosed in the USA every year.

Despite the robust body of evidence supporting HPV vaccine safety and effectiveness, the European Medicines Agency (the European Union’s version of the US FDA) has started a review of human papilloma virus (HPV) vaccines “to further clarify aspects of their safety profile,” although the agency also points out that this review “does not question that the benefits of HPV vaccines outweigh their risks.”

What’s up with HPV vaccine safety?

 

This review was initiated at the request of Denmark (countries can make requests of European regulatory agencies to undergo reviews of drugs). This review will examine the data for two conditions that have been reported, rarely, with HPV vaccines:

  • postural orthostatic tachycardia syndrome (POTS), a difficult-to-diagnose condition in which a change from the supine position  to an upright position causes an abnormally large increase in heart rate, called tachycardia. This can cause symptoms such as dizziness and fainting, as well as headache, chest pain, and weakness.
  • complex regional pain syndrome (CRPS), a chronic pain condition affecting the limbs,

The ESA states that “both conditions can occur in non-vaccinated individuals and it is considered important to further review if the number of cases reported with HPV vaccine is greater than would be expected.” They also have explained that no causal link between these conditions and HPV vaccines have been established.

Thus, the ESA will review available research that could help clarify the frequency of the two conditions after HPV vaccination, and possibly determine if there is any causal link. After the review is completed, the agency will decide whether changes to product information are needed.

 

POTS

The suspicion that postural orthostatic tachycardia syndrome is related to a study published earlier in 2015 by Danish researchers who provided some observational evidence about POTS occurrence after HPV vaccines.

The authors claimed that:

All patients had symptoms consistent with pronounced autonomic dysfunction including different degrees of orthostatic intolerance, severe non-migraine-like headache, excessive fatigue, cognitive dysfunction, gastrointestinal discomfort and widespread pain of a neuropathic character.

The authors also stated that they “found a close chronologic association to the vaccination, but are well aware that this does not necessarily imply a causal relationship (emphasis mine).”

I heavily critiqued this study, focusing on several points:

  • It’s a case report study. In other words, it’s observations that cannot provide us with an answer to the hypothesis, “does the HPV vaccine cause POTS.” Case reports show up in the medical literature all of the time, but the vast majority don’t amount to real evidence for clinical decisions.
  • There are no controls.
  • Small sample size. There were only 35 patients included in the study.
  • Poor temporal association. The study found that the average number of days between vaccination and diagnosing POTS was around 11 days. It is difficult to conceive of how one could even claim an association without a thorough investigation of the confounding factors that may have occurred in the ensuing 11 days that might have lead to POTS.
  • No biological plausibility. To even begin to make a claim of correlation or causation, one has to provide some level of plausibility.
  • Diagnosing POTS. The condition is a very complex, where your heart rate increase suddenly when you stand or sit up from lying down. In the small patient population, there were confounding variables that were not fully explained like heavy exercise by most of the patients prior to the study.
  • POTS is common in teenage and young adult females. Again, without the control group, how did the authors even begin to make this diagnosis. Better yet, did they check for POTS prior to the study? No, they didn’t.
  • Diagnosing POTS. Diagnosing this condition is not easy (pdf). It isn’t done in a minute–a definitive diagnosis requires blood tests, including tests for hormonal deficiencies, a specialized tilt table test under controlled conditions, and a few other tests to get a definitive diagnosis. These researchers diagnosed POTS with one test–heart rate, which can be indicative of at least 1000 different medical conditions. This is not how one gets a definitive diagnosis of POTS.
  • The authors’ bias. I usually don’t care about the authors, unless they are really bad or really good. These authors seem to have a history of bias against the HPV vaccine. If a huge epidemiological study performed by an unbiased group gave us these results, sure I’d be on board. But this group seems to lack any knowledge of what POTS is, let alone establishing a causal link.

I am concerned that the ESA has decided to review the HPV vaccine safety based on such a terrible study. This is very similar to what I recently described happened in Japan with the HPV vaccines–using really bad data to impugn the safety of a very important vaccine.

vaccines-gardasil-cervarix

 

CRPS

Complex regional pain syndrome, like POTS, is a difficult to diagnose illness. Moreover, POTS and CRPS have overlapping symptoms and other clinical features that make them difficult to separate from one another.

In a June 2015 article, Dr Manuel Martínez-Lavín proposed a hypothesis that small fiber neuropathy and dysautonomia could be the common underlying pathogenesis for this group of rare, but severe, reactions that follow HPV vaccination. But this study isn’t based on clinical trials–it is the author’s opinion and conjecture in what can best be described as a low quality journal (with an impact factor less than 1.7).

Dr. Martínez-Lavín, who is from the Rheumatology Department, Instituto Nacional de Cardiología Ignacio Chávez in Mexico City, Mexico, claims that:

The symptoms more often reported are chronic pain with paresthesias, headaches, fatigue, and orthostatic intolerance. Adverse reactions appear to be more frequent after HPV vaccination when compared to other type[s] of immunizations. Different isolated cases and small series have described the development of [CRPS], [POTS], and fibromyalgia after HPV vaccination.”

Basically, Dr Martínez-Lavín proposes a hypothesis that small fiber neuropathy and dysautonomia could be the common underlying pathogenesis for this group of rare, but severe, reactions that follow HPV vaccinations. He wants to make clinicians aware of a “possible association” between the HPV vaccine and the development of these syndromes.

Most importantly, Dr. Martínez-Lavín partially bases his hypothesis on the aforementioned POTS and HPV vaccine study that has been heavily criticized. So one poorly designed, potentially biased study, leads to another huge hypothesis? I’m finding it difficult to see the link.

Updated EMA statement

In November 2015, the European Medicines Agency determined that HPV vaccines are unrelated to the development of either POTS or CRPS. The concluded that there is no causal link, and that observations of POTS and CRPS are not different from the rates that would be observed irrespective of vaccination status in these demographic groups.

Here are some excerpts from their statement:

The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) has completed a detailed scientific review of the evidence surrounding reports of two syndromes, complex regional pain syndrome (CRPS) and postural orthostatic tachycardia syndrome (POTS) in young women given human papillomavirus (HPV) vaccines. These vaccines are given to protect them from cervical cancer and other HPV-related cancers and pre-cancerous conditions.

This review concluded that the evidence does not support a causal link between the vaccines (Cervarix, Gardasil/Silgard and Gardasil-9) and development of CRPS or POTS. Therefore, there is no reason to change the way the vaccines are used or amend the current product information.

PRAC thoroughly reviewed the published research, data from clinical trials and reports of suspected side effects from patients and healthcare professionals, as well as data supplied by Member States. It also consulted a group of leading experts in the field, and took into account detailed information received from a number of patient groups that also highlighted the impact these syndromes can have on patients and families.

Their reasoning was based on solid scientific evidence that overwhelming supports the lack of a causal relationship:

Symptoms of CRPS and POTS may overlap with other conditions, making diagnosis difficult in both the general population and vaccinated individuals. However, available estimates suggest that in the general population around 150 girls and young women per million aged 10 to 19 years may develop CRPS each year, and at least 150 girls and young women per million may develop POTS each year.

The review found no evidence that the overall rates of these syndromes in vaccinated girls were different from expected rates in these age groups, even taking into account possible underreporting. The PRAC noted that some symptoms of CRPS and POTS may overlap with chronic fatigue syndrome (CFS, also known as myalgic encephalomyelitis or ME). Many of the reports considered in the review have features of CFS and some patients had diagnoses of both POTS and CFS. Results of a large published study that showed no link between HPV vaccine and CFS were therefore particularly relevant.

If you don’t have the time to read all of PRAC’s reasoning for dismissing these claims, let’s get to their final conclusion:

The PRAC concluded that the available evidence does not support that CRPS and POTS are caused by HPV vaccines. Therefore there is no reason to change the way the vaccines are used or amend the current product information.

If you’re reading this article because you were researching the relationship between HPV vaccines and these disorders, you can now relax. There is no relationship between POTS or CRPS and HPV cancer prevention vaccines.

 

Summary

Because of the system in which the European Union examines medications, including vaccines, one country, in this case Denmark, can request a review. Obviously, the Danes based this review on a study done within their own country.

I am troubled that one poorly designed study and one poorly developed “hypothesis” (partially based on that one poorly designed study) can lead to an expensive review of the HPV vaccine. And without a doubt, some anti-vaccine website will trumpet this review with some inflammatory headline such as “EMA investigating HPV vaccines.” No, it’s not. It’s reviewing data from some bad studies to determine if there’s anything there. But because of this “investigation,” some families are not going to give their sons and daughters the HPV vaccine, which can and will prevent some very deadly cancers.

Sadly, I’ve heard this story before. MrAndy Wakefield fraudulently alleged a connection between the MMR vaccine and autism which has had the effect of suppressing vaccination rates in many countries. After several billions of dollars in research, we found out what most of us hypothesized–there is no link between vaccines and autism. I don’t think there’s any fraud committed in these studies, but nevertheless the same end-result happens–it is used to cast a shadow on important vaccines.

I know some people ascribe to the precautionary principle, and we should examine observational evidence carefully. I agree to a point–if the data is well developed, and appears to be unbiased, we obviously should examine it. This review of HPV vaccine is a waste of time and money, just because regulatory authorities want to avoid bogus arguments from the antivaccine crowd.

Despite the waste of money and time to do this review of the HPV cancer prevention vaccine, it’s good to know that the European Medicines Agency published a statement that supports my original conclusions that the vaccine is unrelated to either POTS or CRPS. Yes, you can thank me in the comments.

Editor’s note: This article was originally published in July 2015. It has been revised to include a new statement from the European Medicines Agency that a thorough review concludes evidence does not support that HPV vaccines cause CRPS or POTS.

Key citations:

 

 
 
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!
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  • Lemongrass

    Great update!

    “Results of a large published study that showed no link between HPV vaccine and CFS were therefore particularly relevant.”

    Does anyone have a link to that study?

    • I believe it’s this one:

      http://www.ncbi.nlm.nih.gov/pubmed/24001935

      They showed that the rate of CFS post HPV vaccine was the same as the generate rate in the population. It’s impossible to show temporal association if you can’t even find an increased risk.

      I hope this helps.

      • Lemongrass

        Thank you! That does help.

        From the study “The successful implementation of an enhanced pharmacovigilance plan provided immediate reassuring evidence that there was no association between vaccination with Cervarix and an increased risk of chronic fatigue syndromes. This has now also been further demonstrated in more comprehensive epidemiological studies.”

        Wish they listed what those further comprehensive epidemiological studies were. I’ve searched and not come up with much. Grrrrr…

        • There have been several studies, one with >1 million teens, that showed absolutely no CFS.

          Sometimes the absence of evidence is evidence of absence. If an epidemiological study of one million teens never shows any CFS in its results.

          Moreover, there is a total lack of plausibility. How can three injections of an HPV antigen induce whole body neurological disorders, like CFS. Scientific research cannot discover things that are impossible or unlikely. It cannot prove a negative.

          I doubt there will be any other studies published ever about Gardasil and CFS. It’s a waste of time and money, unless some study observes it.

          There’s nothing there.

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  • Dorit Reiss

    Thank you for going over this in such detail. It’s tragic that a vaccine that can save so many lives and prevent so much suffering is attacked based on such unfounded claims.