Vaccines and Autoimmunity

Nicola Luigi Bragazzi, Nancy Agmon-Levin, Lucija Tomljenovic, Yehuda Shoenfeld, Nancy Agmon-Levin, Lucija Tomljenovic

• Publisher: Wiley-Blackwell
• Year: 2015
• ISBN:
  9781118663493
• Edition: 1
• Topic: Scienze biologiche
• Subtopic: Microbiologia

In light of the discovery of Autoimmune Syndrome Induced by Adjuvants, or ASIA, Vaccines and Autoimmunity explores the role of adjuvants – specifically aluminum in different vaccines – and how they can induce diverse autoimmune clinical manifestations in genetically prone individuals.

Vaccines and Autoimmunity is divided into three sections; the first contextualizes the role of adjuvants in the framework of autoimmunity, covering the mechanism of action of adjuvants, experimental models of adjuvant induced autoimmune diseases, infections as adjuvants, the Gulf War Syndrome, sick-building syndrome (SBS), safe vaccines, toll-like receptors, TLRS in vaccines, pesticides as adjuvants, oil as adjuvant, mercury, aluminum and autoimmunity. The following section reviews literature on vaccines that have induced autoimmune conditions such as MMR and HBV, among others. The final section covers diseases in which vaccines were known to be the solicitor – for instance, systemic lupus erythematosus – and whether it can be induced by vaccines for MMR, HBV, HCV, and others.

Edited by leaders in the field, Vaccines and Autoimmunity is an invaluable resource for advanced students and researchers working in pathogenic and epidemiological studies.

Part I
Mosaic of Autoimmunity

Chapter 1
Role of Adjuvants in Infection and Autoimmunity

Eitan Israeli,¹ Miri Blank,¹ and Yehuda Shoenfeld^1,2

¹Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Israel

²Incumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Introduction

Commonly used vaccines are a cost-effective and preventive way of promoting health, compared to the treatment of acute or chronic disease. However, not all vaccines are as efficient and easy to administer as the vaccine against smallpox (Vaccinia). Usually, upon injection of a pure antigen, the antigen is not taken up at the injection site, and an immunological reaction fails. In order to help the immune system to recognize the antigen, adjuvants are added to the antigens during the process of developing and producing a vaccine. For the last few years, researchers have been striving to elucidate the mechanisms by which adjuvants exert their immunological effects. By deciphering these mechanisms, scientists hope to design more efficient and less harmful adjuvants. As of 2013, the action mechanisms of the most used and “veteran” of adjuvants, alum, are being revealed. It seems that alum acts on multiple pathways, each of which can enhance immunological reactions to antigens independently.

Parts of this manuscript were published previously by our group (Israeli et al., 2009). Permission to reuse them was granted by Sage Publications.

The different types of adjuvants

Old and novel adjuvants are currently used in human and animal vaccination programs, as well as in experimental models, some of which are listed in this section.

Aluminum salts

Aluminum salt (alum) is an inorganic reagent that carries the potential to augment immunogenicity. Alum salts include alum phosphate and alum hydroxide, which are the most common adjuvants in human vaccines. The organic compound squalene (originally obtained from shark liver oil and a biochemical precursor to steroids) is sometimes added to the preparation.

Oil-based adjuvants

Oil-based adjuvants (e.g., Freund's adjuvant, pristine, etc.) are commonly found in some formulations of veterinary vaccines. Incomplete Freund's adjuvant (IFA) contains water-in-oil emulsion, while complete Freund's adjuvant (CFA) additionally contains killed mycobacteria. The mycobacteria added to the adjuvant attract macrophages and other cells to the injection site, which enhances the immune response. Thus, CFA is usually used for the primary vaccination, while the incomplete version is applied for boosting. Some novel oil-in-water emulsions are being developed by pharmaceutical companies, such as MF59 (Novartis), AS03 (GalxoSmithKline), Advax (Vaxine Pty), and Qs-21/ISCOMs (see further on).

Virosomes

During the last 2 decades, a variety of technologies have been investigated for their ability to improve the widely used alum adjuvants (Holzeret et al., 1996), which may induce local inflammation. Thus, other novel adjuvants that can also be used as antigen-carrier systems, the virosomes, have been developed. Virosomes contain a membrane-bound hemagglutinin and neuraminidase derived from the influenza virus, both of which facilitate uptake into antigen-presenting cells (APCs) and mimic the natural immune response (Gluck, 1999).

Novel and experimental adjuvants

In the search for new and safer adjuvants, several new ones have been developed by pharmaceutical companies utilizing new immunological and chemical innovations.

Toll-like receptor-related adjuvants

IC31 is a two-component synthetic adjuvant that signals through toll-like receptor (TLR)-9. This novel adjuvant is tested as of 2008 in influenza vaccine combinations (Riedlet et al., 2008). Four others, ASO4, ASO2A, CPG 7907, and GM-CSF, are investigated for highly relevant vaccines, such as those against papilloma virus, hepatitis B, and malaria (Pichichero, 2008). Other TLR-dependent adjuvant candidates are as yet only in clinical development, such as RC-529 and ISS, Flagellin and TLR-agonists. AS02 and AS04 are proprietary adjuvants of GlaxoSmithKline (GSK). AS02 contains MPL and QS-21 in an oil-in-water emulsion. AS04 combines MPL with alum. MPL is a series of 4′monophosphoryl lipid A that varies in the extent and position of fatty acid substitution. It is prepared from lipopolysaccharide (LPS) of Salmonella minnesota R595 by treating the LPS with mild acid and base hydrolysis, followed by purification of the modified LPS. Unmethylated CpG dinucleotides are the reason why bacterial DNA, but not vertebrate DNA, is immunostimulatory. Vertebrate DNA has relatively low amounts of unmethylated CpG compared to bacterial DNA. The adjuvant effect of CpG is enhanced when conjugated to protein antigens. CPG7909, an adjuvant developed by Coley Pharmaceuticals, has been tested in a few vaccines directed at infectious agents (such as Hepatitis B allergen: Creticos et al., 2006) and tumor cells (Alexeevet et al., 2008; Kirkwood et al., 2009).

New formulated adjuvants

MF59 is a submicron oil-in-water emulsion of a squalene, polyoxyethylene sorbitan monooleate (Tween 80), and sorbitan trioleate. MF59 was approved in Europe and is found in several vaccines, including influenza. It has also been licensed to other companies and is being actively tested in vaccine trials. Other oil-in-water emulsions include Montanide (Seppic), adjuvant 65 (in use since the 1960s), and Lipovant. QS-21, a natural product of the bark of the Quillaja saponaria tree, which is native to Chile and Argentina, is currently under investigation (Ghochikyan, 2006). Immune-stimulating complexes (ISCOMs) are honeycomb-like structures composed mainly of Quillaja saponins, cholesterol, phospholipid, and antigen. Some ISCOMs are formed without antigen and then mixed with antigen, so that the antigen is absorbed on to or conjugated with the ISCOM. Specific isoforms of ADVAX, an adjuvant developed in Australia based on inulin (a natural plant-derived polysaccharide consisting of a chain of fructose molecules ending in a single glucose), are prepared and formulated into compositions suitable for use as adjuvants. A synergistic e...