Recently, a study on side effects related to human papillomavirus (HPV) vaccination, which has been an important issue in Japan, was published1. Although the study is flawed, unfortunately, due to the unfounded concerns surrounding the safety of vaccines, even poorly conducted research will almost certainly be used by vaccine skeptics as evidence for the avoidance of vaccine in general. It’s hard not to draw parallels with the unfortunate fallout from the single published study that suggested a link between autism and vaccination. This study, published by Andrew Wakefield in Lancet in 1998, was subsequently retracted in 2010 on the basis on scientific and ethical shortcomings of the research. The theory has since been disproven2, but not without negative consequences to the public’s confidence in vaccines and vaccination strategies.

At present, there are two HPV vaccines marketed in Japan, Cervarix (GlaxoSmithKline) and Gardasil (Merck & Co.). Each vaccine protects against HPV serotypes 16 and 18 which are responsible for approximately 70% of HPV-associated malignancies, the most common being cervical cancer. However, it is now appreciated that HPV is not only a major cause of cervical cancer, but also of anal, vaginal, vulvar, penile, and oropharyngeal cancers.

According to interviewed Japanese vaccines experts, Japan surprisingly displays a high degree of vaccine-skepticism towards HPV vaccines. Specifically, Japan is the only country to have pulled its recommendation for widespread HPV vaccination on the grounds that many patients experienced serious side effects. The main complaint is most commonly known as chronic fatigue syndrome (CFS), which is characterized by long periods of severe fatigue and muscle and joint pains that cannot be attributed to a specific disease. It is generally accepted among managing physicians that these symptoms are real, but experts express that they are almost certain they are coincident to these patients still going through the physiologic changes of puberty.  In addition, the initiation of HPV vaccination coincides with the onset of symptoms of autoimmune disease may first occur, thus it may not be easy to discern whether the symptoms are from the vaccine or from the emergence of a bona fide disease the patient may have. As one of our interviewed experts noted very bluntly, “Simply said, if you were to probe teenagers on how they were feeling, they would “complain” about every symptom you could think of. This doesn’t mean the symptoms aren’t real, just that they’re general and that the vaccine doesn’t cause them.”

In general, there are a number of flaws with the Japanese HPV study. First, the only patients considered in the study were those who complained of side effects, thus there is no consideration for the rates of these side effects among all patients who received an HPV vaccine, and more importantly, examining the general population who did not receive the vaccine. Secondly, the study uses a very small sample of patients. The study only examines the side-effect profile of 120 patients, while close to 3,400,000 patients have already received an HPV vaccine in Japan. Thus, the study itself even supports the finding that an extremely small percentage of patients who have received an HPV vaccine have had symptoms that merit complaining to a physician. Furthermore, because the symptoms definitions are vague and difficult to quantify, much of the diagnostic criteria are subjective. Symptoms tracked included: chronic headache, especially after standing up; abnormal sensation (e.g., coldness of limbs, limb paresthesia, and photophobia); and learning impairment (e.g., lack of concentration). In addition, the study analyzed ten major symptoms, but did not analyze the severity of the symptoms, which would have been beneficial as many of the symptoms were difficult to quantify as mild or severe. Finally, the timing of the vaccination isn’t temporally related to onset of symptoms, as the study authors state that “The time to onset after the first vaccine dose ranged from 1 to 1532 days (average 319.7 ± 349.3 days).” Due to this large time range, it is difficult to rule out non-vaccine factors which may have contributed to the onset or severity of symptoms.

The most troublesome aspect of publication of the HPV study is that vaccination rates overall have been declining even as the availability of highly effective vaccines grows. For pathogens like HPV, vaccination rates have not reached large segments of their target populations, and studies like this only give credence to vaccine opponents and can drive incidence of vaccine-preventable illnesses. Vaccination rates for HPV in females is significantly lower than for other vaccine types despite strong evidence of long-term benefit.  Data on the severity of these cancers along with the efficacy of the vaccine must be carefully considered and promoted to enhance vaccination rates for vulnerable populations. We are already seeing global outbreaks of vaccine-preventable diseases, most notably measles, and based on physician sentiment, things will get worse before they get better. It should be noted that vaccines are not free from safety issues and side effects, as recently discovered for Sanofi’s dengue fever vaccine Dengvaxia, which, due to the disease etiology, can increase the severity of the illness in some young patients3. However, as with all approved pharmaceutical agents, risk-benefit must be considered, and studies considering safety should be expected to be as rigorous as those that determine efficacy. Indeed, the safety of HPV vaccines has been studied outside of Japan, with separate studies in the U.S. and Europe involving tens of thousands of HPV vaccine-recipients being examined, and no link between the vaccine and side effects has been identified 4,5,6. It is unfortunately very easy to scare people into thinking vaccines unsafe, and this is especially worrisome, since we’ve seen that once a single study rings that bell, it is difficult to unring.

  1. Ozawa K, et al. https://link.springer.com/article/10.1007%2Fs40264-017-0574-6
  2. DeStefano F, et al. http://www.jpeds.com/article/S0022-3476(13)00144-3/pdf?ext=.pdf
  3. Stokely S, et al. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6329a3.htm
  4. Klein NP, et al. http://jamanetwork.com/journals/jamapediatrics/fullarticle/1363509
  5. Vichnin M, et al. https://www.ncbi.nlm.nih.gov/pubmed/26107345
  6. Ferguson NM, et al. http://science.sciencemag.org/content/353/6303/1033

 

 

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