This year is the HPV vaccine’s 10th anniversary, as the first cervical cancer vaccine was licensed by the US Food and Drug Administration (FDA) in June 2006. Should we celebrate or not? Arguably the HPV vaccine is one of the most controversial vaccines ever released…

In October 2015 I published the article: “The HPV vaccine controversy: science, media… and marketing”, where I included the information available on the vaccine, focusing on its safety and efficacy. A lot has happened since then, many articles have been published which, instead of clarifying the situation, have rather divided even more both the general public and the scientific community. The result: doctors hesitate to recommend the vaccine, parents and young women are even more confused when they have to decide whether to get vaccinated or not…

In this article I outline the recent events related to the HPV vaccine, focusing on new indications, safety statements and current controversies.

 

HPV-Associated Cancers are on rise

Malignancies related to HPV include cervical, vulvar, vaginal, penile, oropharyngeal, anal, and rectal cancers.

According to a new report from the USA Centers for Disease Control and Prevention (CDC), HPV-associated cancer incidence have increased from 10.8 per 100,000 persons during 2004–2008 to 11.7 per 100,000 persons during 2008–2012. The most common cancers are cervical and oropharyngeal (although not all oropharyngeal cancers are HPV-related).

The report stresses that a large number of these cancers are associated with the HPV types included in the vaccine, thus vaccination may potentially reduce the incidence of cancer in the future.

The same trend is observed in other countries such as the UK: while the incidence rates of cervical cancer for women aged 25-34 initially decreased by 35% between 1985-1987 and 2000-2002, rates have since increased by 50% in this age group.

 

More medical societies urge to increase HPV vaccination rates

Despite many professional organisations recommending HPV vaccination, vaccine uptake in the United States remains low: about 39% of girls and 21% of boys have received the full schedule of HPV vaccines.

Taking into consideration these data, the American Society of Clinical Oncology (ASCO) has recently issued a statement urging to increase vaccination rates. In this article “ASCO stresses (…) the need to increase the proportion of adolescent boys and girls receiving the HPV vaccine (…) which could lead to complete eradication of HPV-related cancers in men and women”. They further emphasize its safety by stating that “Both Gardasil and Cervarix vaccines reported excellent short- and long-term safety results in clinical trials”.

But some issues in the ASCO statement have been questioned, namely the “complete eradication of HPV-related cancers” (as none of the available vaccines is 100% effective), and the “excellent safety results”, as worldwide reports of adolescents with chronic side effects after HPV vaccination continue to be published (see below). In addition, the report does not mention anything about screening tests (Pap smears), which are an indispensable tool for preventing cancer by early detection of precancerous lesions.

 

Changes in the HPV vaccination schedule

The CDC recently published the new 2016 recommended immunization schedule for children and adolescents. The schedule for HPV vaccination introduces the ninevalent (9vHPV) vaccine for males and females. While females may receive any of the three available vaccine types: 9vHPV (Gardasil 9), 4-valent (Gardasil) or 2-valent (Cervarix), only Gardasil 9 or Gardasil may be used for males.

The CDC also states that HPV vaccine should be administered beginning at age 9 years to children and youth with any history of sexual abuse or assault who have not initiated or completed the 3-dose series.

 

More studies confirming reduction in the prevalence of HPV, cervical abnormalities and genital warts 

Reduction of HPV prevalence

An American study confirms previous observations of HPV vaccine impact: within 6 years of vaccine introduction, there was a 64% decrease in the four HPV types included in the vaccine among females aged 14 to 19 years and a 34% decrease among those aged 20 to 24 years.

Decrease in condylomas in women and men

In Denmark, girls and young women have been vaccinated since 2008. A recent study shows a significant reduction in the incidence of genital warts, not only in women, but also in men, This means that the vaccine has caused what is called herd immunity. The study concludes: “The reduction is seen in both women up to 35 years of age and men aged 12 to 29 years, suggesting that HPV vaccination is highly efficient and that herd protection has developed.”

Reduction of abnormal Pap tests in high-risk patients

A new study demonstrated the HPV vaccine is effective in a real-world setting of high-risk patients (low-income females, engaging in high-risk sexual behaviors) many of whom had not completed the HPV vaccine schedule.

After following 4127 girls and young women from 11 through 20 years of age who underwent Pap smears, they found that abnormal cytology was less common in vaccinated vs unvaccinated females (8 vs 13 % respectively). The risk was lower if  the 3-dose vaccine series was completed or if the vaccine was administered from 11 through 14 years of age.

 

The European Medicines Agency concludes HPV vaccine is safe

In my previous article, I mentioned that the European Medicines Agency (EMA) would conduct a safety review of HPV vaccines, mainly due to the numerous reports on severe side effects, not only in lay media, but also in medical journals. The main concern was the occurrence of two particular syndromes, namely complex regional pain syndrome (CRPS) and postural orthostatic tachycardia syndrome (POTS) (see here for more details), suspected to be related with HPV vaccination.

The long awaited EMA review was published in November 2015, and concluded that “the evidence does not support that HPV vaccines (Cervarix, Gardasil, Gardasil 9, Silgard) cause CRPS or POTS. The benefits of HPV vaccines continue to outweigh their risks”. Read their press release here.

After this review, a World Health Organization – Global Advisory Committee on Vaccine safety (GAVCS) Statement on Safety of HPV vaccines followed in December 2015, which declares ” The GACVS has systematically investigated safety concerns raised about HPV vaccines and has issued several reports in this regard. To date, it has not found any safety issue that would alter its recommendations for the use of the vaccine”. The statement refers specifically to CRPS and POTS, but also to the increased incidence of Guillain-Barre syndrome found in a French study (see my previous article).

 

Danish scientists skeptical about EMA’s conclusions, start independent research

It was Denmark that had requested the safety review of HPV vaccines from the EMA, as this country, with a high vaccine uptake, reported that more than 1300 girls and young women with chronic symptoms (POTS, CRPS) have been referred to specialized centers.

Not convinced with EMA’s conclusion, Denmark is conducting its own investigation into the issue. The Ministry of Heath has given 7 million DKK (US$1.01 million) for research leaded by specialists who are seeing girls with symptoms after HPV vaccination and who are independent of the pharmaceutical industry.

 

Nordic Cochrane Centre accuses EMA of maladministration and scientific misconduct

Recently, the reputed Nordic Cochrane Centre filed a complaint to the EMA expressing their concern about EMA’s handling of the HPV vaccine safety issue.

The Nordic group says that the EMA report is flawed, and points out several issues. Briefly:

• The EMA has concluded that there is no causal link between CRPS / POTS and the HPV vaccine, but the Nordic Cochrane group says “The EMA’s official report gives the impression of a unanimous rejection of the suspected harms. However, the EMA’s internal report (…) tells a very different story. This “internal report is confidential but has been leaked,” the group notes, and it “reveals that several experts had the opinion that the vaccine might not be safe and called for further research, but there was nothing about this in the official report.”
• “The EMA asked the pharmaceutical companies to search for side effects of the vaccine in their own databases and did not check the companies’ work for accuracy,” they say. They also allege that their criteria to consider cases as POTS were extremely restrictive: “In the search for cases coded as POTS (…)  almost half (40 cases) are dismissed for not meeting the case definition for POTS”.  “This is extraordinary, as the companies have a huge vested interest in not finding these possible harms in their databases,” the Nordic group comments.
• Another issue is the placebo that was used in the clinical trials of HPV vaccines. “In all the vaccine trials apart from a small one, the control group was given a placebo that contained an aluminium adjuvant, which is suspected of being neurotoxic,” they note. The group quotes information contained in the leaked internal documents: “Initially, the vaccine was compared with a placebo group being vaccinated with physiological serum, whereby the number of adverse reactions was much higher and much more serious than in the control group. After comparing 320 patients in the saline placebo group, a quick move was made to an aluminium-containing placebo, in order to be able to only evaluate the effects of the active substance. However, this distorted the comparison (…)”. “We believe this constitutes scientific misconduct,” the Nordic group says.
• The group highlights the “extreme levels of secrecy” that surround the EMA review process, in which experts who are involved in the process are not named and are bound by lifelong secrecy about what was discussed. Nordic Cochrane argues that instead, all documents involving HPV vaccination safety should be made publicly available.
• They also question whether EMA has behaved fairly, in particular towards Dr. Louise Brinth, the Danish whistle-blower who first described cases of POTS in the medical literature, as EMA accuses her to report on “a sample of patients, apparently chosen to fit a pre-specified hypothesis of vaccine-induced injury”. The Nordic group concludes “We find that the EMA’s comments are unprofessional, misleading, inappropriate and pejorative, and that the EMA’s approach (…) is unscientific”.

Dr Brinth, who cosigns the Nordic Cochrane complaint, has published her own 63-page response to the EMA review (it’s really worth a read).

The situation in Japan

Japan puts in place a scheme to manage symptoms after HPV vaccination

Japan has put in place a scheme to manage symptoms, especially generalized chronic pain, that have arisen after HPV vaccination. Guidelines for the evaluation and management of symptoms that begin after HPV vaccine injection were issued to healthcare professionals and approved by the Japan Medical Association and the Japanese Association of Medical Sciences.

Class action lawsuit filed against Japanese government and vaccine manufacturers

Sixty-three women and girls who reported side effects from cervical cancer vaccines sued the Japanese government and drugmakers. “More plaintiffs are expected to join the suit “, The Japan Times recently reported.  According to the Japanese Ministry of Health, Labor and Welfare, 2,945 of the 3.39 million women who had received the vaccines, or 0.09 percent, have reported side effects.

Scientist accuses WHO, GAVCS, CDC of misconduct

In an open letter of complaint to the World Health Organization (WHO), Japanese Dr. Sin Hang Lee expresses concerns regarding the conduct of certain members of GACVS, WHO, CDC and other scientific/health professionals. “I have come into possession of documentation which leads me to believe multiple individuals and organizations deliberately set out to mislead Japanese authorities regarding the safety of the human papillomavirus (HPV) vaccines, Gardasil and Cervarix”, he writes.  In his letter he explains that there is at least one known mechanism of action explaining why serious adverse reactions occur more often in people injected with HPV vaccines than other vaccines, and why certain predisposed individuals may suffer a sudden unexplained death as a result, but he alleges that this information was deliberately “ignored” by the experts.

 

Potential risk of Primary Ovarian Failure associated with HPV vaccination

The American College of Pediatricians (ACP) issued a statement in January 2016 warning of a potential relationship between Primary Ovarian Failure and HPV vaccination.

“It has recently come to the attention of the College that one of the recommended vaccines could possibly be associated with the very rare but serious condition of premature ovarian failure (POF), also known as premature menopause“, they report.

They further state that, although most physicians are probably unaware of a possible association between the HPV vaccine  and POF, and may not consider reporting cases or prolonged amenorrhea (missing menstrual periods) to the Vaccine Adverse Event Reporting System (VAERS), 213 cases were reported. When the cases are more carefully chosen:  “86/89 cases are associated with Gardasil, 3/89 with Cervarix, and 0/89 with other vaccines administered independently of an HPV vaccine. Using the same criteria, there are only 7 reports of amenorrhea from 1990 through 2005″.

“While there is no strong evidence of a causal relationship between HPV4 and ovarian dysfunction, this information should be public knowledge for physicians and patients considering these vaccines”, they conclude.

A possible association between ovarian problems and the HPV vaccine had been already reported by Dr Deirdre Little, an Australian gynecologist:

It should be mentioned that the ACP statement, as well as Dr. Little’s research have been heavily criticized by other physicians.

 

Conclusions

I was hoping that, with the new available information on the HPV vaccine safety, I could reach a conclusion on how to counsel, as a physician, young women and mothers asking me whether to get the HPV vaccine or not. I was expecting to have a thorough review stating loud and clear the HPV vaccine expected benefits vs. the documented risks.  Unfortunately, no conclusion can be easily drawn so far. It is extremely difficult to find a balance between the scientific evidence -with studies not always well-designed-, the experts’ opinions and the increasing criticism surrounding this vaccine.

While most professional societies urge us to promote vaccination, the constant reports on serious side effects coming from all around the globe cannot be ignored. It’s unfortunate to see a woman dying of a cancer that could have been prevented, but it is equally heart-breaking to see a healthy teenager, full of life, suddenly prostrated in a wheelchair…

I have no doubt that vaccines are an invaluable public health tool against fatal diseases, and it’s imperative that we all continue to believe in vaccines. However, it’s my opinion that the HPV vaccine in particular deserves further study.

The unanswered questions are too many, not only about potential risks, but also about potential benefits. Therefore, I believe that further independent research is urgently warranted – not just in Denmark, but worldwide. With  more than 175 millions vaccine doses distributed in 63 countries, it is certain that a coordinated, global effort would shed light on some aspects of this controversial vaccine.

Acknowledgement

I am genuinely grateful to Ms Caron Ryalls, who kindly contacted me and provided me with some of the information presented here.