Safety and Mechanism of Action of Licensed Vaccine Adjuvants (original) (raw)

Corresponding author 1 st International and 2 nd National Workshop on Vaccine Adjuvants

This workshop was organized by the Cuban Society for Immunology (CSI) with the cooperation of the Latin American Association for Immunology (ALAI), the Finlay Institute, the Center for Genetic Engineering and Biotechnology (CIGB), the American Society for Microbiology (ASM), and Alfa Universal Invest., Corp. Adjuvants help antigens to elicit an early, high and long-lasting immune response with less antigens. In recent years, adjuvants received much attention because of the development of purified recombinant and synthetic peptide vaccine candidates, many of which are poor immunogens and require adjuvants to evoke the desired immune response. Besides, for many years, the only adjuvants available for general use in human vaccines were aluminium salts; but new adjuvants like proteoliposomes are already extensively used. With the use of adjuvants the immune response can be selectively modulated to a Th1 or Th2 response which is very important for protection against diseases caused by intracellular and extracellular pathogens, respectively. To discuss updated aspects concerning the development of adjuvants of importance in human and veterinary vaccines, the Cuban Society for Immunology (CSI) organized from December 5-8 of 2001 The 1 st International and 2 nd National Workshop on Vaccine Adjuvants with the cooperation of the Finlay Institute, the Center for Genetic Engineering and Biotechnology (CIGB), The Latin American Association for Immunology (ALAI) and the American Society for Microbiology (ASM) at the Neptune-Triton Hotel in Havana, Cuba. Dr. Gustavo Sierra (President of the CSI and ALAI, Vicepresident of the Finlay Institute and President of the Expert Vaccines Committee) chaired the meeting that he organized together with Dr. Oliver Pérez (General Secretary of CSI and ALAI). The meeting was opened by stating that the discussion and proceedings should involve the screening and application of new adjuvants for many different kinds of vaccines. The program emphasized vaccination for prophylaxis or therapy in infectious diseases and in therapy of cancer. It also focused on adjuvants as carrier proteins, immunomodulators, appropriate delivery systems, whole organism vectors, liposomes and proteoliposomes. Future meetings may also consider procedures for safetly testing of new adjuvants and regulatory aspects of their application in humans as well as emphasize in vaccine adjuvants already in, or very close to, entering clinical trials. Another interesting point suggested for future meetings was the use of cytolysins as a new approach for immune deviation and the induction of CTL response in vaccine development. Topics of special interest were the role of dendritic cells as natural adjuvants, the ability of adjuvants to selectively modulate the immune response to Th1 or Th2, the advances in adjuvants for cancer vaccines, the rational design of new vectors as antigen-delivery systems, adjuvants for mucosal vaccine delivery, adjuvants that can be used in vaccines against viral or parasitic vaccines and the adjuvant capacity of liposomes and proteoliposomes. Researchers representing twenty-three different academic institutions and three pharmaceutical companies involved in adjuvant research and development attended to the meeting. The most import aim of this workshop was to discuss updated results in the field of adjuvants and to strengthen relationships between researchers and companies dedicated to research and production of new vaccines. The present report is structured in topics which include oral presentations and posters after a summarized explanation of each topic by the chairpersons.

Vaccine adjuvants: Why and how

Human Vaccines & Immunotherapeutics

Novel vaccine strategies include the so-called subunit vaccines, which encompass only the part of the pathogen to which immune recognition results in protection. The high purity of these vaccines make adverse events less likely, but it also makes the vaccines less immunogenic and therefore potentially less effective. Vaccine adjuvants that increase and modulate the immunogenicity of the vaccine are therefore added to solve this problem. Besides aluminum salts, which have been used in vaccines for 90 years, a number of novel vaccine adjuvants have been included in licensed vaccines over the last 30 years. Increasing insight into immunological mechanisms and how to manipulate them has replaced empirical with rational design of adjuvants, leading to vaccine adjuvants with increased and customized immunogenicity profiles without compromising vaccine safety.

An Overview of Vaccine Adjuvants: Current Evidence and Future Perspectives

Vaccines

Vaccinations are one of the most important preventive tools against infectious diseases. Over time, many different types of vaccines have been developed concerning the antigen component. Adjuvants are essential elements that increase the efficacy of vaccination practises through many different actions, especially acting as carriers, depots, and stimulators of immune responses. For many years, few adjuvants have been included in vaccines, with aluminium salts being the most commonly used adjuvant. However, recent research has focused its attention on many different new compounds with effective adjuvant properties and improved safety. Modern technologies such as nanotechnologies and molecular biology have forcefully entered the production processes of both antigen and adjuvant components, thereby improving vaccine efficacy. Microparticles, emulsions, and immune stimulators are currently in the spotlight for their huge potential in vaccine production. Although studies have reported som...

Vaccine Adjuvants: from 1920 to 2015 and Beyond

Vaccines, 2015

The concept of stimulating the body's immune response is the basis underlying vaccination. Vaccines act by initiating the innate immune response and activating antigen presenting cells (APCs), thereby inducing a protective adaptive immune response to a pathogen antigen. Adjuvants are substances added to vaccines to enhance the immunogenicity of highly purified antigens that have insufficient immunostimulatory capabilities, and have been used in human vaccines for more than 90 years. While early adjuvants (aluminum, oil-in-water emulsions) were used empirically, rapidly increasing knowledge on how the immune system interacts with pathogens means that there is increased understanding of the role of adjuvants and how the formulation of modern vaccines can be better tailored towards the desired clinical benefit. Continuing safety evaluation of licensed vaccines containing adjuvants/adjuvant systems suggests that their individual benefit-risk profile remains favorable. Adjuvants contribute to the initiation of the innate immune response induced by antigens; exemplified by inflammatory responses at the injection site, with mostly localized and short-lived effects. Activated effectors (such as APCs) then move to draining lymph nodes where they direct the type, magnitude and quality of the adaptive immune response. Thus, the right match of antigens and adjuvants can potentiate downstream adaptive immune responses, enabling the development of new efficacious vaccines. Many infectious diseases of worldwide significance are not currently preventable by vaccination. Adjuvants are the most advanced new technology in the search for new vaccines against challenging pathogens and for vulnerable populations that respond poorly to traditional vaccines. OPEN ACCESS Vaccines 2015, 3 321

Vaccine adjuvants: Current state and future trends

The problem with pure recombinant or synthetic antigens used in modern day vaccines is that they are generally far less immunogenic than older style live or killed whole organism vaccines. This has created a major need for improved and more powerful adjuvants for use in these vaccines. With few exceptions, alum remains the sole adjuvant approved for human use in the majority of countries worldwide. Although alum is able to induce a good antibody (Th2) response, it has little capacity to stimulate cellular (Th1) immune responses which are so important for protection against many pathogens. In addition, alum has the potential to cause severe local and systemic side-effects including sterile abscesses, eosinophilia and myofascitis, although fortunately most of the more serious side-effects are relatively rare. There is also community concern regarding the possible role of aluminium in neurodegenerative diseases such as Alzheimer's disease. Consequently, there is a major unmet need for safer and more effective adjuvants suitable for human use. In particular, there is demand for safe and non-toxic adjuvants able to stimulate cellular (Th1) immunity. Other needs in light of new vaccine technologies are adjuvants suitable for use with mucosally-delivered vaccines, DNA vaccines, cancer and autoimmunity vaccines. Each of these areas are highly specialized with their own unique needs in respect of suitable adjuvant technology. This paper reviews the state of the art in the adjuvant field, explores future directions of adjuvant development and finally examines some of the impediments and barriers to development and registration of new human adjuvants.

Human prophylactic vaccine adjuvants and their determinant role in new vaccine formulations

Brazilian Journal of Medical and Biological Research, 2012

Adjuvants have been considered for a long time to be an accessory and empirical component of vaccine formulations. However, accumulating evidence of their crucial role in initiating and directing the immune response has increased our awareness of the importance of adjuvant research in the past decade. Nevertheless, the importance of adjuvants still is not fully realized by many researchers working in the vaccine field, who are involved mostly in the search for better target antigens. The choice of a proper adjuvant can be determinant for obtaining the best results for a given vaccine candidate, but it is restricted due to intellectual property and know-how issues. Consequently, in most cases the selected adjuvant continues to be the aluminum salt, which has a record of safety, but predominantly constitutes a delivery system (DS). Ideally, new strategies should combine immune potentiators (IP) and DS by mixing both compounds or by obtaining structures that contain both IP and DS. In addition, the term immune polarizer has been introduced as an essential concept in the vaccine design strategies. Here, we review the theme, with emphasis on the discussion of the few licensed new adjuvants, the need for safe mucosal adjuvants and the adjuvant/immunopotentiating activity of conjugation. A summary of toxicology and regulatory issues will also be discussed, and the Finlay Adjuvant Platform is briefly summarized.

Vaccine Adjuvants: The Current Necessity of Life

Shiraz E-Medical Journal, 2015

Context: Vaccination is considered as the most cost effective method for the prevention of human diseases. For this prevention method, we need certain substances to increase or boost the antibody as well as cell-mediated immune response against various bacterial as well as viral pathogens. Until now, alum was considered as the safest adjuvant for human use, licensed by the United States Food and Drug Administration. Due to the poor adjuvanticity of alum, conventional vaccines require multiple recall injections, at different time intervals, to attain or sustain the optimal immune response. The present review discusses about the necessity of adjuvants for vaccines. Evidence Acquisition: A number of factors such as slow release of antigen (depot effect), more efficient delivery of antigen to draining lymph nodes, non-specific activation of antigen-presenting cells or of B and/or T-lymphocytes, increased uptake of antigen by antigenpresenting cells or increased recruitment of immune cells to the site where the antigen is present, can contribute to increased immune responses to immunization. Many of these factors involve the interaction of various immune system components and specific anatomical features, making them difficult to replicate in model systems in vitro. Results: Despite the development of many potent adjuvant formulations with vaccine antigen during the last 80-90 years, aluminum compounds are still the only approved adjuvants used for routine human vaccines. Conclusions: Based on pre-clinical and preliminary clinical observations, it appears that the range of adjuvants accepted for human vaccines will expand in the coming years.

The safety evaluation of adjuvants during vaccine development: The AS04 experience

Vaccine, 2011

Novel adjuvants that contain immunoenhancer molecules are now present in human vaccines either registered or in clinical trials. These adjuvants have the potential to provide clear benefits in improving the magnitude and duration of various aspects of the adaptive immune response. However, the use of immunoenhancers in vaccine formulations may be perceived as introducing theoretical safety risks that need to be addressed during the course of vaccine development. In addition to classical clinical safety evaluation, the licensing authorities recommend that novel adjuvants should be evaluated in non-clinical toxicology studies, both as separate entities and as part of the final vaccine formulation. We present here our approach for the safety evaluation of adjuvanted vaccines using AS04-adjuvanted vaccines as example. This evaluation consists of three tiers: non-clinical toxicology, adjuvant mode-of-action investigations and clinical safety assessment in controlled clinical trials and post-marketing surveillance. We also discuss how the knowledge of adjuvant mode of action can support the current practice of safety evaluation.

Current adjuvants and new perspectives in vaccine formulation

Expert Review of Vaccines, 2011

Given the important role of adjuvants in prophylactic vaccines, identification and development of new adjuvants with enhanced efficacy and safety is necessary. The use of adjuvants with immunopotentiating properties that can direct the immune responses to humoral or cellmediated immunity and can induce T-cell responses has made it possible to design more protective vaccines. Although current regulations focus on traditional adjuvants, notably aluminum and calcium salts, advances have been made in regulatory considerations. The regulatory agencies for the evaluation of medicinal products are actively drafting guidance on requirements for the evaluation of new adjuvants. This article briefly summarizes the most widely studied adjuvants in vaccination, including those licensed for human vaccines and the regulatory aspects relevant to adjuvant quality at development stages.