Immunologic adjuvant

In immunology, an adjuvant is a substance that potentiates and/or modulates the immune responses to an antigen to improve them.[1] The word "adjuvant" comes from the Latin word adiuvare, meaning to help or aid. "An immunologic adjuvant is defined as any substance that acts to accelerate, prolong, or enhance antigen-specific immune responses when used in combination with specific vaccine antigens."[2]

In the early days of vaccine manufacture, significant variations in the efficacy of different batches of the same vaccine were correctly assumed to be caused by contamination of the reaction vessels. However, it was soon found that more scrupulous cleaning actually seemed to reduce the effectiveness of the vaccines, and that some contaminants actually enhanced the immune response.

There are many known adjuvants in widespread use, including aluminium salts, oils and virosomes.[3]

Overview

Adjuvants in immunology are often used to modify or augment the effects of a vaccine by stimulating the immune system to respond to the vaccine more vigorously, and thus providing increased immunity to a particular disease. Adjuvants accomplish this task by mimicking specific sets of evolutionarily conserved molecules, so called PAMPs, which include liposomes, lipopolysaccharide (LPS), molecular cages for antigen, components of bacterial cell walls, and endocytosed nucleic acids such as double-stranded RNA (dsRNA), single-stranded DNA (ssDNA), and unmethylated CpG dinucleotide-containing DNA.[4] Because immune systems have evolved to recognize these specific antigenic moieties, the presence of an adjuvant in conjunction with the vaccine can greatly increase the innate immune response to the antigen by augmenting the activities of dendritic cells (DCs), lymphocytes, and macrophages by mimicking a natural infection.[5][6]

Inorganic adjuvants

Aluminium salts

There are many adjuvants, some of which are inorganic (such as alum), that also carry the potential to augment immunogenicity.[7][8] Two common salts include aluminium phosphate and aluminium hydroxide. Aluminium salts are the most commonly-used adjuvants in human vaccines. Their adjuvant activity was described in 1926.[9]

The precise mechanism of alum action remains unclear but some insights have been gained. For instance, alum can trigger dendritic cells (DC) and other immune cells to secrete interleukin-1β (IL-1β), an immune signal that promotes antibody production. Alum adheres to the cell’s plasma membrane and rearranges certain lipids there. Spurred into action, the DC picks up the antigen and speeds to a lymph node, where it sticks tightly to a helper T cell and presumably induces an immune response. A second mechanism depends on alum killing immune cells at the injection site although researchers aren’t sure exactly how alum kills these cells. It has been speculated that the dying cells release DNA which serves as an immune alarm. Some studies found that DNA from dying cells causes them to adhere more tightly to helper T cells which ultimately leads to an increased release of antibodies by B cells. No matter what the mechanism is, alum is not a perfect adjuvant because it does not work with all antigens (e.g. malaria and tuberculosis).[10]

Organic adjuvants

Freund's complete adjuvant is a solution of inactivated Mycobacterium tuberculosis in mineral oil developed in 1930. It is not safe enough for human use. A version without the bacteria, that is only oil in water, is known as Freund's incomplete adjuvant. It helps vaccines release antigens for a longer time. Despite the side effects, its potential benefit has led to a few clinical trials.[9]

Squalene is a naturally-occurring organic compound that is used in human and animal vaccines. Squalene is an oil, made up of carbon and hydrogen atoms, produced by plants and is present in many foods. Squalene is also produced by the human liver and present in human sebum.[11] MF59 is an oil-in-water emulsion of squalene adjuvant used in some human vaccines. Over 22 million doses of a vaccine with squalene have been administered with no safety concerns.[12]

The plant extract QS21 is a liposome made up of plant saponins.[13] It is a part of the Shingrix vaccine approved in 2017.[14]

Monophosphoryl lipid A (MPL), a detoxified version of Salmonella minnesota lipopolysaccharide, interacts with TLR4 to enhance immune response. It is a part of the Shingrix vaccine approved in 2017.[15][9]

Adaptive immune response

In order to understand the links between the innate immune response and the adaptive immune response to help substantiate an adjuvant function in enhancing adaptive immune responses to the specific antigen of a vaccine, the following points should be considered:

  • Innate immune response cells such as dendritic cells (DCs) engulf pathogens through a process called phagocytosis.
  • DCs then migrate to the lymph nodes where T cells (adaptive immune cells) wait for signals to trigger their activation.[16]
  • In the lymph nodes, DCs mince the engulfed pathogen and then express the pathogen clippings as antigen on their cell surface by coupling them to a special receptor known as a major histocompatibility complex (MHC).
  • T cells can then recognize these clippings and undergo a cellular transformation resulting in their own activation.[17]
  • γδ T cells possess characteristics of both the innate and adaptive immune responses.
  • Macrophages can also activate T cells in a similar approach (but do not do so naturally).

This process carried out by both DCs and macrophages is termed antigen presentation and represents a physical link between the innate and adaptive immune responses.

Upon activation, mast cells release heparin and histamine to effectively increase trafficking to and seal off the site of infection to allow immune cells of both systems to clear the area of pathogens. In addition, mast cells also release chemokines which result in the positive chemotaxis of other immune cells of both the innate and adaptive immune responses to the infected area.[18][19]

Due to the variety of mechanisms and links between the innate and adaptive immune response, an adjuvant-enhanced innate immune response results in an enhanced adaptive immune response. Specifically, adjuvants may exert their immune-enhancing effects according to five immune-functional activities.[20]

  • First, adjuvants may help in the translocation of antigens to the lymph nodes where they can be recognized by T cells. This will ultimately lead to greater T cell activity resulting in a heightened clearance of pathogen throughout the organism.
  • Second, adjuvants may provide physical protection to antigens which grants the antigen a prolonged delivery. This means that the organism will be exposed to the antigen for a longer duration, making the immune system more robust as it makes use of the additional time by upregulating the production of B and T cells needed for greater immunological memory in the adaptive immune response.
  • Third, adjuvants may help to increase the capacity to cause local reactions at the injection site (during vaccination), inducing greater release of danger signals by chemokine releasing cells such as helper T cells and mast cells.
  • Fourth, they may induce the release of inflammatory cytokines which helps to not only recruit B and T cells at sites of infection but also to increase transcriptional events leading to a net increase of immune cells as a whole.
  • Finally, adjuvants are believed to increase the innate immune response to antigen by interacting with pattern recognition receptors (PRRs) on or within accessory cells.

Toll-like receptors

The ability of the immune system to recognize molecules that are broadly shared by pathogens is, in part, due to the presence of immune receptors called Toll-Like Receptors (TLRs) that are expressed on the membranes of leukocytes including dendritic cells, macrophages, natural killer cells, cells of the adaptive immunity (T and B lymphocytes) and non-immune cells (epithelial and endothelial cells, and fibroblasts).[21]

The binding of ligands – either in the form of adjuvant used in vaccinations or in the form of invasive moieties during times of natural infection – TLR marks the key molecular events that ultimately lead to innate immune responses and the development of antigen-specific acquired immunity.[22][23]

As of 2016, several TLR ligands were in clinical development or being tested in animal models as potential adjuvants.[24]

Medical complications

Humans

Aluminium salts used in many human vaccines are generally regarded as safe.[25]

Animals

Aluminum adjuvants have caused motor neuron death in mice[26] when injected directly onto the spine at the scruff of the neck, and oil-water suspensions have been reported to increase the risk of autoimmune disease in mice.[27] Squalene has caused rheumatoid arthritis in rats already prone to arthritis.[28]

In cats, vaccine-associated sarcoma (VAS) occurs at a rate of between 1 and 10 per 10,000 injections. In 1993, a causal relationship between VAS and administration of aluminum adjuvated rabies and FeLV vaccines was established through epidemiologic methods, and in 1996 the Vaccine-Associated Feline Sarcoma Task Force was formed to address the problem.[29] However, evidence conflicts on whether types of vaccines, manufacturers or factors have been associated with sarcomas.[30]

Controversy

As of 2006, the premise that TLR signaling acts as the key node in antigen-mediated inflammatory responses has been in question as researchers have observed antigen-mediated inflammatory responses in leukocytes in the absence of TLR signaling.[4][31] One researcher found that in the absence of MyD88 and Trif (essential adapter proteins in TLR signaling), they were still able to induce inflammatory responses, increase T cell activation and generate greater B cell abundancy using conventional adjuvants (alum, Freund's complete adjuvant, Freund's incomplete adjuvant, and monophosphoryl-lipid A/trehalose dicorynomycolate (Ribi's adjuvant)).[4]

These observations suggest that although TLR activation can lead to increases in antibody responses, TLR activation is not required to induce enhanced innate and adaptive responses to antigens.

Investigating the mechanisms which underlie TLR signaling has been significant in understanding why adjuvants used during vaccinations are so important in augmenting adaptive immune responses to specific antigens. However, with the knowledge that TLR activation is not required for the immune-enhancing effects caused by common adjuvants, we can conclude that there are, in all likelihood, other receptors besides TLRs that have not yet been characterized, opening the door to future research.

See also

References
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