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Aluminum salts in vaccine − US perspective
Abstract
Aluminum in the form of aluminum hydroxide, aluminum phosphate or alum has been commonly used as an adjuvant in many vaccines licensed by the US Food and Drug Administration. Chapter 21 of the US Code of Federal Regulations [610.15(a)] limits the amount of aluminum in biological products, including vaccines, to 0.85 mg/dose. The amount of aluminum in vaccines currently licensed in the US ranges from 0.85-0.125 mg/dose. Clinical studies have demonstrated that aluminum enhances the antigenicity of some vaccines such as diphtheria and tetanus toxoids. Moreover, aluminum-adsorbed diphtheria and tetanus toxoids are distinctly more effective than plain fluid toxoids for primary immunization of children. There is little difference between plain and adsorbed toxoids for booster immunization. Aluminum adjuvants have a demonstrated safety profile of over six decades; however, these adjuvants have been associated with severe local reactions such as erythema, subcutaneous nodules and contact hypersensitivity.
... A comprehensive review of the existing literature on toxicology of aluminum adjuvants points to a glaring lack of scientific data validating their often claimed excellent safety record [54][55][56]. For example, in a 2022 systematic review and meta-analysis of studies assessing biodistribution, clearance and neurotoxicology of aluminum adjuvants in animal models, Masson et al. identified 31 eligible studies, of which 17 focused on neurotoxicological impacts [30]. ...
... Unsurprisingly, mechanisms of adjuvant toxicity are even less well understood than the mechanisms by which adjuvants enhance vaccine immunogenicity [22]. It is thus perplexing that the allowable amount of aluminum in human vaccines was selected exclusively on the basis of efficacy, not safety considerations [56], even though it is acknowledged that for prophylactic vaccines given to predominantly healthy individuals safety is to be prioritized over efficacy [72,73]. ...
... From these statements it is apparent that significant hurdles still need to be overcome before the safety of both existing and new adjuvants can be adequately assessed. The often heard claims that aluminum adjuvants have a long "established" and "demonstrated" safety record [54][55][56] are thus unsupported. ...
Background:
Medical ethics guidelines require of clinical trial investigators and sponsors to inform prospective trial participants of all known and potential risks associated with investigational medical products, and to obtain their free informed consent. These guidelines also require that clinical research be so designed as to minimize harms and maximize benefits.
Objective:
To examine Merck's scientific rationale for using a reactogenic aluminum-containing "placebo" in Gardasil HPV vaccine pre-licensure clinical trials.
Methods:
We examined the informed consent form and the recruitment brochure for the FUTURE II Gardasil vaccine trial conducted in Denmark; and we interviewed several FUTURE II trial participants and their treating physicians. We also reviewed regulatory documentation related to Gardasil vaccine approval process and the guidelines on evaluation of adjuvants used in human vaccines.
Results:
It was found that the vaccine manufacturer Merck made several inaccurate statements to trial participants that compromised their right to informed consent. First, even though the study protocol listed safety testing as one of the study's primary objectives, the recruitment brochure emphasized that FUTURE II was not a safety study, and that the vaccine had already been proven safe. Second, the advertising material for the trial and the informed consent forms stated that the placebo was saline or an inactive substance, when, in fact, it contained Merck's proprietary highly reactogenic aluminum adjuvant which does not appear to have been properly evaluated for safety. Several trial participants experienced chronic disabling symptoms, including some randomized to the adjuvant "placebo" group.
Conclusion:
In our view, the administration of a reactive placebo in Gardasil clinical trials was without any possible benefit, needlessly exposed study subjects to risks, and was therefore a violation of medical ethics. The routine use of aluminum adjuvants as "placebos" in vaccine clinical trials is inappropriate as it hinders the discovery of vaccine-related safety signals.
... 12,13 Since 1920, various forms of aluminum salts (alum) containing adjuvants have been used as successful adjuvants in many human vaccines, such as tetanus, diphtheria toxoids, and others. 14,15 In general, antigens are bound to the adjuvants via non-covalent binding including electrostatic, hydrophobic interactions, hydrogen bonding, and van der Waals forces. 16 Later in the 1990s, new adjuvants, i.e., the oil-in-water emulsion system (MF59), were developed to deliver influenza vaccine for the elderly. ...
... Aluminium hydroxide is one of the most widely used adjuvants in clinical practice. 14,15 This adjuvant helps boost immune responses and increase the efficacy of vaccines as shown in Figure 2. However, researchers are exploring various particulate adjuvants to replace the commonly used "alum." ...
The NLRP3 inflammasome is pivotal in orchestrating the immune response induced by nanoparticle adjuvants. Understanding the intricate mechanisms underlying the activation of NLRP3 inflammasome by these adjuvants is crucial for...
... The effectiveness of aluminum salts is attributed to factors like their ability to form a depot at the injection site, induce inflammation, and activate dendritic cells and T cells. 3,12,13,[23][24][25][26][27][28][29][30][31][32][33][34] Although aluminum has been used in vaccines for over seven decades, its precise immune mechanism remains not fully understood. ...
... They consist of aluminum hydroxide, aluminum phosphate, or a combination of both and are known to form a depot at the injection site, slowly releasing the vaccine antigen over time, which results in a stronger and prolonged immune response. 3,12,13,[23][24][25][26][27][28][29][30][31][32][33][34]40 They have been shown to enhance the immune response to a wide range of antigens, including those in vaccines for hepatitis B, human papillomavirus (HPV), and pneumococcal disease. Due to their proven safety record, wide-spectrum ability to strengthen immune responses, and ease of manufacture, they remain an attractive option for vaccine development. ...
A comprehensive review of the current landscape and advancements in vaccine adjuvants, providing critical insights into research, development, regulatory licensing, and potential future opportunities for enhancing vaccine efficacy and safety.
... Les recherches seront néanmoins portées sur la production de nouveaux adjuvants sans réelles tentatives pour comprendre les mécanismes exacts d'action des composés déjà utilisés ou les problèmes de sécurité qu'ils pourraient présenter. En 2002, l'administration américaine des denrées alimentaires et des médicaments (Food and Drug Administration (FDA)) écrivait que « le seuil de 15 mg d'alun ou 0,85 mg d'Al par dose vaccinale a été sélectionné empiriquement à partir des données qui ont montré que cette quantité d'Al renforçait l'antigénicité et l'efficacité du vaccin » (Baylor, Egan & Richman, 2002). ...
... Les mécanismes mis en jeu sont encore incomplètement compris (Marrack, McKee & Munks, 2009;Exley, Siesjö & Eriksson, 2010). La FDA a fixé empiriquement le niveau autorisé d'adjuvant à 0,85 mg d'Al par dose de vaccin, sur la base de résultats montrant un bon effet adjuvant à cette concentration (selon Joan May, FDA/CBER (Center for Biologics Evaluation and Research), citée dans (Baylor, Egan & Richman, 2002)). Cette concentration, qui reste sujette à caution, est de plus très imprécise au regard des données du fabricant et fluctuante entre vaccins d'un même lot (Shardlow et al., 2021). ...
La vaccination est une avancée majeure de la médecine moderne ayant permis d’éradiquer certaines maladies et d’endiguer la propagation de nombreuses autres. Malgré une bonne tolérance par la population générale, certains individus présentent des difficultés d’élimination des particules aluminiques utilisées comme adjuvant vaccinaux. Ces patients présentent une lésion histopathologique musculaire caractéristique, biopersistante sur le long terme et composée de cellules immunitaires présentant des inclusions intracellulaires de cristaux aluminiques. Cette lésion, associée à un ensemble d'arthromyalgie, de fatigue chronique et de troubles cognitifs, est appelée myofasciite à macrophages (MFM).Les vaccins à base d’aluminium sont des particules pseudo-infectieuses gérées comme des agents pathogènes par des cellules présentatrices d'antigènes via endocytose et élimination ultérieure par l'intermédiaire de la machinerie xéno/autophagique. Par ailleurs, la littérature scientifique a montré que l’oxy-hydroxyde d'aluminium, l’un des principaux adjuvants, peut perturber la réponse autophagique. Cela conforte l’idée que l’intolérance aux adjuvants aluminiques pourrait être la conséquence d’une interaction de type « gènes x environnement » reposant sur une déficience de l’autophagie dans les cellules de l’immunité comme facteur de susceptibilité individuelle aux particules d’aluminium d’origine vaccinale.Les réponses autophagiques et inflammatoires des cellules immunitaires isolées en réponse aux particules aluminiques n’étant pas totalement caractérisées parmi la population globale. Le travail de thèse présenté dans ce manuscrit a donc eu pour premier objectif d’étudier ces réponses chez des individus sains avant de comparer les résultats avec ceux obtenus chez des individus atteint de MFM. Les données ont démontré que de nombreuses interactions entre les mécanismes d’endocytose, d’autophagie et d’inflammation sont mises en œuvre par les cellules de l’immunité en réponse à la présence de particules d’aluminium. Des expérimentations complémentaires seront nécessaires afin de caractériser finement les différentes intrications entre ces mécanismes. Cependant, certaines observations ont laissé entrevoir de subtiles variations de réponse au sein des cellules immunitaires des patients MFM exposées à des particules aluminiques. Ces cellules ont ainsi présenté un équilibre entre autophagie et endocytose penchant en faveur de l’endocytose et associé à une réponse inflammatoire réduite par rapport aux individus sains. Ces observations sont en accord avec la littérature scientifique actuelle et pourraient être principalement la conséquence plus que la cause de l’état de santé des patients MFM.Suite aux observations in vitro, des analyses exploratoires in vivo ont été menées afin de développer un modèle murin avec des perturbations de l’autophagie pour étudier l’importance de ce mécanisme dans la prise en charge et le devenir des particules aluminiques. Une étude longue a été réalisée pour tester l’efficacité d’un traitement pharmacologique (hydroxychloroquine) à perturber l’autophagie sans induire de toxicité. Nos résultats montrent que, bien qu’apparemment non toxique pour les animaux, le traitement utilisé n’a pas été en mesure de perturber l’autophagie sur le long terme. Par conséquent, l’étude de l’importance du mécanisme autophagique dans la translocation des particules d’aluminium a été réalisée en privilégiant un modèle de KO génétique. Les données ont confirmé les précédentes observations faites sans mettre en avant de rôle majeur de l’autophagie dans le déplacement des particules d’aluminium depuis le site d’injection initial, au regard du faible effectif d’animaux disponibles pour cette étude.En conclusion, ce travail a permis de mettre en évidence une prise en charge des particules aluminiques d’origine vaccinale d’une grande complexité, nécessitant une approche pluridisciplinaire pour être finement décrite.
... Aluminum salt adjuvants are the most commonly used adjuvant in human vaccines licensed by the FDA and regulatory agencies worldwide, and have been administered to billions of individuals over the past 90 years [33][34][35] . Moreover, aluminum salt adjuvants are currently used in infant vaccines against hepatitis B, diphtheria-tetanus-pertussis (DTaP), Haemophilus influenzae type b (Hib), and pneumococcus infectious agents 36 , with an excellent safety profile 37,38 . ...
... Finally, we anticipate the potential use of DCFHP-alum as an important primary vaccine in previously unvaccinated and uninfected individuals, especially in pediatric populations, including infants. Aluminum salt adjuvants are commonly used in infant vaccines and as part of routine childhood immunization schedules, and their excellent safety profile has been established over decades [33][34][35][36][37][38] . In infants and other DCFHP-alum vaccine recipients naive to SARS-CoV-2 infection or vaccination, we would anticipate robust, cross-reactive responses similar to the naive NHPs studied here. ...
While the rapid development of COVID-19 vaccines has been a scientific triumph, the need remains for a globally available vaccine that provides longer-lasting immunity against present and future SARS-CoV-2 variants of concern (VOCs). Here, we describe DCFHP, a ferritin-based, protein-nanoparticle vaccine candidate that, when formulated with aluminum hydroxide as the sole adjuvant (DCFHP-alum), elicits potent and durable neutralizing antisera in non-human primates against known VOCs, including Omicron BQ.1, as well as against SARS-CoV-1. Following a booster ~one year after the initial immunization, DCFHP-alum elicits a robust anamnestic response. To enable global accessibility, we generated a cell line that can enable production of thousands of vaccine doses per liter of cell culture and show that DCFHP-alum maintains potency for at least 14 days at temperatures exceeding standard room temperature. DCFHP-alum has potential as a once-yearly (or less frequent) booster vaccine, and as a primary vaccine for pediatric use including in infants.
... Aluminum salts, such as AH and aluminum phosphate, are the most commonly used adjuvants in vaccines due to their proven ability to enhance immune response. These compounds are utilized in vaccines because of their capacity to act as both a physical depot for antigens and as immunostimulants [14,15]. This dual role makes aluminum an essential component of many vaccines, especially those used to prevent diseases like hepatitis B, diphtheria, tetanus, and pertussis [16][17][18]. ...
Objective: This manuscript describes an innovative, non-destructive, high-throughput method for the quantification of aluminum hydroxide in aluminum-adjuvanted vaccines, eliminating the need of reagents and providing real-time results. The method is based on a spectrophotometric principle, and several model proteins were studied and tested with the aim to simulate the behavior of aluminum-adjuvanted antigens. Methods: As a proof of concept, the MenB vaccine was used, and the titration of aluminum hydroxide (AH) with ethylenediaminetetraacetic acid (EDTA) was used as an orthogonal reference, as it is one of the current release methods for the content determination of aluminum-hydroxide-adjuvanted vaccine drug products (DPs). The factors influencing the spectrophotometric analysis, such as different plate 96/well containers, variation in the sedimentation of the suspension due to component addition errors during formulation, and batch-to-batch variation were studied to assess the method’s robustness. Five concentration levels (ranging from 2.0 to 4.0 mg/mL AH) with two different batches of aluminum hydroxide were each measured with independent preparations performed by three different operators, for a total of four sessions/operator and 20 formulations/session. An in-depth statistical study was carried out with generated data to assess the precision (in terms of intermediate precision and repeatability), accuracy, linearity, and specificity of the method. Results: The novel spectrophotometric method and the official release one (potentiometric) yielded comparable results, demonstrating the potential of this new method as a release test for AH-adjuvanted products. A simple calibration curve enabled the measurement of samples in a 96-well plate in just a few minutes. Conclusions: We developed a novel method for Aluminum concentration determination in Aluminum-containing pharmaceutical products, like alum-adjuvanted vaccines. This method is fast, completely automatable, and as precise and accurate as already-in-place release methods.
... To boost the immune response, an adjuvant is added to the inactivated virus which will improve the vaccine's effectiveness by prolonging the presence of antigen in the body. The commonly used adjuvants are aluminium hydroxide [102] or montanide [103]. Recently, to activate aluminium adjuvants to induce cell-mediated immunity the composite nano adjuvant N-2-HACC-Al NPs were synthesized by the N -2 Hydroxypropyl trimethyl ammonium chloride chitosan (N-2-HACC) and aluminum sulfate (Al2(SO4)3). ...
Newcastle disease is a global disease, spreading quickly during outbreaks in poultry and leading to significant economic loss due to high morbidity, mortality, trade restrictions and embargoes. This disease has been present in India for the past 96 years, since 1928. Antigenic differences among Newcastle disease virus (NDV) strains are resulting in massive outbreaks in vaccinated and un-vaccinated poultry flocks around the globe. Synanthropic bird reservoirs contribute significantly to the extensive genetic diversity of the virus. This diversity, along with the vulnerability of many avian species, has led to diagnostic and vaccination failures. The genetic attributes of the circulating strains in India, meanwhile, remain mostly undisclosed. Ongoing evolution of spectrum of NDV genotypes in India, this review paper underscores the need for vigilant monitoring and adaptation of vaccination strategies to address emerging variants.
... Eine der Möglichkeiten, die Fähigkeit von Nanopartikeln zur Induktion von NET-Bildung mit anschließender Sequestrierung von Nanopartikeln und selbstlimitierender Entzündung zu nutzen, besteht darin, sie in Impfstoffen anzuwenden. Aluminiumbasierte Salze (Alum) werden seit fast 90 Jahren hauptsächlich in Form von Aluminiumoxyhydroxid (AlOOH) oder Aluminiumhydroxid (Al(OH) 3 ) in Impfstoffen verwendet (Baylor et al., 2002;Digne et al., 2002;Vinogradov & Vinogradov, 2014). Die Adjuvanz von Al-haltigen Partikeln hängt von ihrer chemischen und physischen Beschaffenheit ab (Song et al., 2009). ...
... Cosmetics are deemed safe with aluminum concentrations of 2.65% in toothpaste and 0.77% in lipstick [9], and vaccines licensed in the USA are considered safe when containing aluminum ranging from 0.85-0.125 mg per dose [10]. ...
The study aims to investigate the residual and histopathological effects of chronic aluminum chloride (AlCl3) toxicity in the kidney and liver of male rats. After 30-, 60-, and 90-day exposure period, analyses were conducted to assess the toxicity in the kidney and liver. The results showed that the concentration of AlCl3 in the kidney and liver increased significantly in 30-, 60-, and 90-day periods. The effects of oxidative stress on the kidneys and liver were dose- and time-dependent. Levels of malondialdehyde (MDA) significantly increased when exposed to AlCl3 groups. Conversely, the activity of antioxidant parameters, including reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD), significantly decreased in the AlCl3 exposed groups, indicating compromised oxidant mechanisms. Both the kidney and liver exhibited severe tissue damage, including necrosis, fibrosis, and inflammatory cell infiltration, in rats exposed to AlCl3. Kidney sections showed hyperplasia of the epithelial cells lining the renal tubules, resembling finger-like structures. Liver sections displayed severe lobular hyperplasia and an increase in mitotic figures. Our study suggests that AlCl3 has a detrimental impact on these vital organs and emphasizes the importance of monitoring and mitigating aluminum exposure, particularly where it is present in high concentration.
... Multiple studies have demonstrated the effectiveness of IN vaccines in protecting both animal models and people against B. pertussis infections (24,30,34,36,37). aP vaccines utilize the adjuvant alum, to which the antigens included in the formulation are adsorbed, allowing for their presentation to immune cells (38). Alum elicits a Th2-polarized immune response, which leads to the downstream activation of humoral immunity and production of antibodies (39,40). ...
The protection afforded by acellular pertussis vaccines wanes over time, and there is a need to develop improved vaccine formulations. Options to improve the vaccines involve the utilization of different adjuvants and administration via different routes. While intramuscular (IM) vaccination provides a robust systemic immune response, intranasal (IN) vaccination theoretically induces a localized immune response within the nasal cavity. In the case of a Bordetella pertussis infection, IN vaccination results in an immune response that is similar to natural infection, which provides the longest duration of protection. Current acellular formulations utilize an alum adjuvant, and antibody levels wane over time. To overcome the current limitations with the acellular vaccine, we incorporated a novel TLR4 agonist, BECC438b, into both IM and IN acellular formulations to determine its ability to protect against infection in a murine airway challenge model. Following immunization and challenge, we observed that DTaP + BECC438b reduced bacterial burden within the lung and trachea for both administration routes when compared with mock-vaccinated and challenged (MVC) mice. Interestingly, IN administration of DTaP + BECC438b induced a Th1-polarized immune response, while IM vaccination polarized toward a Th2 immune response. RNA sequencing analysis of the lung demonstrated that DTaP + BECC438b activates biological pathways similar to natural infection. Additionally, IN administration of DTaP + BECC438b activated the expression of genes involved in a multitude of pathways associated with the immune system. Overall, these data suggest that BECC438b adjuvant and the IN vaccination route can impact efficacy and responses of pertussis vaccines in pre-clinical mouse models.
... An important factor in meeting these requirements is the selection of an appropriate adjuvant. Until recently, alum was the only adjuvant approved for human use in the United States (Baylor et al., 2002). However, in 2009, the U.S. Food and Drug Administration granted licensure for human use to the first TLR ligand-vaccine, a TLR4 agonistadjuvanted human papillomavirus vaccine (Centers for Disease Control and Prevention, 2010). ...
Tol-like receptor (TLR) agonists, as potent adjuvants, have gained attention in vaccine research for their ability to enhance immune responses. This study focuses on their application in improving vaccine efficacy against key viral infections, including hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), SARS-CoV-2, influenza virus, and flaviviruses, including West Nile virus, dengue virus, and chikungunya virus. Vaccines are crucial in preventing microbial infections, including viruses, and adjuvants play a vital role in modulating immune responses. However, there are still many diseases for which effective vaccines are lacking or have limited immune response, posing significant threats to human health. The use of TLR agonists as adjuvants in viral vaccine formulations holds promise in improving vaccine effectiveness. By tailoring adjuvants to specific pathogens, such as HBV, HCV, HIV, SARS-CoV-2, influenza virus, and flavivirus, protective immunity against chronic and emerging infectious disease can be elicited.
... It makes up about 8% of the mass of the Earth's crust [9]. It is widely used in our everyday lives, from food additives and packaging to building and water treatment [10,11]. Too much aluminium can be harmful to the human body, although it is not an essential element. ...
Al³⁺ excess in the body can cause many diseases. The development of chemosensors for the detection of Al³⁺ is therefore highly desirable. A hydrazide Schiff base compound containing triphenylphosphonium units (ER) was prepared and used as fluorescence turn-on sensor for the sensing of Al³⁺. Detection of Al³⁺ among various metals has been achieved successfully through the formation of Al³⁺-ligand coordination complexes. To detect Al³⁺, the “turn on” property of the fluorogenic chemosensor was investigated. Fluorescence sensing studies were carried out in CH3OH-Water (v/v, 9/1, pH 7.0) at λem = 528 nm. The LOD for sensing of Al³⁺ was found to be 0.129 µM. Using Job’s graph, the stoichiometric ratio of ER- Al³⁺ was determined to be 1:1. The binding constant was determined to be 1.7 × 10⁷ M⁻¹ between Al3 + and the chemosensor ER. Finally, the determination of Al³⁺ in real herbal teas was carried out by using the sensing function of the chemosensor ER.
... For over seven decades, aluminum salts, including aluminum hydroxide, aluminum phosphate, and aluminum potassium sulfate, have demonstrated a safe track record in vaccine formulations [210][211][212][213]. These adjuvants were first employed during the 1930s, 1940s, and 1950s in conjunction with diphtheria, tetanus, pertussis, and poliomyelitis vaccines, as scientific investigations revealed their ability to enhance the immune system's reaction to these immunizations [214,215]. A systematic review with meta-analysis comprehensively analyzed the adverse events after immunization with aluminum-containing diphtheria, tetanus, and pertussis (DTP) vaccines. ...
Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is a prevalent global infectious disease and a leading cause of mortality worldwide. Currently, the only available vaccine for TB prevention is Bacillus Calmette–Guérin (BCG). However, BCG demonstrates limited efficacy, particularly in adults. Efforts to develop effective TB vaccines have been ongoing for nearly a century. In this review, we have examined the current obstacles in TB vaccine research and emphasized the significance of understanding the interaction mechanism between MTB and hosts in order to provide new avenues for research and establish a solid foundation for the development of novel vaccines. We have also assessed various TB vaccine candidates, including inactivated vaccines, attenuated live vaccines, subunit vaccines, viral vector vaccines, DNA vaccines, and the emerging mRNA vaccines as well as virus-like particle (VLP)-based vaccines, which are currently in preclinical stages or clinical trials. Furthermore, we have discussed the challenges and opportunities associated with developing different types of TB vaccines and outlined future directions for TB vaccine research, aiming to expedite the development of effective vaccines. This comprehensive review offers a summary of the progress made in the field of novel TB vaccines.
... Several hypotheses deemed not worthy of research by recalcitrant institutional authorities have yielded verifiable results contrary to what the expert consensus was. For example, claims that vaccine adjuvants were safe have been tested [9] and found cytotoxic to nerve cells in vitro [10]. The illusion of consensus can hamper the progress of a scientific field if those experts holding the consensus still decide which ideas are meritorious. ...
This paper explores the application of the Theory of Constraints (ToC) to optimize knowledge production in research settings. While ToC is traditionally used in manufacturing and project management, its principles can be adapted to improve the efficiency and effectiveness of scientific research. By identifying and addressing bottlenecks and inefficiencies, researchers can enhance productivity and outcomes. This research argues that ToC is applicable to both repetitive and one-off knowledge production processes, offering opportunities for streamlining workflows and resource allocation. Case studies illustrate the potential impact of ToC on collaboration, discoveries, and overall scientific impact. This study contributes to the growing body of literature on management methodologies in research and highlights the need for a continuous improvement mindset in knowledge production. Embracing ToC principles enables researchers and organizations to navigate the complexities of the research landscape more effectively. Introduction The Theory of Constraints (ToC) is a management philosophy and methodology originally developed by Eliyahu M. Goldratt to improve organizational performance[1]. While ToC applies to manufacturing and project management in its original use cases, its principles can also be adapted to knowledge production in a research setting. While this may seem like a tenuous application of TOC, there is great potential in its correct application. The challenge in application is that most people view scientific knowledge production as a one-off production, and not a continuous process. This is true for many projects, however, there are repetitive aspects which are amenable to horizontal expansion with minimal changes in processes. Also, ToC can be applied to one-off production[2]. Theory of constraints at the project management level The ToC approach requires describing scientific production from a bird's eye view. In scientific project management, the researcher first establishes the research question at the outset, and the explicit hypotheses that are to be tested[3]. Typically, a research article will test multiple different hypotheses, and hypotheses will emerge from the work itself, as results come in. Serendipity is also a possibility, as an effect may manifest that is outside of the predicted behavior of the system.
... Moreover, it needs to be accepted that enhancing immunity inevitably leads to some undesired effects [36]. Alum adjuvants are generally deemed safe, and usually held responsible for local adverse reactions such as pain/tenderness at the injection site, accompanied by various degrees of inflammation, erythema, subcutaneous nodules and/or granuloma [37]. Additionally, in susceptible patients, alum adjuvants may trigger allergic reactions of various intensities, which appear to be alum concentration-dependent. ...
Ever since the development of the first vaccine, vaccination has had the great impact on global health, leading to the decrease in the burden of numerous infectious diseases. However, there is a constant need to improve existing vaccines and develop new vaccination strategies and vaccine platforms that induce a broader immune response compared to traditional vaccines. Modern vaccines tend to rely on certain nanotechnology platforms but are still expected to be readily available and easy for large-scale manufacturing and to induce a durable immune response. In this review, we present an overview of the most promising nanoadjuvants and nanoparticulate delivery systems and discuss their benefits from tehchnological and immunological standpoints as well as their objective drawbacks and possible side effects. The presented nano alums, silica and clay nanoparticles, nanoemulsions, adenoviral-vectored systems, adeno-associated viral vectors, vesicular stomatitis viral vectors, lentiviral vectors, virus-like particles (including bacteriophage-based ones) and virosomes indicate that vaccine developers can now choose different adjuvants and/or delivery systems as per the requirement, specific to combatting different infectious diseases.
... High-dose vaccination and the use of adjuvants could improve the decrease in vaccine immune responses due to aging. Appropriate use of adjuvants enhances the rate and magnitude of immune responses against antigens in the vaccine [92][93][94][95]. Aluminum salt-based vaccine adjuvants are used as adjuvants for diphtheria, tetanus, and pertussis (DTaP), haemophilus influenzae B (Hib), pneumococcal, and hepatitis A and B vaccines. ...
Dysbiosis of the gut microbiota with aging contributes to a reduction in important cross-feeding bacterial reactions in the gut and immunosenescence, which could contribute to a decrease in vaccine efficacy. Fever, cough, and fatigue are the main signs of coronavirus disease 2019 (COVID-19); however, some patients with COVID-19 present with gastrointestinal symptoms. COVID-19 vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the best measures to reduce SARS-CoV-2 infection rates and the severity of COVID-19. The immunogenicity of COVID-19 vaccines is influenced by the composition of the gut microbiota, and the immune response to COVID-19 vaccines decreases with age. In this review, we discuss gut microbiota dysbiosis and immunosenescence in the older adults, the role of gut microbiota in improving the efficacy of COVID-19 vaccines, and dietary interventions to improve the efficacy of COVID-19 vaccines in the older adults.
... To determine the effect of an aluminum adjuvant (see characterization results in Figure S1a-d) on the development of skin inflammation, we first employed an imiquimod (IMQ)-induced psoriasis-like skin inflammation mouse model (Figure 1a), in which both Th1 and Th17 cell-mediated adaptive immunity play a role in driving epidermal hyperplasia and scaling [25]. A dose of 840 µg aluminum/mouse was used in our animal study, and this dose is within the recommended range in vaccines for clinical use [26]. It is also a common practice for determining vaccine immunogenicity in a mouse model as an in vivo potency assay, in which a full human dose or even doubled the human dose was used for intraperitoneal (i.p.) injection into each mouse [27,28]. ...
Aluminum salt (AS), one of the most commonly used vaccine adjuvants, has immuno-modulatory activity, but how the administration of AS alone may impact the activation of the skin immune system under inflammatory conditions has not been investigated. Here, we studied the therapeutic effect of AS injection on two distinct skin inflammatory mouse models: an imiquimod (IMQ)-induced psoriasis-like model and an MC903 (calcipotriol)—induced atopic dermatitis-like model. We found that injection of a high dose of AS not only suppressed the IMQ-mediated development of T-helper 1 (Th1) and T-helper 17 (Th17) immune responses but also inhibited the IMQ-mediated recruitment and/or activation of neutrophils and macrophages. In contrast, AS injection enhanced MC903-mediated development of the T-helper 2 (Th2) immune response and neutrophil recruitment. Using an in vitro approach, we found that AS treatment inhibited Th1 but promoted Th2 polarization of primary lymphocytes, and inhibited activation of peritoneal macrophages but not bone marrow derived neutrophils. Together, our results suggest that the injection of a high dose of AS may inhibit Th1 and Th17 immune response-driven skin inflammation but promote type 2 immune response-driven skin inflammation. These results may provide a better understanding of how vaccination with an aluminum adjuvant alters the skin immune response to external insults.
... Nowadays, people are exposed to aluminum (Al 3+ ) from day one of their life and over the entire life cycle. In infants, aluminum "lurks" from vaccines [27] and milk formulas [28]. In adulthood, humans come to contact with aluminum in almost every aspect of their life. ...
Human environment is highly contaminated with aluminum, and aluminum is toxic to majority of tissues, particularly to neurons. In previous decades, aluminum exposure was frequently linked with the onset of Alzheimer’s disease (AD), and increased levels of Al were detected in the brains of individuals with AD. People who live in a certain area are exposed to aluminum in a similar way (they eat the same vegetable and other foodstuffs, use similar cosmetics, and buy medications from the same manufacturer), nevertheless not all of them develop Alzheimer’s disease. Majority of known risk factors for AD promote atherosclerosis and consequently reduce brain blood supply. In this review, we highlighted the significance of local (carotid disease and atherosclerosis of intracranial blood vessels) and systemic hypoxia (chronic obstructive pulmonary disease and anemia) in the development of AD. Nerve tissue is very sophisticated and sensitive to hypoxia and aluminum toxicity. As a side effect of compensatory mechanisms in case of hypoxia, neurons start to uptake aluminum and iron to a greater extent. This makes perfect a background for the gradual onset and development of AD.
... Aluminum is integral to many vaccines, enhancing immunogenicity and effectiveness. 8 Aluminum adjuvants have a well-established safety profile, 9 and are used in many vaccines given in early childhood. 10 However, data from animal studies suggest the theoretical possibility that aluminum adjuvants could influence allergy risk through inducing a T helper 2 cell (Th2)-biased immune response. ...
Objective
To assess the association between cumulative aluminum exposure from vaccines before age 24 months and persistent asthma at age 24 to 59 months.
Methods
A retrospective cohort study was conducted in the Vaccine Safety Datalink (VSD). Vaccination histories were used to calculate cumulative vaccine-associated aluminum in milligrams (mg). The persistent asthma definition required one inpatient or 2 outpatient asthma encounters, and ≥2 long-term asthma control medication dispenses. Cox proportional hazard models were used to evaluate the association between aluminum exposure and asthma incidence, stratified by eczema presence/absence. Adjusted hazard ratios (aHR) and 95% confidence intervals (CI) per 1 mg increase in aluminum exposure were calculated, adjusted for birth month/year, sex, race/ethnicity, VSD site, prematurity, medical complexity, food allergy, severe bronchiolitis, and health care utilization.
Results
The cohort comprised 326,991 children, among whom 14,337 (4.4%) had eczema. For children with and without eczema, the mean (standard deviation [SD]) vaccine-associated aluminum exposure was 4.07 mg (SD 0.60) and 3.98 mg (SD 0.72), respectively. Among children with and without eczema, 6.0% and 2.1%, respectively, developed persistent asthma. Among children with eczema, vaccine-associated aluminum was positively associated with persistent asthma (aHR 1.26 per 1 mg increase in aluminum, 95% CI 1.07, 1.49); a positive association was also detected among children without eczema (aHR 1.19, 95% CI 1.14, 1.25).
Conclusion
In a large observational study, a positive association was found between vaccine-related aluminum exposure and persistent asthma. While recognizing the small effect sizes identified and the potential for residual confounding, additional investigation of this hypothesis appears warranted.
... Vaccines in humans commonly contain from 0.125 mg (Prevenar 13 # , Pfizer, New York, NY) to 0.85 mg (Pediarix # , GSK) of Al 3þ /dose 1 (the volume of a dose is usually 0.5 ml). From the 1960s, the Food and Drug Administration (FDA) empirically fixed the authorized level of adjuvant at 0.85 mg of Al per dose of vaccine, based on results showing a good adjuvant effect at this concentration (according to Joan May, FDA/ CBER, quoted in Baylor et al. 2002). This regulated value has never been changed since that time. ...
Aluminum (Al) salts are commonly used as adjuvants in human and veterinary vaccines for almost a century. Despite this long history of use and the very large number of exposed individuals, data in the literature concerning the fate of these molecules after injection and their potential effects on the nervous system is limited. In the context of (i) an increase of exposure to Al salts through vaccination; (ii) the absence of safety values determined by health regulators; (iii) the lack of robustness of the studies used as references to officially claim Al adjuvant innocuity; (iv) the publication of several animal studies investigating Al salts clearance/biopersistence and neurotoxicity; we have examined in this review all published studies performed on animals and assessing Al adjuvants kinetics, biodistribution, and neuro-modulation since the first work of A. Glenny in the 1920s. The diversity of methodological approaches, results, and potential weaknesses of the 31 collected studies are exposed. A large range of protocols has been used, including a variety of exposure schedule and analyses methods, making comparisons between studies uneasy. Nevertheless, published data highlight that when biopersistence, translocation, or neuromodulation were assessed, they were documented whatever the different in vivo models and methods used. Moreover, the studies pointed out the crucial importance of the different Al adjuvant physicochemical properties and host genetic background on their kinetics, biodistribution, and neuro-modulatory effects. Regarding the state of the art on this key public health topic, further studies are clearly needed to determine the exact safety level of Al salts.
... In the 1960s, the Food and Drug Administration established the approved amount of 0.85 mg Al per dose of vaccine based on adjuvant efficiency [149], without providing results from potential safety protocols. In addition, the simultaneous administration of several Al-containing vaccines was not considered, nor were post-injection kinetics or toxicity levels [150]. ...
Autism spectrum disorder (ASD), schizophrenia, and bipolar disorder are genetically complex and heterogeneous neurodevelopmental disorders (NDDs) resulting from genetic factors and gene-environment (GxE) interactions for which onset occurs in early brain development. Recent progress highlights the link between ASD and (i) immunogenetics, neurodevelopment, and inflammation, and (ii) impairments of autophagy, a crucial neurodevelopmental process involved in synaptic pruning. Among various environmental factors causing risk for ASD, aluminum (Al)containing vaccines injected during critical periods have received special attention and triggered relevant scientific questions. The aim of this review is to discuss the current knowledge on the role of early inflammation, immune and autophagy dysfunction in ASD as well as preclinical studies which question Al adjuvant impacts on brain and immune maturation. We highlight the most recent breakthroughs and the lack of epidemiological, pharmacokinetic and pharmacodynamic data constituting a “scientific gap”. We propose additional research, such as genetic studies that could contribute to identify populations at genetic risk, improving diagnosis, and potentially the development of new therapeutic tools.
... In this context, aluminum adjuvants deserve a special mention. Such distinction is due to its long years of use, beginning in 1926of use, beginning in (Glenny et al., 1926; its proven ability to combine with numerous viral and bacterial antigens (Baylor et al., 2002), high degree of safety, stability, known chemical structure, easy preparation and, above all, low cost (Ghimire 2015; Moyer et al., 2020). For these reasons, the inclusion of these compounds in veterinary vaccines ensures the manufacturer, from the regulatory point of view, lower registration costs and shorter times for the return on investment (Del Giudice et al., 2018). ...
Context: The new generation of immunoenhancers will have to offer solutions to each clinical and technological limitation that currently exists. This innovative context requires periodic technological surveillance by the veterinary biopharmaceutical industry to anticipate technological changes and predict future competitive advantages.
Aims: To evaluate the current status, scientific trends, and technological projections in the use of veterinary immunological adjuvants for productive and companion species in the period 2015 and 2021.
Methods: The bibliometric analysis included scientific articles on adjuvants in veterinary medicine published in English in 2015–2021 and indexed on the Scopus and Web of Science platforms. All relevant records retrieved between 2015 and 2022 were grouped using the EndNote bibliographic manager, while the analysis of the relational metric indicator was performed and viewed by VOSviewer®. Instead, data on the main commercial veterinary vaccine adjuvants in 2022 were collected from the official websites of 20 veterinary vaccine manufacturers with experience in the market.
Results: The academy dedicated 68.2% of its production to disseminating articles with original experimental results with 73.6% being novel notifications about adjuvants of natural, microbial and nanotechnological origin. Industrial production mainly used monoadjuvation (86.9%), inorganic salts adjuvants (48.1%), particularly aluminum hydroxide (43.0%), and classical technology (89.2%) to produce their commercial formulations. Ruminants, swines, and poultry dominated both sectors, with ruminants being the main protagonist.
Conclusions: The new scientific knowledge will not have a significant impact on the veterinary pharmaceutical industry in the short term and the hegemonic continuity of traditional adjuvants, in particular aluminum hydroxide, is expected.
... Some Al-based immune adjuvants have been approved by the FDA. [37] Aluminum is predominantly involved in antibody-mediated (Th2) processes, but hardly any cell-mediated (Th1) immune responses. [38] The humoral immune responses induced by aluminum are mediated by antigen-specific antibodies such as IgG1. ...
Immunomodulation has made remarkable progress in fighting infectious disease and cancer. Conventionally, immunomodulation largely relies on chemical/biochemical agents, which, unfortunately, suffer from sever off‐target adverse effects. Recent insights into nano–bio interactions suggest that nanomaterials can directly participate in immunomodulation. A range of physical and chemical cues at the nano–bio interface have been harnessed to regulate diverse immuno‐signaling for disease control and treatment. In this Minireview, we summarize recent studies on the physical and chemical cues enabled by intrinsic nanomaterials to trigger immunological signaling. First, we discuss physical cues mediated by surface topography, hydrophobicity, charge, and heat at the nano–bio interface for immunomodulation. Then, various nanomaterials enabled chemical cues, such as metal species and oxidative species are outlined. Finally, our perspectives on challenges and possible future directions are provided.
... Çevresel alüminyum maruziyeti çok daha fazla olduğu bilinmektedir Aşılardaki alüminyum miktarına sınırlama getirilmiştir. Örneğin; FDA (Amerikan Gıda ve İlaç İdaresi) doz başına 0.85 mg alüminyuma izin vermektedir (42). ...
Öz
Aşılama 20.yüzyılda halk sağlığının en önemli on küresel başarısından birisidir. Aşıyla
birçok hastalığın önüne geçilmiş, morbidite ve mortalitesi azaltılmıştır. Aşılar güvenirlik
ve etkinlik açısından kendini ispat etmiştir. Bu verilere rağmen Dünya’da aşılama
oranlarının azalmasına yol açabilecek görüşlerin varlığını artırarak sürdürmüştür.
Aşı karşıtlığı Dünya Sağlık Örgütü (DSÖ) tarafından 2019’un önemli on küresel
sağlık probleminden biri olarak tanımlanmıştır. Biz de bu derlememizde aşı karşıtlığı
geniş bir perspektifte ele almayı amaçladık.
Abstract
Vaccination is one of the ten most important global achievements of public health
in the 20th century. Vaccination has prevented many diseases and reduced morbidity
and mortality. Vaccines have proven themselves in terms of safety and effectiveness.
Despite these data, opinions that could lead to a decrease in vaccination rates
in the world continued to increase. Anti-vaccination has been identified by the
World Health Organization (WHO) as one of the ten major global health problems
of 2019. In this review, we aimed to address the anti-vaccine approach from a broad
perspective.
... We tested whether conversion of DSPC to SenC can be provoked in vivo in tissues of TBI BMT mice by stimulation of proliferation similarly to plating in culture. As a proliferation-inducing stimulus, we used sterile wound model that involves injection of a fine suspension of insoluble aluminum hydroxide that is commonly used as an immunoadjuvant 38 . When injected subcutaneously, it induces formation of a local capsule consisting of mesenchymal cells and various immunocytes -the process that involves local mesenchymal cell proliferation 39 . ...
Systemic genotoxic stress is expected to generate senescent cells and accelerate aging. Surprisingly, mice subjected to lethal dose of total body irradiation and rescued by bone marrow transplantation (TBIBMT) showed neither gain of aging-related frailty nor increase in senescence markers. Mesenchymal cells in various tissues of TBIBMT mice do not undergo senescence and stay dormant with unrepaired DNA breaks during the entire life of the animal and activate senescence program only after they are forced into cell divisions ex vivo or in vivo. Accumulation of such dormant senescence-prone cells (DSPC) has no physiological effects under normal life conditions but is associated with impaired wound healing, decelerated tumor growth due to inefficient scaring and stroma formation and rapid increase in frailty and death after placement on a high-fat diet suggesting the involvement of DSPC accumulation in obesity-induced health decline in cancer survivors following genotoxic treatments.
... There is now minimal disagreement on aluminum's neurotoxicity. Nonetheless, the pharmaceutical sector and government entities nowadays believe that the relatively low concentrations of aluminum used in vaccines pose no health threat [17,63] and that the advantages of utilizing immunizations enclosing aluminum adjuvant far overcome any speculative dilemmas [64]. ...
Background: For nearly a century, aluminum hydroxide (alum) has continued to be employed as an adjuvant in vaccinations. It was first applied by immunologist Alexander T. Glenny in 1926 to boost the immune response. Its great efficiency has allowed aluminum to continue to be used to date. Methods: Recognized scientific databases such as Google Scholar, Web of Science, and PubMed were utilized to search for the keywords. The selected works were reviewed and analyzed according to their relevance. Only peer-reviewed articles were included in the analysis. Results: Contemporary research carried out on animals has shown that it has a neurotoxic effect. Furthermore, increased aluminum concentrations in the nervous system tissues of people, who died from an autism condition have been discovered by using advanced imaging techniques. The paradigm shift proposes a reconsideration of the use of the alum-based adjuvants and calls for a careful dissection to avoid incorrect interpretations. This proposal does not constitute an attack on vaccination, as nobody refutes the fact that it has been systematically proven to be effective in saving millions of lives. Unfortunately, scientists, who have investigated the toxicity of aluminum-based adjuvants have been unfairly labeled as "anti-vaxxers". Rather, what they have been questioning is the safety of aluminum as an adjuvant. Conclusions: The present work encourages researchers, health regulatory agencies, and even pharmaceutical companies to allow themselves to think about the possibility that aluminum-based adjuvants could be toxic for susceptible children.
... 18,19 Aluminum salts are the most commonly used adjuvants with well-established safety and efficacy records over the past 70 years and are in use in numerous approved vaccines, including DTaP, Tdap, Hep B, Men B, HPV, and anthrax. [20][21][22] Aluminum salt adjuvants induce primarily humoral Th-2 type immune response and are widely available at low cost. 23,24 In contrast, CpG oligodeoxynucleotide adjuvant is a TLR-9 agonist currently widely used in pre-clinical and clinical testing 2526 but commercially only in the hepatitis B subunit vaccine (Heplisav TM ). ...
Low-cost, refrigerator-stable COVID-19 vaccines will facilitate global access and improve vaccine coverage in low- and middle-income countries. To this end, subunit-based approaches targeting the receptor-binding domain (RBD) of SARS-CoV-2 Spike protein remain attractive. Antibodies against RBD neutralize SARS-CoV-2 by blocking viral attachment to the host cell receptor, ACE2. Here, a yeast-produced recombinant RBD antigen (RBD-L452K-F490W or RBD-J) was formulated with various combinations of aluminum-salt (Alhydrogel®, AH; AdjuPhos®, AP) and CpG 1018 adjuvants. We assessed the effect of antigen-adjuvant interactions on the stability and mouse immunogenicity of various RBD-J preparations. While RBD-J was 50% adsorbed to AH and <15% to AP, addition of CpG resulted in complete AH binding, yet no improvement in AP adsorption. ACE2 competition ELISA analyses of formulated RBD-J stored at varying temperatures (4, 25, 37°C) revealed that RBD-J was destabilized by AH, an effect exacerbated by CpG. DSC studies demonstrated that aluminum-salt and CpG adjuvants decrease the conformational stability of RBD-J and suggest a direct CpG-RBD-J interaction. Although AH+CpG-adjuvanted RBD-J was the least stable in vitro, the formulation was most potent at eliciting SARS-CoV-2 pseudovirus neutralizing antibodies in mice. In contrast, RBD-J formulated with AP+CpG showed minimal antigen-adjuvant interactions, a better stability profile, but suboptimal immune responses. Interestingly, the loss of in vivo potency associated with heat-stressed RBD-J formulated with AH+CpG after one dose was abrogated by a booster. Our findings highlight the importance of elucidating the key interrelationships between antigen-adjuvant interactions, storage stability, and in vivo performance to enable successful formulation development of stable and efficacious subunit vaccines.
Cancer immunotherapy, which leverages the body's immune system to combat cancer, offers the promise of lower toxicity and higher therapeutic efficacy compared to conventional treatments. However, current immunotherapeutic approaches face significant challenges including variable patient response, immune‐related adverse events, and high costs, underscoring the urgent need for innovative strategies. Metal‐based nanomaterials have emerged as a promising avenue in cancer immunotherapy due to their unique physicochemical properties and immune‐regulating capabilities. Despite their potential, concerns about toxicity, incomplete understanding of their immune modulation mechanisms, and early‐stage design strategies hinder their clinical translation. This review summarizes recent advancements in metal‐based nanomaterials for cancer immunotherapy, elucidates the mechanisms by which they enhance antitumor immunity responses, and explores the potential synergistic effects of combining multiple metals. We also discuss key challenges and future perspectives for clinical application, aiming to provide a theoretical foundation for the development of metal‐based immunotherapies and to promote their broader application in cancer treatment.
Vaccination is a groundbreaking approach in preventing and controlling infectious diseases. However, the effectiveness of vaccines can be greatly enhanced by the inclusion of adjuvants, which are substances that potentiate and modulate the immune response. This review is based on extensive searches in reputable databases such as Web of Science, PubMed, EMBASE, Scopus, and Google Scholar. The goal of this review is to provide a thorough analysis of the advances in the field of adjuvant research, to trace the evolution, and to understand the effects of the various adjuvants. Historically, alum was the pioneer in the field of adjuvants because it was the first to be approved for use in humans. It served as the foundation for subsequent research and innovation in the field. As science progressed, research shifted to identifying and exploiting the potential of newer adjuvants. One important area of interest is nano formulations. These advanced adjuvants have special properties that can be tailored to enhance the immune response to vaccines. The transition from traditional alum-based adjuvants to nano formulations is indicative of the dynamism and potential of vaccine research. Innovations in adjuvant research, particularly the development of nano formulations, are a promising step toward improving vaccine efficacy and safety. These advances have the potential to redefine the boundaries of vaccination and potentially expand the range of diseases that can be addressed with this approach. There is an optimistic view of the future in which improved vaccine formulations will contribute significantly to improving global health outcomes.
Background
BK-SE36/CpG is a recombinant blood-stage malaria vaccine candidate based on the N-terminal Plasmodium falciparum serine repeat antigen5 (SE36), adsorbed to aluminium hydroxide gel and reconstituted, prior to administration, with synthetic oligodeoxynucleotides bearing CpG motifs. In healthy Japanese adult males, BK-SE36/CpG was well tolerated. This study assessed its safety and immunogenicity in healthy malaria-exposed African adults and children.
Methods
A double-blind, randomised, controlled, age de-escalating clinical trial was conducted in an urban area of Ouagadougou, Burkina Faso. Healthy participants (n=135) aged 21-45 years (Cohort 1), 5-10 years (Cohort 2) and 12-24 months (Cohort 3) were randomised to receive three vaccine doses (Day 0, 28 and 112) of BK-SE36/CpG or rabies vaccine by intramuscular injection.
Results
One hundred thirty-four of 135 (99.2%) subjects received all three scheduled vaccine doses. Vaccinations were well tolerated with no related Grade 3 (severe) adverse events (AEs). Pain/limitation of limb movement, headache in adults and fever in younger children (all mild to moderate in intensity) were the most frequently observed local and systemic AEs. Eighty-three of BK-SE36/CpG (91%) recipients and 37 of control subjects (84%) had Grade 1/2 events within 28 days post vaccination. Events considered by the investigator to be vaccine related were experienced by 38% and 14% of subjects in BK-SE36/CpG and control arms, respectively. Throughout the trial, six Grade 3 events (in 4 subjects), not related to vaccination, were recorded in the BK-SE36/CpG arm: 5 events (in 3 subjects) within 28 days of vaccination. All serious adverse events (SAEs) (n=5) were due to severe malaria (52-226 days post vaccination) and not related to vaccination. In all cohorts, BK-SE36/CpG arm had higher antibody titres after Dose 3 than after Dose 2. Younger cohorts had stronger immune responses (12–24-month-old > 5-10 years-old > 21-45 years-old). Sera predominantly reacted to peptides that lie in intrinsically unstructured regions of SE36. In the control arm, there were no marked fold changes in antibody titres and participants’ sera reacted poorly to all peptides spanning SE36.
Conclusion
BK-SE36/CpG was well-tolerated and immunogenic. These results pave the way for further proof-of-concept studies to demonstrate vaccine efficacy.
Clinical trial registration
https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=1921, PACTR201701001921166.
As vacinas contra a hepatite B são produzidas pela expressão do gene viral codificado para o antígeno de superfície do vírus da hepatite B (HBsAg) em levedura, há mais de 20 anos. De acordo com os dados da OMS, a vacina de hepatite B tem até três anos de estabilidade quando armazenada entre 2 ºC e 8 ºC. O objetivo deste estudo foi de avaliar se, no momento da liberação, os critérios de qualidade da vacina de hepatite B foram mantidos após sete anos da data de validade. Foram analisados frascos de vacinas multi-dose (10 e 5 doses), sendo três lotes de cada produtor (A, B e C). Todos os lotes foram avaliados quanto às características de aparência visual, potência, endotoxina bacteriana, presença de timerosal, conteúdo de hidróxido de alumínio e pH por meio de testes validados. Os nove lotes avaliados sete anos após a data de expiração tiveram resultados similares quando comparados às concentrações na época de liberação dos lotes, realizada pelo Instituto Nacional de Controle de Qualidade em Saúde (INCQS). Os estudos confirmaram a manutenção da qualidade da vacina após o período de expiração. Estes dados podem subsidiar uma futura avaliação para extensão do prazo de validade das vacinas.
One of the most effective global public health initiatives is vaccination. But despite the abundance of extremely effective vaccines, there are still some infectious diseases for which there are no vaccines. To fully realize the potential of vaccine development for both newly emerging infectious diseases and illnesses for which there are currently no vaccines available, new technologies are required. The COVID-19 mRNA vaccines’ success demonstrates that nanoscale platforms are promising delivery vectors for efficient and secure vaccines. The development of drugs is significantly influenced by nanotechnology. Polymeric nanoparticles can transport drugs, proteins, and vaccine antigens to the desired site of action. Through mucosal administration, polymeric nanoparticles with lower cytotoxicity can shield drugs or antigens from degradation in unfavorable conditions. In addition, the uptake of nanoparticles by antigen-presenting cells can boost and trigger powerful immune responses. Nanomaterials are also frequently used in vaccine delivery systems because they can extend the half-life of the vaccine antigen. Inorganic nanoparticles, polymer-based nanoparticles, nanomaterial vaccines, the idea behind nanomaterial-based vaccines, and applications of nanomaterial-based vaccines in healthcare are the main topics of this review. In the context of drugs and vaccines, the use and potential of nano bases as delivery vehicles and adjuvants are discussed.KeywordsVaccineVaccine developmentNanoparticlesNanomaterial vaccinesDrug
Background:
The effect of the timing of additional doses and the long-term persistence of lyophilized inactivated tissue culture hepatitis A (HA) vaccine (Aimmugen®) on antibodies is unknown.
Methods:
A single-center, cross-sectional, observational study was conducted in collaboration with the Japan Air Self-Defense Force, whose personnel were immunized with Aimmugen® when deployed to endemic areas. Patients who consented to this study after a medical examination with blood sampling between June 2022 and February 2023 were included; HA-IgG level in the residual serum was measured using the chemiluminescent immunoassay method. The exact vaccination history was investigated based on immunization records maintained by the Ministry of Defense, and a questionnaire was used to collect confounding factors.
Results:
Of the 181 participants observed, 49 were in the unvaccinated group, and 132 were in the vaccinated group. Out of the vaccinated group, 6.8 % received either one or two doses, 40.9 % received three doses, and 52.3 % received more than four doses. IgG antibody titers (S/CO value) in each group (0, 1 or 2, 3, and over 4) increased in a frequency-dependent manner, with those vaccinated over four times showing significantly higher IgG antibody titers than all other groups (0.19 ± 0.10 vs 3.66 ± 3.00 vs 7.63 ± 3.57 vs 10.57 ± 1.86, respectively). When the number of months elapsed from the last vaccination to the date of blood collection in each group was plotted against IgG antibody titer, the slope of the regression line flattened out from a decreasing trend in the order 1 or 2, 3, over 4.
Conclusions:
Three doses of Aimmugen® are efficacious, but four or more doses induce more robust and sustained antibody production. Additionally, four or more doses may be effective when there is a need to ensure long-term immunity or risk of prolonged exposure.
Vaccines comprising innovative adjuvants are rapidly reaching advanced translational stages, such as the authorized nanotechnology adjuvants in mRNA vaccines against COVID-19 worldwide, offering new strategies to effectively combat diseases threatening human health. Adjuvants are vital ingredients in vaccines, which can augment the degree, extensiveness, and longevity of antigen specific immune response. The advances in the modulation of physicochemical properties of nanoplatforms elevate the capability of adjuvants in initiating the innate immune system and adaptive immunity, offering immense potential for developing vaccines against hard-to-target infectious diseases and cancer. In this review, we provide an essential introduction of the basic principles of prophylactic and therapeutic vaccination, key roles of adjuvants in augmenting and shaping immunity to achieve desired outcomes and effectiveness, and the physiochemical properties and action mechanisms of clinically approved adjuvants for humans. We particularly focus on the preclinical and clinical progress of highly immunogenic emerging nanotechnology adjuvants formulated in vaccines for cancer treatment or infectious disease prevention. We deliberate on how the immune system can sense and respond to the physicochemical cues (e.g., chirality, deformability, solubility, topology, and chemical structures) of nanotechnology adjuvants incorporated in the vaccines. Finally, we propose possible strategies to accelerate the clinical implementation of nanotechnology adjuvanted vaccines, such as in-depth elucidation of nano-immuno interactions, antigen identification and optimization by the deployment of high-dimensional multiomics analysis approaches, encouraging close collaborations among scientists from different scientific disciplines and aggressive exploration of novel nanotechnologies.
Vaccine hesitancy is an increasing global health threat, and to improve vaccine uptake, it is critical to account for identity-based considerations including racial and ethnic, religious, and contemporary socio-political identities. Using critical consciousness to create awareness of the diverse cultural viewpoints on vaccines can help providers have conversations that are identity aware, equity-focused, and linguistically sensitive with their patients. It is necessary to collaborate with patients, families, communities, and community leaders to share information about vaccines, their safety profiles, and on how to have vaccines readily accessible in each community, to protect children and adolescents against vaccine preventable illnesses.
While the rapid development of COVID-19 vaccines has been a scientific triumph, the need remains for a globally available vaccine that provides longer-lasting immunity against present and future SARS-CoV-2 variants of concern (VOCs). Here, we describe DCFHP, a ferritin-based, protein-nanoparticle vaccine candidate that, when formulated with aluminum hydroxide as the sole adjuvant (DCFHP-alum), elicits potent and durable neutralizing antisera in non-human primates against known VOCs, including Omicron BQ.1, as well as against SARS-CoV-1. Following a booster ~one year after the initial immunization, DCFHP-alum elicits a robust anamnestic response. To enable global accessibility, we generated a cell line that can enable production of thousands of vaccine doses per liter of cell culture and show that DCFHP-alum maintains potency for at least 14 days at temperatures exceeding standard room temperature. DCFHP-alum has potential as a once-yearly booster vaccine, and as a primary vaccine for pediatric use including in infants.
Anthrax infections caused by Bacillus anthracis are an ongoing bioterrorism and livestock threat worldwide. Current approaches for management, including extended passive antibody transfusion, antibiotics, and prophylactic vaccination, are often cumbersome and associated with low patient compliance. Here, we report on the development of an adjuvanted nanotoxoid vaccine based on macrophage membrane-coated nanoparticles bound with anthrax toxins. This design leverages the natural binding interaction of protective antigen, a key anthrax toxin, with macrophages. In a murine model, a single low-dose vaccination with the nanotoxoids generates long-lasting immunity that protects against subsequent challenge with anthrax toxins. Overall, this work provides a new approach to address the ongoing threat of anthrax outbreaks and bioterrorism by taking advantage of an emerging biomimetic nanotechnology.
Background
: Post-vaccination safety is a major public health concern. The effect of host genetic variables on immune response was demonstrated by previous researches. Clarifying whether individual genetic predisposition plays a role on adverse events (AEs) is critical for the prevention of AEs.
Methods
From July 2019 to June 2020, we performed a case-control study among children aged 3-24 months in seven Chinese provinces. Each child received a combination vaccination against diphtheria, tetanus, acellular pertussis, and Haemophilus influenzae type b (DTaP-Hib). Through daily telephone follow-up, we collected AEs within seven days. Oral swab samples were collected for genotyping. The effects of single nucleotide polymorphisms (SNPs) on the risk of AEs were investigated.
Results
304 participants were included in the study. In univariate analysis, we discovered three protective SNPs (rs452204, OR=0.67, P=0.0352; rs9282763 and rs839, OR=0.64, P=0.0256) and one risk SNP (rs9610, OR=2.20, P=0.0397). In multivariate analysis, the effects of rs452204 and rs839 were found to be stable. The interaction between rs452204 and rs9610 was observed (OR=7.25, 95 % CI: 1.44-36.58, P=0.0165).
Conclusion
Our study provided evidence that genetic predisposition was associated with the risk of AEs after DTaP-Hib vaccination, emphasizing the potential application of genetic factors in the prevention of AEs.
Preclinical and clinical trials have demonstrated that cancer vaccines need superior adjuvants than those that are currently licensed. The US Food and Drug Administration (FDA) has approved alum and incomplete Freund's adjuvant for human consumption; however these immunoadjuvants lack potent antitumor immunity or the induction of undesired immunity. In addition, toxicity issues are also concerned with currently licensed immunoadjuvants. On the other hand, desirable output has been achieved with immunostimulatory adjuvants, particularly agonistic as well as nonagonistic ligands for toll-like receptors (TLRs), C-type lectin receptors, retinoic acid-inducible gene I-like receptors and stimulator of interferon genes in terms of antitumor activity as well as potent immunoadjuvant action. Combinations of adjuvants have shown greater efficacy over the single immunoadjuvant. Therefore, in present chapter, we have presented the significance and potential of nanoimmunoadjuvants in generation of humoral and cellular immune response in the treatment of cancer. Moreover, challenges and opportunities have also been highlighted to pave the way for development of newer nanoimmunoadjuvants.
Immunomodulation has made remarkable achievements in fighting against infectious disease and cancer. Conventionally, immunomodulation largely relied on chemical/biochemical agents which, unfortunately, suffer from sever off‐target adverse effects. Recent understandings on nano‐bio interactions suggest that nanomaterials per se can directly participate in immunomodulation. A range of physical and chemical cues at nano‐bio interface have been harnessed to regulate diverse immuno‐signaling for disease control and treatment. In this Minireview, we summarize recent studies of the physical and chemical cues enabled by intrinsic nanomaterials that trigger immunological signaling. Firstly, we discuss physical cues mediated by surface topography, hydrophobicity, charge and heat at nano‐bio interface for immunomodulation. Secondly, various chemical cues, such as metal species and oxidative species are outlined. Finally, our perspectives on the challenge and possible future directions are provided.
It is likely that aluminum compounds will continue to be used with human vaccines for many years as a result of their excellent track record of safety and adjuvanticity with a variety of antigens. For infections that can be prevented by induction of serum antibodies, aluminum adjuvants formulated under optimal conditions are the adjuvants of choice. It is important to select carefully the type of aluminum adjuvant and optimize the conditions of adsorption for every antigen since the degree of adsorption of antigens onto aluminum adjuvants markedly affects immunogenicity. The mechanism of adjuvanticity of aluminum compounds includes formation of a depot at the site of injection from which antigen is released slowly; stimulation of immune-competent cells of the body through activation of complement, induction of eosinophilia, and activation of macrophages; and efficient uptake of aluminum-adsorbed antigen particles by antigen-presenting cells because of their particulate nature and optimal size (< 10 microns). Limitations of aluminum adjuvants include local reactions, production of IgE antibodies, ineffectiveness for some antigens, and inability to elicit cell-mediated immune responses especially cytotoxic T-cell responses. Calcium phosphate, which has adjuvant properties similar to aluminum adjuvants, has the potential advantages of being a natural component of the body and of not increasing IgE production. There is a need for alternative adjuvants, particularly for diseases in which cell-mediated immune responses are important for prevention or cure.
Results are presented obtained when comparable pertussis, diphtheria and tetanus triple antigens, one in saline suspension and the other containing a mineral carrier, were used in the immunization of two similar groups of infants. Fifty per cent, of infants given the saline antigen failed to produce measurable titres of pertussis agglutinin. The reasons for the use of plain antigens are discussed and considered insufficient to warrant their preference to the more potent alum-containing antigen. Delaying the third injection until four or five months after the second produces a higher mean response to all three constituents.
• The effectiveness of immunization to diphtheria, tetanus, and pertussis was studied in a group of infants between 2 and 6 months of age. Two dosage levels were tried. The titers for diphtheria and tetanus antitoxin and for pertussis agglutinin were determined a month after the injections and again at the end of a year. With but one exception, the larger dose resulted in the higher titer. The feasibility and advisability of immunizing infants starting between the second and sixth months was demonstrated. The alum-adsorbed toxoids gave better results than the fluid preparations. Assays in the guinea pig afford some indication of the effectiveness of toxoids in man. Since the size of the dose was found to be so important, the search for more accurate methods of assay is justified.
Using mice in a tetanus vaccination system, we have examined the mode of action of the immunological adjuvant, aluminium hydroxide (Al(OH)3), on antibody titers as measured by an ELISA-method. A profound effect of the adjuvant was observed after primary imunizations, increasing titers about 100-fold compared to plain (not adjuvanted) controls. However, no effect on titers could be attributed to a content of Al(OH)3 in the vaccines when used for booster immunizations, as the increase in titers after boosting was either the same for groups given plain or adsorbed toxoids, or even higher in the groups receiving the plain vaccine. Thus, the effect of Al(OH)3 as an adjuvant seems to be exerted mainly on the primary antibody response. Investigating the mode of action by the adjuvant, we adsorbed a certain amount of toxoid onto varying doses of Al(OH)3. An antigen ELISA revealed that all toxoid had been adsorbed to the Al-gel in the preparations. The antibody titers after immunization showed a significantly higher response to toxoid adsorbed to the higher amount of adjuvant, indicating that this effect was most probably due to free, not antigen-bound, Al-particles. Moreover, this effect could be inhibited when BSA was added in excess to the preparation, thereby blocking the free residues on the Al-gel.
Aluminium hydroxide attracted eosinophils to injection sites in the absence of specific antigenic stimulation. This was markedly reduced by depletion of T cells. These observations suggest that eosinophilia caused by a nonimmunological stimulus required the presence of T cells, and imply that these lymphocytes were'involved in reactions in which specific antigen recognition played no role.
Specific IgE and IgG antibodies were measured in 39 adolescent and adult humans preselected to have less than 0.125 antitoxin units (AU) ml to tetanus antitoxin (IgG) irrespective of previous immunization history. Mean antitoxin values (IgG) measured by sheep red cell hemagglutination (SRBC) increased by 2 logs to 1.49 AU/ml sera for tetanus and by 1 log to 0.025 AU/ml sera for diphtheria. Specific tetanus IgE was noted to increase after immunization from a mean 2.0 +/- 0.2% counts bound to 3.1 +/- 0.6% counts bound, but was not statistically significant. Diphtheria-specific IgE rose significantly (p less than 0.05) from a mean 1.5 +/- 0.2% counts bound to a mean 4.0 +/- 1.2% counts bound in atopic individuals and from a mean 1.2 +/- 0.0% counts bound to a mean 2.2 +/- 0.5% counts bound in nonatopics. These data document the development of tetanus and diphtheria IgE antibodies after booster immunization.
Nonreplicating, purified subunit or synthetic viral vaccines of the future are likely to be weak immunogens that will require
immunopotentiation if they are to be effective. These marginal vaccinescould be improved by combination with potent and safe
immunologic adjuvants. The use of adjuvants should also reduce the amount of purified antigen required for successful immunization,
thus making vaccine production'rnore economical and more feasible. It may be possible to combine the recently developed, relatively
nontoxic synthetic immunoregulators of low molecular weight with antigens in order to modulate preselected compartments of
the immune system. To date, the question of adjuvant safety has not been resolved and represents the major obstacle to the
orderly development of adjuvanted vaccines. The fear of inducing cancer and other immediate or long-term perturbations of
the immune system must be patiently and rationally overcome by basic and applied experimentation and by the development of
appropriate guidelines for studies in humans.
Concern expressed about the incidence of whooping cough in fully vaccinated children in Toronto compared with similar centres in the United States (U.S.) and the lack of a meaningful, official, Canadian standard for whooping cough (pertussis) vaccine has led to a comparison of the major standards in the world for pertussis vaccine, those of the United States and of the World Health Organization (W.H.O.), with a view to recommending an effective formulation for Canada. The U.S. standard accepts a lower estimate for potency of 2·7 protective units (PU) per single dose compared with 4 PU by W.H.O. The U.S. opacity standard, moreover, is denser than that of W.H.O., so that each dose of U.S. vaccine contains more bacteria per dose than vaccines made to the W.H.O. standard, possibly increasing the risk of reactions. The role of adjuvant in adsorbed vaccines is discussed. It is pointed out that the two adjuvants most commonly used, aluminium phosphate and aluminium hydroxide, do not noticeably enhance the potency of the pertussis component of D.T.P. (diphtheria, tetanus, pertussis) vaccines, but do enhance the potency of the diphtheria and tetanus toxoid components and reduce the incidence of post-injection systemic reactions. For these reasons it is recommended that Canadian vaccines be adsorbed and manufactured to the W.H.O. standards of potency and opacity-4 PU per dose with a lower 95% confidence limit of 2 PU on the assay and adjusted to contain 20 × 109 bacteria per dose as measured by the International (W.H.O.) Opacity Reference Preparation. © 1980 The International Association of Biological Standardization.
The authors present a summary of the information yielded by a number of collaborative field and laboratory studies of typhoid vaccines conducted under the auspices of the World Health Organization, comparing, in particular, the results of various controlled field trials carried out in British Guiana, Poland, the USSR and Yugoslavia, and attempting to evaluate the effectiveness of the vaccines in man.Acetone-inactivated typhoid vaccine, which has been established as an international reference preparation, has been proved in field trials to be of a high degree of effectiveness and to confer protection of long duration.Comparison of the results of the field trials with those of laboratory studies indicate that further research is needed in order to develop a test or tests the results of which can be fully correlated with the effectiveness of typhoid vaccines as demonstrated in man.Reference is also made to field studies of paratyphoid vaccines.
Response of infants to pertussis vaccine at 1 week and to
- Butler
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- Wilson
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- Ja Dudgeon
- J Ungar
- N W Beale
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Butler NR, Wilson BDR, Benson PF, Dudgeon JA, Ungar J, Beale AJ. Response of infants to pertussis vaccine at 1 week and to N.W. Baylor et al. / Vaccine 20 (2002) S18–S23 S23 poliomyelitis, diphtheria and tetanus vaccines at 6 weeks. Lancet 1962;2:112–4.
Summary Minutes-Allergenic Products Advisory Committee and Report on Safety Considerations for the Aluminum Component of Alum-precipitated Allergenic Extracts
- Drug Food
- Administration
Food and Drug Administration. Summary Minutes-Allergenic
Products Advisory Committee and Report on Safety Considerations
for the Aluminum Component of Alum-precipitated Allergenic
Extracts, Office of Biologics Research and Review, Biologics
Information Staff. Bethesda: FDA, 1987 (NFN-20).
Adjuvant properties of aluminum and calcium compounds Vaccine design: the subunit and adjuvant approach
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Gupta RK, Rost BE, Relyveld E, Siber GR, Adjuvant properties of aluminum and calcium compounds. In: Powell MF, Newman MJ editors. Vaccine design: the subunit and adjuvant approach. New York: Plenum Press, 1995. p. 229–48.
National Institutes of Health. Minimum requirements for the amount of aluminum adjuvants in toxoids, vaccines and multiple antigens
Department of Health, Education and Welfare, Public Health Service,
National Institutes of Health. Minimum requirements for the amount
of aluminum adjuvants in toxoids, vaccines and multiple antigens
1953.