HPV vaccine adverse effects and the European Medicines Agency

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) began a review of human papillomavirus (HPV) vaccines “to further clarify aspects of their safety profile,” although the agency also points out that this review did not “question that the benefits of HPV vaccines outweigh their risks.” In other words, the EMA examined the HPV vaccine adverse effects, real or imagined.

After a few months of investigation, the EMA came to a conclusion about HPV vaccine adverse effects – there were no major ones. Let’s take a look at this story.

All about HPV vaccines

Genital and oral human papillomavirus (HPV) infections are the most common sexually transmitted infections (STI) in the USA.  HPV is generally transmitted from personal contact during vaginal, anal or oral sex.

It’s important to note that there are more than 150 strains or subtypes of HPV that can infect humans – however, only 40 of these strains are linked to one or more different cancers. Of those 40 strain, most are fairly rare.

Although the early symptoms of HPV infections aren’t serious and many HPV infections resolve themselves without long-term harm, HPV infections are causally linked to many types of cancers in men and women. According to current medical research, here are some of the cancers that are linked to HPV:

In addition, there is some evidence that HPV infections are causally linked to skin and prostate cancers. The link to skin cancer is still preliminary, but there is much stronger evidence that HPV is linked to many prostate cancers.

HPV is believed to cause nearly 5% of all new cancers across the world, making it almost as dangerous as tobacco in that respect. According to the CDC, roughly 79 million Americans are infected with HPV – approximately 14 million Americans contract a new HPV every year. Most individuals don’t even know they have the infection until the onset of cancer. The CDC also states that over 43,000 HPV-related cancers are diagnosed in the USA every year. It may be several times that amount worldwide.

There were two HPV vaccines on the world market before 2014. GSK, also known as GlaxoSmithKline, produced Cervarix, a bivalent (protects against two HPV strains) vaccine. It has been withdrawn from the US market (although available in many other markets), because of the competition from the quadrivalent (immunizes against four different HPV strains) and 9-valent (against nine HPV strains) Gardasil vaccines.

Merck manufactures Gardasil, probably the most popular HPV vaccine in the world. The first version of the vaccine, quadrivalent Gardasil, targets the two HPV genotypes known to cause about 70% of cervical cancer and two other HPV genotypes that cause genital warts. In Europe and other markets, Gardasil is known as Silgard.

The newer Gardasil 9, approved by the FDA in 2014, is a 9-valent vaccine, protecting against HPV Types 6, 11, 16, 18, 31, 33, 45, 52, and 58. It targets the four HPV strains found in the quadrivalent version, along with five additional ones that are linked to cervical and other HPV-related cancers. Both versions of Gardasil are prophylactic, meant to be given to females or males before they become exposed to possible HPV infection through intimate contact.

Gardasil is one of the easiest and best ways to prevent a few dangerous and, to abuse the definition slightly, common cancers that afflict men and women. Without a doubt, the HPV vaccine prevents cancer.

Currently, in the United States, the Advisory Committee on Immunization Practices (ACIP) recommends that preteen girls and boys aged 11 or 12 are vaccinated against HPV. The immunization is also recommended for teenage girls and young women up to the age of 26 who did not receive it when they were younger, and teenage boys and young men up to the age of 21.

Let me sum this all up so that if you come away from this section with nothing else, you get this summary. HPV is a sexually transmitted disease. HPV causes 43,000 cancers a year in the USA alone. The HPV vaccine prevents becoming infected by HPV, which means you are protected from these cancers.

What’s up with HPV vaccine adverse effects?

This EMA review was initiated at the request of Denmark (countries can make requests of European regulatory agencies to undergo reviews of drugs) through the Cochrane Nordic group that seems to have a strong anti-vaccine bias.

This EMA review examined 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 EMA stated 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 EMA reviewed available research that could help clarify the frequency of the two conditions after HPV vaccination, and possibly determine if there is any causal link. We will get to the EMA’s conclusions below, but let’s look at the evidence for these two conditions with respect to HPV vaccine adverse effects.

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 very complex, where the patient’s heart rate increases suddenly when they 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 Danish 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.

 

CRPS

Complex regional pain syndrome, like POTS, is another 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. Furthermore, this whole hypothesis lacks biological plausibility, so it is difficult to take this seriously.

EMA statement on HPV vaccine adverse effects

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 Cochrane Nordic 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 adverse effects. And without a doubt, some anti-vaccine website will trumpet this review with some inflammatory headline such as “EMA investigating HPV vaccines.” And it keeps showing up, as recently as July 2018, when the Cochrane Nordic group once again attackd the vaccine.

Yeah, the EMA did look into these ridiculous claims. It did review 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.

I know some people ascribe to the precautionary principle, and we should always examine the 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 vaccine adverse effects, 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 undergone an extensive re-writing, copyediting, reformatting, and general cleaning. For the usual reasons, this story continues to be a thing with the anti-vaccine religion.

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!