100 years of Bacillus Calmette-Guérin immunotherapy: from cattle to COVID-19.

Bacillus Calmette-Guérin (BCG) is the most widely used vaccine worldwide and has been used to prevent tuberculosis for a century. BCG also stimulates an anti-tumour immune response, which urologists have harnessed for the treatment of non-muscle-invasive bladder cancer. A growing body of evidence indicates that BCG offers protection against various non-mycobacterial and viral infections. The non-specific effects of BCG occur via the induction of trained immunity and form the basis for the hypothesis that BCG vaccination could be used to protect against the severity of coronavirus disease 2019 (COVID-19). This Perspective article highlights key milestones in the 100-year history of BCG and projects its potential role in the COVID-19 pandemic.

Army Liposome Formulation (ALF) family of vaccine adjuvants.

Introduction: From its earliest days, the US. military has embraced the use of vaccines to fight infectious diseases. The Army Liposome Formulation (ALF) has been a pivotal innovation as a vaccine adjuvant that provides excellent safety and potency and could lead to dual-use military and civilian benefits. For protection of personnel against difficult disease threats found in many areas of the world, Army vaccine scientists have created novel liposome-based vaccine adjuvants.Areas covered: ALF consists of liposomes containing saturated phospholipids, cholesterol, and monophosphoryl lipid A (MPLA) as an immunostimulant. ALF exhibited safety and strong potency in many vaccine clinical trials. Improvements based on ALF include: ALF adsorbed to aluminum hydroxide (ALFA); ALF containing QS21 saponin (ALFQ); and ALFQ adsorbed to aluminum hydroxide (ALFQA). Preclinical safety and efficacy studies with ALF, LFA, ALFQ, and ALFQA are discussed in preparation for upcoming vaccine trials targeting malaria, HIV-1, bacterial diarrhea, and opioid addiction.Expert opinion: The introduction of ALF in the 1980s stimulated commercial interest in vaccines to infectious diseases, and therapeutic vaccines to cancer, and Alzheimer's disease. It is likely that ALF, ALFA, and ALFQ, will provide momentum for new types of modern vaccines with improved efficacy and safety.

[Quo vadis in vaccines: From the empirical approach to the new wave of technology]. / Quo vadis en vacunas: desde la aproximación empírica a la nueva oleada tecnológica.

The development of vaccines is a multifactorial process that has evolved and expanded, particularly over the last decades. The search for immunogenic vaccines that are also acceptably safe and tolerable enacted continuous technological advances in this field. In this regard, the technology applied to vaccines can historically be divided into 3 approaches: the empirical approach, the modern approach, and the new technological wave. The empirical approach for vaccine development includes whole micro-organisms, attenuation, inactivation, cell cultures and sub-unit vaccines. The modern approach contributed to leaps and bounds to vaccine development using chemical conjugation, as well as recombinant protein DNA technology and reverse vaccinology. Lastly, the new technological wave includes, among others, bioconjugation, viral vectors, synthetic biology, self-amplification of messenger RNA, generalized modules for membrane antigens, structural vaccinology and the new adjuvants.

Overview of Vaccine Adjuvants: Introduction, History, and Current Status.

Adjuvants are included in sub-unit or recombinant vaccines to enhance the potency of poorly immunogenic antigens. Adjuvant discovery is as complex as it is a multidiscplinary intersection of formulation science, immunology, toxicology, and biology. Adjuvants such as alum, which have been in use for the past 90 years, have illustrated that adjuvant research is a methodical process. As science advances, new analytical tools are developed which allows us to delve deeper into the various mechanisms that generates a potent immune response. Additionally, these new techniques help the field learn about our existing vaccines and what makes them safe, and effective, allowing us to leverage that in the next generation of vaccines. Our goal in this chapter is to define the concept, need, and mechanism of adjuvants in the vaccine field while describing its history, present use, and future prospects. More details on individual adjuvants and their formulation, development, mechanism, and use will be covered in depth in the next chapters.

Adjuvants: Classification, Modus Operandi, and Licensing.

Vaccination is one of the most efficient strategies for the prevention of infectious diseases. Although safer, subunit vaccines are poorly immunogenic and for this reason the use of adjuvants is strongly recommended. Since their discovery in the beginning of the 20th century, adjuvants have been used to improve immune responses that ultimately lead to protection against disease. The choice of the adjuvant is of utmost importance as it can stimulate protective immunity. Their mechanisms of action have now been revealed. Our increasing understanding of the immune system, and of correlates of protection, is helping in the development of new vaccine formulations for global infections. Nevertheless, few adjuvants are licensed for human vaccines and several formulations are now being evaluated in clinical trials. In this review, we briefly describe the most well known adjuvants used in experimental and clinical settings based on their main mechanisms of action and also highlight the requirements for licensing new vaccine formulations.

Ancient Disease, Modern Epidemiology: A Century of Progress in Understanding and Fighting Tuberculosis.

A century's worth of efforts to better understand the epidemiology of tuberculosis (TB) and to develop new vaccines, drugs, preventive interventions, and case-finding approaches have provided important insights and helped to advance the field of epidemiology as a whole. Wade Hampton Frost developed methods for cohort analysis that formed the early basis for adjustment of confounding variables. The streptomycin trial in the United Kingdom in the 1940s introduced random allocation for participants to either the treatment or control group, ensuring blinded treatment assignment and comparable treatment groups, which is now a key element in randomized clinical trials. Research into the bacille Calmette-Guérin vaccine demonstrated the importance of comparative analyses, potential difficulties in generalizability to populations not under study, and the role of meta-analysis for discrepant data-approaches now strongly recommended prior to implementing any novel public health intervention. George Comstock's work on preventive therapy for TB demonstrated the use of epidemiologic methods to evaluate interventions on a population level. Finally, studies from the Consortium to Respond Effectively to the AIDS/TB Epidemic focused on the evaluation of real-world effectiveness and of targeting of high-risk subpopulations. In this article, we discuss how TB research in each of these domains has helped to advance epidemiologic thinking and methodology over the past 100 years.

Designing and building the next generation of improved vaccine adjuvants.

Vaccine adjuvants interact with the immune system, to increase the potency of vaccine antigens. Many of the adjuvants currently available were developed with little understanding of how they worked. Highly pure recombinant antigens are typically very poorly immunogenic due to a lack of exogenous immune activating components such as nucleic acids, lipids, and cell membrane components. In this review we discuss the role of adjuvants and their role as 'delivery systems' or 'immune potentiators'. We also highlight the need for appropriate delivery of immune potentiators with several 'delivery system' adjuvants such as alum, emulsions, liposomes, and polymeric particles. The challenges faced by vaccinologists to create the next generation of vaccines can be solved in-part by developing a greater understanding of the impact of delivery, and an appreciation of the key role of pharmaceutical sciences.

An update on safety and immunogenicity of vaccines containing emulsion-based adjuvants.

With the exception of alum, emulsion-based vaccine adjuvants have been administered to far more people than any other adjuvant, especially since the 2009 H1N1 influenza pandemic. The number of clinical safety and immunogenicity evaluations of vaccines containing emulsion adjuvants has correspondingly mushroomed. In this review, the authors introduce emulsion adjuvant composition and history before detailing the most recent findings from clinical and postmarketing data regarding the effects of emulsion adjuvants on vaccine immunogenicity and safety, with emphasis on the most widely distributed emulsion adjuvants, MF59® and AS03. The authors also present a summary of other emulsion adjuvants in clinical development and indicate promising avenues for future emulsion-based adjuvant development. Overall, emulsion adjuvants have demonstrated potent adjuvant activity across a number of disease indications along with acceptable safety profiles.

The history of MF59(®) adjuvant: a phoenix that arose from the ashes.

The first clinical trial of an MF59(®)-adjuvanted influenza vaccine (Novartis) was conducted 20 years ago in 1992. The product that emerged (Fluad(®), Novartis) was licensed first in Italy in 1997 and is now licensed worldwide in 30 countries. US licensure is expected in the coming years. By contrast, many alternative adjuvanted vaccines have failed to progress. The key decisions that allowed MF59 to succeed in such a challenging environment are highlighted here and the lessons that were learned along the way are discussed. MF59 was connected to vaccines that did not succeed and was perceived as a 'failure' before it was a success. Importantly, it never failed for safety reasons and was always well tolerated. Even when safety issues have emerged for alternative adjuvants, careful analysis of the substantial safety database for MF59 have shown that there are no significant concerns with widespread use, even in more 'sensitive' populations.

The development of vaccines: how the past led to the future.

The history of vaccine development has seen many accomplishments, but there are still many diseases that are difficult to target, and new technologies are being brought to bear on them. Past successes have been largely due to elicitation of protective antibodies based on predictions made from the study of animal models, natural infections and seroepidemiology. Those predictions have often been correct, as indicated by the decline of many infections for which vaccines have been made over the past 200 years.

Cytokine adjuvants for vaccine therapy of neoplastic and infectious disease.

Vaccination, the revolutionary prophylactic immunotherapy developed in the eighteenth century, has become the most successful and cost-effective of medical remedies available to modern society. Due to the remarkable accomplishments of the past century, the number of diseases and pathogens for which a traditional vaccine approach might reasonably be employed has dwindled to unprecedented levels. While this happy scenario bodes well for the future of public health, modern immunologists and vaccinologists face significant challenges if we are to address the scourge of recalcitrant pathogens like HIV and HCV and well as the significant obstacles to immunotherapy imposed by neoplastic self. Here, the authors review the clinical and preclinical literature to highlight the manner by which the host immune system can be successfully manipulated by cytokine adjuvants, thereby significantly enhancing the efficacy of a wide variety of vaccination platforms.

A brief history of tuberculosis in Iran during the 19th and 20th centuries.

The history of tuberculosis as a worldwide fatal illness traces back to antiquity, a well-known disease in ancient civilizations. However, its causative agent remained unidentified until the last decades of the 19th century, when discovered by Robert Koch. In due course, preparation of the BCG vaccine, application of the Mantoux intradermal diagnostic tuberculosis test and administration of proper antituberculosis medications eventually controlled tuberculosis. However, despite these significant advancements tuberculosis remained uneradicated, particularly in developing countries after the emergence of both multidrug-resistant tuberculosis and HIV co-infection. Presented here, is a brief review of the history of tuberculosis in the world as well as its historical background in Iran, mainly during the 19th and 20th centuries.

Glatiramer acetate: evidence for a dual mechanism of action.

Glatiramer acetate is a disease-modifying drug approved for the treatment of relapsing-remitting multiple sclerosis. Since its discovery almost four decades ago, and in particular since the observation of its beneficial clinical effects in the late 1980s and early 1990s, numerous data have been generated and contribute pieces of a puzzle to help explain the mechanism of action of glatiramer acetate. Two major themes have emerged, namely (i) the induction of glatiramer acetate-reactive TH2 immunoregulatory cells, and (ii) the stimulation of neurotrophin secretion in the central nervous system that may promote neuronal repair.

History of bacillus Calmette-Guerin and bladder cancer: an immunotherapy success story.

PURPOSE: We review how the bacillus Calmette-Guerin vaccine evolved to become standard therapy for superficial bladder cancer. MATERIALS AND METHODS: We reviewed the historical literature describing the origin of the bacillus Calmette-Guerin vaccine as an anticancer agent and its singular success as the most effective immunotherapy used against a human neoplasm. RESULTS: The association between tuberculosis and cancer, and the demonstration that bacillus Calmette-Guerin invoked immunological reactivity, inhibiting tumor growth in experimental animal models, led to clinical trials showing that intravesical bacillus Calmette-Guerin eradicated and prevented recurrence of superficial bladder tumors. CONCLUSIONS: For the last 3 decades bacillus Calmette-Guerin therapy has remained the most effective local therapy for superficial bladder cancer, an outstanding example of successful translational medicine in urology.