A recent review by Gruber and Shoenfeld  drew attention to the possibility of a link between the quadrivalent human papillomavirus (HPV) vaccine (Gardasil) and primary ovarian insufficiency [(POI), also known as premature ovarian failure]. This is the most recent in a long line of conditions for which HPV vaccination has been proposed as a causative factor [2,3]. This editorial will examine the background on which the proposed link between HPV vaccination and POI is built.
In the nearly 9 years since the widespread introduction of HPV vaccination, including over 170 million doses of Gardasil, there have been only six cases reporting POI in association with HPV vaccination across three publications. The first was published in 2012 by Little and Ward  and featured a single case study of a 16-year-old girl with POI. Two years later the same authors published a second study featuring three case studies, including the case from the original manuscript . A second series of three case studies was published in 2013 by Colafrancesco et al. . Gruber and Shoenfeld  provide a good overview of the six cases but omit to mention the time between HPV vaccination and the appearance of the first symptoms. None of the women presented with irregular menses until after the third dose of the HPV vaccination, apart from Colafrancesco case 1 who had irregular periods prior to the first HPV vaccination. Of the other five cases only one had an interval between vaccination and first irregular menses of less than a few months (this is the terminology given in ).
AUTOIMMUNE SYNDROME INDUCED BY ADJUVANTS
A number of manuscripts, including Gruber and Shoenfeld , have suggested that the purported link between HPV vaccination and POI could be categorized within a newly proposed condition. In 2011, Agmon-Levin and Shoenfeld (co-author of Colafrancesco et al. ) proposed the existence of autoimmune syndrome induced by adjuvants (ASIA) . However, a recent systematic review  highlighted that the nonspecific nature of the criteria for a diagnosis of ASIA and a lack of biological mechanism means that ASIA has no clinical relevancy.
Little and Ward complained that adverse events following immunization were not recorded beyond 7 months after vaccination. However, they provide no rationale or biological mechanism for including a longer interval between HPV vaccination and onset of POI, other than suggesting adolescent girls may not associate a decline or loss of fertility with vaccination if it occurs slowly over time. As the time between HPV vaccination and the first symptoms of POI increases it becomes more difficult to draw a conclusion of causation, particularly in the absence of a biological mechanism. Little and Ward provide no maximum time period between vaccination and the onset of symptoms beyond which they would consider an association unlikely, and with some claiming a causational relationship even with a 15-year interval between vaccination and symptoms , a defined temporal criterion is essential.
In the first 3 years of the vaccination program in Australia, over 5.8 million doses of Gardasil were distributed, with 83% of females in the school-based program receiving at least one dose , with no evidence of an increase in POI presentation rates. In fact, an analysis by Pellegrino and colleagues  which searched for any reported cases of POI following HPV vaccination found the reporting rate for these events was between 0.065 and 0.14 per 1 000 000 doses (which translates as an approximate rate of 0.039–0.084 per 100 000 person years). Although data on the exact prevalence of POI are sparse, and of poor quality, some studies suggest rates of 22 per 100 000 person years in girls 15–19 years of age in the era prior to HPV vaccine introduction.
Without a plausible biological mechanism we are reliant upon epidemiological studies to refute claims such as these. To conduct such studies, an agreed case definition of POI is required, with initial identification of cases occurring without knowledge of vaccination status or timing. So in essence the claim of an extremely rare reaction to HPV vaccination that results in a poorly defined, uncommon condition is virtually impossible to refute rapidly, and may take years of international collaborative study.
HUMAN PAPILLOMAVIRUS VACCINATION AS A CAUSE OF INFERTILITY IN THE PUBLIC MIND
Vaccination is an issue of significant public interest across the world, especially since the rise of professional antivaccination organizations and the reemergence of vaccine preventable diseases as demonstrated by the recent measles outbreak in Disneyland in California . There is a long history of spurious concerns regarding tetanus toxoid harming vaccination programs in the Philippines and Latin America, endangering newborn infants because of lack of protection against neonatal disease . Much of the audience for antivaccination or vaccine-critical information is online, with social media changing the landscape of vaccination discussions from small, localized groups to a global community.
Authors of scientific manuscripts often present evidence and conclusions with a style that utilizes a collective assumed knowledge of the reader; for example, a case study alone is generally considered insufficient to make a claim of causation because of the high risk of bias . However, when this same evidence is presented to an audience of the general public these nuances are lost and can be used to promote a claim the scientific study did not make.
One of the measures of the impact a scientific study has on the general public is the use of nontraditional metrics such as those presented by Altmetric. Some of the metrics collated by Altmetric include the number and quality of mentions in news articles, on blogs, and on social media. By these metrics Colafrancesco and colleagues  has had a higher impact than 99.95% of the 4.4 million articles assessed. This study appears to be the single biggest influence on the popularization of the idea that HPV vaccination can cause infertility. This assertion is supported by data from Coloma and colleagues  who quantitated posts on social media that linked HPV vaccination and infertility. They showed that increases in social media posts were strongly associated with this study and the associated legal case.
CONFLICT OF INTEREST
Conflict of interest (COI), particularly undeclared, is a growing concern in the scientific community. In 2014, a study was published by Max Wiznitzer in response to Colafrancesco and colleagues, which drew attention to an undeclared conflict of interest of the senior author Yehuda Shoenfeld . Wiznitzer claimed that Shoenfeld was acting as an expert witness for two of the three women featured in the presented case studies. The claim was also made that litigation was still ongoing at the time of publication of Colafrancesco et al., and that this publication may have been used as part of the litigation. A response by Shoenfeld and Tomljenovic  did not dispute these claims. Lucija Tomljenovic is part of the Neural Dynamics Laboratory at the University of British Columbia, which has received significant funding (estimated at $950 000) from the antivaccination group The Dwoskin Family Trust . It could be argued that the COI statement ‘The authors thank the Dwoskin Family Foundation for support’ is inadequate to describe this level of funding. Additionally, in three other studies written by Tomljenovic over the same time period, she states that her work was funded by the Katlyn Fox Foundation. This is another antivaccine organization and it could be reasonably expected that this COI should have been stated. While Deidre Little's public stand against all device or hormonal forms of birth control is not a conflict of interest, knowledge of her stance may affect the context in which her anti-Gardasil stance is viewed.
Clinicians and researchers alike have always acknowledged that case studies are considered at the highest risk of bias and as such are generally ranked at the bottom of the hierarchy of evidence. This increasing recognition has been associated with a decline in the rate of case reports published . Currently, the only evidence presented for a causative link between HPV vaccination and POI is six case studies worldwide over more than 3 years. While postlicensure safety surveillance is critical for all vaccines, including HPV vaccines, young women deserve better than being scared by the over-interpretation of a handful of distressing cases presented without thought to potential bias.
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