1.1. The Formal Philosophy of Language The Problem of Reference The Formal Philosophy of Language The Problem of Reference: Frege & Russell How can words be “about” things? What is the relation between words and the entities they stand for?The problem is probably as old as philosophy itself. It can at least be traced back toAristotle's De Interpretatione . In much philosophy p
Human papilloma virus vaccine and primary ovarian failure: another facet of the autoimmuneinflammatory syndrome induced by adjuvantsHuman Papilloma Virus Vaccine and Primary Ovarian Failure:Another Facet of the Autoimmune/Inflammatory SyndromeInduced by AdjuvantsSerena Colafrancesco1,2, Carlo Perricone1,2, Lucija Tomljenovic1,3, Yehuda Shoenfeld1,4 1Zabludowicz Center for Autoimmune Diseases Sheba Medical Center, Tel-Hashomer, Israel;2Rheumatology Unit, Department of Internal Medicine and Medical Specialities, Sapienza University of Rome, Rome, Italy;3Neural Dynamics Research Group, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada;4Incumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv,Israel Post-vaccination autoimmune phenomena are a major facet of the auto- immune/inflammatory syndrome induced by adjuvants (ASIA) and dif- ferent vaccines, including HPV, have been identified as possible causes.
The medical history of three young women who presented with second- Yehuda Shoenfeld, Department of Medicine B,Chaim Sheba Medical Center, Tel Hashomer, ary amenorrhea following HPV vaccination was collected. Data regard- 52621, Israel. E-mail: Shoenfel@post.tau.ac.il ing type of vaccine, number of vaccination, personal, clinical andserological features, as well as response to treatments were analyzed.
Submission April 24, 2013;accepted June 25, 2013.
ResultsAll three patients developed secondary amenorrhea following HPV vacci- nations, which did not resolve upon treatment with hormone replace- Colafrancesco S, Perricone C, Tomljenovic L, ment therapies. In all three cases sexual development was normal and Shoenfeld Y. Human papilloma virus vaccine genetic screen revealed no pertinent abnormalities (i.e., Turner’s syn- and primary ovarian failure: another facet ofthe autoimmune/inflammatory syndrome drome, Fragile X test were all negative). Serological evaluations showed induced by adjuvants. Am J Reprod Immunol low levels of estradiol and increased FSH and LH and in two cases, specific auto-antibodies were detected (antiovarian and anti thyroid), suggestingthat the HPV vaccine triggered an autoimmune response. Pelvic ultra- sound did not reveal any abnormalities in any of the three cases. All threepatients experienced a range of common non-specific post-vaccine symp-toms including nausea, headache, sleep disturbances, arthralgia and arange of cognitive and psychiatric disturbances. According to these clinicalfeatures, a diagnosis of primary ovarian failure (POF) was determinedwhich also fulfilled the required criteria for the ASIA syndrome.
ConclusionWe documented here the evidence of the potential of the HPV vaccineto trigger a life-disabling autoimmune condition. The increasing numberof similar reports of post HPV vaccine-linked autoimmunity and theuncertainty of long-term clinical benefits of HPV vaccination are a mat-ter of public health that warrants further rigorous inquiry.
American Journal of Reproductive Immunology (2013)ª 2013 John Wiley & Sons Ltd immediately started to complain of burning and heavy sensation in the injected arm, followed by Vaccines against human papilloma virus (HPV) are skin rash and fever. Nausea and stomach aches thought to represent a useful approach in the fight lasted for 2 days after the injection, while in the against cervical cancer. Although vaccines have pro- subsequent 2 weeks, she further complained of ven to be a successful and cost-effective asset for pre- cramping and headache. At the time of the second ventive medicine, local or systemic adverse events, vaccine administration, she reported similar injection following vaccination, have been described. Specifi- site related symptoms, accompanied by sleep distur- cally, there are increasing reports that autoimmune bances, such as insomnia and night sweats. At the disorders can develop after vaccination.1–4 At the time of the third injection, the patient continued to same extent, the association between infectious experience the same symptoms: burning, pain and agents exposure and the development of autoim- heavy sensation in the injected arm, headache and mune diseases is well established.5,6 Recently, a new cramping. Insomnia associated with night sweats syndrome, namely the autoimmune/inflammatory persisted and she started complaining of arthralgia, syndrome induced by adjuvants (ASIA) or Shoen- anxiety and depression. The patient reported that feld’s syndrome,7–12 has been defined, alluding to the her last period occurred shortly after the last injec- key role of adjuvants in inducing autoimmunity. The tion of the HPV vaccine. The hormonal screening syndromes included in ASIA entail immune-medi- showed the presence of increased follicle-stimulating ated conditions that appear following a chronic stim- hormone (FSH) and luteinizing hormone (LH) asso- ulation of the immune system by agents with ciated with very low levels of estradiol. Beta human adjuvant characteristics.7,10 Post-vaccination autoim- mune phenomena represent a major issue of ASIA excluding pregnancy. The karyotype study was 46 and different vaccines, including the HPV vaccine, XX, while molecular studies ruled out Fragile X have been found as possible causes.3,9,13 Primary syndrome and mutated follicle-stimulating hormone ovarian failure (POF) is a clinical condition with com- receptor (FSHR) gene. A pelvic ultrasound did not plex aetiology in which autoimmune mechanisms show any abnormality. According to these clinical represent 20–30% of the cases.14 This assertion is supported by different evidences: the presence of determined. Even though the patient started therapy lymphocytic oophoritis, the detection of ovarian au- with medroxyprogesterone to stimulate bleeding, no toantibodies and the frequent association with other improvement occurred and she continued to experi- autoimmune diseases.14 Herein, we describe three ence abnormal vaginal bleeding, night sweats, hot clinical cases, including two sisters, who developed POF following administration of the HPV vaccine.
Genetic, metabolic and external environmental fac- tors were excluded as POF causes, while the commondenominator was the previous vaccination with HPV This patient (the younger sister of the above- leading to the development of immune-mediated am- mentioned case) received three administrations of the quadrivalent HPV vaccine at the age of 13 underthe same protocol as her sister. At that time, she hadnormal growth and sexual development. The patient complained, 10 days after the first injection, of gen- A young previously healthy girl received three eral symptoms such as depression and sleep distur- administrations of the quadrivalent HPV vaccine (T0, T1 after 4 months, T2 after 9 months) when she was lightheadedness and tremulousness, anxiety, panic 14 years old. Six months before the first injection, attacks and difficulties in focusing/concentrating in the patient had menarche. Her psycho-physical and her school work. She had menarche at the age of sexual development were normal except that at the 15 years, followed by another period 1 month later time she received the first HPV vaccine dose, she and none thereafter. Laboratory analysis showed high serum levels of FSH and LH with undetectable 2 months). After the first vaccination, the patient estradiol. The genetic test for Turner’s syndrome, American Journal of Reproductive Immunology (2013) Fragile X syndrome and FSHR gene was performed vaccine manufacturer, the authors emphasized the and resulted negative. Interestingly, the patient fact that the post-marketing reporting of vaccine tested positive for antiovarian antibodies. She under- adverse events is voluntary and consequently, it is went a pelvic ultrasound without an evidence of not always possible to reliably estimate the fre- abnormalities. In the light of these findings, a diag- quency of such reactions, let alone to establish a nosis of POF was determined and the patient was causal relationship to the vaccine. Further according treated with several different hormonal replacement to the authors, there may potentially be a group for therapies with a poor therapeutic response.
whom the HPV vaccine is contraindicated andbecause the occurrence of POF carries major healthimplications, a long-term follow-up of ovarian func- tion in a cohort of HPV vaccinated woman should The patient received the quadrivalent HPV vaccine in three administrations (T0, T1 after 2 months, T2 POF is a syndrome consisting of primary or sec- after 4 months) at the age of 21 years. Menarche ondary amenorrhoea, hypergonadotropinemia and occurred when she was 13 years old with normal hypoestrogenemia. POF affects 1% of women under monthly periods and a flow of 5–7 days, with mild 40 years of age, 0.1% under 30 and 0.01% of cramps. A normal sexual development was reported.
women under 20 years and it is an important cause Few months after the last injection of HPV vaccine, of infertility and psychological stress.14 POF in young she started complaining of irregular menses (off by women can indeed have significant consequences 1–2 weeks) without an increase in bleeding or pain.
for future health and prospects of motherhood. The The irregular periods worsened and the patient reported on menstruations every 3 months with (referred to oocyte, enzymes or hormones receptors), bleeding only for 2 days. For this reason, she started autoimmune or environmental causes (such as viral infections, chemotherapy, radiotherapy and pelvic improvement occurred and after discontinuation of surgery) or metabolic disturbances.14 The possible therapy, at the age of 23 years, she complained of autoimmune origin for POF has been speculated for amenorrhoea. The laboratory tests showed the pres- a long time,16 and one of the evidence which sup- ence of very low levels of estradiol and increased ports this origin is its frequent association with other FSH and LH. Testosterone, cortisol and prolactin autoimmune diseases (i.e. thyroiditis, Addison’s dis- serum level were found normal. Although the ease, autoimmune polyglandular syndrome, systemic thyroid hormones were also in the normal range, lupus erythematosus, Sjogren’s syndrome, haemolyt- the patients had positive antithyroid peroxidise (TPO) ic anaemia and idiopathic thrombocytopenic pur- antibodies (134 IU/mL, n.v. 0–34). The karyotype pura).17 The presence of autoantibodies reactive to evaluation and the search for Fragile X syndrome dis- different parts of the ovary has been detected in played no aberrations. A transvaginal and pelvic many POF cases and the most commonly recognized ultrasound did not reveal any abnormality. According autoantigens are on the ooplasm, theca, granulose, to these findings and clinical features, a diagnosis of corpus luteum or zona pellucida.18–20 More specific POF was determined. Thus, a therapy with medroxy- antigenic targets of autoantibodies have been identi- progesterone and estradiol was attempted, however, fied in steroid cell enzymes including 3b-hydroxys- it did not improve her clinical condition.
teroid dehydrogenase (3b-HSD), cytochrome P450side-chain cleavage enzyme (P450SCC) and 17a-hydroxylase/17,20 Nonetheless, the detection of such antibodies has Herein, we have described three cases of POF follow- yielded conflicting results because of the different ing HPV vaccination. To the best of our knowledge, stages of disease in which the tests were conducted, an additional case of POF in a 16-year-old young methodological differences and the multiplicity of woman who was vaccinated with the quadrivalent potential immune targets. In our cases, only one of HPV recombinant vaccine has already been reported the three patients had positive antiovarian antibod- by Little and Ward.15 In this case, as in our three ies. Given the difficulties in detecting these antibod- cases, no other possible causes of POF were identi- fied other than the HPV vaccine. Quoting the HPV speculated for the other two cases. Indeed, the pres- American Journal of Reproductive Immunology (2013) Table I The Suggested Criteria of Autoimmune/Inflammatory Syndrome Induced by Adjuvants (ASIA)7 in the Current Three Cases of Post-Human Papilloma Virus Vaccine Manifested Primary Ovarian Failure (POF). Note That for Positive Diagnosis of ASIA, Fulfilment of Either TwoMajor or One Major and Two Minor Criteria is Required 1. Exposure to an external stimuli (infection, vaccine and/or immune adjuvants) prior to clinical manifestations 2. The appearance of ‘typical’ clinical manifestations; Chronic fatigue, un-refreshing sleep or sleep disturbances 3. Removal of inciting agent induces improvement 1. The appearance of autoantibodies (antiovarian, anti-TPO) 2. Other clinical manifestations (e.g. amenorrhoea) 3. Specific HLA (e.g. HLA DRB1, HLA DQB1) 4. Evolvement of an autoimmune disease (POF) ence of antiovarian antibodies in the second case, in one major and two minor criteria is required. The addition to the finding of the anti-TPO antibodies in criteria for ASIA enable the inclusion of patients the third case, lends support to the idea that autoim- with well-defined autoimmune diseases (i.e. multi- mune responses underlying POF can develop follow- ple sclerosis, lupus) as well as those with ill-defined ing HPV vaccination. Moreover, as POF developed in and non-specific yet clinically relevant conditions two sisters, a genetic susceptibility predisposing to (i.e. myalgia, chronic fatigue and cognitive distur- post-vaccination POF is probable. The very unusual bances) under the spectrum of vaccine adjuvant- early age of disease onset may reinforce this sugges- associated conditions.9 The inclusion of the latter tion as it was already observed in other immune- category of manifestations under ASIA is of special mediated diseases.21,22 Furthermore, the patients importance as these non-specific manifestations are experienced not only POF but also a constellation of all too easily ignored or disregarded as irrelevant and other symptoms, including arthralgia, sleep distur- non-vaccine related not only by patients and physi- bances and cognitive dysfunction, consistent with cians, but also by scientists involved in design of the diagnosis of the ASIA syndrome (Table I).7, 9 vaccine trials.28,29 Nonetheless, many ill-definedmedical conditions that fall under the ASIA spec-trum are frequently disabling and thus of significant The three cases of POF described herein clearly ful- Apart from a shared set of clinical manifestations, filled the criteria for the ASIA syndrome (Table I).
the other main common feature in ASIA is the pres- ASIA comprises a group of diseases including post- ence of an immune adjuvant. An adjuvant is defined as ‘any substance that acts to accelerate, prolong or induced autoimmunity,23 Gulf War syndrome,24 enhance antigen-specific immune response’.24 The adjuvant is able to stimulate the immune system and syndrome25,26 and the sick-building syndrome27 to increase the response to a vaccine, without having which share a common set of signs and symptoms.
any specific antigenic effect in itself.24 Vaccines, Shoenfeld and Agmon-Levin7 proposed four major which contain infectious antigens either attenuated and four minor criteria for ASIA (Table I), and to or recombinant, may induce autoimmunity by means diagnose ASIA, fulfilment of either two major or of similar ‘infectious’ mechanisms such as molecular American Journal of Reproductive Immunology (2013) mimicry, epitope spreading, bystander activation and vaccines appear to be autoimmune neurological dis- polyclonal activation.30,31 When this occurs, it can be eases.49,50 For instance, Sutton et al.42 reported five subacute or sometimes a long time after the vaccina- cases of female patients who developed a multifocal tion (i.e. months to years),32–37 which leads to diffi- or atypical demyelinating syndrome within 21 days culties in identifying a definite causality between of immunization with the quadrivalent HPV vaccine.
vaccination and autoimmune phenomena. The latter As hypothesized by the authors, the temporal associ- will most commonly occur in genetically predisposed ation with demyelinating events in these cases may individuals. Indeed, personal or familial susceptibility be explained by the potent immune-stimulatory to autoimmunity and adverse response to a prior properties of HPV virus-like particles which comprise dose of the vaccine both appear to be associated with the vaccine. Similarly, Chang et al.51 reported two a higher risk of post-vaccination autoimmunity.3,9 cases who developed CNS demyelination closely fol-lowing the administration of the HPV vaccine. Acutedisseminated encephalomyelitis in young women (15 and 17 years old) within 3–8 weeks after HPV In the current literature, there are numerous cases vaccination has also been described.52,53 Altogether, substantiating the link between adverse immune these observations led to the hypothesis that the reactions and HPV vaccines, including fatal reactions.
HPV vaccine may have been released too quickly For example, Lee38 recently reported a case of a into the market, in the absence of rigorous safety teenage girl who underwent sudden unexpected evaluations.49,54,55 Indeed, Gardasil appears to have death approximately 6 months after her third Garda- failed to meet a single one of the four criteria sil HPV vaccine booster. The patient experienced required by the FDA for Fast Track approval.54 adverse manifestations shortly after the first dose ofGardasil injection (i.e. dizziness spells, paraesthesia Adjuvants in HPV Vaccines and Assessment of and memory lapses) which were further exacerbated after the 2nd vaccine booster after which she alsodeveloped excessive tiredness (indicative of chronic One of the most commonly used adjuvant in vaccines fatigue), night sweats, loss of ability to use common is aluminium24 which is also present in HPV vaccines.
There are two different brands of the HPV vaccine: the unexpected ‘racing heart’. Although the autopsy quadrivalent Gardasil (MSD) and the bivalent Cer- examination failed to identify any toxicological, varix (GSK). Both are composed of HPV L1 proteins microbiological or anatomical cause of death, further that self-assemble to form virus-like particles but dif- investigations carried by Dr. Lee39 showed that the fer in the use of adjuvants.56 While the first contains post-mortem blood and splenic tissues tested positive only aluminium hydroxyphosphate sulphate, the sec- for HPV-16 L1 gene DNA fragments corresponding to ond contains a combination of an oil-based adjuvant those previously found in 16 separate Gardasil vials monophosphoryl lipid A (MPL) and aluminium from different vaccine lots (suspected to represent hydroxide (a proprietary brand of the vaccine manu- contaminants from the vaccine manufacturing pro- facturer otherwise known as ASO4), thus leading to cess). These findings suggested that the quadrivalent diverse boosts in immune responses between the two HPV vaccine was indeed the most probable causal fac- vaccines.57 Another difference is the medium in tor in this particular case. Specifically, the HPV DNA which the vaccines are produced, Trichoplusiani cells fragments detected in Gardasil vials appeared to be for the Cervarix and Saccharomyces cerevisiae for the firmly bound to the aluminium adjuvant used in the Gardasil. This distinction is even more intriguing vaccine formulation and thus likely protected against because we know the potential of yeast to trigger enzymatic degradation by endogenous nucleases.40 autoimmune responses.58 Nonetheless, a recent large Additionally, thus far HPV vaccination has been observational study on the safety of the quadrivalent linked to several autoimmune diseases, including HPV vaccine allegedly identified no autoimmune safety concerns.59 However, several important biases neuropathies,42–44 systemic lupus erythematosus,3 might have contributed to the negative findings of the pancreatitis,45 vasculitis,46 thrombocytopenic pur- study. Firstly, the study included all women who pura47 and autoimmune hepatitis.48 Of note, the received at least one dose of the vaccine, thus making most prevalent adverse events associated with HPV this particular population less sensitive for the detec- American Journal of Reproductive Immunology (2013) tion of serious adverse reactions (given that such as an expert witness in cases involving adverse vac- events occur with much lesser frequency when fewer cine reaction in the no-fault U.S. National Vaccine doses of the vaccine are administered). Secondly, the Injury Compensation Program. LT, SC and CP research team failed to recruit appropriate expertise declare no conflict of interests. The authors thank for diagnosis of autoimmune disorders. Namely, no the Dwoskin Family Foundation for support.
ophthalmologist were present during the initialscreening of the study participants which is particu- larly surprising in view of the fact that autoimmune 1 Orbach H, Agmon-Levin N, Zandman-Goddard G: Vaccines and conditions of interest that were examined included autoimmune diseases of the adult. Discov Med 2010; 9:90–97.
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Review Committee failed to take into account the fact 3 Gatto M, Agmon-Levin N, Soriano A, Manna R, Maoz-Segal R, that autoimmune manifestations may be non-specific Kivity S, Doria A, Shoenfeld Y: Human papillomavirus vaccine and and not fitting a well-defined autoimmune condi- systemic lupus erythematosus. Clin Rheumatol 2013. [epub ahead of tion9,25,28 yet severely disabling.26,35,60 Of note, the print]. doi: 10.1007/s10067-013-2266-7.
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