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Human Papilloma Virus Vaccine and Primary Ovarian Failure: Another Facet of the Autoimmune/Inflammatory Syndrome Induced by Adjuvants
Abstract
Post-vaccination autoimmune phenomena are a major facet of the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) and different vaccines, including HPV, have been identified as possible causes.
The medical history of three young women who presented with secondary amenorrhea following HPV vaccination was collected. Data regarding type of vaccine, number of vaccination, personal, clinical and serological features, as well as response to treatments were analyzed.
All three patients developed secondary amenorrhea following HPV vaccinations, which did not resolve upon treatment with hormone replacement therapies. In all three cases sexual development was normal and genetic screen revealed no pertinent abnormalities (i.e., Turner's syndrome, Fragile X test were all negative). Serological evaluations showed low levels of estradiol and increased FSH and LH and in two cases, specific auto-antibodies were detected (antiovarian and anti thyroid), suggesting that the HPV vaccine triggered an autoimmune response. Pelvic ultrasound did not reveal any abnormalities in any of the three cases. All three patients experienced a range of common non-specific post-vaccine symptoms including nausea, headache, sleep disturbances, arthralgia and a range of cognitive and psychiatric disturbances. According to these clinical features, a diagnosis of primary ovarian failure (POF) was determined which also fulfilled the required criteria for the ASIA syndrome.
We documented here the evidence of the potential of the HPV vaccine to trigger a life-disabling autoimmune condition. The increasing number of similar reports of post HPV vaccine-linked autoimmunity and the uncertainty of long-term clinical benefits of HPV vaccination are a matter of public health that warrants further rigorous inquiry.
... Concerns raised by the observations of cases of female infertility after human papillomavirus (HPV) vaccination emerged following the publication of two case series, respectively in 2013 and 2014, involving POF in 14-to 21-yearolds [1,5]. Subsequently, safety statements on the absence of risk of infertility after HPV vaccination were made by the World Health Organization (WHO) Global Advisory Committee on Vaccine Safety (GACVS) as well as by the Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration (FDA) [6,7]. ...
... It is worth noting that histological findings on gonad functioning of male rats after HPV vaccination was normal in preclinical trials [15], which confirms that the sensitivity analysis on unknown sex yielded conservative estimates of the PRR. This high PRR estimate, which meets the threshold of a lower bound of 95% CI ≥1, and number of reports ≥3 supports the evidence generated from published case reports and case series on the potential association between HPV vaccine and POF subsequent to declining menstrual function in girls aged between 14 and 21 years [1,5]. The observed increase in POF events reported in the VAERS after the first HPV vaccine introduction (2006) should be interpreted with caution as the reporting of ADRs is known to be influenced by the novelty of the product [16]. ...
... There were 281 reports of HPV vaccine and POF events following the first approval (in 2006) till 14 May 2018, and reports significantly increased among adolescents below 20 years of age as expected due the indicated age to vaccinate against HPV and peak coverages in the female population [17][18][19][20]. This is consistent with the age of patients reported in the published case series [1,5], with a mean of 16.5 years. Using an arbitrary time frame of POF onset date, this study showed that almost a third of POF reports with time of onset fell within 31 days to 1 year, a period that might be of concern. ...
IntroductionThere have been public health concerns about a potential association between human papillomavirus (HPV) vaccines and premature ovarian failure (POF) in young women.Objective
To identify a potential safety signal of POF after HPV vaccination using the United States (US) Vaccine Adverse Event Reporting System (VAERS) database.Methods
We manually selected relevant MedDRA preferred terms related to POF and identified in VAERS all POF reports in women less than 40 years of age between 2 July 1990 and 14 May 2018, followed by a review of narratives to confirm the cases. We conducted descriptive analyses on age, POF type, HPV vaccine type (HPV2, HPV4, HPV9), time to onset of POF, and dose rank. We described trends in reporting over time and assessed a potential safety signal using the proportional reporting ratio (PRR).ResultsOf the 228,341 eligible POF reports, 281 (0.1%) were suspected to be associated with HPV vaccines. Median patient age was 15 years (range 11–39 years). POF events consisted mainly of amenorrhea (80.4%) and premature menopause (15.3%). Mean number of reported POF events significantly increased after the first HPV vaccine launch in 2006 with 22.2 POF cases/year up from 1.4 POF cases/year before the launch. PRR was 46.1 (95% confidence interval: 31.7–67.2) and sensitivity analyses yielded similar estimates.Conclusion
Our study suggests the presence of a potential safety signal of POF associated with HPV vaccination, which may only be partly attributed to notoriety bias. Due to the well-known limitations of spontaneous reporting data, further investigations are warranted.
... The concept of protecting public health by immunization also existed before Rockefeller patent medicine and Gates patent vaccines invested a great deal in medical education to influence promotion of drug sale and to vaccinate the public with pathogen-specific vaccines in toxic media and associated debates and controversies. 1,2,4,5,12,13,17,18,[20][21][22][23][24]28,[30][31][32][33][36][37][38][39][40][59][60][61][62][63][66][67][68]70,73,77,83,93,94,96,97,110,111,116,128,[136][137][138][139][140][141][142][143][144][146][147][148][149][150]156,158,[160][161][162][163][164][165][166][168][169][170][171][172]174,175,181,[189][190][191][192][193][194][195][196][197]205,206,212 Seven/eight decades ago, vaccines were considered relatively safe and effective in promoting/boosting immunity and preventing diseases when healthy children (2 years or older) were vaccinated with few dead/inactivated pathogens (eg, measles, mumps, diphtheria, smallpox) that were prepared in saline solutions. The overall review of data on epidemiological studies and/or comparison of vaccinated and unvaccinated children at different settings around the globe, despite variations in methods and procedures, suggest that natural exposures to infective agents (eg, measles and mumps) are associated with lower rates of mortality from chronic diseases such as atherosclerotic and cardiovascular diseases 31 ...
... Vaccine approval voting is conducted through FDA (eg, VRBPAC) or CDC (eg, ACIP) committees, whose members are often industry, government employers or grantees (principal investigators) who receive funding to study and patent drugs/vaccines and to collaborate with manufacturers for large scale development and for marketing to the general public, healthy or not. 2,8,18,70 An example of vaccine propaganda is found in the marketing of HPV vaccines (Gardasil or Cervarix) that were approved to target the young generation, claiming to prevent cervical cancer. Segments of papilloma virus (types 6,11,18) and recombinant DNA technologies are used in media/incipient that has combination of Al, PS80, SIO2, Saponin. ...
... Segments of papilloma virus (types 6,11,18) and recombinant DNA technologies are used in media/incipient that has combination of Al, PS80, SIO2, Saponin. 8 143 Review of related data suggest that HPV vaccines and adjuvants are associated with mild or severe adverse reactions (VAERS), including autoimmune diseases, fibromyalgia, tachycardia, ovarian failure, fatigue, without any benefits in preventing incidences of cervical and related cancers 8,12,14,66,70,71,108,110,136,[137][138][139]143, † † † † † † † † ' ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ . In a comprehensive review 14 Giannotta and Giannotta described the mechanisms of adverse effects of vaccines (eg, HPV) and incipient in autonomic neuronal system and development of autism spectrum disorder (ASD), fatigue and vaccine-induced altered behaviors of immune cells (microglial and astrocytes) in the brain and associated loss of BBB. ...
From Rockefeller's support of patent medicine to Gates' patent vaccines, medical establishment invested a great deal in intellectual ignorance. Through the control over medical education and research it has created a public illusion to prop up corporate profit and encouraged the lust for money and power. An overview of data on cancer and vaccine sciences, the status of Americans' health, a survey of repeated failed projects, economic toxicity, and heavy drug consumption or addiction among young and old provide compelling evidence that in the twentieth century nearly all classic disease categories (congenital, inheritance, neonatal, or induced) shifted to increase induced diseases. Examples of this deceptology in ignoring or minimizing, and mocking fundamental discoveries and theories in cancer and vaccine sciences are attacks on research showing that (a), effective immunity is responsible for defending and killing pathogens and defective cancerous cells, correcting and repairing genetic mutations; (b) viruses cause cancer; and (c), abnormal gene mutations are often the consequences of (and secondary to) disturbances in effective immunity. The outcomes of cancer reductionist approaches to therapies reveal failure rates of 90% (+/‐5) for solid tumors; loss of over 50 million lives and waste of $30‐50 trillions on too many worthless, out‐of‐focus, and irresponsible projects. Current emphasis on vaccination of public with pathogen‐specific vaccines and ingredients seems new terms for drugging young and old. Cumulative exposures to low level carcinogens and environmental hazards or high energy electronic devices (EMF; 5G) are additional triggers to vaccine toxicities (antigen‐mitochondrial overload) or “seeds of immune destruction” that create mini electrical shocks (molecular sinks holes) in highly synchronized and regulated immune network that retard time‐energy‐dependent biorhythms in organs resulting in causes, exacerbations or consequences of mild, moderate or severe immune disorders. Four generations of drug‐dependent Americans strongly suggest that medical establishment has practiced decades of intellectual deception through its claims on “war on cancer”; that cancer is 100, 200, or 1000 diseases; identification of “individual” genetic mutations to cure diseases; “vaccines are safe”. Such immoral and unethical practices, along with intellectual harassment and bullying, censoring or silencing of independent and competent professionals (“Intellectual Me Too”) present grave concerns, far greater compared with the sexual harassment of ‘Me Too’ movement that was recently spearheaded by NIH. The principal driving forces behind conducting deceptive and illogical medical/cancer and vaccine projects seem to be; (a) huge return of investment and corporate profit for selling drugs and vaccines; (b) maintenance of abusive power over public health; (c) global control of population growth via increased induction of diseases, infertility, decline in life‐span, and death.
An overview of accidental discoveries that we established and extended since 1980s, on models of acute and chronic ocular inflammatory diseases, provides series of the first evidence for a direct link between inflammation and multistep immune dysfunction in tumorigenesis and angiogenesis. Results are relevant to demonstrate that current emphasis on vaccinating the unborn, newborn, or infant would induce immediate or long‐term immune disorders (eg, low birth weight, preterm birth, fatigue, autism, epilepsy/seizures, BBB leakage, autoimmune, neurodegenerative or digestive diseases, obesity, diabetes, cardiovascular problems, or cancers). Vaccination of the unborn is likely to disturb trophoblast‐embryo‐fetus‐placenta biology and orderly growth of embryo‐fetus, alter epithelial‐mesenchymal transition or constituent‐inducible receptors, damage mitochondria, and diverse function of histamine‐histidine pathways. Significant increased in childhood illnesses are likely due to toxicities of vaccine and incipient (eg, metals [Al, Hg], detergents, fetal tissue, DNA/RNA) that retard bioenergetics of mitochondria, alter polarization‐depolarization balance of tumoricidal (Yin) and tumorigenic (Yang) properties of immunity.
Captivated by complex electobiology of immunity, this multidisciplinary perspective is an attempt to initiate identifying bases for increased induction of immune disorders in three to four generations in America. We hypothesize that (a) gene‐environment‐immune biorhythms parallel neuronal function (brain neuroplasticity) with super‐packages of inducible (adaptive or horizontal) electronic signals and (b) autonomic sympathetic and parasympathetic circuitry that shape immunity (Yin‐Yang) cannot be explained by limited genomics (innate, perpendicular) that conventionally explain certain inherited diseases (eg, sickle cell anemia, progeria). Future studies should focus on deep learning of complex electrobiology of immunity that requires differential bioenergetics from mitochondria and cytoplasm. Approaches to limit or control excessive activation of gene‐environment‐immunity are keys to assess accurate disease risk formulations, prevent inducible diseases, and develop universal safe vaccines that promote health, the most basic human right.
... 21 Subsequently, 2 case series, each with 3 patients, described POI diagnosed after receipt of 4vHPV. 22,23 One of the case series included the patient from the 2012 case report. 22 These publications and subsequent media reports of similar cases have generated a specific concern about a potential causal relationship between HPV vaccines and POI. ...
... Evaluation was negative for known causes of POI with the exception of positive serum anti-ovarian antibodies, which, as mentioned above, is a nonvalidated test. 23 The third patient experienced menarche at age 13 years and received 3 doses of 4vHPV at age 21. She began to experience irregular menses after the third dose and received OCP until age 23. ...
... Her evaluation was negative with the exception of positive antithyroidperoxidase antibodies, which are not implicated as an autoimmune etiology for POI. 23 Passive surveillance reports on HPV vaccines and POI Pellegrino et al 42 analyzed publicly available data in major national surveillance databases for adverse events (AE) following administration of vaccines or drugs using codes for "premature ovarian failure," "premature ovarian insufficiency," "premature menopause," and "primary ovarian failure." The authors found 1 case in the Australian database, 2 cases in the European database, and 4 cases in the US Vaccine Adverse Reporting System (VAERS). ...
Human papilloma virus is the primary causative agent for cervical cancer, and vaccination is the primary means of preventing anogenital cancers caused by human papilloma virus infection. Despite the availability of human papilloma virus vaccines for over a decade, coverage rates lag behind the other vaccines. Public concerns regarding safety of human papilloma virus vaccines have been identified as an important barrier to vaccination, including concerns that the human papilloma virus vaccine causes primary ovarian insufficiency, driven in part by isolated reports of ovarian failure following the human papilloma virus vaccine. We summarize published peer-reviewed literature on human papilloma virus vaccines and primary ovarian insufficiency reviewing information contained in the case reports and series. Health care providers should address any patient concerns about primary ovarian insufficiency and the human papilloma virus vaccine by acknowledging the case reports but noting the lack of association found in a recently published epidemiologic study of approximately 60,000 females. Current evidence is insufficient to suggest or support a causal relationship between human papilloma virus vaccination and primary ovarian insufficiency.
... Similar to any other vaccine, the HPV vaccine can cause major pain at the injection site as well as fainting and dizziness [45][46][47]. However, there have also been reports of more serious side effects [48][49][50][51][52][53][54][55][56][57][58][59]. With the rising number of these reports, experts around the world have been calling for more studies and improved postmarketing surveillance [56,59]. ...
... However, there have also been reports of more serious side effects [48][49][50][51][52][53][54][55][56][57][58][59]. With the rising number of these reports, experts around the world have been calling for more studies and improved postmarketing surveillance [56,59]. ...
... Numerous studies have pointed to a spectrum of side effects of the HPV vaccine, ranging from common mild vaccine effects such as pain at the injection site [46] to more severe effects such as chronic pain syndrome and chronic fatigue [59]; Guillain-Barré syndrome, spinal cord inflammation, and venous blood clots [55]; autoimmune diseases such as ovarian failure [56][57][58]; and postural orthostatic tachycardia syndrome with chronic pain [59]. ...
Background: Designing web-based informational materials regarding the human papillomavirus (HPV) vaccine has become a
challenge for designers and decision makers in the health authorities because of the scientific and public controversy regarding
the vaccine’s safety and effectiveness and the sexual and moral concerns related to its use.
Objective: The study aimed to investigate how cultural sensitivity (CS) is articulated in the explanatory informational materials
on the HPV vaccine that are posted on the websites of the Israeli health authorities. In addition, the study examined the effect of
transparency on the expression of CS in the informational materials.
Methods: The study employed a quantitative and qualitative content analysis of the texts of explanatory informational materials
published on the Arabic and Hebrew websites of the Israel Ministry of Health and the Clalit health maintenance organization
(HMO).
Results: The findings revealed the differences in the dimensions of CS (based on the CS model by Resnicow) between the
informational materials targeting the majority Jewish population and those targeting the minority Arab population. Indeed, the
research findings point to a paradox. On the one hand, the materials appealing to the conservative Arab population exhibited CS,
in that the sexual context of the vaccine was missing. On the other hand, analysis of Resnicow's deep dimensions showed that
disregarding the sexual context does not allow the relevant target audience to reflect on the barriers and concerns. In addition,
the way the information was provided exhibited a lack of transparency regarding the CS dimensions (surface and deep).
Conclusions: The public health authorities have 2 main objectives in the context of vaccinations. One is to raise the vaccination
rates and the other is to provide full and culturally sensitive information to give the public the tools to make intelligent decisions.
The findings of this study indicated that despite the high uptake rate for HPV vaccination in the Arab population, the health
authorities did not exercise full transparency and CS in transmitting the association between engaging in sexual relations and the
necessity of the vaccination. Thus, the major challenge for the health authorities is to find ways to implement the objective of
communicating information about the vaccination in a way that is transparent and culturally sensitive, even if this raises questions
and fears among the public deriving from their culture.
... Studies have found that parents are more likely to have safety concerns about the HPV vaccine 7,8 for their female than for male adolescents, which informs their ultimate decision to refuse the vaccine. Safety concerns specific to the female gender include brief case reports linking the HPV vaccine to reduced fertility via induction of primary ovarian insufficiency, 9,10 even though these reports have been debunked by a systematic review of the evidence. 11 On the other hand, despite evidence that has consistently identified provider recommendation as a strong predictor of HPV vaccination for boys, 8,12 several studies have noted that providers are less likely to recommend vaccination for male children. ...
... 20 Misconceptions about the HPV vaccine and the female child are wide-ranging. 6 They include claims that the HPV vaccine is associated with infertility, 9,10 and that vaccinating young girls may be perceived as an endorsement for the initiation of sexual activity. 29,30 These misconceptions may explain our findings, which are suggestive of an increased sense of misguided protectiveness toward female children by parents regarding HPV vaccination. ...
Amid subpar uptake of HPV vaccination in the United States, gender-generated disparities in HPV vaccination uptake have the potential to perpetuate existing disparities in HPV-associated cancers. Yet few studies have investigated the influence of parent-child gender on intentions to refuse HPV vaccination due to safety concerns/side effects. This study used nationally representative data, spanning 2010-2019, from the National Immunization Survey-Teen (NIS-Teen). NIS-Teen respondents are parents/guardians or primary caregivers of adolescents 13-17 years old living in the United States. Over the study period, intentions to refuse HPV vaccination due to safety concerns rose among all parent-child gender pairings but were highest among respondent mothers regarding their unvaccinated daughters. The results revealed a statistically significant increased likelihood of having intentions to refuse HPV vaccination due to safety concerns among all parent-child combinations compared with father-son pairs. These odds were consistently highest among mother-daughter pairs. In 2019, compared with father-son pairs, fathers were 1.94 (95% CI: 1.21-3.12) times more likely to report the intention to not vaccinate against HPV for their daughters, while mothers were 2.23 (95% CI: 1.57-3.17) and 2.87 (95% CI: 2.02-4.09) times more likely to report intentions to refuse HPV vaccination for their sons and daughters, respectively. These findings were persistent and constantly increased over the 10-year study period. Interventions aimed at correcting gender-based misperceptions and countering misinformation about the safety of the HPV vaccine are warranted.
... The patients who were treated with oral contraceptive pills to treat the abnormalities were diagnosed eventually with POI. Furthermore, Colafrancesco et al [103] described three patients with secondary amenorrhea, after HPV vaccination in which hormone replacement therapy did not ameliorate the symptoms. The patients had normal sexual development and no genetic abnormalities presented with low levels of estradiol and abnormally high levels of FSH which was suggestive of POI. ...
Adjuvants, as the name indicates, are adjoined material aimed to assist in functioning as when added to vaccines they are meant to boost the effect and strongly stimulate the immune system. The response of the immune system can be unpredictable, and the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) was developed to address possible adverse reactions of an autoimmune and inflammatory type that may be caused by adjuvants. While ASIA, as a syndrome, was coined and defined in 2011; reports describing patients with vague and nonspecific clinical symptoms following vaccinations appeared much earlier. In other words, ASIA came to define, arrange, and unite the variety of symptoms, related to autoimmunity, caused not by the vaccine itself, rather by the adjuvant part of the vaccine such as aluminum, among others. Accordingly, the introduction of ASIA enabled better understanding, proper diagnosis, and early treatment of the disorder. Furthermore, ASIA was shown to be associated with almost all body systems and various rheumatic and autoimmune diseases such as SLE, APS, and systemic sclerosis. In addition, the correlation between COVID-19 and ASIA was noticed during the pandemic. In this review, we summarized the reported effects of adjuvants and medical literature before and after ASIA was defined, the several ways ASIA can manifest and impact different systems of the body, and the incidences of ASIA during the COVID-19 pandemic. It is important to clarify, that vaccines are among, if not the, most effective means of fighting infectious diseases however, we believe that vaccines manufacturing is not above criticism, particularly when it comes to added substances possessing a risk of side effects.
... Three unrelated cases of female patients developing menstrual cycle abnormalities in Austria following HPV vaccine administration were reported [62]. Colafrancesco and colleagues described three cases of secondary amenorrhea after HPV vaccination; the patients' symptoms did not improve with administration of hormone replacement therapy [63]. ...
Since vaccines are in fact manufactured chemical compounds such as drugs, the appearance of side effects following their use is not surprising. Similarly, as the main goal of vaccines is to stimulate the immune system bringing out the production of protective antibodies, autoimmune-related side effects as a consequence of increased immune activity do not seem irrational. Fortunately, the rate of such side effects is low; however, the importance of reporting adverse events following vaccinations, understanding the mechanisms behind their appearance, making early diagnosis, and appropriate treatment cannot be overemphasized. In fact, autoimmune-related side effects of vaccines, particularly those based on adjuvants, were reported long before the introduction of the autoimmune/inflammatory syndrome induced by adjuvants (ASIA). Nevertheless, ASIA gathered and united the side effects of vaccines under one title, a step which helped organize the research and call for better immune stimulators than adjuvants. New technologies and methods of making vaccines were clearly noticed during the pandemic of COVID-19 after the introduction of mRNA-based vaccines. In our current paper, we introduce the notion of side effects to vaccines, particularly those of autoimmune nature, the mechanisms of ASIA, and the main vaccines linked with the syndrome including the recent COVID-19 vaccines. The transition from side effects to ASIA is the main idea behind our work.
... Up to now, the association between HPV vaccination and related secondary reproductive conditions is still uncertain. Some studies have proposed that the possible mechanisms of the association between HPV vaccine and premature menopause (PM) may include HPV vaccine triggering autoimmune diseases to cause PM [58,80], or the adjuvant aluminum in the vaccine inducing anti-ovarian positive antibody [81]. However, our results found a statistically signigicant association between HPV vaccination and adverse reproductive events, so a real association cannot be judged out [18,82]. ...
Purpose
Three licensed human papillomavirus (HPV) vaccines (Cervarix, Gardasil, and Gardasil 9) have been effectively used to prevent infection with oncogenic HPV types; however, many adverse events (AEs) have also been reported following their vaccinations. We assessed AE profiles after receiving the HPV vaccines based on the reported data from Vaccine Adverse Event Reporting System (VAERS).
Methods
The AE data associated with Cervarix, Gardasil, and Gardasil 9 were retrieved from VAERS database respectively. The combinatorial biomedical statistical methods were used to identify the statistically significant AEs. The Gamma-Poisson Shrinker (GPS) model with gender/age stratification was applied to ascertain the serious adverse events (SAEs) related to the three licensed HPV vaccines. The AE profiles were classified and represented by the Ontology of Adverse Events (OAE) for further analysis.
Results
As of July 31, 2020, VAERS recorded 3,112, 31,606, and 6,872 AE case reports for Cervarix, Gardasil, and Gardasil 9, respectively. Our Frequentist statistical methods identified 135 Cervarix-enriched AEs, 55 Gardasil-enriched AEs, and 17 Gardasil 9-enriched AEs. Based on the OAE hierarchical classification, these AEs were clustered in the AEs related to behavioral and neurological conditions, immune system, nervous system, and reproductive system. Combined with GPS modeling, 46 unique statistically significant SAEs were founded to be associated with at least one of the three vaccines.
Conclusions
Our study led to the better understanding of the AEs associated with the licensed HPV vaccines. The hypotheses on the cause and effect relationships between the HPV vaccination and specific AEs deserve further epidemiological investigations as well as clinical trial studies.
... They are usually safe but may influence innate and adaptive immune systems via activation of B lymphocytes, alterations in immunological balance, and molecular mimicry and may activate the autoimmune response in genetically susceptible subjects [10,27]. The endocrine system was reported as a target of ASIA syndrome caused by adjuvants of HPV, HBV, and influenza vaccines [11,28,29]. Subacute thyroiditis was the most reported autoimmune/inflammatory phenomenon after vaccination [4,5], while type 1 diabetes mellitus was rarely reported as a manifestation of ASIA caused by vaccines [11]. ...
Purpose
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccines have been reported to trigger immune side effects. Type 1 diabetes as a manifestation of autoimmune/inflammatory syndrome induced by adjuvants has been reported in a limited number of cases after vaccinations. A few type 1 diabetes cases after SARS-CoV-2 vaccination have been reported. This study aims to report type 1 diabetes cases associated with the mRNA-based SARS-CoV-2 vaccination.
Methods
We report four cases of type 1 diabetes mellitus after mRNA-based SARS-CoV-2 vaccine, BNT162b2 (Pfizer–BioNTech). In the medical history, one subject had autoimmune thyroid disease. All patients had autoantibodies against glutamate decarboxylase.
Results
In the presented case series, type 1 diabetes developed a few weeks after BNT162b2 vaccination. After developing type 1 diabetes, the insulin dose requirements of all patients decreased rapidly, and the need for insulin therapy in three patients disappeared during follow-up. Acute deterioration of glucose regulation in a patient followed by BNT162b2 administration may be due to vaccine-induced autoimmune diabetes.
Conclusion
Vaccination with BNT162b2 may trigger type 1 diabetes.
... One of the possible routes for this disruption to occur involves the association between aluminum and autoimmune disorders. Colafrancesco et al. (2013) reported antiovarian antibodies -biomarkers of an autoimmune response -in a young woman who experienced premature ovarian failure (POF), the kind of failure not expected to occur until menopause, after receiving an HPV vaccination. Gruber and Shoenfeld (2015) explored the possible link between aluminum in HPV shots and POV. Ward (2012, 2014) documented case studies of young women experiencing menstrual disorders that developed into POV. ...
The falling birth rate in the United States may be owed to multiple factors, the human papilloma virus (HPV) vaccines being among them. Here I examine again the hypothesis that the likelihood of having been pregnant at least once was reduced for women aged 25 to 29 between 2007 and 2018 who received one of the HPV vaccines compared with peers who did not. Data from the National Health and Nutrition Examination Survey (NHANES) representing 7.5 million women in the United States were used. The age-range was limited in order to compare women in the optimal age-range for child-bearing who received at least one HPV shot during the study period against peers who did not. Given that the HPV vaccines are aimed at preventing cervical cancer, but not at reducing or enhancing fertility, the opportunity and choice to receive such a vaccine should be about equal across all the women in the sampled age-range and time frame. Analysis revealed that only 47% of HPV vaccine recipients had ever conceived as contrasted with 69% of comparable peers who did not receive any HPV shot. If pregnancies after receiving such a shot were unaffected by it, the women in both groups should be equally likely or unlikely to get pregnant. Nevertheless, even when covariate controls for marital status, age, education, income, race/ethnicity, obesity and smoking were used, a multivariate logistic regression showed a reduced likelihood of pregnancy in the HPV vaccinated women (OR 0.66; 95% CI 0.438, 0.998): women who received the HPV vaccine were less likely to have been or to become pregnant during the time frame examined. The reasonable conclusion is that receiving an HPV vaccination reduces female fertility. If the shot were aiming to be a birth-control vaccine the observed result would not be anomalous. But it is, and there is other research showing that at least two of the viruses targeted by all the HPV vaccines on the market, 16 and 18, can cause sterility in both females and males and are also associated with so-called “spontaneous” abortions and premature ovarian failure in pregnant female carriers of those pathogens.
... AAS were available for 40,949 (34.1%) articles; 11,001 (26.9%) articles had a score of 0, 29,694 (72.5%) articles had a score of 1-99, and 244 (0.6%) had a score of 100-999. Ten (0.02%) articles had an AAS of greater than 1000 (Belva et al., 2016;Buck Louis et al., 2016;Colafrancesco et al., 2013;Grieger et al., 2018;Griffin, 1991;Karayiannis et al., 2018;Levine et al., 2017;Mínguez-Alarcón et al., 2018;Vercellini et al., 2013, Zhang et al., 2017. ...
Research question
What are the most influential articles in reproductive biology journals from 1980-2019 according to Altmetric Attention Score (AAS), number of citations, and Relative Citation Ratio (RCR)?
Design
Cross-sectional study of reproductive biology articles published and indexed in NIH Open Citation Collection from 1980-2019. Data was downloaded on 20 May 2021. The 100 articles with highest AASs, RCRs, and number of citations were analyzed.
Results
21 reproductive biology journals were identified, including 102,303 articles published from 1980-2019. There were 227 reproductive biology classics due to overlap among lists. Compared to the 100 articles with highest AASs (after excluding articles featured on both lists), the 100 top-cited articles were older (2014 vs. 2001, mean difference [95% CI] 13.5 [11.5, 15.5]), less likely to be open access (64% vs. 85%), more likely to be reviews (42% vs. 12%), and less likely to be observational studies (9% vs. 51%) and randomized clinical trials (0 vs. 5%). These same trends were observed in analyses comparing the 100 articles with highest AASs to the 100 articles with highest RCRs. The most common topic was assisted reproduction, but prominent topics included infertility for top-AAS articles, reproductive technology in animals for top-cited articles, and polycystic ovary syndrome for top-RCR articles.
Conclusions
Formerly, influential articles in reproductive biology journals were evaluated by absolute citation rates and subject to limitations of conventional bibliometric analysis. This is the first comprehensive study to use altmetrics and citation-based metrics to identify reproductive biology classics.
... Menstrual changes following vaccination are indeed not so unusual, given that such modifications were observed after vaccination for other microbes, like the human papilloma virus [17], or human hormones, such as human chorionic gonadotropin [18]. Such disturbances could likely be ascribed to the inflammatory/immunological reaction ensuing from adjuvants comprised in the vaccines, at least in some cases [19]. However, we cannot discard that the COVID-19-related spike protein could exert a causative pathogenic role, as similar changes in menstrual cycles have been recorded during COVID-19 infection [20]. ...
We investigated menstrual irregularities after the first and second doses of the COVID-19 vaccine. Women answered a customised online questionnaire (ClinicalTrial.gov ID: NCT05083065) aimed to assess the vaccine type, the phase of the menstrual cycle during which the vaccine was administered, the occurrence of menstrual irregularities after the first and second doses, and how long this effect lasted. We excluded women with gynaecological and non-gynaecological diseases, undergoing hormonal and non-hormonal treatments, in perimenopause or menopause, as well as those who had irregular menstrual cycles in the last 12 months before vaccine administration. According to our data analysis, approximately 50–60% of reproductive-age women who received the first dose of the COVID-19 vaccine reported menstrual cycle irregularities, regardless of the type of administered vaccine. The occurrence of menstrual irregularities seems to be slightly higher (60–70%) after the second dose. Menstrual irregularities after both the first and second doses of the vaccine were found to self-resolve in approximately half the cases within two months. Based on these results, we suggest to consider these elements during the counselling of women who receive the COVID-19 vaccine, letting them know about the potential occurrence of temporary and self-limiting menstrual cycle irregularities in the subsequent month(s).
... Nevertheless, and on the basis of the literature review, it has been one of the most frequently repeated postulations. In this context, it is worth mentioning that at low rates and despite that case-control studies are still scarce, HPV vaccine has been related to primary ovarian failure [23] and to Guillain-Barré Syndrome [24], albeit not implying a causal association. The difficulty in proving a causal relationship between the clinical manifestations of the diseases and the use of adjuvants in vaccines should be noted since several studies do not confirm the role of adjuvants in the development of autoimmune diseases [25]. ...
AimTo describe a case series of thyrotoxicosis likely triggered by SARS-CoV-2 vaccination and to warn physicians about this potential correlation. To report clinical, laboratory and imaging findings and provide further information that goes in line with the underlying mechanisms.Methods
Single-center case series based on all the information collected in the hospital medical records, as well as the temporal sequence between the onset of symptoms and COVID-19 vaccination.ResultsWe report 8 cases with thyrotoxicosis after SARS-CoV-2 vaccination. 4 cases of Graves’ disease (GD), 2 cases of subacute painful thyroiditis (SAT), 1 case of concurrent GD and SAT and 1 case of atypical subacute thyroiditis. Five patients received BNT162b2 mRNA vaccine, 3 patients 1273 mRNA vaccine. The onset of symptoms following vaccination ranged from 10 to 14 days in six of eight patients and from 7 to 8 weeks in two patients.Conclusions
Several hypotheses have been proposed to explain the potential correlation between SARS-CoV-2 vaccination and thyrotoxicosis, including immune system hyper-stimulation, molecular mimicry and Autoimmune/Autoinflammatory Syndrome Induced by Adjuvants (ASIA). We should pay greater attention to thyroid disorders in patients receiving vaccine against SARS-CoV-2.
... There was a report that suggested that there is a possible role of a genetic predisposition to vaccine-induced autoimmune disease (40). This is a possible and accepted risk compared to the benefit that this vaccine offers against different cancers. ...
Human papillomavirus (HPV) is one of the most widespread human pathogens. For a long time, it was treated as an opportunistic infection, but it is in actuality one of the most dangerous carcinogens. It is responsible for numerous malignancies: Cervical, penile, oropharyngeal, vaginal, vulvar and some anal neoplasia. The need for a long-term solution was evident and thus HPV vaccines were proven to be a viable solution. Women and men who have sex with men, and young men are included in the vaccination template. A thorough review using PubMed and other databases that included articles on vaccine templates and targeted male patients was carried out. After review of all of the studies conducted on this subject, there is a clear benefit for HPV vaccination for men. Yet, even with the introduction of a national vaccine program for HPV for women and girls in most developed countries, regarding the male vaccine program, few countries have established a national program. Still, a gender-neutral vaccine remains a controversial issue. It is important to monitor the impact of HPV vaccine in men and the benefits that occur, to inform and spread the results in order to implement this vaccine program worldwide. Any monitoring plan regarding the HPV vaccination must include HPV prevalence, anogenital warts, and anal cancer. The largest impact regarding the range of this type of vaccine is the surveillance of the specific targeted population. HPV vaccine is a very efficient immunization method. Women are obviously the first target, but there are still many contradictions regarding men. Most of the reasons reside in the cost-efficiency aspect, but there is still great debate regarding the most efficient vaccine in the male population.
... 3 A number of other case reports followed, comprising 5 additional cases. 3,4 Unfortunately, case reports like these sometimes gain an amount of attention in the press and on social media that does not always correspond to their scientific significance. ...
Importance
Anecdotal case reports have suggested an association between human papillomavirus (HPV) vaccination and primary ovarian insufficiency, but observational studies of HPV and primary ovarian insufficiency are rare, and their findings do not support an association. However, available studies have been limited by statistical power, and concerns about infertility after vaccination are associated with lower levels of uptake of the cancer-preventing vaccine in many countries.
Objective
To evaluate the risk of primary ovarian insufficiency after quadrivalent human papillomavirus (4HPV) vaccination.
Design, Setting, and Participants
This retrospective cohort study with follow-up from 2007 to 2016 used nationwide data for 996 300 Danish-born girls and women aged 11 to 34 years. Cox proportional hazards regression was used to estimate hazard ratios (HRs) of primary ovarian insufficiency diagnoses by 4HPV vaccination status with adjustment for age, calendar period, and a propensity score summarizing health care use. Data were analyzed from October 2020 to January 2021.
Exposures
Receiving 4HPV vaccination compared with receiving no vaccination.
Main Outcomes and Measures
The main outcome was hospital contacts for primary ovarian insufficiency, and the main outcome measures were HRs comparing rates of primary ovarian insufficiency among vaccinated and unvaccinated individuals.
Results
During 6 781 166 person-years of follow-up among 996 300 girls and women aged 11 to 34 years (505 829 vaccinated individuals [50.8%] and 490 471 unvaccinated individuals [49.2%]), 144 individuals were diagnosed with primary ovarian insufficiency, including 54 individuals diagnosed after 4HPV vaccination. The median (interquartile range) age of primary ovarian insufficiency diagnosis was 26.94 (12.68) years. The adjusted HR of primary ovarian insufficiency comparing 4HPV vaccination to no vaccination was 0.96 (95% CI, 0.55-1.68).
Conclusions and Relevance
This study found no association between HPV vaccination and primary ovarian insufficiency. However, given the rarity of the outcome in this study, the presence of a clinically relevant increase in rate of diagnosis cannot be excluded.
... Recently, POF was observed following HPV vaccination [77]. Responses of the autoimmune system to vaccines are a major aspect of autoimmune/inflammatory syndromes. ...
As one of the problems and diseases for women before 40 years, premature ovarian failure (POF) could be characterized by amenorrhea, low estrogen levels, infertility, high gonadotropin levels, and lack of mature follicles. Causes of the disease involve some genetic disorders, autoimmunity diseases, and environmental factors. Various approaches have been employed to treat POF, however with limited success. Today, stem cells are used to treat POF, since they have the potential to self-repair and regenerate, and are effective in treating ovarian failure and infertility. As mesenchymal stem cell (MSC) could simultaneously activate several mechanisms, many researchers consider MSC transplantation to be the best and most effective approach in cell therapy. A good source for mesenchymal stem cells is human umbilical cord (HUCMSC). Animal models with cyclophosphamide are required for stem cell treatment and performance of HUCMSC transplantation. Stem cell therapy could indicate the levels of ovarian markers and follicle-stimulating hormone receptor. It also increases ovarian weight, plasma E2 levels, and the amount of standard follicles. Herein, the causes of POF, effective treatment strategies, and the effect of HUCMSC transplantation for the treatment of premature ovarian failure are reviewed. Many studies have been conducted in this field, and the results have shown that stem cell treatment is an effective approach to treat infertility.
... Although published work overwhelmingly supports the efficacy of the current prophylactic HPV vaccines, there has been a great deal of publicity and numerous studies carried out on potential vaccine-related adverse events [1][2][3][4]. The general consensus is that there is no strong evidence that these are increased when compared to other similar adjuvant-containing products although this is still a controversial subject since there are some reports which claim increased adverse reactions in relation to the HPV vaccines [2,5]. ...
There are >200 different types of human papilloma virus (HPV) of which >51 infect genital epithelium, with the ~14 of these classed as high-risk being more commonly associated with cervical cancer. During development of the disease, high-risk types have an increased tendency to develop a truncated non-replicative life cycle, whereas low-risk, non-cancer-associated HPV types are either asymptomatic or cause benign lesions completing their full replicative life cycle. HPVs can also be present as non-replicative so-called “latent” infections and they can also show superinfection exclusion, where cells with pre-existing infections with one type cannot be infected with a different HPV type. Thus, the HPV repertoire and replication status present in an individual can form a complex dynamic meta-community which changes with respect to both time and exposure to different HPV types. In light of these considerations, it is not clear how current prophylactic HPV vaccines will affect this system and the potential for iatrogenic outcomes is discussed in light of recent outcome data.
... 3 The importance of the study of the genetic factors is undoubtedly a royal key for opening the minds to the blind section of the disease etiology. It is understood that apoptosis enhancement in aging ovaries, 4 follicle maturation cessation, deficit of either granulosa or germ cells 4,5 and activation of unripe follicles are involved in the POF creating pathway which is induced by the followings: Autoimmune diseases such as Hashimoto, 6 viruses like human papillomavirus and cytomegalovirus, surgery, chemotherapy, radiation, defects in chromosome X and consequent destruction/disruption and/ or deletion of X-linked genes (Turner syndrome and fragile X). [7][8][9] Moreover, single gene defects and metabolic disorders including galactosemia, toxins and lifestyle factors like smoking could cause idiopathic POF. 10,11 A group of these patients have normal pregnancy due to the possible occurrence of a cyclic ovarian function. ...
... The possible pathogenesis between POI and HPV vaccines were multifactorial, such as autoimmune response prompted by HPV vaccines 12 and the adjuvant adverse effect of vaccine 13 . A possible relationship between POI and HPV vaccination has been proposed in view of the temporal vaccine-event association 12 . ...
We detected disproportionate reports of premature ovarian insufficiency (POI) and related events, including amenorrhea, menstruation irregular, FSH increased, and premature menopause, following human papillomavirus (HPV) vaccine from FDA Vaccine Adverse Event Reporting System (VAERS). The signal was detected by the methods of Bayesian Confidence Propagation Neural Network (BCPNN) and Multi-item Gamma Poisson Shrinker (MGPS). When both methods detected a positive result, a signal was generated. Besides, time-scan map is drawn based on the IC value and 95%CI of BCPNN, if the IC curve showed a steady upward trend and the 95%CI narrowed, the signal was stable and strong association.The results showed that there were not POI reports of HPV vaccine, but VAERS received a total of 2, 389, 27 POI related events for HPV2, HPV4, HPV9 respectively from the year of marketed to 2018. No signal was detected for HPV2. HPV4-POI ralated events were all detected as signals by two methods. There was only one signal of menstruation irregular for HPV9. Time scan of HPV4-POI ralated events showed those signals were stability and strong association, but not for HPV9. Our results only represent statistical association between HPV vaccine and POI related events, causal relationship needs further investigation.
... Recently, a small number of case reports [12][13][14] and anecdotes in the popular press [15, 16] have given rise to concerns among some that the HPV vaccine causes lowered fertility by inducing primary ovarian insufficiency (POI). These concerns were refuted by a recent population-based cohort study of nearly 200,000 women that found no association between the HPV vaccine and POI [17]. ...
Background
Human papillomavirus (HPV) vaccines have been recommended as primary prevention of HPV-related cancers for over 10 years in the United States, and evidence reveals decreased incidence of HPV infections following vaccination. However, concerns have been raised that HPV vaccines could decrease fertility. This study examined the relationship between HPV immunization and self-reported infertility in a nationally representative sample.
Methods
Data from the 2013–2016 National Health and Nutrition Examination Survey were analyzed to assess likelihood of self-reported infertility among women aged 20 to 33, who were young enough to have been offered HPV vaccines and old enough to have been queried about infertility (n = 1114). Two logistic regression models, stratified by marital history, examined potential associations between HPV vaccination and infertility. Model 1 assessed the likelihood of infertility among women who had never been pregnant or whose pregnancies occurred prior to HPV vaccination. Model 2 accounted for the possibility of latent and/or non-permanent post-vaccine infertility by including all women 20–33 years old who reported any 12-month period of infertility.
Results
8.1% reported any infertility. Neither model revealed any association between HPV vaccination at any age and self-reported infertility, regardless of marital status.
Conclusion
There was no evidence of increased infertility among women who received the HPV vaccine. These results provide further evidence of HPV vaccine safety and should give providers confidence in recommending HPV vaccination. Further research should explore protective effects of HPV vaccines on female and male fertility.
... Depending upon the age at diagnosis, the probability of a genetic, autoimmune, enzymatic disorders, infections, iatrogenic or idiopathic cause will be more or less likely. But other rare causes of POF should always be noted for example Colafrancesco et al; documented the evidence of the potential of the HPV vaccine to trigger a life-disabling autoimmune condition including POF (Colafrancesco S, 2013). Irrespective of the aetiology, the most disturbing POF-related problems to every young woman are lower fertility or even infertility. ...
Hormonal infertility is of growing concern. This is even more important in my environment where there is poor knowledge of endocrine-related infertility. Female infertility occurs in about 37% of all infertile couples and hormonal disorders account for more than half of these.
This dissertation focuses on how to gain an understanding of the prevalence, aetiologies and management of female infertility of endocrine origin in a regional centre as well as any probable vulnerable age range with a view to identifying any lacuna in current practice and provide appropriate recommendations.
This observational study probes deeply and analyses retrospectively 2 years of empirical data using a whole target population of women with endocrine-related infertility between January 2015 and January 2017 in Iye Hospital, Ibadan, Nigeria.
From 350 infertile women, 132cases (34.9%) suffered from primary infertility and 228 (65.1%) suffered from secondary infertility. Most infertile women 205 (58.5%) were in the age group of 30-39 years. Only 58 (17.2%) were in the age group of 20-29 years while 79(22.5%) were between the age range 40-50yrs. 8(2.3%) of patients analyzed were above 50 years. The average length of marriage for infertile couples in this review was 6-years. Of the 350 patients studied, infertility related to hormonal factor was 41(11.7%). Of all hormonal causes 41(100%), anovulation 38(92.6%) was the commonest and by projection, 38(10.85%) of anovulatory problems are present in infertility of all-causes in this study.
One-third of couples 10(24.4%) referred required IVF or ICSI. In all, 7(17.1%) of couples had laparoscopic ovarian drilling after a failed medical treatment.
9(21.95%) of the 41 couples in this review, achieved a pregnancy of which 2(4.89%) were independent of treatment. Of those couples who reached a diagnosis, 10 (24.4%) were offered IUI, IVF or ICSI as a first-line treatment. 17(41.4%) were offered ovulation induction with clomiphene citrate. Ovarian drilling for PCOS was done in 7(17.1%) of patients in this review.
The main conclusion that can be drawn from this study is not the differences in data values between theory and practice but in confirming from both literature review and empirical data that ovulatory disorders are the most prevalent cause of hormonal infertility, and hyperprolactinaemia should be ruled out in any case of hormonal infertility. Other endocrine disorders, which can lead to female infertility by interacting and impairing the normal reproductive ovarian function should be excluded in women with infertility of hormonal origin
KEYWORDS: Hormonal infertility, Endocrine, Amenorrhea, PCOS, GnRH, FSH, and LH
DESIGN: Retrospective study.
SETTING: Iye Hospital, Challenge, Ibadan, Nigeria.
INTERVENTION: None
... Yehuda Shoenfeld has admitted that most ASIA patients have ME/ CFS [19]. There has been a tendancy, however, to extend the ASIA concept to immune diseases beyond ME/CFS, to include autoimmune diseases of post-vaccinal onset, such as Sjogren syndrome [212], narcolepsy [213], antiphospholipid syndrome [214], and primary ovarian failure [215], as well as lymphoma [216]. It is true that idiopathic ME/ CFS (up to around 60 %) may suffer from autoimmune responses [217,218] and that ASIA shares similarities with undifferentiated connective tissue disease [219]. ...
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multifactorial and poorly undersood disabling disease. We present epidemiological, clinical and experimental evidence that ME/CFS constitutes a major type of adverse effect of vaccines, especially those containing poorly degradable particulate aluminum adjuvants. Evidence has emerged very slowly due to the multiplicity, lack of specificity, delayed onset, and frequent medical underestimation of ME/CFS symptoms. It was supported by an epidemiological study comparing vaccinated vs unvaccinated militaries that remained undeployed during Gulf War II. Affected patients suffer from cognitive dysfunction affecting attention, memory and inter-hemispheric connexions, well correlated to brain perfusion defects and associated with a stereotyped and distinctive pattern of cerebral glucose hypometabolism. Deltoid muscle biopsy performed to investigate myalgia typically yields macrophagic myofasciitis (MMF), a histological biomarker assessing longstanding persistency of aluminum agglomerates within innate immune cells at site of previous immunization. MMF is seemingly linked to altered mineral particle detoxification by the xeno/autophagy machinery. Comparing toxicology of different forms of aluminum and different types of exposure is misleading and inadequate and small animal experiments have turned old dogma upside down. Instead of being rapidly solubilized in the extracellular space, injected aluminum particles are quickly captured by immune cells and transported to distant organs and the brain where they elicit an inflammatory response and exert selective low dose long-term neurotoxicity. Clinical observations and experiments in sheep, a large animal like humans, confirmed both systemic diffusion and neurotoxic effects of aluminum adjuvants. Post-immunization ME/CFS represents the core manifestation of “autoimmune/inflammatory syndrome induced by adjuvants” (ASIA).
... Numerous studies have pointed to a spectrum of side effects of the HPV vaccine, ranging from common mild vaccine effects such as pain at the injection site [46] to more severe effects such as chronic pain syndrome and chronic fatigue [59], Guillain-Barré syndrome, spinal cord inflammation, and venous blood clots [55], autoimmune diseases such as ovarian failure [56][57][58] and postural orthostatic tachycardia syndrome (POTS) with chronic pain [59]. The online explanatory materials noted mild side effects that are not critical or severe and that pass within a short period of time, as well as a limited number of more serious side effects that were described as rare. ...
Background: Designing online informational materials regarding the human papilloma virus (HPV) vaccine has become a challenge for designers and decision-makers in the health authorities due to the scientific and public controversy regarding the vaccine's safety and effectiveness as well as the sexual and moral concerns related to the vaccine.
Objective: To investigate how cultural sensitivity is articulated in the informational materials explaining the HPV vaccine that are posted online on the websites of the Israeli health authorities. In addition, the study strives to examine the effect of transparency on the expression of cultural sensitivity in the informational materials.
Methods: Quantitative and qualitative content analysis of the texts of explanatory informational materials published on the online Arabic and Hebrew websites of the Israel Ministry of Health and the Clalit HMO.
Results: The findings reveal differences in the dimensions of cultural sensitivity (based on Resnicow's cultural sensitivity model) between the informational materials targeting the majority Jewish population and those targeting the minority Arab population. Indeed, the research findings point to a paradox. On the one hand, the materials appealing to the conservative Arab population exhibited cultural sensitivity in that the sexual context of the vaccine was missing. On the other hand, analysis of Resnicow's deep dimensions shows that disregarding the sexual context does not allow the relevant target audience to reflect on the barriers and concerns. In addition, the way the information was provided exhibited a lack of transparency regarding the cultural sensitivity dimensions (surface and deep).
Conclusions: The public health authorities have two main objectives in the context of vaccinations. One is to raise the vaccination rates and the other is to provide full and culturally sensitive information to give the public the tools to make intelligent decisions. The findings of this study indicated that despite the high uptake rate for HPV vaccination in the Arab population, the health authorities did not exercise full transparency and cultural sensitivity in transmitting the association between engaging in sexual relations and necessity of the vaccination. Thus, the major challenge for the health authorities is to find ways to implement the objective of communicating information about the vaccination in a way that is transparent and culturally sensitive, even if this raises questions and fears among the public deriving from their culture.
... Numerous studies have pointed to a spectrum of side effects of the HPV vaccine, ranging from common mild vaccine effects such as pain at the injection site [46] to more severe effects such as chronic pain syndrome and chronic fatigue [59], Guillain-Barré syndrome, spinal cord inflammation, and venous blood clots [55], autoimmune diseases such as ovarian failure [56][57][58] and postural orthostatic tachycardia syndrome (POTS) with chronic pain [59]. The online explanatory materials noted mild side effects that are not critical or severe and that pass within a short period of time, as well as a limited number of more serious side effects that were described as rare. ...
... 88,89 The main concerns raised about the safety of HPV vaccination have focused on death following vaccination, 88,89 autoimmune and neurological conditions, [90][91][92][93][94][95][96][97][98] and premature ovarian insufficiency (POI) or ovarian failure. [99][100][101][102][103][104][105] Addressing myth 3 ...
Human papillomavirus (HPV) vaccine uptake consistently lags behind that of other adolescent vaccines. In 2017, uptake of a single HPV vaccine dose and HPV vaccine series completion was 66% and 49%, respectively, compared to uptake of tetanus, diphtheria, and acellular pertussis vaccine (89%) and quadrivalent meningococcal conjugate vaccine (85%). Reasons for not vaccinating adolescents again HPV are varied, and in many cases, are rooted in commonly spread myths and misperceptions about the vaccine. In this review, we address five key myths – HPV vaccination is not effective at preventing cancer; Pap smears are sufficient to prevent cervical cancer; HPV vaccination is not safe; HPV vaccination is not needed since most infections are naturally cleared by the immune system; 11–12 years of age is too young to vaccinate. For each myth, we summarize the scientific evidence refuting the myth and provide speaking prompts for healthcare professionals to communicate about HPV vaccination.
... Since Gardasil FDA approval in 2006, case series and case reports describing patients with suspected severe side effects to the HPV vaccines have been emerging from several countries [6][7][8][9][10][11][12][13][14][15][16][17][18]. The symptoms described by independent researchers are quite similar and include long-lasting excessive fatigue, severe headache, cognitive dysfunction, gastrointestinal discomfort, widespread neuropathic pain, sleep disturbance, and motor alteration such as tremor and/or myoclonus. ...
This article reviews the case series reported from several countries describing patients with suspected severe side effects to the HPV vaccines. The described symptom clusters are remarkably similar and include disabling fatigue, headache, widespread pain, fainting, gastrointestinal dysmotility, limb weakness, memory impairment episodes of altered awareness, and abnormal movements. This constellation of symptoms and signs has been labeled with different diagnoses such as complex regional pain syndrome (CRPS), postural orthostatic tachycardia syndrome (POTS), small fiber neuropathy (SFN), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), or fibromyalgia. It is known that autoimmunity and autoantibodies are present in a subset of patients with CRPS, POTS, SFN, ME/CFS, and fibromyalgia. This article proposes that vaccine-triggered, immune-mediated autonomic dysfunction could lead to the development of de novo post-HPV vaccination syndrome possibly in genetically susceptible individuals. Being cognizant that a temporal relationship between vaccination and symptom onset does not necessarily equate to causality, mounting evidence of case series calls for well-designed case-control studies to determine the prevalence and possible causation between these symptom clusters and HPV vaccines. Since personalized medicine is gaining momentum, the use of adversomics and pharmacogenetics may eventually help identify individuals who are predisposed to HPV vaccine adverse events.
... In the past, the hypothesis of a correlation between the Hepatitis B vaccine and MS in adolescents, supported by reports of temporal association between vaccine shot and disease onset was sufficient to fuel controversies on the use of vaccine in subjects with other ADs [21][22][23][24]. This lesson about the effect of publications about possible links between ADs and a vaccine should thus be considered when the safety of a vaccine is debated; the risk of misinterpretation of association is particularly high when we consider autoimmune disease and the HPV vaccine, because this vaccine is recommended for young females (but also for males) in whom the incidence of autoimmune disease is high [25]. Therefore the role of pharmacovigilance surveillance remains of fundamental importance in allowing the scientific community to detect unknown or rare events possibly related to the vaccine. ...
Background
In the literature conflicting opinions are detectable on the onset of adverse events as autoimmune disease post HPV vaccine and often case reports describes the onset of one of these events, but don’t emerge a clear relationship and we don’t have data to support it.
Methods
We carried out a systematic review to identify all scientific publications dealing with the correlation between vaccine anti-papillomavirus and new onset of autoimmune diseases. We searched the main scientific databases (PubMed, Sciverse Scopus, Web of knowledge and Cochrane Central Register of Controlled Clinical Trials) for the following search terms: “vaccine”; “anti-papillomavirus”; “autoimmune”; “disease”; “disorder”. To evaluate the safety of HPV vaccines, the dichotomous data on the number of subjects experiencing an autoimmune disorder in the study vaccine group and the placebo group were extracted from each study with subsequent determination of the risk ratios and their 95% confidence intervals. We combined data statistically using a random effects model.
Results
We conduct a meta-analysis on six studies on bivalent and quadrivalent HPV vaccine. The total number of subjects included in the meta-analysis comprised 243,289 in the vaccine group and 248,820 in control groups. Four of the six trials had a Jadad score of 3 or 4 indicating an adequate trial quality. The most frequent autoimmune disease observed across the six studies were musculoskeletal,CNS conditions and endocrinological conditions . The results of the meta-analysis demonstrated no correlation between autoimmune disorders and HPV vaccines (pooled OR 1.038, 95% CI 0.689-1.562).
Conclusions
No correlation was identified for bivalent and quadrivalent HPV vaccines. It’s therefore essential to correctly inform the general population in order to try to increase both Italian and international vaccination coverage.
Ovarian aging is a complex process influenced by multiple factors, such as age, genetics, neuroendocrine, social psychology, environment, and behavior. Understanding the risk factors of ovarian aging is essential for delaying or preventing ovarian aging, which can improve a woman’s quality of life and happiness and considerably reduce the medical burden. This chapter expounds on the influence of these critical factors on ovarian function.
Introduction: The most important factor initiating cervical cancer is human papilloma virus (HPV) infection; although the HPV vaccine can significantly prevent the infection in women, there is contradictory findings about its side effects such as premature ovarian failure (POF). The present systematic review was conducted with aim to determine the association between this vaccine and POF.
Methods: This study was conducted by search in the reliable databases of PubMed, Web of Science, Google Scholar, Embase, and Scopus by two researchers independently based on the PICO guidelines and the use of Mesh terms including Papillomavirus vaccine, Human Papillomavirus Recombinant Vaccine Quadrivalent, Primary Ovarian Insufficiency and Premature Ovarian Failure. Newcastle - Ottawa checklist was used to evaluate the quality of articles.
Results: After review and evaluation of the quality of 128 primary articles, finally 7 articles were included in the systematic review. According to the results of population-based studies, there was no significant relationship between the HPV vaccine and POF; but there are case series which support the association between the HPV vaccine and POF. They declared that the cause of this complication was the induction of autoimmune response by the vaccine and the side-effects of the adjuvant used in it.
Conclusion: Considering that the HPV vaccine is currently the most effective approach in preventing cervical cancer, it seems more reasonable to use preventive benefits of this vaccine. Further studies emphasizing the possible side effects of the vaccine can minimize the challenges associated with this vaccine in the future.
Human Papillomavirus Vaccine Human papilloma virus Premature ovarian failure
Background:
Since 2012, reports of primary ovarian insufficiency (POI) temporally associated with receipt of human papillomavirus (HPV) vaccine have been published leading to questions about a potential causal association. A Vaccine Safety Datalink study did not find an increased risk for POI after vaccination. We reviewed the Vaccine Adverse Event Reporting System (VAERS) to describe POI reports.
Methods:
We searched VAERS, a U.S. passive surveillance system, for domestic POI reports received from 01/01/1990 to 12/31/2017 after any vaccination. The search used both Medical Dictionary for Regulatory Activity Preferred Terms and a text-based search for POI and its symptoms. All reports were reviewed, and the American College of Obstetricians and Gynecologists (ACOG) guidelines for POI diagnosis were applied. Data mining for disproportionate reporting was conducted.
Results:
Six hundred fifty-two reports met the search criteria and clinical review identified 19 POI reports. Most reports (n = 16) were received between 2013 and 2017. The median age at vaccination was 14.5 years (range 10-25 years) and the median interval between first dose of vaccination and reporting the event to VAERS was 43 months (range 4-132 months; mean 59.6 months). Four reports met ACOG diagnostic criteria; one with an underlying cause (47XXX chromosomal abnormality) reported. Eleven reports documented menstrual irregularity ≥ 3 months; 5 had ≥ 1 laboratory test result used to diagnose POI. Eighteen of 19 reports described receipt of HPV vaccine with or without other vaccines. Other vaccines reported were meningococcal conjugate vaccine, hepatitis A, varicella and tetanus toxoid, reduced diphtheria toxoid and acellular pertussis. Disproportionate reporting was found for three relevant coding terms after HPV vaccination.
Conclusions:
POI is rarely reported to VAERS. Most reports contained limited diagnostic information and were submitted after published cases of POI following HPV vaccination. Results of our review do not suggest a safety concern.
Vaccines for the past 300 years have played a crucial role in curbing infectious diseases. The development of effective and safe vaccines has significantly reduced morbidity and mortality caused by infectious diseases. Moreover, recent advancements in vaccinology, immunology, microbiology, and genetic engineering have led to novel advancement in vaccine development. This advancement has been quite evident in the current COVID-19 pandemic, where the swift development and approval of vaccines has stopped the spread of SARS-CoV-2 infection. Additionally, the COVID-19 vaccine has saved patients from severe complications and even death. Despite vaccines’ recent advancements and advantages, it would be naïve to believe that vaccines cannot cause adverse reactions. Moreover, evidence suggests vaccines’ involvement in developing inflammatory and autoimmune conditions through molecular mimicry, bystander activation, and cross-reactivity. Additionally, the adjuvants and preservatives added in the vaccine formulations may trigger an autoimmune response. As vaccines are administered to healthy individuals, in many cases to children, any adverse complications can have serious consequences. This chapter mainly focuses on mechanisms of vaccine induced autoimmunity, different vaccines reported for such autoimmune conditions, so that the existing knowledge could help in developing safe and effective vaccines.
Introduction:
COVID-19 has had a calamitous impact on the global community. The current death toll far exceeds 6 million and large numbers of patients are experiencing long-term medical and psychiatric morbidity from the infection. The immunopathology of severe COVID-19 is now better understood. In severely affected patients, there is a chaotic, destructive immune response triggered by SARS-CoV-2, where autoimmunity features prominently.
Areas covered:
COVID-19 vaccines ensure a coordinated, balanced immune response to future SARS-CoV-2 infection. The rapid global deployment of effective COVID-19 vaccines has been hindered by financial, logistical and political barriers. Of concern is increasing vaccine hesitancy caused by unfounded conspiracy theories of vaccine adverse effects, often fueled by misinformation and disinformation on social media.
Expert opinion:
This perspective discusses the potential impact of the so-called autoimmune/autoinflammatory syndrome caused by adjuvants (ASIA) on COVID-19 vaccine uptake. Proponents of the ASIA syndrome have inappropriately linked infertility to HPV vaccines and have recently suggested antigenic cross-reactivity between SARS-CoV-2 and ovarian follicles. COVID-19 vaccines have also been linked to ASIA and unfounded fear of infertility is a leading cause of vaccine hesitancy. Vaccine hesitancy caused by spurious disorders such as ASIA are likely to harm individuals and delay global vaccination efforts leading to emergence of vaccine and monoclonal antibody resistant mutants, thereby prolonging the COVID-19 pandemic.
Introduction:
Premature ovarian failure (POF) is one of the important causes of infertility in females. To date, no efficient preventive pharmacological treatment has been offered to prevent POF. Therefore, it is necessary to focus on strategies that provide a normal reproductive lifespan to females at risk of developing POF.
Areas covered:
Recently, attention has been drawn to discovering pathways involved in primordial follicle activation, as the inhibition of this process might maintain the stock of primordial follicles and therefore, prevent POF. In vitro and animal studies have resulted in the discovery of several of these pathways that can be used to develop new treatments for POF. These studies show crosstalk of these pathways at different levels. One of the important crossing points of many of these pathways involves anti-Mullerian hormone (AMH). Herein, we discuss different aspects of this topic by reviewing related published articles indexed in PubMed and Web of Science as of December 2021.
Expert opinion:
Although the findings seem promising, most of the studies were conducted on animals, and the interaction between these factors and the possible outcomes of their administration in the long term are still unknown. Therefore, further investigation is necessary to assess these aspects.
To estimate the effects of early cervical lesions (ECL) on female reproductive function and IVF/ICSI cycle outcomes, a retrospective cohort study involving 111 infertile women from 2014 to 2019 was performed. Thirty-seven women with a history of ECL and seventy-four controls, undergoing IVF/ICSI cycles, were included in the ECL group and comparison group respectively. Demographic characteristics, ovarian reserve, and IVF/ICSI cycle outcomes of both groups were collected. Basal serum FSH level, AMH level, AFC, number of oocytes retrieved and matured, normal fertilization rate, embryo available rate, blastocyst formation rate, implantation rate, pregnancy rate, and cumulative live birth rate (CLBR) were assessed and compared. We observed that while both groups were similar concerning baseline features, significantly more women in the ECL group were diagnosed as poor ovarian response (POR), compared with those in the comparison group (27.0% vs. 10.8%, P=0.003). The pregnancy rate and LBR for a complete cycle were both significantly lower in the ECL group (38.5% vs. 58.8%, P=0.021; 28.9% vs. 48.2%, P=0.025, respectively). The conservative and optimal CLBRs for up to four complete cycles in the ECL group were also lower than those in the comparison group (40.5% vs. 55.4%, P=0.140; 45.9% vs. 67.6%, P=0.028). Longer time intervals (over one year) between ECL diagnosis/treatment and assisted reproductive technology (ART) cycle start negatively affected the pregnancy rate and LBR. In conclusion, female patients with ECL history seemingly have a lower ovarian reserve, reduced pregnancy rate, and decreased live birth rate (LBR), compared with age-matched women undergoing IVF/ICSI.
In this review we summarize current data on prevalence, etiology and pathogenesis resulting in premature ovarian insufficiency (POI). In particular, genetic, autoimmune, metabolic, iatrogenic disorders as well as unfavorable impact of environmental factors represent key pathogenetic mechanisms underlying POI development. Clinical picture of this disease is mainly manifested by oligo- and amenorrhea as well as genitourinary menopausal syndrome (GUMS). Special attention is paid to a link between such clinical signs and psychosocial discomfort not being a life-threatening condition but still able to markedly lower quality of woman’s life and considered as a comorbidity with type 2 diabetes mellitus, osteoporosis and cardiovascular diseases. Hormone replacement therapy (HRT) serves as the first-line therapeutic approach for treating POI, which is performed according to the principles similar to those used to perform menopausal hormone therapy (MHT) in case of natural menopause that should be continued until reaching at least the average age for the onset of menopause. Topical estriol therapy eliminates GUMS symptoms, which in turn positively affects sexual function and woman’s psychosocial status and contributes to improved quality of life. The data from recent studies examining topical estriol therapy in POI demonstrated high efficacy and safety. Finally, we also discuss diverse strategies to support reproductive function in women with POI.
The effects of HPV vaccination on embryo yield and pregnancy outcomes in IVF cycles with fresh embryo transfer (ET) were investigated. First, embryo yielding rates (EYR) in 2795 cycles with and without HPV vaccination were compared by retrospective cohort study design. EYR of HPV vaccinated and non-vaccinated patients were not significantly different (OR, 1.66; 95% CI, 0.76–3.63). Second, ET outcomes were compared for 155 HPV vaccine + cycles and 465 HPV vaccine - cycles after matching for ages and cycle attempt number. The differences in the number of retrieved oocytes (10.2 ± 6.1, 11.2 ± 6.7; p = .161), mature (MII) oocytes (8.7 ± 5.7, 9.8 ± 6.3; p = .088), two pronuclear zygotes (2PN) (5.4 ± 4.1, 6.1 ± 4.6; p = .110) and fertilisation rates (0.62 ± 0.23, 0.62 ± 0.23; p = .539) were insignificant between the two groups. Moreover, positive (OR, 0.74; 95% CI, 0.47–1.16), clinical (0.60; 0.36–1.01) and the ongoing pregnancy (0.55; 0.30–1.01) rates were lower in the HPV vaccinated group but the difference was not statistically significant.
• IMPACT STATEMENT
• What is already known on this subject? There are recent case studies that report premature ovarian insufficiency (POI) following a post-vaccination autoimmune response against the HPV vaccine. These studies suggest that the possible trigger for the immune reaction might be the immunogen content of the vaccine. However, the number of clinical studies investigating the effects of the HPV vaccine on reproductive function and in vitro fertilisation outcomes is limited.
• What do the results of this study add? In contrast to the case reports suggesting impaired reproductive and ovarian functions in HPV vaccinated patients, this study finds that in IVF patients HPV vaccinated and non-vaccinated women have similar EYR, MII, 2PN, oocyte counts, fertilisation rates, positive, clinical and ongoing pregnancy rates.
• What are the implications of these findings for clinical practice and/or further research? The results suggest the HPV vaccine does not have a negative impact on embryo yielding rates oocyte counts and fertilisation rates, positive, clinical and ongoing pregnancy rates in IVF treatments. Hence, they can be safely used for primary prevention against cervical cancer.
An adjuvant is an immunological or pharmacological substance or group of substances that can be added to a given agent to enhance its effect in terms of efficacy, effectiveness and potency. Different mechanisms have been hypothesized underlying the action of the adjuvant, including boosting immune (innate and adaptive) response: this generally results in sparing the necessary amount of the agent and can potentially reduce the frequency of the needed number of therapeutic interventions. Adjuvants can be commonly found in vaccines, immunization products, mineral oils, cosmetics, silicone breast implants and other therapeutic/medical devices, being usually safe and effective. However, in a fraction of genetically susceptible and predisposed subjects, the administration of adjuvants may lead to the insurgence of serious side-effects, called “autoimmune/inflammatory syndrome by adjuvants” (ASIA) or Shoenfeld’s syndrome. The present review is aimed at focusing on the “endocrine pebbles” of the mosaic of autoimmunity and of the ASIA syndrome, collecting together 54 cases of sub-acute thyroiditis, 2 cases of Hashimoto’s thyroiditis, 11 cases of primary ovarian failure/primary ovarian insufficiency, 13 cases of autoimmune diabetes type 1, and 1 case of autoimmune adrenal gland insufficiency occurred after exposure to adjuvants.
Background:
Because of the limited number of subjects in prelicensure studies, autoimmune diseases and other rare adverse effects of vaccines may go undetected. Since 2006, millions of human papillomavirus (HPV) vaccine doses have been distributed and a considerable amount of postlicensure safety data has been generated. The objective of this study was to review available HPV postlicensure safety studies and to summarize risk estimates of autoimmune and other rare diseases.
Methods:
For this systematic review and meta-analysis, we searched literature databases to identify any postlicensure safety studies related to HPV vaccination and autoimmune adverse events from inception to April 16, 2019. Pooled risk estimates were computed using fixed- or random-effects models if at least 2 estimates per disease and per HPV vaccine were available.
Results:
Twenty-two studies met our inclusion criteria. The studies applied various methodologies and used different types of data sources and outcome definitions. Quadrivalent HPV vaccine (4vHPV) was most commonly assessed. Type 1 diabetes mellitus, immune thrombocytopenia purpura and thyroiditis diseases were most frequently reported. The meta-analysis was conducted on 35 diseases corresponding to 48 pooled risk estimates. Majority of the pooled estimates showed no significant effect (n = 43). Three negative (paralysis, immune thrombocytopenia purpura and chronic fatigue syndrome) and 2 positive (Hashimoto and Raynaud diseases) associations were detected.
Conclusion:
Our study demonstrated an absence of clear association between HPV vaccines and autoimmune and other rare diseases. The review also highlights the need for more systematic collaborations to monitor rare safety adverse events.
Premature ovarian insufficiency (POI) refers to a continuum of decreasing ovarian function in women before the age of 40. To date, the cause of POI in the majority of cases remain unresolved. Many cases has been linked to genetic, toxic, infections, enzymatic and iatrogenic causes.
A key function of the immune system is to identify and differentiate “self” and “non self” i.e. tolerance. Loss of self-tolerance results in an immune response against self-tissues and thus autoimmunity. Various investigations have highlighted the role of autoimmunity and its pertinence to POI. Several potential immune antigenic targets in the ovary have been reported to be involved in autoantibody induced autoimmune attack. The presence of lymphocytic oöphorits in ovarian samples of patients with POI provides histopathological evidence of autoimmune ovarian involvement. Finally, POI is strongly associated with other autoimmune conditions including for instance Addison disease, autoimmune polyglandular syndrome (APS) −1, APS-4, hypothyroidism, and diabetes mellitus among other autoimmune diseases. Taken together, these lines of evidence provide strong basis that support the role of autoimmunity as a potential cause of disease etiopathogenesis. Continuing research is increasingly providing more insight into the complex disease process. The aim of this review is to summarize the current literature related to the autoimmune nature of POI.
Premature ovarian insufficiency (POI) is a clinical syndrome defined by loss of ovarian activity before the age of 40 years and has a potentially devastating effect upon women's health, both physically and psychologically. An underlying autoimmune disease has been identified in approximately 20% of patients with POI, the most common of which are disorders of the thyroid and adrenal glands. Nevertheless, in the majority of cases, the etiology is unknown. The damage mechanism to the ovary is usually caused by antibodies, and autoimmune POI is usually characterized by cellular infiltration of the theca cells of growing follicles by various inflammatory cells. Yet, other various factors and proteins of unknown clinical significance are present.
The major diagnostic tool for otherwise idiopathic POI is the presence of autoantibodies against various ovarian components that strongly support the option of autoimmune etiology of POI.
Treatment of the underlying cause of POI is the main strategy, although immunosuppressive therapy should be considered in a selected population of well-defined autoimmune POI and, as in idiopathic POI, in whom the resumption of ovarian activity is possible.
Background:
Arthritis and arthralgia are reported as adverse events following immunization with various vaccines.
Objective:
To better understand current knowledge of arthritis and arthralgia as an adverse event following immunization.
Methods:
A systematic literature review of Pubmed, Embase, and Cochrane Library was conducted. Data extraction was performed by two independent reviewers. No restrictions on dates were imposed and all types of vaccine studies with primary data were reviewed.
Results:
Of 343 included studies, there were 206 clinical trials, 90 observational studies, and 47 case reports. Influenza was the most commonly studied vaccine (n = 91, 24.4%). Of the 155 (45.2%) studies addressing causality assessment, 84 studies (54.2%) revealed the assessment method. Only seven clinical trials and 12 observational studies reported a measure of association. Four of these studies examined worsening of arthritic conditions in patients with pre-existing disease. Rigorous assessment of causality was not performed in most studies and many observational studies were prone to bias.
Conclusions:
The current evidence linking vaccination to incident arthritis or worsening of arthritic conditions is too heterogeneous and incomplete to infer a causal association. Recommendations for future studies include use of consistent, standardized case definitions and causality assessments, better control of confounding and minimization of bias, and inclusion of measures of associations.
We describe a form of the autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome) in commercial sheep, linked to the repetitive inoculation of aluminum-containing adjuvants through vaccination. The syndrome shows an acute phase that affects less than 0.5 % of animals in a given herd, it appears 2-6 days after an adjuvant-containing inoculation and it is characterized by an acute neurological episode with low response to external stimuli and acute meningoencephalitis, most animals apparently recovering afterward. The chronic phase is seen in a higher proportion of flocks, it can follow the acute phase, and it is triggered by external stimuli, mostly low temperatures. The chronic phase begins with an excitatory phase, followed by weakness, extreme cachexia, tetraplegia and death. Gross lesions are related to a cachectic process with muscular atrophy, and microscopic lesions are mostly linked to a neurodegenerative process in both dorsal and ventral column of the gray matter of the spinal cord. Experimental reproduction of ovine ASIA in a small group of repeatedly vaccinated animals was successful. Detection of Al(III) in tissues indicated the presence of aluminum in the nervous tissue of experimental animals. The present report is the first description of a new sheep syndrome (ovine ASIA syndrome) linked to multiple, repetitive vaccination and that can have devastating consequences as it happened after the compulsory vaccination against bluetongue in 2008. The ovine ASIA syndrome can be used as a model of other similar diseases affecting both human and animals. A major research effort is needed in order to understand its complex pathogenesis.
Silicon has a molecular mass of 28 daltons. In nature, silicon is found as silicon dioxide (silica) or in a variety of silicates (e.g., in talc or asbestos). Furthermore, silicon is present in silicones, polymerized siloxanes, which are often used as medical silicones in breast implants. Silicon exposure is associated with different systemic autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, progressive systemic sclerosis, and vasculitis. Remarkably, silicon in silicone-filled breast implants is considered to be safe, not increasing the risk of developing autoimmune diseases. We analyzed the impact of silicone-filled breast implants on the immune system in 32 consecutive patients attending a specialized autoimmunity clinic. All 32 patients had silicone implant incompatibility syndrome and complaints fulfilling the diagnostic criteria of ASIA (autoimmune/inflammatory syndrome induced by adjuvants). Furthermore, in 17 of the 32 patients, a systemic autoimmune disease was diagnosed, and 15 of the 32 patients had an impaired humoral immune system. Patients developed symptoms and signs after long-term follow-up, suggesting that these symptoms and signs started after implant aging and/or rupture. We postulate that silicon in silicone-filled breast implants may increase the risk of developing (auto) immune diseases and immune deficiencies.
The rationale behind current worldwide human papilloma virus (HPV) vaccination programs starts from two basic premises, 1) that HPV vaccines will prevent cervical cancers and save lives and, 2) have no risk of serious side effects. Therefore, efforts should be made to get as many pre-adolescent girls vaccinated in order to decrease the burden of cervical cancer. Careful analysis of HPV vaccine pre- and post-licensure data shows however that both of these premises are at odds with factual evidence and are largely derived from significant misinterpretation of available data.
We carried out a systematic review of HPV vaccine pre- and post-licensure trials to assess the evidence of their effectiveness and safety. We find that HPV vaccine clinical trials design, and data interpretation of both efficacy and safety outcomes, were largely inadequate. Additionally, we note evidence of selective reporting of results from clinical trials (i.e., exclusion of vaccine efficacy figures related to study subgroups in which efficacy might be lower or even negative from peer-reviewed publications). Given this, the widespread optimism regarding HPV vaccines long-term benefits appears to rest on a number of unproven assumptions (or such which are at odd with factual evidence) and significant misinterpretation of available data. For example, the claim that HPV vaccination will result in approximately 70% reduction of cervical cancers is made despite the fact that the clinical trials data have not demonstrated to date that the vaccines have actually prevented a single case of cervical cancer (let alone cervical cancer death), nor that the current overly optimistic surrogate marker-based extrapolations are justified. Likewise, the notion that HPV vaccines have an impressive safety profile is only supported by highly flawed design of safety trials and is contrary to accumulating evidence from vaccine safety surveillance databases and case reports which continue to link HPV vaccination to serious adverse outcomes (including death and permanent disabilities). We thus conclude that further reduction of cervical cancers might be best achieved by optimizing cervical screening (which carries no such risks) and targeting other factors of the disease rather than by the reliance on vaccines with questionable efficacy and safety profiles.
We read with great interest the analysis by Mello et al.(1) on how Merck & Co., Inc. (Merck) influenced state human papillomavirus (HPV) vaccination policymaking. The exclusive reliance on Merck for scientific information on behalf of the legislators is unfortunate, especially in the light of independent research which has repeatedly warned that drug companies may manipulate clinical trial designs and subsequent data analysis and reporting to make their drugs look better and safer.(2-4) Indeed, careful scrutiny of Gardasil clinical trials shows that their design, as well as data reporting and interpretation, were largely inadequate.(4-6) (Am J Public Health. Published online ahead of print July 19, 2012: e1-e2. doi:10.2105/AJPH.2012.300837).
We have used EXAFS and NRVS spectroscopies to examine the structural changes in the FeMo-cofactor active site of the α-70(Ala) variant of Azotobacter vinelandii nitrogenase on binding and reduction of propargyl alcohol (PA). The Mo K-edge near-edge and EXAFS spectra are very similar in the presence and absence of PA, suggesting PA does not bind at Mo. By contrast, Fe EXAFS spectra show a clear and reproducible change in the long Fe-Fe interaction at ~3.7 Å on PA binding with the apparent appearance of a new Fe-Fe interaction at 3.99 Å. An analogous change in the long Mo-Fe 5.1 Å interaction is not seen. The NRVS spectra exclude the possibility of large-scale structural change of the FeMo-cofactor involving breaking the μ(2) Fe-S-Fe bonds of the Fe(6)S(9)X core. The simplest chemically consistent structural change is that the bound form of PA is coordinated at Fe atoms (Fe6 or Fe7) adjacent to the Mo terminus, with a concomitant movement of the Fe away from the central atom X and along the Fe-X bond by about 0.35 Å. This study comprises the first experimental evidence of the conformational changes of the FeMo-cofactor active site on binding a substrate or product.
All drugs are associated with some risks of adverse reactions. Because vaccines represent a special category of drugs, generally given to healthy individuals, uncertain benefits mean that only a small level of risk for adverse reactions is acceptable. Furthermore, medical ethics demand that vaccination should be carried out with the participant's full and informed consent. This necessitates an objective disclosure of the known or foreseeable vaccination benefits and risks. The way in which HPV vaccines are often promoted to women indicates that such disclosure is not always given from the basis of the best available knowledge. For example, while the world's leading medical authorities state that HPV vaccines are an important cervical cancer prevention tool, clinical trials show no evidence that HPV vaccination can protect against cervical cancer. Similarly, contrary to claims that cervical cancer is the second most common cancer in women worldwide, existing data show that this only applies to developing countries. In the Western world cervical cancer is a rare disease with mortality rates that are several times lower than the rate of reported serious adverse reactions (including deaths) from HPV vaccination. Future vaccination policies should adhere more rigorously to evidence-based medicine and ethical guidelines for informed consent.
Antibodies to multiple ovarian antigens have been proposed as markers of ovarian autoimmunity. The role of ovarian autoantibodies has been widely discussed in the pathophysiology of premature ovarian failure and unexplained infertility, but the autoantigens are yet to be identified. Three immunodominant ovarian autoantigens, α-actinin 4 (αACTN4), heat shock 70 protein 5 (HSPA5) and β-actin (ACTB), have been identified using anti-ovarian antibody-positive sera from women with idiopathic premature ovarian failure (n=50) and women undergoing IVF (n=695), using mass spectrometry. These autoantigens were subsequently validated using Western blot, immunohistochemistry and enzyme-linked immunosorbent assay. These autoantigens are localized to different components of the ovary such as the ooplasm of the oocyte, theca, granulosa, corpus luteum and zona pellucida. All the above antigens were found to be expressed in the ooplasm throughout follicular development. All the autoantigens are expressed specifically in the oocyte except αACTN4. The three autoantigens could contribute to the array of biomarkers to be used for developing specific and sensitive tests for diagnosis of women at risk of premature ovarian failure and IVF failure due to ovarian autoimmunity and could give an insight into the molecular mechanisms involved in the pathophysiology of these conditions.
Sick building syndrome (SBS) is a term coined for a set of clinically recognizable symptoms and ailments without a clear cause reported by occupants of a building. In the 1990s the term "functional somatic syndromes" was applied to several syndromes, including SBS, multiple chemical sensitivity, repetition stress injury, the side effects of silicone breast implants, the Gulf War syndrome (GWS), chronic fatigue syndrome, the irritable bowel syndrome, and fibromyalgia. Recently, Shoenfeld and Agmon-Levin suggested that four conditions--siliconosis, macrophagic myofascitis, the GWS, and post-vaccination phenomena--which share clinical and pathogenic resemblances, may be included under a common syndrome entitled the "autoimmune (auto-inflammatory) syndrome induced by adjuvants". Comparison of the clinical manifestations, symptoms, and signs of the four conditions described by Shoenfeld and Agmon-Levin with those described for SBS shows that nine out of ten main symptoms are present in all 5 conditions. Shoenfeld and Agmon-Levin further propose several major and minor criteria, which, although requiring further validation, may aid in the diagnosis of this newly defined syndrome. We propose here that SBS may also be included as a part of "Shoenfeld's syndrome".
Guillain-Barré syndrome (GBS) is a rare autoimmune disorder, the incidence of which is estimated to be 0.6-4/100,000 person/year worldwide. Often, GBS occurs a few days or weeks after the patient has had symptoms of a respiratory or gastrointestinal microbial infection. The disorder is sub-acute developing over the course of hours or days up to 3 to 4 weeks. About a third of all cases of Guillain-Barré syndrome are preceded by Campylobacter jejuni infection. C. jejuni strains isolated from GBS patients have a lipooligosaccharide (LOS) with a GM1-like structure. Molecular mimicry between LOS and the peripheral nerves as a cause of GBS was demonstrated in animal models of human GBS. Following the "swine flu" virus vaccine program in the USA in 1976, an increase in incidence of GBS was observed and the calculated relative risk was 6.2. Later studies have found that influenza vaccines contained structures that can induce anti-GM1 (ganglioside) antibodies after inoculation into mice. More recent information has suggested that the occurrence of GBS after currently used influenza and other vaccines is rare. GBS involves genetic and environmental factors, may be triggered by infections or vaccinations, and predisposition can be predicted by analyzing some of these factors.
Approaches for cervical cancer prevention are changing. Screening still remains the most effective method for cervical cancer prevention. Guidelines are moving to an older group of women to be screened less frequently with combinations of technologies that include biomarkers and cytology. HPV vaccination is an appropriate option for this older group of women as well, should the woman not wish to make her decision about vaccination until 21 years of age, the age of screening. Parents making decisions about HPV vaccination for their young adolescent daughters need to be fully informed that only continued screening prevents cervical cancer. HPV vaccination reduces the possibility of their daughter having an abnormal Pap test by 10% if the vaccines have not waned by the time the young adolescent becomes sexually active. HPV vaccine efficacy must last at least 15 years to contribute to the prevention of cervical cancers. At this time, protection against cervical intraepithelial neoplasia grade 2/3 (CIN 2/3) is 5 years for Gardasil and 8.4 years for Cervarix. The value of the current protection HPV vaccines offer will be viewed differently by different women. Physicians' ethical duties are to provide full explanation of the risks and benefits of adding HPV vaccination to the ongoing screening programs, and to support women in their personal choice for cervical cancer prevention.
The story of epidemiologists and surrogate variables is one of a classic love–hate relationship. Epidemiologists love surrogates because many studies would not be possible without them. When events are rare or the time between an intervention and the outcome is long, surrogate variables are used to fill the gap. Epidemiologists hate surrogate variables because they introduce an additional step in the chain between intervention (or exposure) and outcome, and thus an additional source of error. To introduce surrogates means to increase uncertainty — and, perhaps, an error.
A recent “collection of misleading surrogate end points” reminds us that caution is warranted: examples from this collection include the Cardiac Arrhythmia Suppression Trial in which a group of patients with asymptomatic or mildly symptomatic ventricular arrhythmia after myocardial infarction were treated with encainide or flecainide. Both drugs are used to suppress ventricular arrhythmia (the surrogate end point), but they were actually associated with excess mortality (the relevant outcome). In another case, patients treated with fluoride developed the desired increase in bone mineral density at the lumbar spine (the surrogate end point) but suffered from a higher rate of vertebral fractures than the control group.1 Assessing whether surrogate variables actually measure what they purport to measure (ie, for their validity) is therefore required. Available instruments, however, can only test if a surrogate correctly indicates the direction of an effect — that …
Infectious agents contribute to the environmental factors involved in the development of autoimmune diseases possibly through molecular mimicry mechanisms. Hence, it is feasible that vaccinations may also contribute to the mosaic of autoimmunity. Evidence for the association of vaccinations and the development of these diseases is presented in this review. Infrequently reported post-vaccination autoimmune diseases include systemic lupus erythematosus, rheumatoid arthritis, inflammatory myopathies, multiple sclerosis, Guillain-Barré syndrome, and vasculitis. In addition, we will discuss macrophagic myofasciitis, aluminum containing vaccines, and the recent evidence for autoimmunity following the use of human papillomavirus vaccine.
HEN DO PHYSICIANS KNOW ENOUGH ABOUT THE beneficial effects of a new medical interven- tiontostartrecommendingorusingit?When istheavailableinformationaboutharmfulad- verse effects sufficient to conclude that the risks outweigh the potential benefits? If in doubt, should physicians err on the side of caution or on the side of hope? These questions are at the core of all medical decision making. It is a com- plicated process because medical knowledge is typically in- complete and ambiguous. It is especially complex to make decisions about whether to use drugs that may prevent dis- ease in the future, particularly when these drugs are given to otherwise healthy individuals. Vaccines are examples of such drugs, and the human papillomavirus (HPV) vaccine is a case in point. zur Hausen, winner of the Nobel Prize in Physiology or Medicine in 2008, discovered that oncogenic HPV causes cervical cancer. 1-4 His discovery led to characterization of the natural history of HPV infection, an understanding of mechanisms of HPV-induced carcinogenesis, and eventu- allytothedevelopmentofprophylacticvaccinesagainstHPV infection.
To investigate the association between human papillomavirus (HPV) vaccination and autoimmune manifestations compatible with systemic lupus erythematosus (SLE) or SLE-like disease, the medical history of six women who presented with SLE or SLE-like disease following HPV immunization was collected. Data regarding type of vaccine, number of immunization, family and personal, clinical and serological features, as well as response to treatments were analyzed. In the reported cases, several common features were observed, such as personal or familial susceptibility to autoimmunity or adverse response to a prior dose of the vaccine, both of which may be associated with a higher risk of post-vaccination autoimmunity. Favorable response to immunosuppressant was observed in all patients. In the current study, a temporal association between immunization with HPV vaccine and the appearance of a spectrum of SLE-like conditions is reported. Additionally, among the patients described, several common features were observed that may enable better identification of subjects at risk. Further studies are required to assess the safety of immunization with the HPV vaccine in patients with autoimmune-rheumatic diseases or in subject at risk of autoimmunity as well as the potential beneficial effect of preventive immunosuppressants.
A traditional infectious disease vaccine is a preparation of live attenuated, inactivated or killed pathogen that stimulates immunity. Vaccine immunologic adjuvants are compounds incorporated into vaccines to enhance immunogenicity. Adjuvants have recently been implicated in the new syndrome named ASIA autoimmune/inflammatory syndrome induced by adjuvants. The objective describes the frequencies of post-vaccination clinical syndrome induced by adjuvants. We performed a cross-sectional study; adverse event following immunization was defined as any untoward medical occurrence that follows immunization 54 days prior to the event. Data on vaccinations and other risk factors were obtained from daily epidemiologic surveillance. Descriptive statistics were done using means and standard deviation, and odds ratio adjusted for potential confounding variables was calculated with SPSS 17 software. Forty-three out of 120 patients with moderate or severe manifestations following immunization were hospitalized from 2008 to 2011. All patients fulfilled at least 2 major and 1 minor criteria suggested by Shoenfeld and Agmon-Levin for ASIA diagnosis. The most frequent clinical findings were pyrexia 68 %, arthralgias 47 %, cutaneous disorders 33 %, muscle weakness 16 % and myalgias 14 %. Three patients had diagnosis of Guillain-Barre syndrome, one patient had Adult-Still's disease 3 days after vaccination. A total of 76 % of the events occurred in the first 3 days post-vaccination. Two patients with previous autoimmune disease showed severe adverse reactions with the reactivation of their illness. Minor local reactions were present in 49 % of patients. Vaccines containing adjuvants may be associated with an increased risk of autoimmune/inflammatory adverse events following immunization.
Saccharomyces cerevisiae is best known as the baker's and brewer's yeast, but its residual traces are also frequent excipients in some vaccines. Although anti-S. cerevisiae autoantibodies (ASCAs) are considered specific for Crohn's disease, a growing number of studies have detected high levels of ASCAs in patients affected with autoimmune diseases as compared with healthy controls, including antiphospholipid syndrome, systemic lupus erythematosus, type 1 diabetes mellitus, and rheumatoid arthritis. Commensal microorganisms such as Saccharomyces are required for nutrition, proper development of Peyer's aggregated lymphoid tissue, and tissue healing. However, even the commensal nonclassically pathogenic microbiota can trigger autoimmunity when fine regulation of immune tolerance does not work properly. For our purposes, the protein database of the National Center for Biotechnology Information (NCBI) was consulted, comparing Saccharomyces mannan to several molecules with a pathogenetic role in autoimmune diseases. Thanks to the NCBI bioinformation technology tool, several overlaps in molecular structures (50-100 %) were identified when yeast mannan, and the most common autoantigens were compared. The autoantigen U2 snRNP B″ was found to conserve a superfamily protein domain that shares 83 % of the S. cerevisiae mannan sequence. Furthermore, ASCAs may be present years before the diagnosis of some associated autoimmune diseases as they were retrospectively found in the preserved blood samples of soldiers who became affected by Crohn's disease years later. Our results strongly suggest that ASCAs' role in clinical practice should be better addressed in order to evaluate their predictive or prognostic relevance.
Medical practitioners in nine countries submitted samples of Gardasil® (Merck & Co.) to be tested for the presence of human papillomavirus (HPV) DNA because they suspected that residual recombinant HPV DNA left in the vaccine might have been a contributing factor leading to some of the unexplained post-vaccination side effects. A total of 16 packages of Gardasil® were received from Australia, Bulgaria, France, India, New Zealand, Poland, Russia, Spain and the United States. A nested polymerase chain reaction (PCR) method using the MY09/MY11 degenerate primers for initial amplification and the GP5/GP6-based nested PCR primers for the second amplification were used to prepare the template for direct automated cycle DNA sequencing of a hypervariable segment of the HPV L1 gene which is used for manufacturing of the HPV L1 capsid protein by a DNA recombinant technology in vaccine production. Detection of HPV DNA and HPV genotyping of all positive samples were finally validated by BLAST (Basic Local Alignment Search Tool) analysis of a 45-60 bases sequence of the computer-generated electropherogram. The results showed that all 16 Gardasil® samples, each with a different lot number, contained fragments of HPV-11 DNA, or HPV-18 DNA, or a DNA fragment mixture from both genotypes. The detected HPV DNA was found to be firmly bound to the insoluble, proteinase-resistant fraction, presumably of amorphous aluminum hydroxyphosphate sulfate (AAHS) nanoparticles used as adjuvant. The clinical significance of these residual HPV DNA fragments bound to a particulate mineral-based adjuvant is uncertain after intramuscular injection, and requires further investigation for vaccination safety.
There are not many public health issues where views are as extremely polarized as those concerning vaccines, and Merck's HPV vaccine Gardasil is a case in point. Ever since gaining the FDA's approval in 2006, Merck has been heavily criticized for their overly aggressive marketing strategies and lobbying campaigns aimed at promoting Gardasil as a mandatory vaccine. Subsequently, questions have been raised as to whether it was appropriate for vaccine manufacturers to partake in public health policies when their conflicts of interests are so obvious. Some of their advertising campaign slogans, such as "cervical cancer kills x women per year" and "your daughter could become one less life affected by cervical cancer," seemed more designed to promote fear rather than evidence-based decision making about the potential benefits of the vaccine. Although, conflicts of interests do not necessarily mean that the product itself is faulty, marketing claims should be carefully examined against factual science data. Currently Gardasil vaccination is strongly recommended by the U.S. and other health authorities while public concerns about safety and efficacy of the vaccine appear to be increasing. This discrepancy leads to some important questions that need to be resolved. The current review examines key issues of this debate in light of currently available research evidence.
Premature ovarian failure in a well adolescent is a rare event. Its occurrence raises important questions about causation, which may signal other systemic concerns. This patient presented with amenorrhoea after identifying a change from her regular cycle to irregular and scant periods following vaccinations against human papillomavirus. She declined the oral contraceptives initially prescribed for amenorrhoea. The diagnostic tasks were to determine the reason for her secondary amenorrhoea and then to investigate for possible causes of the premature ovarian failure identified. Although the cause is unknown in 90% of cases, the remaining chief identifiable causes of this condition were excluded. Premature ovarian failure was then notified as a possible adverse event following this vaccination. The young woman was counselled regarding preservation of bone density, reproductive implications and relevant follow-up. This event could hold potential implications for population health and prompts further inquiry.
Macrophagic myofasciitis (MMF) was initially described as an emerging entity of unknown cause with characteristic features on muscle biopsy by French myopathologists in 1993. The main clinical symptoms in affected patients included diffuse myalgia, arthralgia and fatigue which are steroid responsive. The biopsy from deltoid muscle showed aggregates of macrophages containing pathognomonic crystalline inclusions detected on electron microscopy. © 2012 The Authors. Neuropathology and Applied Neurobiology © 2012 British Neuropathological Society.
Adjuvants may induce autoimmune diseases in susceptible individuals, a phenomenon recently defined as autoimmune/inflammatory syndrome induced by adjuvants (ASIA). Patients with both antiphospholipid antibodies (aPL) and the genetic coagulopathy factor V Leiden (FVL) are frequently found. We therefore evaluated whether adjuvant can induce aPL in heterozygous FVL mice. aPL were measured in naïve mice and at 1 and 5 months after immunization with either complete or incomplete Freund's adjuvant (CFA, IFA) in FVL and control C57/B6 background mice. We defined antibody levels 3 SD above the mean of C57/B6 mice immunized with adjuvant as positive (specificity of 99%). For β(2)GPI-dependent aPL, 28.6% (6/21) of FVL mice 5 months after immunization with adjuvant (both IFA and CFA) were positive compared with 4.8% (1/22) of FVL mice 1 month after adjuvant and 0% of naïve FVL and C57/B6 mice (0/16, p < 0.001). aPL levels correlated with behavioral hyperactivity in the staircase test. FVL mice immunized with adjuvant did not develop β(2)GPI-independent aPL. We hypothesize that the FVL aPL association is not a coincidence, but that chronic coagulation defects combined with external inflammatory stimuli analogous to adjuvant may induce aPL and also antiphospholipid syndrome, thus supporting the notion of ASIA.
Aluminium oxyhydroxide (alum), a nanocrystalline compound forming agglomerates, has been used in vaccines for its immunological adjuvant effect since 1927. Alum is the most commonly used adjuvant in human and veterinary vaccines, but the mechanisms by which it stimulates immune responses remain incompletely understood. Although generally well tolerated, alum may occasionally cause disabling health problems in presumably susceptible individuals. A small proportion of vaccinated people present with delayed onset of diffuse myalgia, chronic fatigue and cognitive dysfunction, and exhibit very long-term persistence of alum-loaded macrophages at the site of previous intramuscular (i.m.) immunization, forming a granulomatous lesion called macrophagic myofasciitis (MMF). Clinical symptoms associated with MMF are paradigmatic of the recently delineated 'autoimmune/inflammatory syndrome induced by adjuvants' (ASIA). The stereotyped cognitive dysfunction is reminiscent of cognitive deficits described in foundry workers exposed to inhaled Al particles. Alum safety concerns will largely depend on whether the compound remains localized at the site of injection or diffuses and accumulates in distant organs. Animal experiments indicate that biopersistent nanomaterials taken up by monocyte-lineage cells in tissues, such as fluorescent alum surrogates, can first translocate to draining lymph nodes, and thereafter circulate in blood within phagocytes and reach the spleen, and, eventually, slowly accumulate in the brain.
In this study we analyzed the clinical and demographic manifestations among patients diagnosed with immune/autoimmune-mediated diseases post-hepatitis B vaccination. We aimed to find common denominators for all patients, regardless of different diagnosed diseases, as well as the correlation to the criteria of Autoimmune (Auto-inflammatory) Syndrome induced by Adjuvants (ASIA).
We have retrospectively analyzed the medical records of 114 patients, from different centers in the USA, diagnosed with immune-mediated diseases following immunization with hepatitis-B vaccine (HBVv). All patients in this cohort sought legal consultation. Of these, 93/114 patients diagnosed with disease before applying for legal consultation were included in the study. All medical records were evaluated for demographics, medical history, number of vaccine doses, peri-immunization adverse events and clinical manifestations of diseases. In addition, available blood tests, imaging results, treatments and outcomes were recorded. Signs and symptoms of the different immune-mediated diseases were grouped according to the organ or system involved. ASIA criteria were applied to all patients.
The mean age of 93 patients was 26.5 ± 15 years; 69.2% were female and 21% were considered autoimmune susceptible. The mean latency period from the last dose of HBVv and onset of symptoms was 43.2 days. Of note, 47% of patients continued with the immunization program despite experiencing adverse events. Manifestations that were commonly reported included neuro-psychiatric (70%), fatigue (42%) mucocutaneous (30%), musculoskeletal (59%) and gastrointestinal (50%) complaints. Elevated titers of autoantibodies were documented in 80% of sera tested. In this cohort 80/93 patients (86%), comprising 57/59 (96%) adults and 23/34 (68%) children, fulfilled the required criteria for ASIA.
Common clinical characteristics were observed among 93 patients diagnosed with immune-mediated conditions post-HBVv, suggesting a common denominator in these diseases. In addition, risk factors such as history of autoimmune diseases and the appearance of adverse event(s) during immunization may serve to predict the risk of post-immunization diseases. The ASIA criteria were found to be very useful among adults with post-vaccination events. The application of the ASIA criteria to pediatric populations requires further study.
The human ovary is commonly the target of an autoimmune attack leading to the ovarian dysfunction which can be manifested as premature ovarian failure (POF), polycystic ovary syndrome (PCOS), unexplained infertility as well as endometriosis. In case of POF, the evidence for an autoimmune etiology is based on the presence of lymphocytic oophoritis, autoantibodies to ovarian antigens and association with other autoimmune disorders, which was clearly documented in many studies. The search for antiovarian antibodies has been undertaken in numerous studies, especially in patients with POF, however their results are still conflicting particularly due to difference in laboratory methods as well as many ovarian components being potential antigens. On the other side the autoimmune etiology of PCOS is still debated and was documented in some cases. Association of PCOS with non-organ specific autoimmune disorders is controversial; however association with autoimmune thyroid disease was well demonstrated in some studies.
Macrophagic myofasciitis (MMF) is characterized by specific muscle lesions assessing long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients are middle-aged adults, mainly presenting with diffuse arthromyalgias, chronic fatigue, and cognitive dysfunction. Representative features of MMF-associated cognitive dysfunction (MACD) include (i) dysexecutive syndrome; (i) visual memory; (iii) left ear extinction at dichotic listening test. In present study we retrospectively evaluated the progression of MACD in 30 MMF patients. Most patients fulfilled criteria for non-amnestic/dysexecutive mild cognitive impairment, even if some cognitive deficits seemed unusually severe. MACD remained stable over time, although dysexecutive syndrome tended to worsen. Long-term follow-up of a subset of patients with 3 or 4 consecutive neuropsychological evaluations confirmed the stability of MACD with time, despite marked fluctuations.
Chronic fatigue syndrome (CFS) is characterized by unexplained fatigue that lasts for at least 6 months with a constellation of other symptoms. Most cases start suddenly, and are usually accompanied by a flu-like illness. It is a symptom-based diagnosis of exclusion, the pathogenesis of which is unknown. Studies have examined and hypothesized about the possible biomedical and epidemiologic characteristics of the disease, including genetic predisposition, infections, endocrine abnormalities, and immune dysfunction and psychological and psychosocial factors. Recently, the AISA (autoimmune/inflammatory syndrome induced by adjuvants) syndrome was recognized, indicating the possible contribution of adjuvants and vaccines to the development of autoimmunity.
An observational safety study of the quadrivalent human papillomavirus vaccine (HPV4) in women was conducted. This report presents findings from autoimmune surveillance. Design. Subjects were followed for 180days after each HPV4 dose for new diagnoses of 16 prespecified autoimmune conditions.
Two managed care organizations in California. Subjects. Number of 189,629 women who received ≥1 dose of HPV4 between 08/2006 and 03/2008.
Potential new-onset autoimmune condition cases amongst HPV4 recipients were identified by electronic medical records. Medical records of those with ≥12-month health plan membership prior to vaccination were reviewed by clinicians to confirm the diagnosis and determine the date of disease onset. The incidence of each autoimmune condition was estimated for unvaccinated women at one study site using multiple imputations and compared with that observed in vaccinated women. Incidence rate ratios (IRR) were calculated. Findings were reviewed by an independent Safety Review Committee (SRC).
Overall, 1014 potential new-onset cases were electronically identified; 719 were eligible for case review; 31-40% were confirmed as new onset. Of these, no cluster of disease onset in relation to vaccination timing, dose sequence or age was found for any autoimmune condition. None of the estimated IRR was significantly elevated except Hashimoto's disease [IRR=1.29, 95% confidence interval: 1.08-1.56]. Further investigation of temporal relationship and biological plausibility revealed no consistent evidence for a safety signal for autoimmune thyroid conditions. The SRC and the investigators identified no autoimmune safety concerns in this study.
No autoimmune safety signal was found in women vaccinated with HPV4.
In the last years numerous reports describing a possible association between administration of vaccines and development of autoimmune phenomena and overt autoimmune disease were published. Possible mechanisms of induction of autoimmune phenomena by vaccines and their excipients are probably similar to those implicated in induction by infectious agents. Here we report the case of an 11-year-old girl who developed autoimmune hepatitis type II after four weeks from vaccination against human papillomavirus. The possible relationships between the use of adjuvated vaccine against papillomavirus and autoimmune hepatitis are discussed. Although we do not provide evidence for a causal link, we suggest that the occurrence of the autoimmune hepatitis may be related to the stimulation of immune system by adjuvated-vaccine, that could have triggered the disease in a genetically predisposed individual. Therefore a monitoring of liver function test following administration of vaccine against papillomavirus may be useful in adolescent girl with signs of hepatopathy, as jaundice, dark urine or hepatomegaly, to early identify and to promptly treat autoimmune liver disorders.