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Aluminium adjuvants should not be used as placebos in clinical trials
... 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 In general, outcomes of an acute inflammation (eg, responses to infective agents) are lymphocytederived clonal expansion, increased synthesis of pathogen-(or allergen) specific antibodies and memory cells. ...
... Inactivated (or live) pathogens in vaccines, on their own, are immunogens (stimuli or immune disruptors) and could over-stimulate immunity. According to manufacturer's inserts, governmental or published scientific data, majority of pathogen-specific vaccines are prepared in media containing combinations of metals, chemicalsbiological agents such as aluminum (Al, as hydroxide or phosphate salts), mercury (Hg, thimerosal), detergents, solvents or preservatives [eg, CTAB, polymyxin, neomycin, saponin, formaldehyde, silica and derivatives, solutes (sorbitol, polysorbate 80 or 20, Tween 20), glyphosate-herbicide, octylphenol ethoxylate or octoxynol-10 (Triton X-100)], genetically engineered DNA/RNA, yeast extracts, fetal tissues and organ parts or fragments 12,14,24,37,38,67,73,74,77,94,96,128,[130][131][132]141,144,148,152,153,156,165,167,168 § § § § § § § § ' ********* . Majority of these vaccine ingredients are not natural agents and do not participate in biochemical pathways in human physiology. ...
... 36,72,84,85,91,92,153,183 Excess amount of copper (free) could be detrimental to respiratory chain reactions and generation of toxic hydroxyl radicals (HO 0 ) causing oxidative damage not only to mitochondria, but also other extracellular-intracellular proteins or nucleic acids and lipids (Fenton reaction) and tissue oxido-redox potentials. 1,5,14,20,29,[31][32][33][34][35][36][37][38][39]53,55,72,73,78,84,85,[88][89][90][91][92]155,182,183 Furthermore, copper and Zn +2 (another trace element and antioxidant) are involved in detoxifying mitochondrial ROS and superoxide dismutase1 (SOD1) activities, regulation of Cu-mediated production of O 2 /ROS. Related studies suggest that trace elements (Cu, zinc, Fe), influence regulations of transport of triglycerides in gastrointestinal tract and are important in the function of red blood cells and endoplasmic reticulum activities. ...
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.
... Thus, the potential risks from vaccines remain currently ill-understood and controversial. A further obfuscation to our understanding of potential risks from vaccinations stems from the persistent use of aluminum (Al) adjuvants-containing placebos in vaccine trials [7]. Indeed, contrary to popular assumptions of inherent safety of Al in vaccines, there is now compelling data from both human and animal studies which implicates this most widely used adjuvant in the pathogenesis of disabling neuroimmuno-inflammatory conditions [8][9][10][11]. ...
... Like most other vaccine safety trials, the trials for the HPV Gardasil vaccine utilized an Al-containing placebo [21,22] and hence the safety profile of the vaccine remains obscured by the use of a potentially toxic placebo [7]. Thus, in order to investigate better, the safety profile of Gardasil, as well as the Al adjuvant, in the current study, we evaluated and compared the effects of Al and whole HPV vaccine formulation versus that of a true placebo on behavioral, neurohistological and autoimmune parameters in young female C57BL/6 mice. ...
... From the literature cited above as well as the present study, it is obvious that Al in adjuvant form is neither inactive nor harmless and hence cannot constitute as a valid placebo. Commenting on the routine practice of using Al-based adjuvants as placebos in vaccine trials Exley recently stated that it is necessary to make a very strong scientific case for using a placebo which is itself known to result in side effects and that no scientific vindication for such practice is found in the relevant human vaccination literature [7]. Conceivably, there is even less justification for using a novel and more potent Al formulation than those that have been in standard use (Al phosphate and hydroxide). ...
Vaccine adjuvants and vaccines may induce autoimmune and inflammatory manifestations in susceptible individuals. To date most human vaccine trials utilize aluminum (Al) adjuvants as placebos despite much evidence showing that Al in vaccine-relevant exposures can be toxic to humans and animals. We sought to evaluate the effects of Al adjuvant and the HPV vaccine Gardasil versus the true placebo on behavioral and inflammatory parameters in female mice. Six-week-old C57BL/6 female mice were injected with either, Gardasil, Gardasil + pertussis toxin (Pt), Al hydroxide, or, vehicle control in amounts equivalent to human exposure. At 7.5 months of age, Gardasil and Al-injected mice spent significantly more time floating in the forced swimming test (FST) in comparison with vehicle-injected mice (Al, p = 0.009; Gardasil, p = 0.025; Gardasil + Pt, p = 0.005). The increase in floating time was already highly significant at 4.5 months of age for the Gardasil and Gardasil + Pt group (p ≤ 0.0001). No significant differences were observed in the number of stairs climbed in the staircase test which measures locomotor activity. These results indicate that differences observed in the FST were unlikely due to locomotor dysfunction, but rather due to depression. Moreover, anti-HPV antibodies from the sera of Gardasil and Gardasil + Pt-injected mice showed cross-reactivity with the mouse brain protein extract. Immunohistochemistry analysis revealed microglial activation in the CA1 area of the hippocampus of Gardasil-injected mice. It appears that Gardasil via its Al adjuvant and HPV antigens has the ability to trigger neuroinflammation and autoimmune reactions, further leading to behavioral changes.
... Thus the potential risks from vaccines remain currently ill-understood and controversial. A further obfuscation to our understanding of potential risks from vaccinations stems from the persistent use of aluminum (Al) adjuvantscontaining placebos in vaccine trials [7]. Indeed, contrary to popular assumptions of inherent safety of Al in vaccines there is now compelling data from both human and animal studies which implicates this most widely used adjuvant in the pathogenesis of disabling neuroimmuno-inflammatory conditions [8][9][10][11]. ...
... Like most other vaccine safety trials, the trials for the HPV Gardasil vaccine utilized an Al-containing placebo [21,22] and hence the safety profile of the vaccine remains obscured by the use of a potentially toxic placebo [7]. Thus, in order to investigate better the safety profile of Gardasil, as well as the Al adjuvant, in the current study, we evaluated and compared the effects of Al and whole HPV vaccine formulation versus that of a true placebo on behavioral, neurohistological and autoimmune parameters in young female C57BL/6 mice. ...
... From the literature cited above as well as the present study, it is obvious that Al in adjuvant form is neither inactive nor harmless and hence cannot constitute as a valid placebo. Commenting on the routine practice of using Albased adjuvants as placebos in vaccine trials Exley recently stated that it is necessary to make a very strong scientific case for using a placebo which is itself known to result in side effects and that no scientific vindication for such practice is found in the relevant human vaccination literature [7]. Conceivably, there is even less justification for using a novel and more potent Al formulation than those that have been in standard use (Al phosphate and hydroxide). ...
... For example, aluminium adjuvant has been administered to both the experimental and control groups in the vast majority of randomised clinical trials on HPV vaccines, thus masking aluminium adjuvant's potentially harmful effects. 34 Aluminium adjuvants, new or old, should be evaluated for benefits and harms on their own merits. While the consequences of adding aluminium to vaccines have been discussed broadly, no systematic review has been conducted to assess the effects of aluminium adjuvants across different types of vaccines. ...
Objectives
To assess the benefits and harms of aluminium adjuvants versus placebo or no intervention in randomised clinical trials in relation to human vaccine development.
Design
Systematic review with meta-analysis and trial sequential analysis assessing the certainty of evidence with Grading of Recommendations Assessment, Development and Evaluation (GRADE).
Data sources
We searched CENTRAL, MEDLINE, Embase, LILACS, BIOSIS, Science Citation Index Expanded and Conference Proceedings Citation Index-Science until 29 June 2021, and Chinese databases until September 2021.
Eligibility criteria
Randomised clinical trials irrespective of type, status and language of publication, with trial participants of any sex, age, ethnicity, diagnosis, comorbidity and country of residence.
Data extraction and synthesis
Two independent reviewers extracted data and assessed risk of bias with Cochrane’s RoB tool 1. Dichotomous data were analysed as risk ratios (RRs) and continuous data as mean differences. We explored both fixed-effect and random-effects models, with 95% CI. Heterogeneity was quantified with I ² statistic. We GRADE assessed the certainty of the evidence.
Results
We included 102 randomised clinical trials (26 457 participants). Aluminium adjuvants versus placebo or no intervention may have no effect on serious adverse events (RR 1.18, 95% CI 0.97 to 1.43; very low certainty) and on all-cause mortality (RR 1.02, 95% CI 0.74 to 1.41; very low certainty). No trial reported on quality of life. Aluminium adjuvants versus placebo or no intervention may increase adverse events (RR 1.13, 95% CI 1.07 to 1.20; very low certainty). We found no or little evidence of a difference between aluminium adjuvants versus placebo or no intervention when assessing serology with geometric mean titres or concentrations or participants’ seroprotection.
Conclusions
Based on evidence at very low certainty, we were unable to identify benefits of aluminium adjuvants, which may be associated with adverse events considered non-serious.
... The aluminium content of a vaccine is never trivial [37]. There is a long history of testing the efficacy of childhood vaccines against false placebos and warnings against this practice continue to go unheeded [38]. It should be a matter of concern that a recent freedom of information act request (FOIA Case Number 50882, and HHS Appeal No.; 19-0083-AA) revealed that the NIH were unable to provide a single study relied upon by them in relation to the safety of injection of aluminium adjuvants in infants. ...
Background
Aluminium salts are the most common adjuvants in infant vaccines. The aluminium content of a vaccine is provided by the manufacturer and is indicated on the patient information leaflet. There is no independent verification, for example by the European Medicines Agency, of the aluminium content of infant vaccines.
Methods
We have measured the aluminium content of thirteen infant vaccines using microwave-assisted acid and peroxide digestion followed by transversely heated graphite furnace atomic absorption spectrometry. Our data are compared with manufacturer’s data using full statistical analyses including Bayesian methods.
Results
We found that only three vaccines contained the amount of aluminium indicated by the manufacturer. Six vaccines contained a statistically significant (P < 0.05) greater quantity while four vaccines contained a statistically significant (P < 0.05) lower quantity. The range of content for any single vaccine varied considerably, for example, from 0.172 to 0.602 mg/vaccine for Havrix.
Conclusions
The data have raised specific questions about the significance of the aluminium content of vaccines and identified areas of extremely limited information. Since aluminium is a known toxin in humans and specifically a neurotoxin, its content in vaccines should be accurate and independently monitored to ensure both efficacy and safety.
... Aluminum (Al) is regarded as the third most abundant element and the most common metal in the earth's crust (Farina et al., 2002). Exposure to Al is principally through drinking water, food (spices, corn and yellow cheese), pharmaceutical compounds (antacids, deodorants, vaccines and allergen injections), utensils and the environment (Yokel et al., 2008, andExley, 2011). Aluminum is considered an environmental and industrial pollutant that causes a broad spectrum of toxicity. ...
... 17 18 Criticisms have been raised of the prelicensure randomised clinical trials, that forms the body of evidence for the approval of Gardasil, a Merck Sharp & Dohme Corp manufactured human papilloma virus (HPV) vaccine made of recombinant HPV types 6, 11, 16 and 18 L1 virus-like particles. [19][20][21][22][23] One criticism is the use of amorphous aluminium hydroxyphosphate sulfate (AAHS) as a comparator in the prelicensure trials. 20 23 However, the European Medicines Agency (EMA) and the WHO conclude high vaccine safety and efficacy. ...
The Merck Sharp & Dohme Corp aluminium adjuvant ‘amorphous aluminium hydroxyphosphate sulfate’ (AAHS), primarily used in the Gardasil vaccines against human papilloma virus, has been criticised for lack of evidence for its safety. Documentation from Danish authorities and answers from the European Medicines Agency (EMA) suggest that AAHS may not have been sufficiently evaluated. Documentation from the Danish Medicines Agency shows discrepancies in the trial documents of two prelicensure clinical trials with Gardasil in 2002 and 2003. For both trials, the Agency seems to have authorised potassium aluminium sulfate as the adjuvant and not AAHS. In addition, the participants in the trial launched in 2002 were informed that the comparator was saline, even though the comparator was AAHS in an expedient consisting of L-histidine, polysorbate-80, sodium borate and sodium chloride. According to the EMA, AAHS was first introduced in Europe in 2004 as the adjuvant in Procomvax, a vaccine against the hepatitis B virus and Haemophilus influenza type b. The EMA reports that AAHS was introduced without any prelicensure safety evaluation. The adjuvant is described by the company to be both physically and functionally distinct from all other previously used aluminium adjuvants. There is a need for rigorous evaluation of benefits and harms of the adjuvant AAHS.
... In the light of these elements, we thus agree with the conclusion of Goullé and Grangeot-Keros that health authorities should design specific multidisciplinary experimental protocols to clarify Al adjuvants toxicokinetics and hazards, instead of accept the use of Al-adjuvants as placebos in clinical trials [31]. It will be of particular importance to map the fate and effect of particles of Al adjuvant beyond the vaccine injection site. ...
... For that reason, vaccine trials often treat an Al adjuvant-containing injection as a harmless "placebo" (a comparison benchmark or control treatment) or they use another Al-containing vaccine to treat a "control group, " despite evidence that Al in vaccine-relevant exposures is universally toxic to humans and animals [9,90,91]. Its use in a supposed "placebo" or in any "control" treatment in vaccine trials is indefensible [95]. It is precisely analogous to comparing fire A against fire B, to make the argument that since A is no hotter than B, A is therefore not a fire. ...
Over the last 200 years, mining, smelting, and refining of aluminum (Al) in various forms have increasingly exposed living species to this naturally abundant metal. Because of its prevalence in the earth’s crust, prior to its recent uses it was regarded as inert and therefore harmless. However, Al is invariably toxic to living systems and has no known beneficial role in any biological systems. Humans are increasingly exposed to Al from food, water, medicinals, vaccines, and cosmetics, as well as from industrial occupational exposure. Al disrupts biological self-ordering, energy transduction, and signaling systems, thus increasing biosemiotic entropy. Beginning with the biophysics of water, disruption progresses through the macromolecules that are crucial to living processes (DNAs, RNAs, proteoglycans, and proteins). It injures cells, circuits, and subsystems and can cause catastrophic failures ending in death. Al forms toxic complexes with other elements, such as fluorine, and interacts negatively with mercury, lead, and glyphosate. Al negatively impacts the central nervous system in all species that have been studied, including humans. Because of the global impacts of Al on water dynamics and biosemiotic systems, CNS disorders in humans are sensitive indicators of the Al toxicants to which we are being exposed.
(PDF) Aluminum-induced entropy in biological systems: Implications for neurological disease. Journal of Toxicology, 2014, Article ID 491316, 27 pages, 2014. doi:10.1155/2014/491316.. Available from: https://www.researchgate.net/publication/333582751_Aluminum-induced_entropy_in_biological_systems_Implications_for_neurological_disease_Journal_of_Toxicology_2014_Article_ID_491316_27_pages_2014_doi1011552014491316 [accessed Jun 03 2019].
... Since there is no requirement to demonstrate the safety of ABAs one could quickly surmise that adverse events following vaccination are the direct or indirect effects of ABAs. This is almost certainly true as the phenotypes of most adverse events are unrelated to the disease being treated and are reproduced, at least in the short term, in 'clinical approval trials' where ABAs are the ill thought through placebos [5]. It is almost certainly the widespread use of ABAs and/or other aluminium-adjuvanted vaccines as placebos in vaccine safety trials that have guaranteed clinical approval of many vaccines. ...
Abstract Aluminium salts are by far the most commonly used adjuvants in vaccines. There are only two aluminium salts which are used in clinically-approved vaccines, Alhydrogel® and AdjuPhos®, while the novel aluminium adjuvant used in Gardasil® is a sulphated version of the latter. We have investigated the physicochemical properties of these two aluminium adjuvants and specifically in milieus approximating to both vaccine vehicles and the composition of injection sites. Additionally we have used a monocytic cell line to establish the relationship between their physicochemical properties and their internalisation and cytotoxicity. We emphasise that aluminium adjuvants used in clinically approved vaccines are chemically and biologically dissimilar with concomitantly potentially distinct roles in vaccine-related adverse events.
... The control groups in some of the clinical trials for HPV vaccines received solutions containing Al Tomljenovic, Spinosa, and Shaw 2013) instead of the standard saline solution. The Al itself may produce side effects (Exley 2011) including damage to ovaries (Colafrancesco et al. 2013;Fu et al. 2014). Finding no marked differences in ovarian function between subjects who received the vaccine and those who received the Al-containing placebo might fail to determine adverse events attributed to Al. ...
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 who were 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.
... If Aluminum hydroxide (Alhydrogel®) and aluminum phosphate (Adjuphos®) are commercially available, the new generation adjuvant amorphous aluminum hydroxyphosphate sulfate (AAHS) used in Gardasil® is a Merck proprietary adjuvant [25]. To our knowledge, this adjuvant is not available for independent experimental safety studies, which may raise ethical problems since it has been placed in both vaccine and placebo in Gardasil premarket trials [26]. ...
... A systematic cross-sectional study of 12 published studies showed a slight increase of adverse events in the HPV-vaccinated group, but this information must take account of the quasi-systematic use of control groups that received aluminum adjuvants in the form of a placebo containing the adjuvant or, more rarely, the hepatitis A vaccine (11 of the 12 publications analyzed, comprising 29,533 of the 29,600 patients studied) [34]. Despite this major bias [35], European Medicines Agency (EMA) issued a negative opinion on the existence of an association between HPV-vaccination and increasing of adverse events [36]. Some pharmaco-epidemiological studies were seemingly in support of this opinion [37,38], but having focused on most specific auto-immune diseases, they have excluded CFS, RPS, and POTS from their investigations. ...
We reviewed the three toxicokinetic reference studies commonly used to suggest that aluminum (Al)-based adjuvants are innocuous. A single experimental study was carried out using isotopic 26Al (Flarend et al., Vaccine, 1997). This study used aluminum salts resembling those used in vaccines but ignored adjuvant uptake by cells that was not fully documented at the time. It was conducted over a short period of time (28days) and used only two rabbits per adjuvant. At the endpoint, Al elimination in the urine accounted for 6% for Al hydroxide and 22% for Al phosphate, both results being incompatible with rapid elimination of vaccine-derived Al in urine. 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. (Vaccine, 2002) used a high MRL (2mg/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. (Vaccine, 2011) only considered solubilized Al, with erroneous calculations of absorption duration. Systemic Al particle diffusion and neuro-inflammatory potential were omitted. The MRL they used was both inappropriate (oral Al vs. injected adjuvant) and still too high (1mg/kg/d) regarding recent animal studies. Both paucity and serious weaknesses of reference studies strongly suggest that novel experimental studies of Al adjuvants toxicokinetics should be performed on the long-term, including both neonatal and adult exposures, to ensure their safety and restore population confidence in Al-containing vaccines.
... For that reason, vaccine trials often treat an Al adjuvant-containing injection as a harmless "placebo" (a comparison benchmark or control treatment) or they use another Al-containing vaccine to treat a "control group, " despite evidence that Al in vaccine-relevant exposures is universally toxic to humans and animals [9,90,91]. Its use in a supposed "placebo" or in any "control" treatment in vaccine trials is indefensible [95]. It is precisely analogous to comparing fire A against fire B, to make the argument that since A is no hotter than B, A is therefore not a fire. ...
Over the last 200 years, mining, smelting, and refining of aluminum (Al) in various forms have increasingly exposed living species to this naturally abundant metal. Because of its prevalence in the earth’s crust, prior to its recent uses it was regarded as inert and therefore harmless. However, Al is invariably toxic to living systems and has no known beneficial role in any biological systems. Humans are increasingly exposed to Al from food, water, medicinals, vaccines, and cosmetics, as well as from industrial occupational exposure. Al disrupts biological self-ordering, energy transduction, and signaling systems, thus increasing biosemiotic entropy. Beginning with the biophysics of water, disruption progresses through the macromolecules that are crucial to living processes (DNAs, RNAs, proteoglycans, and proteins). It injures cells, circuits, and subsystems and can cause catastrophic failures ending in death. Al forms toxic complexes with other elements, such as fluorine, and interacts negatively with mercury, lead, and glyphosate. Al negatively impacts the central nervous system in all species that have been studied, including humans. Because of the global impacts of Al on water dynamics and biosemiotic systems, CNS disorders in humans are sensitive indicators of the Al toxicants to which we are being exposed.
... Une étude transversale systématique de 12 études publiées a montré un sur-risque de niveau modéré dans le groupe vacciné contre l'HPV mais cette information doit tenir compte de l'utilisation quasi-systématique de groupes contrôles ayant reçu des adjuvants aluminiques, sous la forme d'un placebo contenant l'adjuvant ou, plus rarement, du vaccin contre l'hépatite A (soit 11 des 12 publications analysées, regroupant 29 533 des 29 600 patientes étudiées) [34]. Passant outre ce biais majeur [35], l'EMA a émis un avis négatif sur l'existence d'une association [36]. Des études pharmaco-épidémiologiques sont apparemment allées dans le même sens [37,38], mais, uniquement attachées à l'études des grandes maladies auto-immunes spécifiques, elles ont exclu de leur investigation les syndromes de SFC, SDR et STPO, ne permettant pas de conclure. ...
We reviewed the three reference toxicokinetic studies commonly used to suggest innocuity of aluminum (Al)-based adjuvants. A single experimental study was carried out using isotopic ²⁶Al (Flarend et al., 1997). This study ignored adjuvant cell capture. It was conducted over a short period of time (28 days) and used only two rabbits per adjuvant. At the endpoint, Al retention was 78% for aluminum phosphate and 94% for aluminum hydroxide, both results being incompatible with quick elimination of vaccine-derived Al in urines. Tissue distribution analysis omitted three important retention sites: the injected muscle, the draining lymph node and bone. Two theoretical studies have evaluated the potential risk of vaccine Al in infants, by reference to the oral Minimal Risk Level (MRL) extrapolated from animal studies. Keith et al., 2002 used a too high MRL (2mg/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 absorbed Al, with erroneous calculations of absorption duration. They ignored particulate Al captured by immune cells, which play a role in systemic diffusion and the neuro-inflammatory potential of the adjuvant. MRL they used was both inappropriate (oral Al vs injected adjuvant) and far too high (1mg/kg/d) with regard to experimental studies of Al-induced memory and behavioral changes. Both paucity and serious weaknesses of these studies strongly suggest that novel experimental studies of Al adjuvants toxicokinetics should be performed on the long-term, including post-natal and adult exposures, to ensure innocuity and restore population confidence in Al-containing vaccines.
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... A opinião desde então veio mudando acerca do efeito e dos níveis que o Al tem sido consumido. Atualmente, estudos indicam que o Al tem sido consumido em doses superiores àquelas no passado, sendo estes níveis superiores aos considerados seguros para consumo humano, inclusive na formula de alimentos infantis (Burrell & Exley, 2010;Exley, 2011;Ogimoto et al., 2012). O Al pode estar relacionado com diversas doenças de cunho neurodegenerativo, sendo o efeito em geral visualizado em pessoas mais velhas, as quais acumularam ao longo dos anos o metal no cérebro. ...
Acid soils reduce crop yield, not only by affecting nutrient availability, but also by increasing the presence of toxic element forms, such as aluminum (Al), in its most reactive form. The combination of these two factors has negative consequences to the plant, for example reduction in root growth and biomass production. Oats are considered Al tolerant if compared to wheat and barley, but there is a large variation inside the species. In poaceae, mechanisms related to exclusion as well as to detoxification have been identified and several genes have been associated to Al tolerance. This study aimed to identify QTLs associated to Al tolerance using field and hydroponic phenotypic of a recombinant inbred population, and identify sequences with homology to genes associated to Al tolerance in other species. Three QTLs associated to hydroponic Al tolerance were identified in the map generated to UFRGS 17 x UFRGS 930598 population, explaining 64% of the phenotypic variation. A sequence similar to the ALMT1 gene was identified. The UFRGS 17 allele was predicted to contain five introns an six eons and to code a protein with six transmembrane domains. In UFRGS 930598, the first predicted exon and part of the first intron were not cloned. A sequence similar to the STOP1 gene was partially identified with 89% of homology to the Brachypodium distachyon homologous sequence.
... 2) Aluminum adjuvants are neurotoxin and associated with a set of autoimmune/inflammatory disorders [23] and autism [24]. These adjutants should not be used as placebos in clinical trial studies [25]. ...
Objectives: Despite the positive effects of vaccines on control of many infectious diseases, they are not completely safe. The purpose of this article is to draw attention to the problems associated with newborns and infants immunization. Methods: For each subject, a review of electronic sources was carried out in the PubMed and Google Scholar using appropriate key words. Results: For different reasons including: the differences between the immune systems of newborns/children and adults, sever adverse events and inefficacy of vaccines, deceptive advertising and inadequate parental awareness about vaccines and vaccination; newborns and children are at risk and accordingly a decline in public confidence is observed. Conclusions: The revision of vaccination age changing (at least for some vaccines) in order to maintain newborns/children's health and to prevent the return of infectious diseases is required. To achieve this goal, new retrospective and prospective studies to reassess the safety, efficacy, quality and protection duration of vaccines, proper implementation of good clinical practice, establishment of a network vaccine safety database by collaboration of international organizations, vaccine manufacturers and academic centers for sharing of information and enhancement of awareness of healthcare professionals and people about immunization at global level are needed.
... Food and Drug Administration (FDA) does set an upper limit for Al in vaccines at no more than 850 μg/dose (Baylor et al. 2002), it is important to note that this amount was selected empirically from data showing that Al in such amounts enhanced the antigenicity of the vaccine, rather than from existing safety data or from the basis of toxicological considerations (Baylor et al. 2002). However, in preventative vaccination where a vaccine is administered to healthy individuals, a compromise in efficacy for additional margins of safety should not necessarily be viewed as an unreasonable expectation The consequence of this view is best reflected in the fact that a large number of vaccine trials use an Al adjuvantcontaining placebo or another Al-containing vaccine as the "control group" despite much evidence showing that Al in vaccine-relevant exposures is toxic to humans and animals (Gherardi et al. 2001;Couette et al. 2009;Li et al. 2009;Shaw and Petrik 2009;Passeri et al. 2011; and that therefore its use as a placebo in vaccine trials is scientifically untenable (Exley 2011). That the safety issue of Al in vaccines has indeed been overlooked by the regulators (for more than 90 years since these compounds have been in Although Al is clearly neurotoxic, a common assertion is that humans obtain much more Al from diet than from vaccines and that therefore, the adjuvant form of Al does not represent a toxicological risk (Offit and Jew 2003). ...
This chapter presents answers to the most common misconceptions regarding the safety of aluminium (Al) compounds in vaccines by providing an overview of what is currently known about Al adjuvants, in particular, and their modes of action and mechanisms of potential toxicity. It gives a brief overview of the crucial role of Al in a variety of neurological disorders and then elaborates on the unresolved controversy about Al adjuvant safety. Al adjuvants exert their immunostimulatory effect through many different actions, which impinge on both the innate and adaptive immune systems. Some of the actions are activation of the NLRP3 inflammasome pathway, and protection of antigens, resulting in prolonged delivery. The risks associated with vaccine-derived Al are threefold: it can persist in the body, it can trigger pathological immunological responses, and it can make its way into the central nervous system (CNS).
... Human exposure to Al is mainly through food (spices, corn and yellow cheese), drinking water, pharmacological compounds (antacids, deodorants, vaccines and allergen injections), utensils and the environment [2,3]. Al has been suggested to cross the blood-brain barrier via transferrin (ironbinding protein) and is responsible for causing neurodegeneration by virtue of binding to glial and neuronal cells [4,5]. ...
Metals are considered as important components of a physiologically active cell, and imbalance in their levels can lead to various diseased conditions. Aluminium (Al) is an environmental neurotoxicant, which is etiologically related to several neurodegenerative disorders like Alzheimer's, whereas zinc (Zn) is an essential trace element that regulates a large number of metabolic processes in the brain. The objective of the present study was to understand whether Zn provides any physiological protection during Al-induced neurodegeneration. Male Sprague Dawley rats weighing 140-160 g received either aluminium chloride (AlCl3) orally (100 mg/kg b.wt./day), zinc sulphate (ZnSO4) in drinking water (227 mg/L) or combined treatment of aluminium and zinc for 8 weeks. Al treatment resulted in a significant decline in the cognitive behaviour of rats, whereas zinc supplementation caused an improvement in various neurobehavior parameters. Further, Al exposure decreased (p ≤ 0.001) the levels of neurotransmitters, acetylcholinesterase activity, but increased (p ≤ 0.001) the levels of L-citrulline as well as activities of nitric oxide and monoamine oxidase in the brain. However, zinc administration to Al-treated animals increased the levels of neurotransmitters and regulated the altered activities of brain markers. Western blot of tau, amyloid precursor protein (APP), glial fibrillary acidic protein (GFAP), ubiquitin, α-synuclein and Hsp 70 were also found to be elevated after Al exposure, which however were reversed following Zn treatment. Al treatment also revealed alterations in neurohistoarchitecture in the form of loss of pyramidal and Purkinje cells, which were improved upon zinc co-administration. Therefore, the present study demonstrates that zinc improves cognitive functions by regulating α-synuclein and APP-mediated molecular pathways during aluminium-induced neurodegeneration.
... For that reason, vaccine trials often treat an Al adjuvant-containing injection as a harmless "placebo" (a comparison benchmark or control treatment) or they use another Al-containing vaccine to treat a "control group, " despite evidence that Al in vaccine-relevant exposures is universally toxic to humans and animals [9,90,91]. Its use in a supposed "placebo" or in any "control" treatment in vaccine trials is indefensible [95]. It is precisely analogous to comparing fire A against fire B, to make the argument that since A is no hotter than B, A is therefore not a fire. ...
Over the last 200 years, mining, smelting, and refining of aluminum (Al) in various forms have increasingly exposed living species to this naturally abundant metal. Because of its prevalence in the earth's crust, prior to its recent uses it was regarded as inert and therefore harmless. However, Al is invariably toxic to living systems and has no known beneficial role in any biological systems. Humans are increasingly exposed to Al from food, water, medicinals, vaccines, and cosmetics, as well as from industrial occupational exposure. Al disrupts biological self-ordering, energy transduction, and signaling systems, thus increasing biosemiotic entropy. Beginning with the biophysics of water, disruption progresses through the macromolecules that are crucial to living processes (DNAs, RNAs, proteoglycans, and proteins). It injures cells, circuits, and subsystems and can cause catastrophic failures ending in death. Al forms toxic complexes with other elements, such as fluorine, and interacts negatively with mercury, lead, and glyphosate. Al negatively impacts the central nervous system in all species that have been studied, including humans. Because of the global impacts of Al on water dynamics and biosemiotic systems, CNS disorders in humans are sensitive indicators of the Al toxicants to which we are being exposed.
... The design of double blind placebo controlled (DBPC) vaccination studies use (essentially toxic) aluminium adjuvants in placebo formulations, clearly adding unnecessarily to an individual's aluminium body burden. This anomaly makes it extremely difficult to assess the safety or risks of each study appropriately [53]. Furthermore, risk assessments frequently refer to the comparably, much higher environmental exposures to aluminium. ...
We are living in an “aluminium age” with increasing bioavailability of the metal for approximately 125 years, contributing significantly to the aluminium body burden of humans. Over the course of life, aluminium accumulates and is stored predominantly in the lungs, bones, liver, kidneys and brain. The toxicity of aluminium in humans is briefly summarised, highlighting links and possible causal relationships between a high aluminium body burden and a number of neurological disorders and disease states.
Aluminium salts have been used as depot-adjuvants successfully in essential prophylactic vaccinations for almost 100 years, with a convincing positive benefit-risk assessment which remains unchanged.
However, allergen-specific immunotherapy commonly consists of administering a long-course programme of subcutaneous injections using preparations of relevant allergens. Regulatory authorities currently set aluminium limits for vaccines per dose, rather than per treatment course. Unlike prophylactic vaccinations, numerous injections with higher proportions of aluminium-adjuvant per injection are applied in SCIT and will significantly contribute to a higher cumulative life dose of aluminium. While the human body may cope robustly with a daily aluminium overload from the environment, regulatory cumulative threshold values in immunotherapy need further addressing. Based on the current literature, predisposing an individual to an unusually high level of aluminium, such as through subcutaneous immunotherapy, has the potential to form focal accumulations in the body with the propensity to exert forms of toxicity. Particularly in relation to longer-term health effects, the safety of aluminium adjuvants in immunotherapy remains unchallenged by health authorities. The possibility of providing an effective means of measuring aluminium accumulation in patients undergoing long-term SCIT treatment as well as reducing their aluminium body burden, is discussed.
... However, no such regulations exist and the amount of aluminium salt which is included as an adjuvant is wholly determined by its immuno-efficacy in tandem with the respective antigen or allergen. Indeed it is an anomaly of many trials of the safety of aluminiumadjuvanted vaccines and immunotherapies that the (essentially toxic) aluminium adjuvant is considered to be the appropriate placebo in such clinical trials [6]. ...
Sub-cutaneous immunotherapy is an effective treatment for allergy. It works by helping to modify or re-balance an individual's immune response to allergens and its efficacy is greatly improved by the use of adjuvants, most commonly, aluminium hydroxide. Aluminium salts have been used in allergy therapy for many decades and are assumed to be safe with few established side-effects. This assumption belies their potency as adjuvants and their potential for biological reactivity both at injection sites and elsewhere in the body. There are very few data purporting to the safety of aluminium adjuvants in allergy immunotherapy and particularly so in relation to longer term health effects. There are, if only few, published reports of adverse events following allergy immunotherapy and aluminium adjuvants are the prime suspects in the majority of such incidents. Aluminium adjuvants are clearly capable of initiating unwanted side effects in recipients of immunotherapy and while there is as yet no evidence that such are commonplace it is complacent to consider aluminium salts as harmless constituents of allergy therapies. Future research should establish the safety of the use of aluminium adjuvants in sub-cutaneous allergy immunotherapy.
... Al salts are the most widely used adjuvants today and have been since the 1920s [14]. The fact that they can trigger pathological immunological responses and a cascade of unwanted health effects has been relatively under-appreciated to date [16][17][18][19][20][21][22][23][24][25][26][27]30,45,72,73,80,84,89]. Nevertheless, it is clear that the problem with vaccine-derived Al is three-fold: it can persist in the body, it can trigger pathological immunological responses and it can make its way into the CNS where it can drive further deleterious immuno-inflammatory and excitotoxic processes [15,16,27,70,72,73,[78][79][80]. ...
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the benefits and harms of aluminium adjuvants used in a vaccine or an excipient versus the same vaccine or excipient, but having a different type of aluminium adjuvant formulation, or a different concentration, or with a different particle size.
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the benefits and harms of aluminium adjuvants used in vaccines versus placebo or no intervention, taking into consideration the type of the vaccine, and the type, size and concentration of aluminium adjuvant. © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Aluminium (Al) is one of the most prominent metals in the environment and is responsible for causing several neurological disorders, including Alzheimer's disease. On the other hand, zinc (Zn) is an essential micronutrient that is involved in regulating brain development and function. The present study investigates the protective potential of Zn in the uptake of (14) C-labeled amino acids and glucose and their turnover in rat brain slices during Al intoxication. Male Sprague Dawley rats (140-160 g) were divided into four different groups: normal control, Al treated (100 mg/kg body weight/day via oral gavage), Zn treated (227 mg/liter in drinking water), and Al + Zn treated. Radiorespirometric assay revealed an increase in glucose turnover after Al exposure that was attenuated after Zn treatment. Furthermore, the uptake of (14) C-labeled glucose was increased after Al treatment but was appreciably decreased upon Zn supplementation. In addition, the uptakes of (14) C-lysine, (14) C-leucine, and (14) C-aspartic acid were also found to be elevated following Al exposure but were decreased after Zn treatment. Al treatment also caused alterations in the neurohistoarchitecture of the brain, which were improved after Zn coadministration. Therefore, the present study suggests that Zn provides protection against Al-induced neurotoxicity by regulating glucose and amino acid uptake in rats, indicating that Zn could be a potential candidate for the treatment of various neurodegenerative disorders. © 2015 Wiley Periodicals, Inc.
© 2015 Wiley Periodicals, Inc.
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.
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.
Immune challenges during early development, including those vaccine-induced, can lead to permanent detrimental alterations of the brain and immune function. Experimental evidence also shows that simultaneous administration of as little as two to three immune adjuvants can overcome genetic resistance to autoimmunity. In some developed countries, by the time children are 4 to 6 years old, they will have received a total of 126 antigenic compounds along with high amounts of aluminum (Al) adjuvants through routine vaccinations. According to the US Food and Drug Administration, safety assessments for vaccines have often not included appropriate toxicity studies because vaccines have not been viewed as inherently toxic. Taken together, these observations raise plausible concerns about the overall safety of current childhood vaccination programs. When assessing adjuvant toxicity in children, several key points ought to be considered: (i) infants and children should not be viewed as "small adults" with regard to toxicological risk as their unique physiology makes them much more vulnerable to toxic insults; (ii) in adult humans Al vaccine adjuvants have been linked to a variety of serious autoimmune and inflammatory conditions (i.e., "ASIA"), yet children are regularly exposed to much higher amounts of Al from vaccines than adults; (iii) it is often assumed that peripheral immune responses do not affect brain function. However, it is now clearly established that there is a bidirectional neuro-immune cross-talk that plays crucial roles in immunoregulation as well as brain function. In turn, perturbations of the neuro-immune axis have been demonstrated in many autoimmune diseases encompassed in "ASIA" and are thought to be driven by a hyperactive immune response; and (iv) the same components of the neuro-immune axis that play key roles in brain development and immune function are heavily targeted by Al adjuvants. In summary, research evidence shows that increasing concerns about current vaccination practices may indeed be warranted. Because children may be most at risk of vaccine-induced complications, a rigorous evaluation of the vaccine-related adverse health impacts in the pediatric population is urgently needed.
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.
Aluminium adjuvants potentiate the immune response, thereby ensuring the potency and efficacy of typically sparingly available antigen. Their concomitant critical importance in mass vaccination programmes may have prompted recent intense interest in understanding how they work and their safety. Progress in these areas is stymied, however, by a lack of accessible knowledge pertaining to the bioinorganic chemistry of aluminium adjuvants, and, consequently, the inappropriate application and interpretation of experimental models of their mode of action. The objective herein is, therefore, to identify the many ways that aluminium chemistry contributes to the wide and versatile armoury of its adjuvants, such that future research might be guided towards a fuller understanding of their role in human vaccinations.
The study assessed the immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted cervical cancer vaccine in healthy Korean women aged 15-25 years.
Phase IIIB, double-blind, randomised (2:1), multi-centre trial was conducted in Korea from June 2007 to March 2008. The study enrolled 225 women in the HPV (N=149) and placebo (N=76) groups who received three doses of HPV-16/18 AS04-adjuvanted vaccine or placebo (aluminium hydroxide) administered intramuscularly at 0, 1, and 6 months and were followed until one month post-dose 3. Serum samples were collected pre-vaccination and one month post-dose 3. Safety and reactogenicity data were collected throughout.
In this trial, 208 women completed the study (141 in HPV group; 67 in placebo group). At month 7, all initially seronegative women had seroconverted for HPV-16 and HPV-18 antibodies with anti-HPV-16 and anti-HPV-18 geometric mean titres of 9,351.4 El.U/mL (95% CI, 8,145.5 to 10,735.8) and 4204.1 El.U/mL (95% CI, 3,626.5 to 4,873.6), respectively. Initially seropositive women showed similar increase in geometric mean titre levels. Compliance to the three dose vaccination course was 95.3% in HPV and 89.5% in placebo group. Solicited local (pain) and general (fatigue, myalgia or headache) symptoms were commonly reported in both groups. Three serious adverse events were reported (two in HPV group; one in placebo group), all unrelated to vaccination by the investigator; all recovered.
The HPV-16/18 AS04-adjuvanted vaccine was highly immunogenic with a clinically acceptable safety profile in Korean women. This study was in line with previous global studies in Europe, North America, and Brazil. (ClinicalTrials.gov number, NCT 00485732.).
The quadrivalent HPV types 6, 11, 16, 18 vaccine (Gardasil®) is a recombinant vaccine comprising purified virus-like particles derived from the L1 capsid proteins of HPV types 6, 11, 16 and 18.
The vaccine was highly immunogenic. Geometric mean titres (GMTs) and seroconversion rates for all four HPV types at month 7 in males aged 10–15 years were noninferior to those in females aged 16–23 years, and those in males aged 9–15 years were noninferior to those in females aged 9–15 years. In addition, GMTs and seroconversion rates in males aged 16–26 years receiving the vaccine were higher than those receiving amorphous aluminium hydroxyphosphate sulfate adjuvant (AAHS) control.
The quadrivalent HPV vaccine was significantly more effective than AAHS control at decreasing the incidence of HPV 6-, 11-, 16- or 18-related external genital lesions (primary endpoint) in a randomized, double-blind, placebo-controlled, multicentre study in males aged 16–26 years. The most common clinical endpoint was HPV 6- and 11-related condyloma; efficacy was robust against these lesions.
The vaccine is also expected to be protective against genital warts in males aged 9–15 years, as the immune response in males of this age group was noninferior to that in males aged 16–26 years.
The quadrivalent HPV vaccine was generally well tolerated in males aged 9–26 years. The most common adverse events reported were injection-site related, and most of these were of mild to moderate severity.
The recent swine H1N1 influenza outbreak demonstrated that egg-based vaccine manufacturing has an Achille's heel: its inability to provide a large number of doses quickly. Using a novel manufacturing platform based on transient expression of influenza surface glycoproteins in Nicotiana benthamiana, we have recently demonstrated that a candidate Virus-Like Particle (VLP) vaccine can be generated within 3 weeks of release of sequence information. Herein we report that alum-adjuvanted plant-made VLPs containing the hemagglutinin (HA) protein of H5N1 influenza (A/Indonesia/5/05) can induce cross-reactive antibodies in ferrets. Even low doses of this vaccine prevented pathology and reduced viral loads following heterotypic lethal challenge. We further report on safety and immunogenicity from a Phase I clinical study of the plant-made H5 VLP vaccine in healthy adults 18–60 years of age who received 2 doses 21 days apart of 5, 10 or 20 µg of alum-adjuvanted H5 VLP vaccine or placebo (alum). The vaccine was well tolerated at all doses. Adverse events (AE) were mild-to-moderate and self-limited. Pain at the injection site was the most frequent AE, reported in 70% of vaccinated subjects versus 50% of the placebo recipients. No allergic reactions were reported and the plant-made vaccine did not significantly increase the level of naturally occurring serum antibodies to plant-specific sugar moieties. The immunogenicity of the H5 VLP vaccine was evaluated by Hemagglutination-Inhibition (HI), Single Radial Hemolysis (SRH) and MicroNeutralisation (MN). Results from these three assays were highly correlated and showed similar trends across doses. There was a clear dose-response in all measures of immunogenicity and almost 96% of those in the higher dose groups (2×10 or 20 µg) mounted detectable MN responses. Evidence of striking cross-protection in ferrets combined with a good safety profile and promising immunogenicity in humans suggest that plant-based VLP vaccines should be further evaluated for use in pre-pandemic or pandemic situations.
Trial Registration
ClinicalTrials.gov NCT00984945
Immunization of girls against oncogenic human papillomavirus (HPV) types before sexual debut is important for cervical cancer prevention. This phase III blinded, randomized, controlled trial in adolescent girls assessed safety of the HPV-16/18 AS04-adjuvanted vaccine.
Girls (mean age 12 years) in 12 countries received the HPV-16/18 L1 virus-like particle AS04-adjuvanted vaccine (N = 1,035) or hepatitis A virus vaccine as control (N = 1,032) at 0, 1, and 6 months. The primary objective was to compare the occurrence of serious adverse events (SAEs) between groups. HPV-16 and HPV-18 antibody titers were assessed by enzyme-linked immunosorbent assay post-vaccination.
Up to study month 7, 11 girls in the HPV-16/18 vaccine group reported 14 SAEs and 13 girls in the control group reported 15 SAEs. The difference in SAE incidence between groups was .20% (95% CI, -.78, 1.20). No SAE in the HPV-16/18 vaccine group was considered related to vaccination or led to withdrawal. The incidence of solicited local and general symptoms up to 7 days post-vaccination was moderately higher with the HPV-16/18 vaccine than with control. The incidence of unsolicited symptoms, new onset of chronic diseases, and medically significant conditions was similar between groups. All girls seroconverted for both antigens after three doses of the HPV-16/18 vaccine; geometric mean titers were 19,882.0 and 8,262.0 EU/mL for anti-HPV-16 and -18 antibodies, respectively, in initially seronegative girls.
The HPV-16/18 AS04-adjuvanted vaccine was generally well tolerated and immunogenic when administered to young adolescent females, the primary target of organized vaccination programs.
To assess whether vaccination against human papillomavirus (HPV) increases the risk of miscarriage.
Pooled analysis of two multicentre, phase three masked randomised controlled trials
Multicentre trials in several continents and in Costa Rica.
26 130 women aged 15-25 at enrolment; 3599 pregnancies eligible for analysis.
Participants were randomly assigned to receive three doses of bivalent HPV 16/18 VLP vaccine with AS04 adjuvant (n=13 075) or hepatitis A vaccine as control (n=13 055) over six months.
Miscarriage and other pregnancy outcomes.
The estimated rate of miscarriage was 11.5% in pregnancies in women in the HPV arm and 10.2% in the control arm. The one sided P value for the primary analysis was 0.16; thus, overall, there was no significant increase in miscarriage among women assigned to the HPV vaccine arm. In secondary descriptive analyses, miscarriage rates were 14.7% in the HPV vaccine arm and 9.1% in the control arm in pregnancies that began within three months after nearest vaccination.
There is no evidence overall for an association between HPV vaccination and risk of miscarriage.
Clinical Trials NCT00128661 and NCT00122681.
The safety of the immune complexes composed of yeast-derived hepatitis B surface antigen (HBsAg) and antibodies (abbreviated as YIC) among healthy adults and chronic hepatitis B patients has been proved in phase I and phase IIa trial. A larger number of patients for study of dosage and efficacy are therefore needed.
Two hundred forty two HBeAg-positive chronic hepatitis B patients were immunized with six injections of either 30 microg YIC, 60 microg of YIC or alum adjuvant as placebo at four-week intervals under code. HBV markers and HBV DNA were monitored during immunization and 24 weeks after the completion of immunization. The primary endpoint was defined as loss of HBeAg, or presence of anti-HBe antibody or suppression of HBV DNA, while the secondary endpoint was both HBeAg seroconversion and suppression of HBV DNA. Statistical significance was not reached in primary endpoints four weeks after the end of treatment among three groups, however, at the end of follow-up, HBeAg sero-conversion rate was 21.8% (17/78) and 9% (7/78) in the 60 microg YIC and placebo groups respectively (p = 0.03), with 95% confidence intervals at 1.5% to 24.1%. Using generalized estimating equations (GEEs) model, a significant difference of group effects was found between 60 microg YIC and the placebo groups in terms of the primary endpoint. Eleven serious adverse events occurred, which were 5.1%, 3.6%, and 5.0% in the placebo, 30 microg YIC and 60 microg YIC groups respectively (p>0.05).
Though statistical differences in the preset primary and secondary endpoints among the three groups were not reached, a late and promising HBeAg seroconversion effect was shown in the 60 microg YIC immunized regimen. By increasing the number of patients and injections, the therapeutic efficacy of YIC in chronic hepatitis B patients will be further evaluated.
ChiCTR.org ChiCTR-TRC-00000022.
Currently, there are various approaches for developing therapeutic vaccines for chronic hepatitis B patients. Previously, an antigen-antibody-based therapeutic vaccine (YIC) has been conducted in a double-blind placebo controlled phase IIb clinical trial in 242 chronic hepatitis B patients. At the end of follow-up for 24 weeks, HBeAg sero-conversion rate was 21.6% in the 60 μg immunized group, compared to 9% in the alum immunized control group (p=0.03). To analyze the correlation between HBeAg-seroconversion, and decrease of serum HBsAg and HBV DNA, serum samples were back quantified for serum HBsAg and HBV DNA collected at baseline, end of treatment, and end of follow-up from patients who were treated either with 60 μg of YIC, or with placebo. Patients were dichotomized to HBeAg sero-converted and non-converted groups in comparison with patients in the placebo group. The correlations between HBeAg seroconversion and the decrease of HBsAg, HBV DNA and ALT levels during study period were analyzed using a logistic regression model. Results showed marked and sustained reduction of HBsAg, HBV DNA and ALT level in HBeAg sero-converted patients compared to those in patients of HBeAg non-converted and placebo groups. Reduction of HBV DNA and elevation of ALT was markedly associated with HBeAg seroconversion with an adjusted OR of 0.09 (95%CI: 0.01-0.62) and 0.08 (95%CI: 0.02-0.37) respectively after adjusted by age and sex, while reduction of HBsAg level was close to of significance (p=0.054). Analysis indicated that HBeAg sero-conversion was a reasonable endpoint for therapeutic vaccination.
India has the highest number of annual incident cases and mortality rates for cervical cancer worldwide. This study was conducted to assess the immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted cervical cancer vaccine in healthy Indian women aged 18-35 years old.
This double-blind, randomized (1:1), controlled and multicenter trial with two parallel groups, the Vaccine and Placebo groups, included 354 subjects in four centers across India. Subjects were given GlaxoSmithKline's HPV-16/18 AS04-adjuvanted cervical cancer vaccine or aluminum hydroxide placebo according to a 0, 1 and 6 month schedule and followed up until month 7. Serum samples were drawn at pre-vaccination and at month 7. Safety data were collected throughout the study.
A total of 330 subjects completed the study. One month post-Dose 3, all initially seronegative subjects in the Vaccine group had seroconverted for HPV-16 and HPV-18 antibodies with anti-HPV-16 and anti-HPV-18 geometric mean titer levels of 10226.5 EL.U/ml (95% confidence interval: 8847.1-11821.0) and 3953.0 EL.U/ml (95% confidence interval: 3421.8-4566.8), respectively. Initially seropositive subjects also showed an increase to similar geometric mean titer levels. Six serious adverse events (two in the Vaccine group and four in the Placebo group), all unrelated to vaccination, were reported. Commonly reported solicited local (injection-site pain) and general (fatigue, headache and fever) symptoms were similar in both groups. Compliance to the three-dose vaccination course was >97%.
The AS04-adjuvanted HPV-16/18 cervical cancer vaccine was highly immunogenic and generally well-tolerated making it a potential tool for prevention and control of cervical cancer in India.
The current influenza pandemic calls for a safe and effective vaccine. We assessed the safety and immunogenicity of eight formulations of 2009 pandemic influenza A H1N1 vaccine produced by ten Chinese manufacturers.
In this multicentre, double-blind, randomised trial, 12 691 people aged 3 years or older were recruited in ten centres in China. In each centre, participants were stratified by age and randomly assigned by a random number table to receive one of several vaccine formulations or placebo. The study assessed eight formulations: split-virion formulation containing 7.5 microg, 15 microg, or 30 microg haemagglutinin per dose, with or without aluminium hydroxide adjuvant, and whole-virion formulation containing 5 microg or 10 microg haemagglutinin per dose, with adjuvant. All formulations were produced from the reassortant strain X-179A (A/California/07/2009-A/PR/8/34). We analysed the safety (adverse events), immunogenicity (geometric mean titre [GMT] of haemagglutination inhibition antibody), and seroprotection (GMT >or=1:40) of the formulations. Analysis was by per protocol. Two sites registered their trial with ClinicalTrials.gov, numbers NCT00956111 and NCT00975572. The other eight studies were registered with the State Food and Drug Administration of China.
12 691 participants received the first dose on day 0, and 12 348 participants received the second dose on day 21. The seroprotection rate 21 days after the first dose of vaccine ranged from 69.5% (95% CI 65.9-72.8) for the 7.5 microg adjuvant split-virion formulation to 92.8% (91.9-93.6) for the 30 microg non-adjuvant split-virion formulation. The seroprotection rate was 86.5% (796 of 920; 84.1-88.7) in recipients of one dose of the 7.5 microg non-adjuvant split-virion vaccine compared with 9.8% (140 of 1432; 8.3-11.4) in recipients of placebo (p<0.0001). One dose of the 7.5 microg non-adjuvant split-virion vaccine induced seroprotection in 178 of 232 children (aged 3 years to <12 years; 76.7%, 70.7-82.0), 211 of 218 adolescents (12 years to <18 years; 96.8%, 93.5-98.7), 289 of 323 adults (18-60 years; 89.5%, 85.6-92.6), and 118 of 147 adults older than 60 years (80.3%, 72.9-86.4), meeting the European Union's licensure criteria for seroprotection in all age-groups. In children, a second dose of the 7.5 microg formulation increased the seroprotection rate to 97.7% (215 of 220, 94.8-99.3). Adverse reactions were mostly mild or moderate, and self-limited. Severe adverse effects occurred in 69 (0.6%, 0.5-0.8) recipients of vaccine compared with one recipient (0.1%, 0-0.2) of placebo. The most common severe adverse reaction was fever, which occurred in 25 (0.22%; 0.14-0.33) recipients of vaccine after the first dose and four (0.04%; 0.01-0.09) recipients of vaccine after the second dose compared with no recipients of placebo after either dose.
One dose of non-adjuvant split-virion vaccine containing 7.5 microg haemagglutinin could be promoted as the formulation of choice against 2009 pandemic influenza A H1N1 for people aged 12 years or older. In children (aged <12 years), two 7.5 mug doses might be needed.
Sinovac Biotech, Hualan Biological Bacterin, China National Biotec Group, Beijing Tiantan Biological Products, Changchun Institute of Biological Products, Changchun Changsheng Life Sciences, Jiangsu Yanshen Biological Technology Stock, Zhejiang Tianyuan Bio-Pharmaceutical, Lanzhou Institute of Biological Products, Shanghai Institute of Biological Products, and Dalian Aleph Biomedical.
There is an urgent need for a vaccine that is effective against the 2009 pandemic influenza A (H1N1) virus.
A split-virus, inactivated candidate vaccine against the 2009 H1N1 virus was manufactured, and we evaluated its safety and immunogenicity in a randomized clinical trial. Subjects were between 3 and 77 years of age, stratified into four age groups. The immunization schedule consisted of two vaccinations, 21 days apart. Subjects were injected with placebo or with vaccine, with or without alum adjuvant, at doses of 7.5 microg, 15 microg, or 30 microg. Serologic analysis was performed at baseline and on days 21 and 35.
A total of 2200 subjects received one dose, and 2103 (95.6%) received the second dose, of vaccine or placebo. No severe adverse side effects associated with the vaccine were noted. In the nonadjuvanted-vaccine groups, injection-site or systemic reactions, most mild in nature, were noted in 5.5 to 15.9% of subjects. Among the subjects receiving 15 microg of nonadjuvanted vaccine, a hemagglutination-inhibition titer of 1:40 or more was achieved by day 21 in 74.5% of subjects between 3 and 11 years of age, 97.1% of subjects between 12 and 17 years, 97.1% of subjects between 18 and 60 years, and 79.1% of subjects 61 years of age or older; by day 35, the titer had been achieved in 98.1%, 100%, 97.1%, and 93.3% of subjects, respectively. The proportion with a titer of 1:40 or more was generally highest among the subjects receiving 30 microg of vaccine, with or without adjuvant. Vaccine without adjuvant was associated with fewer local reactions and greater immune responses than was vaccine with adjuvant.
These data suggest that a single dose of 15 microg of hemagglutinin antigen without alum adjuvant induces a typically protective immune response in the majority of subjects between 12 and 60 years of age. Lesser immune responses were seen after a single dose of vaccine in younger and older subjects. (ClinicalTrials.gov number, NCT00975572).
If one was asked to produce a set of 'Trump Cards' based upon 'Forces of Nature Defining Life on Earth' then which card would be 'Top Trump'? I was recently chastised on the Darwin Today website for suggesting Darwin and 'natural selection' rather than, for example, Newton and 'gravity'. Although there is no denying the significance of gravity, my argument in favour of natural selection is simply that gravity is just one factor that contributes towards an outcome which ultimately is defined by natural selection. Both the beauty and the brilliance of natural selection are reflected in its omnipotence to explain the myriad observations of life and, as I will affirm herein, its explanation of the biological essentiality of aluminium and silicon is no exception.
Macrophagic myofasciitis and chronic fatigue syndrome are severely disabling conditions which may be caused by adverse reactions to aluminium-containing adjuvants in vaccines. While a little is known of disease aetiology both conditions are characterised by an aberrant immune response, have a number of prominent symptoms in common and are coincident in many individuals. Herein, we have described a case of vaccine-associated chronic fatigue syndrome and macrophagic myofasciitis in an individual demonstrating aluminium overload. This is the first report linking the latter with either of these two conditions and the possibility is considered that the coincident aluminium overload contributed significantly to the severity of these conditions in this individual. This case has highlighted potential dangers associated with aluminium-containing adjuvants and we have elucidated a possible mechanism whereby vaccination involving aluminium-containing adjuvants could trigger the cascade of immunological events which are associated with autoimmune conditions including chronic fatigue syndrome and macrophagic myofasciitis.
Aluminum-containing adjuvants are an important component of many vaccines because they safely potentiate the immune response. The structure and properties of aluminum hydroxide adjuvant, aluminum phosphate adjuvant and alum-precipitated adjuvants are presented in this review. The major antigen adsorption mechanisms, electrostatic attraction and ligand exchange, are related to the adjuvant structure. The manner by which aluminum-containing adjuvants potentiate the immune response is related to the structure, properties of the adjuvant and adsorption mechanism. Immunopotentiation occurs through the following sequential steps: inflammation and recruitment of antigen-presenting cells, retention of antigen at the injection site, uptake of antigen, dendritic cell maturation, T-cell activation and T-cell differentiation.
Molecular and supramolecular bioinorganic chemistry: applications in medical sciences
- C Exley
- In
- Merce Alr
- J Felcman
- Mal
Exley C. In: Merce ALR, Felcman J, Recio MAL, editors. Molecular and supramolecular bioinorganic chemistry: applications in medical sciences. New York: Nova Science Publishers Inc.; 2009. p. 45–68.