Immunopotentiators in Modern Vaccines

Virgil Schijns, Derek O'Hagan

• Publisher: Academic Press
• Year: 2016
• ISBN:
  9780128040959
• Edition: 2
• Topic: Medicine
• Subtopic: Immunology

Immunopotentiators in Modern Vaccines, Second Edition, provides in-depth insights and overviews of the most successful adjuvants, those that have been included in licensed products, also covering the most promising technologies that have emerged in recent years. In contrast to existing books on the subject, the chapters here provide summaries of key data on the mechanisms of action of the individual vaccine adjuvants.

In addition, the book covers key aspects of how the technologies might be further developed and what might be their limitations, while also giving an overview of what made the most advanced adjuvant technologies successful.

• Provides contributions from leading international authorities in the field
• Features immunopotentiators classified by function, with well-illustrated, informative figures presenting the interaction between the immunopotentiators and the host immune system
• Lists advantages and potential hurdles for achieving a practical application for each specific immunopotentiator
• Offers US FDA perspectives which highlight how future adjuvants will be approved for new generation vaccines

Chapter 1

Vaccine Adjuvants' Mode of Action

Unraveling ‘‘the Immunologist's Dirty Little Secret”

V.E.J.C. Schijns Wageningen University, The Elst, Wageningen, The Netherlands Epitopoietic Research Corporation (ERC), Schaijk, The Netherlands and Belgium

Abstract

Most modern vaccines, based only on well-defined purified antigens, are usually insufficient for proper immune induction in the absence of co-administrated immunostimulatory components called adjuvants (adjuvare (Latin) to help). Vaccine adjuvants come in many forms, which are not unified by a common structure. The choice of a suitable adjuvant for a certain vaccine antigen formulation is often difficult due to the fact that little is known about the mechanisms underlying adjuvant activity in general. As a result, the local and systemic reactions of the antigen–adjuvant combination have to be determined by trial and error. Because of this uncertainty adjuvants have been called “the immunologist's dirty little secret” (Janeway, 1989). Ideally, future vaccines contain adjuvants with predictable activity. During the last decades we have learned in more detail how adaptive immune responses in a normal individual evolve. A number of immunological theories may explain the critical mechanisms underlying adjuvanticity, each of them championing either distinct pathways or distinct key steps within immunological pathways. Here, the most important concepts are discussed in relation to the most recent knowledge in vaccine adjuvant activity.

Keywords

Antibodies; Antigen-presenting cells; Adjuvant; Dendritic cells; Immune system; Vaccines

Introduction

The immune system has evolved to free the host from potentially noxious pathogens and to identify and attack abnormal, potentially tumorigenic cells. Upon first exposure to a pathogen, the immune system reacts with the “natural” innate and subsequent primary adaptive immune responses. Primary adaptive immune responses need at least a few days to develop before they become effective immune effector responses. This delay in the primary natural immune response is the reason for the variable success of the naive host to attack the invading microorganism in the case of a rapidly replicating invader, which is not stopped by innate immune functions. Vaccination induces an “artificial” immune response against microorganisms ideally facilitating the formation of long-lived T and B memory cells to conserved antigens, which become rapidly activated after secondary infection. In addition, vaccination may generate readily available immune effector elements, such as circulating antibodies with various functional capacities.

Classic vaccines come in two form, either as attenuated, less virulent, replicating microorganisms, which, however, may carry the risk of reversion to virulence and adverse reactions in immunocompromised individuals, or as nonreplicating inactivated microbes or their components. The latter category is most safe and therefore preferred. Unfortunately, immunization with purified antigen alone is usually insufficient for proper immune induction. Initiation, amplification, and guidance of an appropriate adaptive immune response of sufficient magnitude and duration therefore requires the coadministration of immunostimulatory components called adjuvants [adjuvare (Latin) meaning to help]. Many different types of adjuvants have been described, which are not unified by a common structure. The proper choice of adjuvant for a certain vaccine formulation is often difficult. The onset, magnitude, and type of immune pathway and the duration of immune response of the antigen–adjuvant combination are often unpredictable. This is largely due to the fact that little is known about the mechanisms underlying adjuvant activity in general. In addition, depending on the antigen–adjuvant combination, the local and systemic reactions may vary. Therefore, it is difficult to predict what type of immune reaction and immune effector response will be elicited to the vaccine antigen by the chosen adjuvant. Moreover, the side effects often cannot be foreseen. Therefore, adjuvants have been called “the immunologist's dirty little secret.”⁵⁸ Although vaccines are the most successful medical invention of the past century, it is obvious that future vaccines require adjuvants with predictable activity.

Today we know that adaptive immune responses in a normal individual initially involve the activation of antigen-specific T-helper cells, which amplify and regulate—via either soluble cytokines or membrane-bound costimulatory molecules—the activities of antimicrobial effector cells, microbiocidal macrophages, cytolytic T cells, and/or B cells. Activation of naive antigen-specific T-helper cells occurs in lymphoid organs, like the lymph nodes, by dendritic cells (DCs), the so-called professional antigen-presenting cells (APCs). Upon delivery or expression of antigen in peripheral tissues, DCs take up the antigen via pinocytosis, phagocytosis, or following infection by the microorganism. During virulent infection, DCs receive stimuli from (structures of) the pathogen, leading to maturation and activation. In the absence of these stimuli, DCs are presumed to tolarize antigen-specific T helper cells, resulting in insufficient priming for an effective T helper cell–dependent immune response. Currently, a number of immunological theories may explain the critical mechanisms underlying adjuvanticity, each of them championing either distinct pathways or different key steps in immunological pathways.^107,108 Here, the most important concepts are discussed in relation to the most recent knowledge in vaccine adjuvant activity.

Adjuvants Provide Start Signals for Immune Reactivity and Guide the Response to an Acceptable Magnitude

As mentioned earlier, vaccination aims to generate memory immune effector responses of adaptive T and/or B cells specific for a, preferentially conserved, epitope of the pathogen, tumor, or allergen of interest. T helper cells are critical amplifiers and guiders of antigen-specific immune effector cell reactions, such as those of B cells and cytolytic T cells. In addition, they amplify the microbiocidal activity of macrophages. Hence, the priming and clonal expansion of antigen-specific T helper cells is initially critical for adequate adaptive immunity. According to the two-signal model of immune reactivity, activation of T helper cells, apart from the delivery of antigen signals to T cell receptors (signal 1), critically depends on costimulatory signals (signal 2) in the form of soluble cytokines or membrane-bound surface molecules at the time of antigen recognition. According to the classic two-signal model, antigen presentation in the absence of costimulation results in T-cell anergy, tolerance, or deletion.^13,16,73

Following on from these thoughts, efficient vaccines should be able to amplify and direct adaptive immune responses, most of which are under regulatory control of antigen-specific major histocompatibility complex (MHC) class II–restricted T helper cells. Although the two-signal theory is well accepted and sustained by numerous publications, it does not explain all immunological events and is at variance with other experimental data.

Regulation of Immune Responses by Antigen Delivery (Signal 1)

Naive T cells continuously survey and recirculate between lymph nodes and the spleen. They are unable to access the nonlymphoid areas of the body. Only memory and effector cells can do this. To be recognized by antigen-specific T and B cells of the adaptive immune system, antigen administered as a vaccine to peripheral tissues, like skin and muscle tissue, must first reach the peripheral lymphoid organs. Mice lacking secondary lymph nodes, due to a genetic mutation or as a result of surgical ablation, are strongly compromised in cellular and humoral responses.⁶⁴ Also, interruption of afferent lymphatic vessels prevents immune responses.^11,35 Antigen present within peripheral tissues drains to regional lymph nodes, either in free form or after uptake by local immature DCs. Especially DCs can prime naive T cells and are, therefore, called professional APCs and also “nature's adjuvant.”^10,122

On arrival in the lymph node, DCs have processed the antigen in peptide fragments, which are then exposed in MHC molecules on their cell surface (signal 1). According to the geographical concept of immune induction¹³⁵ and the classical depot theory ^33,34,51 this facilitation of signal 1 expression in secondary lymphoid organs is most critical for immune reactivity and a durable immune response, respectively [see Fig. 1.1 (upper panel) and Fig. 1.2].

A number of observations are in accordance with this view. Kündig et al. ^7...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• List of Contributors
• Preface
• Chapter 1. Vaccine Adjuvants' Mode of Action: Unraveling ‘‘the Immunologist's Dirty Little Secret”
• Chapter 2. The Role of Inflammasomes in Adjuvant-Driven Humoral and Cellular Immune Responses
• Chapter 3. Dendritic Cells as Targets of Vaccines and Adjuvants
• Chapter 4. Host-Derived Cytokines and Chemokines as Vaccine Adjuvants
• Chapter 5. Discovery of Immune Potentiators as Vaccine Adjuvants
• Chapter 6. Current Status of Toll-Like Receptor 4 Ligand Vaccine Adjuvants
• Chapter 7. Flagellins as Adjuvants of Vaccines
• Chapter 8. Toll-Like Receptor 7 and 8 Agonists for Vaccine Adjuvant Use
• Chapter 9. CpG Oligodeoxynucleotides as Adjuvants for Clinical Use
• Chapter 10. Advax Adjuvant: A Potent and Safe Immunopotentiator Composed of Delta Inulin
• Chapter 11. Natural Vaccine Adjuvants and Immunopotentiators Derived From Plants, Fungi, Marine Organisms, and Insects
• Chapter 12. Polymeric Particles as Vaccine Delivery Systems
• Chapter 13. MF59: A Safe and Potent Adjuvant for Human Use
• Chapter 14. The Development of the Adjuvant System AS01: A Combination of Two Immunostimulants MPL and QS-21 in Liposomes
• Chapter 15. Development and Evaluation of AS04, a Novel and Improved Adjuvant System Containing 3-O-Desacyl-4′- Monophosphoryl Lipid A and Aluminum Salt
• Chapter 16. ISCOMATRIX Adjuvant in the Development of Prophylactic and Therapeutic Vaccines
• Chapter 17. Development and Evaluation of CAF01
• Chapter 18. Mineral Adjuvants
• Chapter 19. Toxin-Based Mucosal Adjuvants
• Chapter 20. Adjuvants for Skin Vaccination
• Chapter 21. Vaccination to Treat Noninfectious Diseases: Surveying the Opportunities
• Chapter 22. A Framework for Evaluating Nonclinical Safety of Novel Adjuvants and Adjuvanted Preventive Vaccines
• Conclusions—“Getting Better”
• Index