Symposium Kicks Off Autoimmunity Congress on May 16th in Lisbon
The fifth International Symposium on Vaccines, sponsored by the Children's Medical Safety Research Institute (CMSRI), has announced its line-up of speakers for the upcoming event in Portugal. Held the first day of the biennial Autoimmunity Congress, the Symposium draws medical researchers from around the world to share the latest research on vaccine safety and the potential links between vaccine adjuvants and adverse autoimmune reactions. To see the full program agenda, click here.
"Critical research on this topic is not always welcomed at events that are sponsored, in large part, by the makers of vaccines, but it is vital that the scientists who are courageously examining potential causes of today's epidemic of autoimmune disorders are able to share and discuss their findings," said Claire Dwoskin, founder and president of CMSRI. "The collaborative research projects that are conceived at -- or as a result of -- this symposium are truly groundbreaking."
The organizer of the symposium is renowned aluminum toxicity expert, Dr. Christopher Exley, professor of bioinorganic chemistry at Keele University in England. Exely and his team of researchers will be presenting at the symposium, in addition to the speakers listed below. The following are abstracts for each of the presentations (note: CMSRI-funded research is highlighted in purple).
Visualising aluminium in the human brain
Matthew Mold & Christopher Exley, The Birchall Centre, Lennard Jones Laboratories, Keele University, UK.
Human exposure to aluminium has frequently been implicated in disease progression and most notably in neurodegenerative conditions, including Alzheimer’s disease [1]. Toxicity of the metal ion in vivo occurs through myriad pathways, of which its inclusion as the most commonly used adjuvant in human vaccinations has been linked to autoimmunity (or autoinflammatory) syndrome induced by adjuvants (ASIA) [2]. Using the complementary methods of transversely heated graphite furnace atomic absorption spectroscopy (TH-GFAAS) and lumogallion fluorescence microscopy, we have investigated the total quantity of aluminium and its location within human brain tissue, across multiple disease states.
Aluminium in brain tissues of donors diagnosed with genetically triggered or familial Alzheimer’s disease revealed extremely high concentrations in excess of 10μg/g tissue dry wt. and predominantly, the extracellular deposition of the metal ion [3]. More recently, we have reported on the distribution of aluminium in autism spectrum disorder (ASD). Interestingly, intracellular aluminium was observed predominantly in non-neuronal, glial-like cells. The study additionally revealed some of the highest aluminium concentrations yet recorded [4]. We are now focusing our efforts on analysing brain tissues from donors diagnosed with multiple sclerosis, to draw comparisons of the distribution of aluminium across these complex neurological disorders.
The evidence for the ASIA syndrome -The registry and epidemiological studies
A. Watad Sheba Medical Center, Department of Medicine 'B'- Sheba Medical Center- Tel-Hashomer- Israel., Tel Hashomer, Israel
Vaccine induced autoimmune reactions are not so common and, as such, difficult to capture, being often under-reported and under-represented in the extant scholarly literature. However, recent large cohort studies and meta-analyses have confirmed at least some of them, including Guillain-Barrè syndrome after influenza vaccination, immune thrombocytopenic purpura after measles, mumps and rubella vaccine, viscerotropic and neurotropic diseases after yellow fever immunization, neurological complications after oral poliovirus vaccine and smallpox immunization. “Autoimmune/inflammatory syndrome induced by adjuvants” (ASIA) syndrome appears to be a valuable umbrella term to collect and describe clinical symptoms and reactions arising after vaccines/ /silicone/ and some mineral oil exposure. Thus, ASIA syndrome includes those clinical conditions in which the exposure to an adjuvant leads to an aberrant autoimmune response. However, the vaccine attributable risk appears to be low and, undoubtedly, the benefits offered from vaccinations or immunotherapies outweigh vaccine- and immunotherapy-related adverse events. On the other hand, the classical paradigm of the actual routine pharmacovigilance/vaccine vigilance system based on three stage-approach (namely, signal detection, development of a causality hypothesis, and testing of the causality hypothesis) is plagued by some limitations, in that it is not sufficient to understand suspected harms that are poorly defined and whose pathophysiology are multi-factorial and not completely understood. Furthermore, estimations of risk at the population level fail to acknowledge that vaccines/immunotherapies may cause harm in subgroups with specific, individual-level risk factors for adverse events following immunization. The establishment of an international “ASIA syndrome registry” may contribute to an increased awareness of ASIA syndrome and help physicians to identify patients at a greater risk of autoimmune diseases following the exposure to vaccines and other adjuvants, providing a useful tool to systematize this rare condition.
Suspected adverse effects after human papillomavirus vaccination: a temporal relationship between vaccine administration and the appearance of symptoms in Japan
S. Ikeda
Intractable Disease Care Center, Shinshu University Hospital, Matsumoto, Japan
In Japan, after receiving human papillomavirus (HPV) vaccination, a significant number of adolescent girls experience various symptoms, the vast majority of which have been ascribed to chronic regional pain syndrome (CRPS), orthostatic intolerance, and/or cognitive dysfunction.
However, a causal link has not been established between HPV vaccination and the development of these symptoms. Between June 2013 and December 2016, we examined symptoms and objective findings in 163 female patients who had received HPV vaccination. We used newly defined diagnostic criteria for accurate inclusion of patients who experienced adverse symptoms after HPV vaccination. Consequently, 43 females were excluded. Among the remaining 120 patients, 30 were diagnosed as having definite vaccine-related symptoms, and 42 were diagnosed as probable. Among these 72 girls, the age at initial vaccination ranged from 11 to 19 years (average 13.6±1.6 years), the age at appearance of symptoms ranged from 12 to 20 years
(average 14.4±1.7 years), and the incubation period after the first vaccine dose ranged from 1 to 1532 days (average 319.5±344.3 days). These 72 patients received the HPV vaccine between May 2010 and April 2013. The first affected girl developed symptoms in October 2010, and the last two affected girls developed them in October 2015. Over the previous 14 months, we have not seen any female patients who were freshly affected by these symptoms. Based on these sequential events, it is likely that HPV vaccination plays some role for the transiently high prevalence of the previously mentioned symptoms including CRPS and autonomic and cognitive dysfunctions. Additionally, I will present HLA genotypes of the affected girls, which is helpful
for the understanding of the pathogenesis in this unexpected disorder after HPV vaccination.
HPV vaccination syndrome. A new tragic fibromyalgia model?
M. Martinez-Lavin1
1Jefe. Departamento de Reumatología, Chief, Rheumatology Department, Instituto Nacional de Cardiología. México
Several independent investigators have described the onset of a chronic illness soon after HPV vaccination. This illness is characterized by headache, fatigue, widespread pain, dizziness and nausea, among other vexing symptoms. This cluster of symptoms has been dubbed “HPV vaccination syndrome”. Profound dysautonomia and small fiber neuropathy have been reported in these cases. In the largest published series of 45 girls with HPV vaccination syndrome, 53% of them fulfilled the ACR 2010 fibromyalgia diagnostic criteria.
Dysautonomia and small fiber neuropathy are frequent findings in fibromyalgia. Dorsal root ganglia sodium channels have been implicated in the pathogenesis of fibromyalgia’s neuropathic pain. Therapies used in fibromyalgia directed to restore autonomic nervous system resilience could theoretically help post-HPV vaccination cases. New sodium channel blockers are being developed. These new compounds could become effective analgesics. On the other hand, HPV vaccination syndrome severity and clear-cut inception could become a new tragic model for
fibromyalgia dysautonomic-neuropathic nature.
HPV and Lupus: the virus, the vaccine and the disease
Y. Segal1, M. Calabrò2, D. Kanduc3, Y. Shoenfeld1,4
1Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, affiliated with the Sackler Faculty of Medicine, Tel-Aviv University, Israel
2Department of Emergency and Organ Transplantation, University of Bari, Italy
3Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari,
Italy
4Incumbent of the Laura Schwarz-Kipp chair for research of autoimmune diseases, Sackler
Faculty of Medicine, Tel Aviv University, Israel
Systemic lupus erythematosus (SLE) is a well-known, wide-spread autoimmune disease,
involving multiple organ systems, with a multifaceted, widely unmapped etiopathogenesis. Recently a new aspect of morbidity has been described among SLE patients: infection with human papilloma virus (HPV). We set out to review data regarding the intricate relationship between the two and attempt to determine whether HPV may pose as a contributing factor to the development of SLE.
We relate to epidemiological, molecular and clinical data. We’ve found evidence in all these fields suggesting HPV to be involved in the pathogenesis of SLE: increased prevalence of HPV infection among SLE patients; vast molecular homology between viral peptides and human proteins associated with SLE; several reports of SLE development post HPV vaccination. Our findings suggest a possible involvement of HPV infection in the induction of SLE, via a mechanism of immune cross reaction due to molecular homology.
We review clinical, epidemiological and molecular data suggesting involvement of HPV
infection in the pathogenesis of SLE. We suggest these findings may justify the development of new HPV vaccines containing viral peptides which bear no homology to the human proteome, in order to avoid possible adverse immune crossreactivity.
Cardiac arrest following HPV vaccination
S. Dahan1,2, Y. Segal1,2, M. Eldar4, D. Kanduc5, Y. Shoenfeld1,3
1Zabludowicz Center for Autoimmune Diseases Sheba Medical Center, Tel-Hashomer, Israel
2Sackler Faculty of Medicine, Tel Aviv University, Israel
3Incumbent of the Laura Schwarz-Kipp chair for research of autoimmune diseases, Sackler
Faculty of Medicine, Tel Aviv University, Israel
4The Neufeld Cardiac Research Institute, The Heart Institute, Chaim Sheba Medical Center,
Ramat Gan, Israel
5Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari,
Italy
The development of vaccines has proven to be a successful and cost-effective for global human health, and they represent an essential part of preventive modern medicine. It is obvious that vaccines are administered to millions of people worldwide, and that not everyone develops serious adverse manifestations. Hence, clearly there are some prior susceptibilities that make some people more at risk of experiencing an adverse reaction to vaccination than others.
There are three HPV vaccines administered as of date: the bivalent Cervarix vaccine, the quadrivalent Gardasil vaccine and the newly introduced 9-valent vaccine. The vaccine is composed of virus-like particles of the L1 major capsid proteins of different HPV serotypes.
First launched in 2006, the aim was to substantially reduce the burden associated with HPV related neoplasms. And indeed, the vaccine has been found to be effective, providing a long-lasting protection against HPV infection and premalignant lesions.
There appears to be a fine balance between the efficacy of vaccines and their potential toxicity. This is because the same mechanisms that drive the immune-stimulatory effect of vaccines have the capacity to provoke a variety of autoimmune adverse reactions.
In the current literature, there are numerous cases substantiating the link between adverse autoimmune reactions and HPV vaccines. Herein we present a case report of a 20 years-old young adult who developed fatal arrhythmia and cardiac arrest following the administration of the HPV vaccine.
Immunogenicity and Safety of Viral and Bacterial Vaccinations in Lupus Subjects
N. Bragazzi1
1University of Genoa, School of Public Health- Department of Health Sciences DISSAL, Genoa, Italy
Systemic lupus erythematosus (SLE) is a chronic, complex, multi-factorial, systemic
autoimmune disease, in which immune system impairment and dysfunction result by virtue of the disease itself as well as by the effects of treatment modalities employed. Immune dysregulations occur including complement system dysfunction. Infectious agents are known to complicate the disease course in 25-45% of SLE patients. In this oral communication, a discussion of the immunogenicity and safety of viral and bacterial vaccinations in SLE subjects will be envisaged. For this purpose, we have carried out a comprehensive literature search, mining different scholarly electronic databases, including ISI Web of Science (WoS), Scopus, MEDLINE/PubMed, Google-Scholar, Directory of Open Access Journals (DOAJ), EbscoHOST, Scirus, Science Direct, Cochrane Library and ProQuest. Proper string made up of a key-words including 'SLE', 'vaccination', 'safety' and 'efficacy' has been used. Collecting the available evidence, we can maintain that vaccination in SLE patients is proven to be immunogenic.
Concerns regarding vaccine safety are postulated, yet no direct relationship between vaccination and disease exacerbation were established. While live virus vaccines are generally contraindicated in immunosuppressive states, generally live attenuated vaccinations are recommended in SLE patients on a case-to-case basis. In SLE patients, clinical parameters such as vaccination during disease exacerbations have not been intensively studied and therefore while apparently safe, vaccination is generally recommended while disease is quiescent.
Elucidating the relationship between the concentration of aluminium salts used in vaccines and the subsequent events occurring at the injection site.
Emma Shardlow, Matthew Mold, Christopher Exley, The Birchall Centre, Lennard-Jones Laboratories, Keele University, UK
Aluminium salts remain the most commonly used adjuvant in clinical vaccinations despite an increasing number of adverse reactions being observed in individuals inoculated with such formulations. While current FDA regulations permit the inclusion of no more than 850 μg/dose Al within these preparations, the scientific rationale behind the introduction of this limit remains poorly justified. This study aims to explore how the concentration of aluminium in vaccines influences the biological processes occurring at the site of injection. The hydrodynamic size of adjuvanted model vaccines showed a strong linear dependency on the concentration of aluminium included within the preparations, which influenced both the cytotoxicity and uptake of the material in a model phagocytic cell line. These experiments provide an initial basis for the refinement of the amount of aluminium used within clinical vaccines, which will improve the safety of these formulations without comprising their efficacy.
Experimental evaluation of the toxicokinetics of aluminum-based adjuvants: what’s wrong in the reference studies?
Jean-Daniel Masson1*, Guillemette Crépeaux1,2*, François-Jérôme Authier1, Christopher Exley3, Romain K Gherardi11 INSERM U955 E10, « Biologie du système neuromusculaire », Faculté de Médecine, Université Paris , France2 Génétique médicale comparée des affections neuromusculaires, Ecole Nationale Vétérinaire d’Alfort, Maisons-Alfort, France3 The Birchall Centre, Lennard-Jones Laboratories, Keele University, UK
The hypothesis suggesting that aluminum (Al)-based adjuvants are innocuous is based on 3 toxicokinetic reference studies that we examined in the light of current scientific knowledge.
The single experimental study was carried out using isotopic 26Al (Flarend et al., 1997). This study ignored adjuvant uptake by cells and was conducted over a short period of time, using only 2 rabbits per adjuvant. At the endpoint, Al urinary elimination accounted for 6% for Al hydroxide and 22% for Al phosphate, which is incompatible with rapid urinary elimination of vaccine-derived Al. Then two theoretical studies have evaluated the potential risk of vaccine Al in infants, by reference to an oral « minimal risk level » (MRL) extrapolated from animal studies. Keith et al. 2002 used a high MRL (2 mg/kg/d), an erroneous model of 100% immediate absorption of vaccine Al, and did not consider renal and blood-brain barrier immaturity. Mitkus et al. (2011) only considered solubilized Al, with erroneous calculations of absorption duration. The used MRL was both inappropriate (oral Al vs. injected adjuvant) and still too high (1 mg/kg/d) regarding recent animal studies. Indeed we recently observed a non-linear dose-response using Al hydroxide on mice, suggesting that the view that Al adjuvant neurotoxicity and biopersistence obeys “the dose makes the poison” rule of classical chemical toxicity appears overly simplistic. Thus analyze of reference studies and recent experimental data both strongly suggest that novel studies of Al adjuvants toxicokinetics are needed to ensure their safety and restore population confidence in Al-containing vaccines.
Neurodevelopmental Toxicity of Vaccines in a Rodent Model
Housam Eidi1, Janice Yoo1, Michael Kuo1 and Christopher A. Shaw1 1 Dept. of Ophthalmology and Visual Sciences, University of British Columbia, Canada
Throughout neural development, the immune system plays integral roles by affecting neurogenesis, synaptogenesis, neuronal migration, and axon guidance. These functions for immune molecules suggest that perinatal immunotoxic insults can also mediate pathological responses in neurodevelopmental disorders, including autism spectrum disorder (ASD). Although immune challenges induced by vaccination have been suggested to cause autoimmune and inflammatory conditions (i.e., “ASIA”), it is often assumed that vaccine-induced immune stimulation does not affect brain development. Moreover, despite the fact that many vaccines contain constituents, such as aluminum, formalin and no declared inorganic contaminations, which have been associated with adverse neurological and immune outcomes, the entire pediatric vaccination schedule has never been tested for neurodevelopmental toxicity outcomes.
The present study aims at evaluating the effects of pediatric vaccination on brain development and neuromotor behaviour using a mouse model system.
In total 16 litters of C57BL/6J mice were divided into 4 experimental groups: control, mice injected with mouse weight equivalent dose of the current U.S. pediatric vaccination schedule, mice injected with triple doses of the vaccines, and mice injected with aluminum phosphate adjuvant in the amount found in the vaccination schedule. Animals were assessed for reflex development, neuromotor ability and ASD-related neurobehavioural abnormalities (NBAs), including impaired social interactions, anxiety, and cognitive function.
Our preliminary data show abnormal repetitive behaviors (barbering) and NBAs, such as decreased preference for social novelty in a social interaction test and altered anxiety behaviour in a light-dark box test in the treatment groups when compared to controls. Mice will be euthanized and these behavioral alternations will be further examined by biological and histological analysis.
Cerebral 18F-FDG PET for diagnosing aluminum hydroxide-induced macrophagic myofasciitis
Blanc-Durand Paul, Van Der Gucht Axel, Guedj Eric, Aoun-Sebaiti Mehdi, Gherardi Romain K., Itti Emmanuel, Authier F. Jérôme Reference Center for Neuromuscular Disorders, H. Mondor Hospital, Assistance Publique-Hôpitaux de Paris ; INSERM U955-Team 10, Paris Est-Creteil University, France. (10) INSERM U955-GRC Amyloid Research Institute, Créteil, France.
Macrophagic myofasciitis (MMF) is a condition observed in patients with abnormal long-term persisting aluminum hydroxide within body. A peculiar pattern of cerebral glucose hypometabolism involving occipito-temporal cortex and cerebellum was reported in patients with MMF. Aim was to generate and evaluate a support vector machine (SVM) procedure to classify patients between healthy or MMF 18F-FDG brain profiles.
18F-FDG PET brain images of 119 patients with MMF and 64 healthy subjects were retrospectively analyzed. The whole-population was divided into two groups; a training set (100 MMF, 44 healthy subjects) and a testing set (19 MMF, 20 healthy subjects). Dimensionality reduction was performed using a t-map from statistical parametric mapping (SPM) and a SVM with a linear kernel was trained on the training set. To evaluate the performance of the SVM classifier, values of sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV) and accuracy (Acc) were calculated.
The SPM12 analysis on the training set exhibited the already reported hypometabolism pattern involving occipito-temporal and fronto-parietal cortices, limbic system and cerebellum. The SVM procedure, based on the t-test mask generated from the training set, correctly classified MMF patients of the testing set with following Se, Sp, PPV, NPV and Acc: 89%, 85%, 85%, 89%, and 87%.
This original and individual approach including a SVM could help to classify patients between healthy or MMF metabolic brain profiles using 18F-FDG-PET. Machine learning algorithms are promising for computer-aided diagnosis but will need further validation in prospective cohorts.
Clinicopathologic studies in lambs repetitively inoculated with aluminum adjuvant containing products
Asín1, J. Molín1, M. Pérez1, P. Pinczowski1, M. Gimeno1, M Pascual-Alonso1, N. Navascués, A1. Muniesa1, I. de Blas1, G. María1, D. Lacasta1, A. Fernández1, L. de Pablo2, M. Mold3, C. Exley3, D. de Andrés2, R. Reina2, L. Luján1 1. University of Zaragoza, Spain 2. Institute of Agrobiotechnology, CSIC-Public University of Navarra, Spain 3. The Birchall Centre, Keele University, Keele, Staffordshire, UK
The use of aluminum-containing vaccine adjuvants is widespread in the Spanish small ruminant industry. These compounds were related to an episode of vaccine adverse reactions which gave rise to a process known today as the ovine ASIA syndrome.
An in vivo model of this syndrome was established. Eighty-four lambs were selected, divided into three groups (n=28 each) and submitted to an intensive inoculation program with: i) Vaccines containing aluminum hydroxide as adjuvant; ii) The adjuvant only; iii) PBS. Nineteen inoculations were performed during 15 months. A comprehensive in vivo follow-up was performed, including clinical examinations and behavioral and cognitive tests. After euthanasia, the pathology of different tissues was studied grossly, microscopically and by electron microscopy. The presence of aluminum in tissues was studied by energy dispersive X-ray spectroscopy, graphite furnace atomic absorption spectroscopy and lumogallion fluorescent staining.
Animals in the vaccinated and adjuvant-inoculated groups presented persistent injection-site granulomas with intramacrophagic aluminum. Persistency was higher in the vaccinated group (p<0.001), reaching 15 months in some cases. There was translocation of aluminum to the regional lymph nodes (p<0.001) and lumbar spinal cord (p<0.001). Vaccinated and adjuvant-inoculated animals showed an increase in aggressive interactions (p<0.001) and stereotypies (p<0.001) and a decrease in affiliative interactions (p<0.001) when compared with the control group. Differences were more marked with higher number of doses applied.
Repetitive inoculation of aluminum-hydroxide only or combined into commercial vaccines to experimental lambs induces highly persistent injection site granulomas, accumulation of aluminum in distant tissues and changes in the inter-individual interaction patterns.
The Children’s Medical Safety Research Institute is a sponsor of the Autoimmunity Congress and a nonprofit organization dedicated to funding independent research into the causes of autoimmune diseases and to promoting awareness of scientifically validated and published findings. www.cmsri.org
