Studies on the correlation between human papilloma virus vaccine and premature ovarian failure

Wen-Ming Cao,Shu-Ling Zhang,Xiu-Rong Wang,Li-Li Yu,Na Yu

1Shandong Changle People’s Hospital,Changle People’s Hospital,No.278 Limin Road,Changle Country,Weifang 262400,China.2Shandong Provincial Third Hospital,No.5 Qingnian East Road,Lixia District,Jinan 250014,China.

Abstract

Keywords:Cervical cancer,Human papilloma virus vaccine,Premature ovarian failure

Applications of human papilloma virus vaccines

Cervical cancer is one of the most common gynecologic malignancies of the female reproductive system,adding 530,000 new cases annually worldwide and 132,000 new cases in China.99.7% of cervical cancers are caused by persistent human papilloma virus (HPV) infection and 70% of cervical cancers are related to HPV types 16 and 18 [1].High-risk HPV persistence of infection causes precancerous changes in the cervix and cervical cancer.HPV belongs to the Papillomaviridae family,which is double-stranded DNA viruses with a non-enveloped coat.Over 40 subtypes of HPV can infect the mucosal epithelium,of which 15 are high-risk HPVs for cervical cancer (16,18,31,33,35,39,45,51,52,56,58,59,68,73,and 82).

At present three HPV vaccines have been approved by the U.S.Food and Drug Administration (FDA).All HPV vaccines that are approved in the US are composed of virus-like particles produced by recombinant technology.This type of vaccine has no biological activity and thus is not infectious.Currently in China,there are three HPV vaccines authorized for the prevention of cervical HPV-caused diseases or cancers:Cervarix vaccine,Gardasil 4 vaccine and Gardasil 9 vaccine.Cervarix vaccine can protect against infections caused by HPV type 16 and type 18,namely timely assistance.Gardasil 4 is for the prevention of HPV type 16,type18,type 6 and type 11,namely icing on the cake,and it is recommended in China for ages 20–45 years.The Gardasil 9 developed by Merton covers HPV 6,11,16,18,31,33,45,52,and 58 and can significantly reduce the incidence of cervical cancer by 90%,and also prevents most genital warts,and it is recommended in China for ages 16–26 years.On April 21,2020,the first batch of 93,643 doses of bivalent HPV vaccine produced by Xiamen University and Xiamen Wantai in China.

At present three HPV vaccines have been approved by the U.S.Food and Drug Administration (FDA).All HPV vaccines that are approved in the US are composed of virus-like particles produced by recombinant technology [2].This type of vaccine has no biological activity and thus is not infectious.Currently in China,there are three HPV vaccines authorized for the prevention of cervical HPV-caused diseases or cancers:Cervarix vaccine,Gardasil 4 vaccine and Gardasil 9 vaccine.Cervarix vaccine can protect against infections caused by HPV type 16 and type 18,namely timely assistance.Gardasil 4 is for the prevention of HPV type 16,type18,type 6 and type 11,namely icing on the cake,and it is recommended in China for ages 20–45 years.The Gardasil 9 developed by Merton covers HPV 6,11,16,18,31,33,45,52,and 58 and can significantly reduce the incidence of cervical cancer by 90%,and also prevents most genital warts,and it is recommended in China for ages 16–26 years.On April 21,2020,the first batch of 93,643 doses of bivalent HPV vaccine produced by Xiamen University and Xiamen Wantai in China.

According to the US Centers for Disease Control and Prevention (CDC),if the coverage rate of HPV vaccine under the age of 12 is increased to 80%,it is estimated that 53,000 cases of cervical cancer can be prevented.And a large number of large-scale phase III clinical trials have confirmed the safety and efficiency of HPV vaccine against corresponding diseases.vaccine [3].Yet,by far,people are still concerned about the safety of the HPV vaccine and it remains a major concern for vaccination.According to statistics,for every 100,000 doses of vaccine,hundreds of adverse reactions are reported.But most of these are general reactions,such as pain,swelling,redness,itching,fever,nausea and dizziness at the injection site,which can be relieved in a short time,and serious adverse reactions are rare.According to CDC and the adverse event reporting system of FDA,there are 11,916 cases of adverse events after HPV vaccination.94% of these events are considered minor events,including dizziness,syncope,nausea,pain at the injection site,headache,fever and rash.6% are considered to be serious adverse events,including acute idiopathic polyneuritis,venous thromboembolism and death.Then CDC and FDA analyzed these serious adverse events and concluded that there was no obvious causal relationship between these events and the vaccine.

Whether the human papilloma virus vaccine contributes to premature ovarian failure

Some of the concern about the HPV vaccine impacting fertility is due to individual case reports of ovarian failure following HPV vaccination.During 2012,it was reported that a 16-year-old girl had premature ovarian failure (POF) after receiving the quadrivalent HPV vaccine,which affected ovarian function.Two further cases,each with 3 patients following quadrivalent HPV vaccination,were later diagnosed with POF.These individual case reports have raised concerns about the possible cause-and-effect relationship between HPV vaccination and ovarian dysfunction and POF.To date,there is no evidence,however,to suggest a link between HPV vaccination and POF [4].

POF represents the failure of the ovaries of adult women before 40 years of age as a result of certain causes,with menopausal symptoms such as amenorrhea,infertility,sweating,irritability,a decrease in estradiol,an increase in follicle stimulating hormone (FSH) and luteinizing hormone.With the recent advances in evidence-based medicine and the increasing evidence base,it is increasingly recognized that ovarian failure represents a rapidly evolving disease with a variety of etiologies and symptoms [5].POF has a complex etiology that is linked to age and ethnicity.The older the age,the higher the incidence,according to studies:0.1% for ages less than 20 years,1% for ages 20–30 years,and 10% for ages 30–40 years.POF is also associated with race,Chinese (5%),African-American (14%),and Japanese (1%).Besides,there are the following relevant factors:genetic factors,immune factors,iatrogenic factors,environmental and infectious factors,psychological factors,idiopathic POF [6].Publication of case reports and case series of premature ovarian failure following human papilloma virus vaccination

Little and Ward [7] presented three cases of patients diagnosed with POF that were chronologically linked to HPV vaccination.In the first case,a 16-year-old girl developed menstrual irregularities about one year after the first dose of the quadrivalent HPV vaccine and amenorrhoea a further year later.It was reported earlier as an individual case and tests showed FSH levels,a normal karyotype,a negative fragile X-sequence test,and negative thyroid and adrenal antibodies.In the second case with cerebral palsy,the patient had a menarche at 11 years of age and began taking oral contraceptives at 12 years of age.She received three doses of quadrivalent HPV vaccine from 12 to 13 years of age,and at 18 years of age developed amenorrhea,stopped taking oral contraceptives,and was later diagnosed with POF.It was assumed that the premature ovarian insufficiency (POI) may have previously been poor,but the contraceptive pills covered up the symptoms.In the third case,the patient had the menarche at age of 10 years and was vaccinated with the quadrivalent HPV vaccine at age 14 to 15 years.She began to have irregular menstrual cycles shortly after the third dose and was amenorrheic for the following year;she was diagnosed with POF near her 17th birthday and was not tested genetically.Colafrancesco [8] and others reported three cases of POI,of which two are sisters.One received three doses of quadrivalent HPV vaccine at the age of 14 years and developed menstrual irregularities after the first dose.The sister,who received three doses of the quadrivalent HPV vaccine at 13 years of age,experienced menarche at 15 years of age,second menstrual period one month later,and no menstrual period since then.Both sisters’ FSH levels and estradiol confirmed POF.All tests for known causes of POF were negative,apart from the positive serum anti-ovarian antibody test (unrecognized) previously mentioned.The third patient experienced menarche at 13 years of age and had three doses of quadrivalent HPV vaccine at 21 years of age.She began menstrual irregularities following the third dose and took oral contraceptives until the age of 23.Following discontinuation of the contraceptive pill,amenorrhea developed and a later diagnosis of POF,tested negative for all relevant parameters,apart from a positive test for anti-thyroid peroxidase antibodies,but this was not considered as a factor in autoimmune POF.

These anti-vaccine activists always magnify the safety risks indefinitely,but underestimate the huge economic and health benefits of vaccines.They believe that if it is not 100% perfect,then the vaccine is worthless.Such behavior is stupid,harmful and worthy of everyone’s vigilance.The above are all the cases of POF caused by HPV vaccine retrieved.But here’s the truth.

Pellegrino [9] and others used disease codes for “premature ovarian failure”,“premature menopause” and “primary ovarian insufficiency” to identify drugs in national monitoring databases and publish data on vaccine-use adverse events.The authors have found one case in the Australian database,two cases in the European database,and four cases in the US Vaccine Adverse Event Reporting System,a national self-reporting system for national-level adverse events for vaccines marketed in the United States administered jointly by CDC and FDA.The authors provided no clinical presentation of these cases.Their estimated adverse event reports per million doses of quadrivalent HPV vaccine were 0.065 (US) and 0.14 (Australia).Beyond the above,the authors performed a search of the US National Inpatient Sample database for records of discharges of cases of POF and failed to discover any increase in the number of confirmed cases of POF in patients aged 15–17 years after HPV vaccination.

Arana [10] and others performed an analysis of 2009–2015 adverse effects of quadrivalent HPV vaccine reporting to VAERS.A clinical review of the authors,performed as part of the analysis,was conducted for all reported cases with selected prespecified diseases (including POI).Out of the 17 cases that met the POI search criteria,there were 15 cases in which there was not enough information to support the diagnosis of POF.Many reports are indirect information from the internet or others.There were only 2 cases of POF in which the diagnosis made by the doctor was made:one 23-year-old patient at 1.5 weeks and the other 16-year-old patient at 1 month after receiving the quadrivalent HPV vaccine.The authors pointed out that the reported rate of adverse reactions to the quadrivalent HPV vaccine per million doses was 0.28%.

Naleway [11] and others conducted in a retrospective cohort study to evaluate the increased risk of unexplained POF after vaccination with HPV or any other recommended vaccine at a site of the Vaccine Safety Data System.Of the 28 patients with unspecified POF identified after August 1,2006 (the date of HPV vaccine introduction),only one patient had received HPV vaccine before developing symptoms.This patient developed primary amenorrhea and was assumed to be vaccinated with HPV vaccine about 23 months before symptoms occurred.What the authors did not find was that HPV vaccination,along with other recommendations,raised the risk of POF.Age-adjusted risk ratio for POF after HPV vaccination is 0.30 (95% confidence interval:0.07–11.36).

Discussions

The potential causal link between HPV vaccination and POF is largely rooted in six case reports in the literature.The analysis of the cases is helpful in generating the scientific information that is needed for hypothesis testing.But it cannot be applied to determine causality.Although Arana and others [10] and Pellegrino and others [9] reported in their analysis of passive monitoring databases patients diagnosed with POI after HPV vaccination,it is possible that these patients duplicate those reported by Colafrancesco and others [8],as passive monitoring databases admit all persons to reports of adverse events regardless of the source of information.Collectively,passive monitoring data are not available to identify the link between vaccination and the risks of any adverse event,but they are of greatest value when they reveal safety signals that might be linked to the vaccine and raise hypotheses that are testable against a more stable system.

There was no evidence to support a cause-and-effect link between the HPV vaccine and POF in the 6 case reports,except for the chronological sequence of symptoms that developed after vaccination with the quadrivalent HPV vaccine.Elapsed time between the first dose of the quadrivalent HPV vaccine and the development of symptoms ranged from 8 months to 24 months.The time between vaccination and the development of symptoms can be long and highly variable,thereby rendering it more challenging to draw conclusions about the connection between HPV vaccination and POF.No evidence suggests that any of these cases had the uncommon type of POF associated with autoimmunity assumed by the authors.Despite the fact that one patient has anti-ovarian antibodies,the test is associated with a high false-positive rate and does not provide a reliable diagnosis as an autoimmune etiology of POF.If there is straightforward evidence that the vaccine component triggers are linked to adverse events,the studies would have been useful to explain causality,but no existing evidence supports this.Additionally,the authors did not evaluate patients with POF on an ongoing basis in accordance with the American College of Obstetrics and Gynecology and other organizational recommended evaluation approaches (including karyotype,anti-adrenal antibodies,and fragile X pre-mutations).

The passive monitoring database analysis shows that POF after vaccination with the quadrivalent HPV vaccine is uncommon.Due to the fact that POF is a rare disease and no rational biological mechanism explains the heightened risk of POF after HPV vaccination,if there is no clear biomarker connecting the vaccine to the diseases.It is necessary to conduct epidemiological studies to assess the association.The authors of the original article have found an epidemiological study that assessed the connection between the HPV vaccine and POF.There was no found increased risk of unexplained POF after HPV vaccination from this retrospective cohort study of about 60,000 women who had been vaccinated with the HPV vaccine.Certainly not enough to draw a definitive conclusion from only one study,but this study at least shows that no convincing evidence yet supports that the HPV vaccine raises the risk of POF in young women.

The American College of Obstetrics and Gynecology,the American Academy of Pediatrics,the American Academy of Family Physicians,and the American Cancer Society all fully support the CDC’s recommendation for the widespread introduction of HPV vaccination among adolescents and young adults.

Healthcare professionals,in particular paediatricians and obstetricians and gynaecologists,require awareness of available case reports to manage questions about POF and HPV vaccines,focusing attention on the recently released epidemiological study of 60,000 adolescents and young adult females,the results of which failed to provide a sufficient correlation between the two.The latest HPV vaccine position paper released by the World Health Organization cites the opinion of the Global Advisory Committee on vaccine safety:based on the available evidence,there are no safety concerns about HPV vaccination.Therefore,we do not need to panic,HPV vaccine can rest assured.

Finally,it is concluded that HPV vaccination will not cause POF.