HPV vaccine systematic review – anti-vaxxers and Cochrane

Back in May 2018, I wrote an analysis of a new HPV vaccine systematic review that clearly showed that not only was the HPV vaccine very safe, but it was also effective in significantly reducing the risks of cervical cancer. This was powerful and robust evidence that the HPV vaccine is one of the best tools in reducing HPV-related cancers. And that the vaccine is extremely safe, possibly the safest of all the very safe vaccines on the market.

For those who aren’t science nerds like me, you should know systematic reviews are at the pinnacle of the hierarchy of biomedical research. These type of reviews are one of the foundations of science-based medicine (SBM).

The idea of SBM is …to answer the question “what works?” we must give more importance to our cumulative scientific knowledge from all relevant disciplines.

Now I’ve said that systematic reviews are not perfect. For example, the Cochrane Database is considered one of the premier organizations that perform systematic and meta-reviews in the biomedical sciences. If I am looking to determine if there is evidence supporting a medical claim, I look there first. As a scientist, I don’t take their conclusions at face value – for example, they have made egregious errors in systematic reviews of acupuncture quackery in the past. Like all scientific literature, one must examine a systematic review (whether published in Cochrane or any other journal) with a critical eye. Is there bias in including or excluding data? Do they overstate the conclusion? Do they rely upon unusual or bad statistical analyses?

Recently, one Cochrane group has attacked the aforementioned HPV vaccine systematic review, written by another Cochrane group. Time to take a look at that.

All about HPV and 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 41,000 HPV-related cancers are diagnosed in the USA every year.

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 41,000 cancers a year in the USA alone. The HPV vaccine prevents becoming infected by HPV, which means you are protected from these cancers.

HPV vaccine systematic review – Cochrane v. Cochrane

The first HPV vaccine systematic review, by Marc Arbyn et al. and published in the Cochrane Database of Systematic Reviews, examined 26 different clinical studies with over 73,000 participants. The researchers searched several databases of clinical trials to find randomized clinical trials that compared safety and efficacy in females offered HPV vaccines with a placebo group (that usually included vaccine adjuvants).

To cut to the chase, the researchers found that the HPV vaccine reduced the risk of these cervical pre-cancerous lesions, which are associated with HPV16 or HPV 18, from 341 to 157 for every 10,000 women. HPV vaccination also reduced the risk of any pre-cancerous lesion from 559 to 391 per 10,000 in this group. Essentially, the researchers found significant reductions in the incidence of cervical intraepithelial neoplasia (which can be a precursor of cervical cancer). In addition, they found no safety signals of adverse events.

In other words, this was a perfectly fine HPV vaccine systematic review that showed that the HPV vaccines were both very safe and very effective.

The second part of this battle of Cochranes comes from Cochrane Nordic, a branch of the Cochrane Collaboration. They published a paper in BMJ Evidence Based Medicine that blasted the Arbyn et al. article. You’d think that two branches of Cochrane were at war with each other.

Essentially, the latter article criticized the first one for being biased and ignoring evidence. They wrote:

Part of the Cochrane Collaboration’s motto is ‘Trusted evidence’. We do not find the Cochrane HPV vaccine review to be ‘Trusted evidence’, as it was influenced by reporting bias and biased trial designs. We believe that the Cochrane review does not meet the standards for Cochrane reviews or the needs of the citizens or healthcare providers that consult Cochrane reviews to make ‘Informed decisions’, which also is part of Cochrane’s motto. We recommend that authors of Cochrane reviews make every effort to identify all trials and their limitations and conduct reviews accordingly.

Their major points were that they ignored a Gardasil9 trial, they ignored funding sources, and they didn’t include enough randomized, double-blind trials. We’ll get to a point by point takedown of their anti-HPV vaccine bias, but let’s take a look the authors and Cochrane Nordic.

Thomas Jefferson

First, the latter paper was co-authored by Thomas Jefferson. Other than the name of one of the first Presidents of the United States, many of you may not know much about Jefferson. I have mostly ignored him because he’s such a biased anti-vaccine zealot, it’s hard to take anything he writes with any level of scientific seriousness.

In an article in ScienceBasedMedicine, Marc Crislip makes quick work of the anti-vaccine rants of Jefferson. Much of Jefferson’s nonsense is about the flu vaccine, which is decidedly unscientific and, ironically, filled with extreme bias.

He generally takes the narrow perspective on the efficacy of the flu vaccine, that of preventing a case of influenza in an exposed individual and argues that the clinical trials that demonstrate efficacy are too flawed to make recommendations.

After listening to an interview with Jefferson by an avowed anti-vaccine conspiracist, Dr. Crislip came to this conclusion:

…suggests a conspiracy theorist  who has a narrow viewpoint and ignores or misstates his own studies and the studies of others and prefers a simple message to the complexity of influenza and its many complications. What comes across in his interview, and in his written, and presumably carefully considered oeuvre, is buckets of anti-influenza vaccine bias; someone who has an opinion first which he defends with the narrowest of data second.

If you want unbiased and thoughtful discussions of vaccines, you won’t find that with Thomas Jefferson.

Cochrane Nordic

Furthermore, Cochrane Nordic is the center of anti-vaccine bias, especially against the HPV vaccine. They have filed several complaints with the European Medicines Agency, essentially the FDA for the European Union, about safety issues with the HPV vaccine. They have focused on postural orthostatic tachycardia syndrome (POTS) based on a series of case reports, which rank near the bottom of the hierarchy of biomedical research. They also have tried to claim a link between the HPV vaccine and complex regional pain syndrome (CPRS).

Both POTS and CPRS are difficult to diagnose, and they are both relatively common in the target group of the HPV vaccine – teens. Moreover, a link lacks any biological plausibility.

The European Medicines Agency rejected the complaints from Cochrane Nordic:

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 overwhelmingly 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.

In other words, the European Medicines Agency firmly rejected the anti-vaccine complaints about the HPV vaccine because they were unfounded and unsupported by all of the scientific evidence.

In addition, in a review of the literature regarding the HPV vaccine and POTS, they authors stated:

There is currently no conclusive evidence to support a causal relationship between the HPV vaccine and POTS. It is of utmost importance to recognize that although temporal associations may be observed, conclusions of causality cannot be drawn from case reports and case series due to the small sample size and lack of control population inherent to this type of scientific literature. If POTS does develop after receiving the HPV vaccine, it would appear to do so in a small subset of individuals and would be difficult to distinguish from the normal prevalence and incidence of the disorder.

Now to the biased anti HPV vaccine systematic review

Let’s get back to the Cochrane Nordic article published in BMJ Evidence Based Medicine. Dr. Vincent Iannelli at Vaxopedia did an excellent job critiquing Cochrane Nordic’s anti-HPV vaccine systematic review. Let me summarize his key points:

  1. They keep talking about placebos. As I wrote before, although placebos can be used in some vaccine clinical trials, it is highly unethical to do trials that potentially place the placebo group in harm’s way of a potentially dangerous and deadly disease.
  2. They criticize the HPV vaccine systematic review for ignoring the “studies” mentioned above which the European Medicines Agency rejected. In other words, the systematic review did not include the case studies, probably because they are generally biased studies that lack controls. Those types of studies are almost always excluded from systematic reviews.
  3. They go on and on about POTS and CPRS. See above.

Summary

I’m not going to hold my breath and presume that the anti-vaccine religion will ignore this whining article from an anti-vaccine thought center. Their complaints about the HPV vaccine systematic review are without merit.

At this time, the original HPV vaccine systematic review, by Arbyn et al., stands as quality research that shows the safety of the HPV vaccine. Moreover, it provides us with solid evidence that it actually prevents cervical cancer. Cochrane Nordic has provided us with no robust evidence that the original systematic review is wrong in its analysis or conclusions.

In other words, there’s nothing to see there.

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!