Autoimmune Rev. 2019 Apr; 18 (4): 415-425. doi: 10.1016 / j.autrev.2018.12.005. Epub 2019 Feb 14.
Lethal immunoglobulins: autoantibodies and sudden cardiac death
Sudden cardiac death (SCD) is an unexpected death due to cardiac causes that occur in a short period of time (generally within 1 hour of the onset of symptoms) in a person with known or unknown heart disease. Patients with cardiomyopathies, myocarditis, ischemic heart disease and cardiac canalopathies are at risk of SCD. However, a certain percentage of SCD autopsy-negative cases in young people (<35 years) remain unexplained even after a post-mortem genetic test. Autoantibodies to cardiac proteins can potentially be involved in the pathogenesis of various heart diseases and in the onset of unexplained SCD. In this review we analyze clinical and animal studies that clarify the prevalence of these autoantibodies in patients with different cardiac pathologies and their pathophysiological relevance. We propose a classification of autoantibodies associated with heart disease and focus on their molecular and cellular effects. The beta-antibodies of the adrenergic receptor and the anti-muscarinic antibodies of the acetylcholine receptor influence the electrophysiological properties of the myocardium and have been reported as independent predictors of SCD in patients with various cardiac pathologies. The autoimmune mechanism is proposed for heart-related adverse reactions following vaccination of human papillomavirus (HPV). The sharing of pentapeptides between HPV antigens, adrenergic receptors and muscarinic acetylcholine receptors supports this hypothesis. The dysregulating effects of autoantibodies against calcium and potassium ion channels may be the basis for autoimmune phenocope of cardiac genetic channelopathies, which are also associated with SCD.
Drug Saf. 2017 Dec;40(12):1219-1229. doi: 10.1007/s40264-017-0574-6.
Suspected adverse effects after vaccination against human papillomavirus: a temporal relationship between vaccine administration and the appearance of symptoms in Japan
INTRODUCTION: In Japan, after receiving vaccination against human papillomavirus, a significant number of teenagers experienced various symptoms, most of which were attributed to regional chronic pain syndrome, orthostatic intolerance and / or cognitive dysfunction. However, a causal link has not been established between vaccination against human papillomavirus and the development of these symptoms.
TARGET: The purpose of this study was to clarify the temporal relationship between human papillomavirus vaccination and the appearance of post-vaccination symptoms.
METHODS: Between June 2013 and December 2016, we examined symptoms and objective outcomes in 163 female patients who had received human papillomavirus vaccination. We used newly defined diagnostic criteria for the accurate inclusion of patients who experienced adverse symptoms after vaccination against human papillomavirus; these diagnostic criteria were created for this study and therefore their validity and reliability have not been established.
RESULTS: A total of 43 women were excluded. Of the remaining 120 patients, 30 were diagnosed with defined vaccine-related symptoms and 42 were diagnosed as likely. Among these 72 patients, the age at initial vaccination ranged from 11 to 19 years (on average 13,6 ± 1,6 years) and the age at the onset of symptoms ranged from 12 to 20 years (on average 14,4 ± 1,7 years). Patients received the initial human papillomavirus vaccine injection between May 2010 and April 2013. The first affected girl developed symptoms in October 2010 and the last two affected girls developed symptoms in October 2015. Onset time after the first vaccinedose ranged from 1 to 1532 days (average 319,7 ± 349,3 days).
CONCLUSIONS: The vaccination period against human papillomavirus has significantly overlapped with the development of unique symptoms after vaccination. Based on these sequential events, it is suggested that human papillomavirus vaccination is related to the transiently high prevalence of the previously mentioned symptoms, including regional chronic pain syndrome and neurological and cognitive dysfunctions in vaccinated patients.
Indian J Med Ethics. 2017 Apr-Jun;2(2):82-88.
Lessons learned in Japan from adverse reactions to the HPV vaccine: a medical ethics perspective
The human papillomavirus (HPV) vaccine has been associated with a number of serious adverse reactions. The range of symptoms is diverse and they develop in a multilayered fashion over a long period of time. The argument for the safety and efficacy of the HPV vaccine has the following flaws: (i) the genetic basis of autoimmune diseases is not taken into account and arguments which do not take this into account cannot ensure the safety of the vaccine; (ii) HPV immune evasion mechanisms, which require the HPV vaccine to maintain an extraordinarily high antibody level for a long period of time for it to be effective, are not taken into account; and (iii) the vaccine efficacy limits. We also discuss various issues that emerged during the development, promotion and distribution of the vaccine, as well as the pitfalls encountered in monitoring adverse events and in epidemiological verification.
Autoimmune Rev. 2016 Nov; 15 (11): 1054-1061. doi: 10.1016 / j.autrev.2016.07.030. Epub 2016 Aug 1.
From HBV to HPV: vaccine design for large and intensive vaccination campaigns around the world
HBsAg and HPV L1 proteins - the HBV and HPV antigens used in current vaccines - share amino acid sequences with human proteins such as cardiomyopathy-associated protein 5, titinic, arginine deiminase protein, ubiquitin-ligase protein E3 RNF19A, bassoon, G protein coupled fatty acid receptor, insulin isoform 2 and mitogenated protein kinase kinase kinase 10, among others. Many shared peptides are also part of immunopositive epitopes. The data 1) support the possibility of cross-reactions between the two viral antigens and human proteins which, when altered, can be associated with neuropsychiatric, cardiovascular and metabolic diseases such as multiple sclerosis, amyotrophic lateral sclerosis, diabetes and sudden death; 2) confirm the concept that only vaccines based on unique sequences for pathogens could cancel potential risks of cross-reactivity in vaccination protocols.
Immunol Res. 2017 Feb;65(1):106-116. doi: 10.1007/s12026-016-8820-z.
Severe somatoform syndrome and dysautonomic syndromes after HPV vaccination: case series and literature review
Hum Vaccin Immunother. 2016 Oct 2; 12 (10): 2662-2665. doi: 10.1080 / 21645515.2016.1192737. Epub 2016 Jun 13.
Adverse events following HPV immunization in Australia: Establishment of a clinical network.
OBJECTIVE: To formalize a collaborative national Adverse Events Following Immunization Clinical Assessment Network (AEFI-CAN) following the expansion of the Australian Human Papillomavirus (HPV) immunization program to boys in 2013.
METHODS: AEFI-CAN linked state-based vaccine safety clinics and the Department of Health including the Therapeutic Goods Administration (TGA). Monthly teleconferences held to discuss HPV related cases. AEFI conditions of interest recorded in a centralized database.
RESULTS: Between 1st January 2013 - 31st October 2014, 118 HPV AEFI were documented, 56% in males. The median age was 13 y (range 12-16 years). The majority of AEFI reports were after dose 1 (59%). 76 of 118 (64%) AEFI were seen in a vaccine safety clinic: 62% in Victoria, NSW (16%), South Australia (9%) and Western Australia (8%). Eight TeleHealth consultations were undertaken. AEFI were categorized as: rash 24% of reports (n = 28), urticaria / angioedema 23% (n = 27), anaphylaxis 3% (n = 4). Syncope was also reported (n = 12, 10%) and other neurological events (n = 22, 19%).
CONCLUSIONS: We demonstrated the advantages of a national network, providing a collaborative approach to AEFI review and management. The vaccine safety network has applicability to any vaccination program, and has potential to collaborate more broadly with regional pharmacovigilance partners such as New Zealand.
Clin Rheumatol. 2015 Jul; 34 (7): 1165-9. doi: 10.1007 / s10067-015-2969-z. Epub 2015 May 20.
Hypothesis: Human papillomavirus vaccination syndrome - small fiber neuropathy and dysautonomia could be its underlying pathogenesis.
Vaccination has been one of the most effective public health measures in the history of medicine. However, seemingly inexplicit adversereactions have been described after the injection of the newer vaccines vs. human papillomavirus (HPV). The symptoms more often reported are chronic pain with paresthesias, headaches, fatigue, and orthostatic intolerance. Adverse reactions appear to be more frequent after HPV vaccination when compared to other type of immunizations. Different isolated cases and small series have described the development of complex regional pain syndrome (CRPS), postural orthostatic tachycardia syndrome (POTS), and fibromyalgia after HPV vaccination. These are illnesses often difficult to diagnose that have overlapping clinical features. Sympathetic nervous system dysfunction seems to play a major role in the pathogenesis of these syndromes. Also, small fiber neuropathy has been recently recognized in CRPS, POTS, and fibromyalgia. This article forwards the hypothesis that small fiber neuropathy and dysautonomia could be the common underlying pathogenesis to the group of rare, but severe reactions that follow HPV vaccination. Clinicians should be aware of the possible association between HPV vaccination and the development of these difficult to diagnose painful dysautonomic
Pediatr Dermatol. 2015 Mar-Apr; 32 (2): e48-9. doi: 10.1111 / pde.12516. Epub 2015 Feb 18.
Lichenoid drug eruption after vaccination with human papillomavirus
Curr Drug Saf. 2014 Mar;9(1):65-8.
Human papilloma virus vaccine associated uveitis.
PURPOSE: To report a possible association between human papilloma virus (HPV) vaccination and uveitis.
METHODS: Spontaneous reports from the National Registry of Drug-Induced Ocular Side effects, World Health Organization and Food and Drug Administration were collected on uveitis associated with human papilloma virus vaccination. A MEDLINE search was performed using keywords "uveitis," "iritis," "iridocyclitis," "human papilloma virus," "Cervarix", and "Gardasil."
MAIN OUTCOME MEASURES: Data garnered from spontaneous reports included the age, gender, adverse drug reaction (ADR), date of administration, concomitant administration of other vaccinations, time until onset of ADR, other systemic reactions, and dechallenge and rechallenge data.
RESULTS: A total of 24 case reports of uveitis associated with human papilloma virus vaccination were identified, all cases were female, and the median age was 17. Median time from HPV vaccination to reported ADR was 30 days (range 0-476 days).
DISCUSSION: According to World Health Organization criteria, the relationship between human papilloma virus vaccination and uveitis is "possible." Causality assessments are based on the time relationship of drug administration, uveitis development and re-challenge data.
CONCLUSIONS: Clinicians should be aware of a possible bilateral uveitis and papillitis following HPV vaccination.
BMJ Case Rep. 2012 May 8; 2012. pii: bcr0220125797. doi: 10.1136 / bcr.02.2012.5797.
Hypersensitivity reaction to human papillomavirus vaccine due to polysorbate 80.
A 17-year-old girl reported generalized urticaria, eyelid angioedema, rhino-conjunctivitis, dyspnoea and wheezing 1 h after third intramuscular administration of quadrivalent human papilloma virus vaccine (Gardasil). She was treated with antihistamine, and corticosteroids with prompt relief of rhinitis and dyspnoea, while urticaria and angioedema lasted 24 h. Intradermal test with Gardasil, which contains polysorbate 80 (PS80), resulted positive, while skin tests with the bivalent vaccine were negative. Prick test performed with PS80 resulted positive in the patient and negative in ten healthy controls. The CD203 basophil activation test result was negative for PS80 at all the tested dilutions and specific IgE was not found. As flu vaccine was recommended, the authors skin tested two flu vaccine, one containing PS80 (Fluarix, GSK), which resulted positive and another flu vaccine with no adjuvant or preservative (Vaxigrip, Sanofi Pasteur MSD), which gave negative results. The patient then received Vaxigrip without adverse reactions.
Dermatology. 2010;221(3):197-200. doi: 10.1159/000319852.
The quadrivalent human papillomavirus vaccine: erythema multiforme and cutaneous side effects after administration.
The quadrivalent human papillomavirus (qHPV) vaccine, the first vaccine for use in the prevention of cervical cancer and condyloma acuminatum, was approved in June 2006. In 2008, the mass media reported suspected links between the qHPV vaccine and serious adverse events; however, several studies have found that the vaccine is safe and the main adverse events are mild local reactions. Erythema multiforme (EM) is an acute self-limited cutaneous or mucocutaneous syndrome characterized by the abrupt onset of symmetric target lesions. The clinical manifestations and histological features of EM, Stevens-Johnson syndrome and toxic epidermal necrolysis show considerable overlap, and they are classically considered to represent a spectrum of skin disorders. We present a case of EM following qHPV vaccination to review the cutaneous side effects of this vaccine and the possibility of more serious side effects with the administration of booster doses.
BMJ. 2008 Dec 2; 337: a2642. doi: 10.1136 / bmj.a2642.
Hypersensitivity reactions to human papillomavirus vaccine in Australian schoolgirls: retrospective cohort study.
OBJECTIVE: To describe the outcomes of clinical evaluation, skin testing, and vaccine challenge in adolescent schoolgirls with suspected hypersensitivity to the quadrivalent human papillomavirus vaccine introduced in Australian schools in 2007.
DESIGN: Retrospective cohort study.
SETTING: Two tertiary paediatric allergy centers in Victoria and South Australia, Australia.
PARTICIPANTS: 35 schoolgirls aged 12 to 18.9 years with suspected hypersensitivity reactions to the quadrivalent human papillomavirusvaccine.
MAIN OUTCOME MEASURES: Clinical review and skin prick and intradermal testing with the quadrivalent vaccine and subsequent challenge with the vaccine.
RESULTS: 35 schoolgirls with suspected hypersensitivity to the quadrivalent human papillomavirus vaccine were notified to the specialized immunization services in 2007, after more than 380 000 doses had been administered in schools. Of these 35 schoolgirls, 25 agreed to further evaluation. Twenty three (92%) experienced reactions after the first dose. Thirteen (52%) experienced urticaria or angio-oedema, and of these, two experienced anaphylaxis. Thirteen had generalized rash, one with angio-oedema. The median time to reaction was 90 minutes. Nineteen (76%) underwent skin testing with the quadrivalent vaccine: all were skin prick test negative and one was intradermal test positive. Eighteen (72%) were subsequently challenged with the quadrivalent vaccine and three (12%) elected to receive the bivalent vaccine. Seventeen tolerated the challenge and one reported limited urticaria four hours after the vaccine had been administered. Only three of the 25 schoolgirls were found to have probable hypersensitivity to the quadrivalent vaccine.
CONCLUSION: True hypersensitivity to the quadrivalent human papillomavirus vaccine in Australian schoolgirls was uncommon and most tolerated subsequent doses.
SAGE Open Med. 2019 Jan 8; 7: 2050312118822650. doi: 10.1177 / 2050312118822650. eCollection 2019.
A cross-sectional study of the relationship between reported human papillomavirus vaccine exposure and the incidence of reported asthma in the United States.
OBJECTIVES: Asthma is a chronic disorder that affects persons of all ages impacting the quality of their lives. This cross-sectional hypothesis-testing study evaluated the relationship between human papillomavirus vaccine and the risk of an incident asthma diagnosis in a defined temporal period post-vaccination.
METHODS: The 2015-2016 National Health and Nutrition Examination Survey data were examined for a group of 60,934,237 weighted persons between 9 and 26 years old in Statistical Analysis Software.
RESULTS: Reported incident asthma significantly clustered in the year of reported human papillomavirus vaccination. When the data were separated by gender, the effects observed remained significant for males but not females.
CONCLUSION: The results suggest that human papillomavirus vaccination resulted in an excess of 261,475 asthma cases with an estimated direct excess lifetime cost of such persons being US $ 42 billion. However, it is unclear what part of the vaccine and / or vaccinemedium may have increased an individual's susceptibility to an asthma episode, whether the asthma diagnosis represented one asthma episode or if it is chronic, and how much therapeutic support was needed (if any) and for how long, which would impact cost. Despite the negative findings in this study, routine vaccination is an important public health tool, and the results observed need to be viewed in this context.
BMC Neurol. 2018 Dec 28;18(1):222. doi: 10.1186/s12883-018-1233-y.
Myasthenia gravis following human papillomavirus vaccination: a case report.
BACKGROUND: Myasthenia gravis (MG), an autoimmune neuromuscular disorder, occurs owing to autoantibodies against acetylcholine receptors. MG symptoms can be triggered by various vaccines. Many studies have evaluated the safety and adverse events of the human papillomavirus (HPV) vaccine. Here, we present a life-threatening case of ocular and bulbar MG symptoms after HPV vaccination and a brief literature review.
CASE PRESENTATION: A 23-year-old woman presented with binocular diplopia, ptosis, dysarthria, and dysphagia, which occurred on the 3rd day after the second HPV vaccine administration. She was diagnosed with MG based on history, clinical features, and test results. Her symptoms deteriorated on the 3rd day after admission, and she was transferred to the intensive care unit with mechanical ventilation. On the 7th day after admission, due to discomfort in the right chest, pulmonary embolism was suspected. A tracheostomy was performed on the 14th day of mechanical ventilation. In the 4th week, the tracheostomy tube was removed; all symptoms had completely resolved at discharge. She was followed up for 5 months without recurrence or further treatment.
CONCLUSION: HPV vaccination may cause MG owing to unexpected abnormal autoimmune responses. Additional studies are needed to clarify the possible causal relationship between the HPV vaccine and neurological complications and to evaluate the safety of the vaccine.
Cureus. 2018 Sep 24; 10 (9): e3352. doi: 10.7759 / cureus.3352.
Simultaneous Bilateral Optic Neuritis Following Human Papillomavirus Vaccination in a Young Child.
Vaccination-induced optic neuritis is not common. The development of optic neuritis following various vaccinations have been reported, suggesting a possible association between optic neuritis and vaccination. Of those reported cases, influenza vaccines have been the most common. Although rare, those patients who developed optic neuritis following HPV vaccination also presented with other central nervous system (CNS) demyelinating syndromes, especially following a booster dose. We present a rare case of simultaneous isolated bilateral optic neuritis following the first dose of an HPV vaccination in a young child. She received treatment with a systemic corticosteroid that resulted in a good clinical outcome without developing any demyelinating disease.
mmunol Res. 2018 Dec;66(6):744-754. doi: 10.1007/s12026-018-9036-1.
Autonomic dysfunction and HPV immunization: an overview.
Correction to: Autonomic dysfunction and HPV immunization: an overview. [Immunol Res. 2018]
This article reviews the case series reported from several countries describing patients with suspected severe side effects to the HPVvaccines. 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 HPVvaccines. 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.
Reumatol Clin. 2018 Jul - Aug; 14 (4): 211-214. doi: 10.1016 / j.reuma.2018.01.014. Epub 2018 Mar 13.
HPV vaccination syndrome: A clinical mirage, or a new tragic fibromyalgia model.
Independent investigators have described the onset of a chronic painful dysautonomic syndrome soon after human papillomavirus (HPV) vaccination. The veracity of this syndrome is hotly debated. Many of the reported post-HPV vaccination cases fullfill fibromyalgia diagnostic criteria. This article discusses the arguments favoring the existence of a syndrome associated to HPV vaccination. We proposed that fibromyalgia dysautonomic-neuropathic model could help in the diagnostic and therapeutic process in those patients in whom the onset of a painful chronic illness began after HPV immunization. On the other hand, if its veracity is corroborated, HPV vaccination syndrome may become a new tragic fibromyalgia model.
Autoimmune Rev. 2014 Jul; 13 (7): 736-41. doi: 10.1016 / j.autrev.2014.01.054. Epub 2014 Jan 24.
On the relationship between human papilloma virus vaccine and autoimmune diseases.
The human papilloma virus (HPV) vaccines were introduced to reduce the incidence of cervical cancer. The bivalent vaccine is effective against HPV-16, -18, -31, -33 and -45 while the quadrivalent vaccine is effective against HPV-16, 18, 31, 6 and 11 types. The immunization, recommended for adolescent females, has led to high vaccine coverage in many countries. Along with the introduction of the HPV vaccines, several cases of onset or exacerbations of autoimmune diseases following the vaccine shot have been reported in the literature and pharmacovigilance databases, triggering concerns about its safety. This vaccination program, however, has been introduced in a population that is at high risk for the onset of autoimmune diseases, making it difficult to assess the role of HPV vaccine in these cases and no conclusive studies have been reported thus far. We have thus analyzed and reviewed comprehensively all case reports and studies dealing with either the onset of an autoimmune disease in vaccinated subject or the safety in patients with autoimmune diseases to define the role of the HPV vaccines in these diseases and hence its safety. A solid evidence of causal relationship was provided in few cases in the examined studies, and the risk vs. benefit of vaccination is still to be solved. The on-going vigilance for the safety of this vaccine remains thus of paramount importance.
J Investig Med High Impact Case Rep. 2014 Mar 18; 2 (1): 2324709614527812. doi: 10.1177 / 2324709614527812. eCollection 2014 Jan-Mar.
Postural Orthostatic Tachycardia With Chronic Fatigue After HPV Vaccination as Part of the "Autoimmune / Auto-inflammatory Syndrome Induced by Adjuvants": Case Report and Literature Review.
We report the case of a 14-year-old girl who developed postural orthostatic tachycardia syndrome (POTS) with chronic fatigue 2 months following Gardasil vaccination. The patient suffered from persistent headaches, dizziness, recurrent syncope, poor motor coordination, weakness, fatigue, myalgias, numbness, tachycardia, dyspnea, visual disturbances, phonophobia, cognitive impairment, insomnia, gastrointestinal disturbances, and a weight loss of 20 pounds. The psychiatric evaluation ruled out the possibility that her symptoms were psychogenic or related to anxiety disorders. Furthermore, the patient tested positive for ANA (1: 1280), lupus anticoagulant, and antiphospholipid. On clinical examination she presented livedo reticularis and was diagnosed with Raynaud's syndrome. This case fulfills the criteria for the autoimmune / auto-inflammatory syndrome induced by adjuvants (ASIA). Because human papillomavirus vaccination is universally recommended to teenagers and because POTS frequently results in long-term disabilities (as was the case in our patient), a thorough follow-up of patients who present with relevant complaints after vaccination is strongly recommended.
Front Neurol. 2014 Nov 28; 5: 230. doi: 10.3389 / fneur.2014.00230. eCollection 2014.
Clinical features in patients with long-lasting macrophage myofascitis
Macrophage myofascitis (MMF) is an emerging condition characterized by specific muscle lesions that evaluate the long-term abnormal persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients are usually middle-aged adults, mainly presenting with diffuse arthromyalgia, chronic fatigue and marked cognitive deficits unrelated to pain, fatigue or depression. The clinical features usually correspond to those observed in chronic fatigue syndrome / myalgic encephalomyelitis. Representative features of MMF associated cognitive dysfunction include dysexecutive syndrome, visual memory impairment and left ear extinction on the dichotic listening test. Most patients meet the criteria for mild non-amnesic / dysexecutive cognitive impairment, although some cognitive deficits appear unusually severe. Cognitive dysfunction seems stable over time, despite marked fluctuations. The evoked potentials can show anomalies in line with the involvement of the central nervous system, with a neurophysiological pattern that suggests demyelination. Cerebral perfusion SPECT shows a pattern of widespread cortical and subcortical anomalies, with hypoperfusions related to cognitive deficiencies. The combination of musculoskeletal pain, chronic fatigue and cognitive disorders generates chronic disabilities with possible social exclusion. Classical therapeutic approaches are usually unsatisfactory and make patient care difficult.
Autoimmune Rev. 2019 May 4. pii: S1568-9972 (19) 30109-0. doi: 10.1016 / j.autrev.2019.05.006. [Epub ahead of print]
Myalgia syndrome and chronic fatigue following immunization: macrophage myofascitis and animal studies support the link with persistence and adjuvant spread of aluminum in the immune system.
Myalgic encephalomyelitis / Chronic fatigue syndrome (ME / CFS) is a multifactorial and poorly deficient disabling disease. We present epidemiological, clinical and experimental evidence that ME / CFS constitutes an important type of adverse effect of vaccines, in particular those containing particularly degradable aluminum adjuvants. Evidence emerged very slowly due to multiplicity, lack of specificity, delayed onset and frequent medical underestimation of ME / CFS symptoms. It was supported by an epidemiological study that compared the vaccinated military against the unvaccinated military that remained defenseless during the second Gulf War. Affected patients suffer from cognitive dysfunctions affecting attention, memory and inter-hemispheric connections, well correlated with cerebral perfusion defects and associated with a stereotyped and characteristic model of cerebral glucose hypometabolism. Deltoid muscle biopsy performed to investigate myalgia typically produces macrophage myofascite (MMF), a histological biomarker that assesses the long-lasting persistence of aluminum agglomerates within innate immune cells at the site of previous immunization. MMF is apparently linked to the detoxification of mineral particles altered by the xenon / autophagy machinery. The comparison between toxicology of different forms of aluminum and different types of exposure is misleading and inadequate and small animal experiments have overturned the old dogma. Instead of being rapidly solubilized in the extracellular space, the injected aluminum particles are quickly captured by the immune cells and transported to distant organs and to the brain where they provoke an inflammatory response and exert selective neurotoxicity at low selective doses. Clinical observations and experiments on sheep, a large animal like humans, have confirmed both the systemic spread and the neurotoxic effects of aluminum adjuvants. ME / CFS post-immunization represents the main manifestation of "adjuvant-induced autoimmune / inflammatory syndrome" (ASIA).
J Inorg Biochem. 2012 Dec; 117: 85-92. doi: 10.1016 / j.jinorgbio.2012.08.015. Epub 2012 Aug 30.
Detection of human papillomavirus (HPV) L1 gene DNA possibly bound to particulatealuminum adjuvant in the HPV vaccine Gardasil.
Medical practitioners in nine countries submitted samples of Gardasil (Merck & Co.) to be tested for the presence of humanpapillomavirus (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 Gardas 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 aluminumhydroxyphosphate sulfate (AAHS) nanoparticles used as adjuvant. The clinical significance of these residual HPV DNA fragments boundto a particulate mineral-based adjuvant is uncertain after intramuscular injection, and requires further investigation for vaccination safety.
Curr Med Chem. 2014 Mar;21(7):932-40.
Melting profiles may affect detection of residual HPV L1 gene DNA fragments in Gardasil®.
Gardasil® is a quadrivalent human papillomavirus (HPV) protein-based vaccine containing genotype-specific L1 capsid proteins of HPV-16, HPV-18, HPV-6 and HPV-11 in the form of virus-like-particles (VLPs) as the active ingredient. The VLPs are produced by a DNArecombinant technology. It is uncertain if the residual HPV L1 gene DNA fragments in the vaccine products are considered contaminants or excipients of the Gardasil® vaccine. Because naked viral DNA fragments, if present in the vaccine, may bind to the insoluble amorphous aluminum hydroxyphosphate sulfate (AAHS) adjuvant which may help deliver the foreign DNA into macrophages, causing unintended pathophysiologic effects, experiments were undertaken to develop tests for HPV L1 gene DNA fragments in the final products of Gardasil® by polymerase chain reaction (PCR) and direct DNA sequencing. The results showed that while the HPV-11 and HPV-18 L1gene DNA fragments in Gardasil® were readily amplified by the common GP6 / MY11 degenerate consensus primers, the HPV-16 L1gene DNA may need specially designed non-degenerate PCR primers for amplification at different regions of the L1 gene and different stringency conditions for detection. These variable melting profiles of HPV DNA in the insoluble fraction of the Gardasil® vaccine suggest that the HPV DNA fragments are firmly bound to the aluminum AAHS adjuvant. All methods developed for detecting residual HPV DNA in the vaccine Gardasil® for quality assurance must take into consideration the variable melting profiles of the DNA to avoid false negative results.
J Clin Neuromuscul Dis. 2016 Sep;18(1):37-40. doi: 10.1097/CND.0000000000000130.
Small Fiber Neuropathy Following Vaccination.
OBJECTIVE: To identify clinical and quantitative relationship between vaccinations and small fiber neuropathy (SFN). SFN refers to damaged unmyelinated or thinly myelinated sensory and / or autonomic fibers. Diagnosis is primarily based on clinical presentation. Intraepidermal nerve fiber density can provide diagnostic confirmation with a sensitivity of 88% and a specificity of 91%. However, the possible association between vaccination and small fiber polyneuropathy is not well defined.
METHODS: Case study.
RESULTS: Fourteen-year-old white adolescent girl presented with intractable generalized pain for 1.5 years. Burning dysesthetic pain began in the lower back and progressed to all extremities 9 days following human papillomavirus vaccination. The pain persisted despite various pain medications. Examination was significant for allodynia of right scapula (T4-T6) and decreased pinprick sensation in feet. MRI Brain with and without contrast, MR Face, Orbit with and without contrast, and MR Cervical, Lumbar spines with and without contrast were all normal. Nerve Conduction Studies / Electromyogram studies were unremarkable, and skin biopsy of the right thigh and foot showed low intraepidermal nerve fiber density with normal sweat gland nerve fiber density.
CONCLUSIONS: This case report describes an acute onset of non-length-dependent SFN potentially related to human papillomavirusvaccine administration. Literature review includes several similar case studies, and various pathological processes have been proposed for vaccine-associated polyneuropathies. Some theories describe immune-mediated hypersensitivity to the solvents / adjuvants and / or invasion of nervous system through a prolonged, less virulent infection. However, the lack requires that evidence must be carefully reviewed.
Intern Med. 2016; 55 (21): 3181-3184. Epub 2016 Nov 1.
Two Cases of Acute Disseminated Encephalomyelitis Following Vaccination Against Human Papilloma Virus.
We herein present two cases of acute disseminated encephalomyelitis (ADEM) following vaccination against human papilloma virus (HPV). Case 1 experienced diplopia and developed an unstable gait 14 days after a second vaccination of Cervarix. Brain magnetic resonance imaging (MRI) showed an isolated small, demyelinating lesion in the pontine tegmentum. Case 2 experienced a fever and limb dysesthesia 16 days after a second vaccination of Gardasil. Brain MRI revealed hyperintense lesion in the pons with slight edema on a T2-weighted image. Both cases resolved completely. It is important to accumulate further data on confirmed cases of ADEM temporally associated with HPV vaccination.
J Toxicol Environ Health A. 2018; 81 (14): 661-674. doi: 10.1080 / 15287394.2018.1477640. Epub 2018 Jun 11.
A lowered probability of pregnancy in females in the USA aged 25-29 who received a humanpapillomavirus vaccine injection.
Birth rates in the United States have recently fallen. Birth rates per 1000 females aged 25-29 fell from 118 in 2007 to 105 in 2015. One factor may involve the vaccination against the human papillomavirus (HPV). Shortly after the vaccine was licensed, several reports of recipients experiencing primary ovarian failure emerged. This study analyzed information gathered in National Health and Nutrition Examination Survey, which represented 8 million 25-to-29-year-old women residing in the United States between 2007 and 2014. Approximately 60% of women who did not receive the HPV vaccine had been pregnant at least once, whereas only 35% of women whowere exposed to the vaccine had conceived. For married women, 75% who did not receive the shot were found to conceive, while only 50% who received the vaccine had ever been pregnant. Using logistic regression to analyze the data, the probability of having been pregnant was estimated for females who received an HPV vaccine compared with females who did not receive the shot. Results suggest that females who received the HPV shot were less likely to have ever been pregnant than women in the same age group who did not receive the shot. If 100% of females in this study had received the HPV vaccine, data suggest the number of women having ever conceived would have fallen by 2 million. Further study into the influence of HPV vaccine on fertility is thus warranted.
Clin Pediatr (Phila). 2018 May; 57 (5): 603-606. doi: 10.1177 / 0009922817728701. Epub 2017 Sep 4.
Autoimmunity, Autonomic Neuropathy, and the HPV Vaccination: A Vulnerable Subpopulation.
Clin Rheumatol. 2017 Oct; 36 (10): 2169-2178. doi: 10.1007 / s10067-017-3768-5. Epub 2017 Jul 20.
Serious adverse events after HPV vaccination: a critical review of randomized trials and post-marketing case series.
Erratum to: Serious adverse events after HPV vaccination: a critical review of randomized trials and post-marketing case series. [Clin Rheumatol. 2017]
This article critically reviews HPV vaccine serious adverse events described in pre-licensure randomized trials and in post-marketing case series. HPV vaccine randomized trials were identified in PubMed. Safety data were extracted. Post-marketing case series describing HPVimmunization adverse events were reviewed. Most HPV vaccine randomized trials did not use inert placebo in the control group. Two of the largest randomized trials found significantly more severe adverse events in the tested HPV vaccine arm of the study. Compared to 2871 women receiving aluminum placebo, the group of 2881 women injected with the bivalent HPV vaccine had more deaths on follow-up (14 vs. 3, p = 0.012). Compared to 7078 girls injected with the 4-valent HPV vaccine, 7071 girls receiving the 9-valent dose had more serious systemic adverse events (3.3 vs. 2.6%, p = 0.01). For the 9-valent dose, our calculated number needed to seriously harm is 140 (95% CI, 79–653) [DOSAGE ERROR CORRECTED]. The number needed to vaccinate is 1757 (95% CI, 131 to infinity). Practically, none of the serious adverse events occurring in any arm of both studies were judged to be vaccine-related. Pre-clinical trials, post-marketing case series, and the global drug adverse reaction database (VigiBase) describe similar post-HPV immunization symptom clusters. Two of the largest randomized HPV vaccine trials unveiled more severe adverse events in the tested HPV vaccine arm of the study. Nine-valent HPV vaccine has a worrisome number needed to vaccinate / number needed to harm quotient. Pre-clinical trials and post-marketing case series describe similar post-HPV immunization symptoms.
J Investig Med High Impact Case Rep. 2014 Oct 28; 2 (4): 2324709614556129. doi: 10.1177 / 2324709614556129. eCollection 2014 Oct-Dec.
Adolescent Premature Ovarian Insufficiency Following Human Papillomavirus Vaccination: A Case Series Seen in General Practice.
Three young women who developed premature ovarian insufficiency following quadrivalent human papillomavirus (HPV) vaccination presented to a general practitioner in rural New South Wales, Australia. The unrelated girls were aged 16, 16, and 18 years at diagnosis. Each had received HPV vaccinations prior to the onset of ovarian decline. Vaccinations had been administered in different regions of the state of New South Wales and the 3 girls lived in different towns in that state. Each had been prescribed the oral contraceptive pill to treat menstrual cycle abnormalities prior to investigation and diagnosis. Vaccine research does not present an ovary histology report of tested rats but does present a testicular histology report. Enduring ovarian capacity and duration of function following vaccination is unresearched in preclinical studies, clinical and postlicensure studies. Postmarketing surveillance does not accurately represent diagnoses in adverse event notifications and can neither represent unnotified cases nor appears incident statistics with vaccine course administration rates. The potential significance of a case series of adolescents with idiopathic premature ovarian insufficiency following HPV vaccination presenting to a general practice warrants further research. Preservation of reproductive health is a primary concern in the recipient target group. Since this group includes all prepubertal and pubertal young women, demonstration of ongoing, uncompromised safety for the ovary is urgently required. This matter needs to be resolved for the purposes of population health and public vaccine confidence.
BMJ Case Rep. 2012 Sep 30; 2012. pii: bcr2012006879. doi: 10.1136 / bcr-2012-006879.
Premature ovarian failure 3 years after menarche in a 16-year-old girl following human papillomavirus vaccination.
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 counseled regarding preservation of bone density, reproductive implications and relevant follow-up. This event could hold potential implications for population health and prompts further inquiry.
Am J Reprod Immunol. 2013 Oct; 70 (4): 309-16. doi: 10.1111 / aji.12151. Epub 2013 Jul 31.
Human papilloma virus vaccine and primary ovarian failure: another facet of the autoimmune / inflammatory syndrome induced by adjuvants.
PROBLEM: 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.
METHOD OF STUDY: 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.
RESULTS: 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 (ie, 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 HPVvaccine 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.
CONCLUSION: 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.
Curr Opin Obstet Gynecol. 2015 Aug; 27 (4): 265-70. doi: 10.1097 / GCO.0000000000000183.
A link between human papilloma virus vaccination and primary ovarian insufficiency: current analysis.
PURPOSE OF REVIEW: The cause of primary ovarian insufficiency (POI) is multifactorial. Known causes include external factors such as chemotherapy, radiotherapy, exposure to endocrine-disrupting chemicals, infections that lead to a permanent insult to the ovary, autoimmune conditions, and genetic causes. An association between the quadrivalent antihuman papilloma vaccine (HPV4) and POI was recently suggested.
RECENT FINDINGS: An increasing number of cases of POI post-HPV4 are being reported. Possible mechanisms for the suspected effect of HPV on female reproductive function are a toxic effect or an autoimmune response. The trigger could be the vaccine immunogen contents or the adjuvants, the latter are used to increase the immune reaction. The adjuvant in HPV4 contains aluminum. Animal models have shown aluminum exposure to inhibit expression of female reproductive hormones and to induce histologic changes in the ovaries. Specific genetic compositions may be more susceptible to developing an autoinflammatory syndrome after exposure to an environmental factor.
SUMMARY: The mechanisms responsible for POI are not yet fully understood. Although case reports cannot establish causation, awareness of a possible link between HPV4 and POI will help to identify and manage future cases that may arise.
Expert Opin Drug Saf. 2015; 14 (9): 1387-94. doi: 10.1517 / 14740338.2015.1073710. Epub 2015 Jul 28.
The safety of human papilloma virus-blockers and the risk of triggering autoimmune diseases.
INTRODUCTION: With the safety of human papilloma virus vaccine (HPVv) being questioned, this article aims to assess the risks and benefits of the commercially available HPVv. Within the last decade, two vaccines (Gardasil and Cervarix) have been put on the market to prevent infection with the most oncogenic HPV subtypes. Both vaccines contain aluminum adjuvants that are meant to cause a hyper stimulated immune response to prevent HPV infection.
AREAS COVERED: The purpose of this paper is to consider the safety of these two vaccines based on the data from the US Vaccine Adverse Event Reporting System (VAERS) and case reports.
EXPERT OPINION: The current HPVv are both effective and generally safe. However, it should be noted that autoimmune side effects have been reported in several studies. Further research should be done to understand the relationship between HPVv and autoimmunity.
Vaccine. 2017 Aug 24; 35 (36): 4761-4768. doi: 10.1016 / j.vaccine.2017.06.030. Epub 2017 Jul 24.
Human papillomavirus vaccination and risk of autoimmune diseases: A large cohort study of over 2million young girls in France.
BACKGROUND: Whether human papillomavirus (HPV) vaccination could induce or trigger autoimmune diseases (AID) has been questioned, and potentially contributes to low immunization coverage in France. This study evaluated the association between HPV vaccination and the risk of AID using routinely collected data sources.
METHODS: All girls aged 13-16years between 2008 and 2012, covered by the general health insurance scheme and without history of HPV vaccination or AID, were included and followed using French nationwide databases. Fourteen neurological, rheumatological, haematological, gastrointestinal or endocrine AID, were identified from ICD-10 codes allocated to hospital stays and long-term illnesses or by marker drugs. Their incidence was compared between girls exposed and non-exposed to HPV vaccination, using a Cox model adjusted for inclusion year, geographic area, socio-economic indicators, healthcare use level and other immunizations.
RESULTS: Among 2,252,716 girls, 37% received HPV vaccine and 4,096 AID occurred during a mean follow-up time of 33months. The incidence of AID was not increased after exposure to HPV vaccination, except for Guillain-Barré syndrome (GBS) (incidence rate of 1.4 among exposed [20 cases] versus 0.4 per 100,000 PY among unexposed [23 cases]; adjusted HR: 3.78 [ 1.79-7.98]). This association persisted across numerous sensitivity analyzes and was particularly marked in the first months following vaccination. Under the hypothesis of a causal relationship, this would result in 1-2 GBS cases attributable to HPV vaccine per 100,000 girls vaccinated.
CONCLUSIONS: Our study provides reassuring results regarding the risk of AID after HPV vaccination, but an apparently increased risk of GBS was detected. Further studies are warranted to confirm this finding.
Pharmaceut Reg Affairs S12:001. doi: 10.4172/2167-7689.S12-001
Death after Quadrivalent Human Papillomavirus (HPV) Vaccination: Causal or Coincidental?
Tomljenovic L, Shaw CA (2012)
The proper understanding of a true risk from vaccines is crucial for avoiding unnecessary adverse reactions (ADRs). However, to this date no solid tests or criteria have been established to determine whether adverse events are causally linked to vaccinations. Objectives: This research was carried out to determine whether or not some serious autoimmune and neurological ADRs following HPV vaccination are causal or merely coincidental and to validate a biomarker-based immunohistochemical (IHC) protocol for assessing causality in case of vaccination-suspected serious adverse neurological outcomes. Methods: Post-mortem brain tissue specimens from two young women who suffered from cerebral vasculitistype symptoms following vaccination with the HPV vaccine Gardasil were analyzed by IHC for various immunoinflammatory markers. Brain sections were also stained for antibodies recognizing HPV-16L1 and HPV-18L1 antigen which are present in Gardasil. Results: In both cases, the autopsy revealed no anatomical, microbiological nor toxicological findings that might have explained the death of the individuals. In contrast, our IHC analysis showed evidence of an autoimmune vasculitis potentially triggered by the cross-reactive HPV-16L1 antibodies binding to the wall of cerebral blood vessels in all examined brain samples. We also detected the presence of HPV-16L1 particles within the cerebral vasculature with some HPV-16L1 particles adhering to the blood vessel walls. HPV-18L1 antibodies did not bind to cerebral blood vessels nor any other neural tissues. IHC also showed increased T-cell signaling and marked activation of the classical antibody-dependent complement pathway in cerebral vascular tissues from both cases. This pattern of complement activation in the absence of an active brain infection indicates an abnormal triggering of the immune response in which the immune attack is directed towards self-tissue. Conclusions: Our study suggests that HPV vaccines containing HPV-16L1 antigens pose an inherent risk for triggering potentially fatal autoimmune vasculopathies. Practice implications: Cerebral vasculitis is a serious disease which typically results in fatal outcomes when undiagnosed and left untreated. The fact that many of the symptoms reported to vaccine safety surveillance databases following HPV vaccination are indicative of cerebral vasculitis, but are unrecognized as such (ie, intense persistent migraines, syncope, seizures, tremors and tingling, myalgia, locomotor abnormalities, psychotic symptoms and cognitive deficits), is a serious concern in light of the present findings. It thus appears that in some cases vaccination may be the triggering factor of fatal autoimmune / neurological events. Physicians should be aware of this association.
Vaccines and Neuroinflammation
Giannotta G, Giannotta N
Abstract Background: Post-vaccination adverse reactions (AEs) are a reason of strong debate among scientists. Unfortunately, we often make the mistake of discussing just the epidemiology but not the molecular biology. The action mechanism of the vaccines is still not fully known despite the fact that aluminum adjuvants have been used for about 100 years. Hypothesis: We hypothesized a link between vaccinations and neuroinflammation. The peripheral proinflammatory cytokines (IL-1β, IL-6, and TNF-α), expressed after the injection of the vaccines can reach the brain and can cause neuroinflammation after microglia activation. Elevated pro-inflammatory cytokines, particularly TNF-α, have been described in studies regarding the cytokines profile in autistic children. IL-1β represents a cytokine that controls the local pro-inflammatory cascade and thereby affects the balance between protective immunity and destructive inflammation. A subgroup of children with ASD (Autism Spectrum Disorder) has developed neuroinflammation. Several postmortem studies have confirmed the activation of microglia and neuroinflammation. A recent study has shown the presence of aluminum in the brain of individuals with autism and this aluminum was also found in microglia cells. Aluminum from vaccines is redistributed to numerous organs, including brain, where it accumulates. Each vaccine adds to this tissue different level of aluminum. Aluminum, like mercury, activates microglia leading to chronic brain inflammation and neurotoxicity. Conclusion: The molecular mechanisms presented here demonstrate how peripheral cytokines, expressed after vaccination, can cause neuroinflammation in some subjects, after microglia activation, depending on the immunogenetic background and the innate immune memory.
Clin Case Rep Rev, 2019 doi: 10.15761 / CCRR.1000454 Volume 5: 1-12
Post-vaccination inflammatory syndrome: a new syndrome
Giannotta G1 * and Giannotta N2
Context: The relationship between vaccines and neuroinflammation have consistent molecular biology bases. In a recent paper we have already analyzed this kind of relationship.
hypothesis: In this paper, we have gained additional evidence to support the link between vaccines and neuroinflammation. Furthermore, we found the molecular bases that support the link between HPV vaccines and certain adverse events (AEs). The peripheral proinflammatory cytokines (IL-1β, IL-6, and TNF-α), expressed after the injection of the vaccines can reach the brain and can cause neuroinflammation after microglia activation. After vaccine injection significant systemic immune activation may occur with signs suggesting reactive brain inflammation, such as acute crying, fever, restlessness and failure to eat. It is a warning of danger to the brain in front of which we should reflect before causing irreversible damage. We also hypothesized the existence of a post-vaccination inflammatory syndrome caused by the proinflammatory cytokines strongly expressed after HPV vaccine injections. In addition, the molecular explanation of the chronic pain that has affected many girls in the world, including the complex regional pain syndrome (CRPS) in Japanese girls.
Conclusion: All vaccines can cause neuroinflammation. HPV vaccines can cause a post-vaccination inflammatory syndrome characterized by chronic pain and neuroinflammation. In this case, the phenomena of central sensitization is responsible for all the symptoms associated with chronic pain. The strong expression of proinflammatory cytokines, secreted after HPV vaccinations, brings to process that can produce irreversible neurological results in HPV vaccinated girls.