Immunologic adjuvant


In immunology, an adjuvant is a substance that increases or modulates the immune response to a vaccine. 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."
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 some contaminants actually enhanced the immune response.
There are many known adjuvants in widespread use, including potassium alum, various plant and animal derived oils and virosomes.

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 pathogen-associated molecular patterns, which include liposomes, lipopolysaccharide, molecular cages for antigens, components of bacterial cell walls, and endocytosed nucleic acids such as RNA, double-stranded RNA, single-stranded DNA, and unmethylated CpG dinucleotide-containing DNA. 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, lymphocytes, and macrophages by mimicking a natural infection.

Types

Aluminium salts

There are many adjuvants, some of which are inorganic, that carry the potential to augment immunogenicity. Alum was the first aluminium salt used for this purpose, but has been almost completely replaced by aluminium hydroxide and aluminium phosphate for commercial vaccines. Aluminium salts are the most commonly used adjuvants in human vaccines. Their adjuvant activity was described in 1926.
The precise mechanism of aluminium salts remains unclear but some insights have been gained. It was formerly thought that they function as delivery systems by generating depots that trap antigens at the injection site, providing a slow release that continues to stimulate the immune system. However, studies have shown that surgical removal of these depots had no impact on the magnitude of IgG1 response.
Alum can trigger dendritic cells and other immune cells to secrete Interleukin 1 beta, an immune signal that promotes antibody production. Alum adheres to the cell's plasma membrane and rearranges certain lipids there. Spurred into action, the dendritic cells pick up the antigen and speed to lymph nodes, where they stick tightly to a helper T cell and presumably induce 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. However, recent research indicates that alum formulated in a nanoparticle form rather than microparticles can broaden the utility of alum adjuvants and promote stronger adjuvant effects.

Organic adjuvants

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.
Squalene is a naturally occurring organic compound 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 as a precursor to cholesterol and is present in human sebum. MF59 is an oil-in-water emulsion of squalene adjuvant used in some human vaccines. As of 2021, over 22 million doses of one vaccine with squalene, FLUAD, have been administered with no severe adverse effects reported. AS03 is another squalene-containing adjuvant. In addition, squalene-based O/W emulsions have also been shown to stably incorporate small molecule TLR7/8 adjuvants and lead to enhanced adjuvanticity via synergism.
The plant extract QS-21 is a liposome loaded with saponins extracted from the tree Quillaja saponaria.
Monophosphoryl lipid A, a detoxified version of the lipopolysaccharide toxin from the bacterium Salmonella Minnesota, interacts with the receptor TLR4 to enhance immune response.
The combination of QS-21, cholesterol and MPL forms the adjuvant AS01 which is used in the Shingrix vaccine approved in 2017, as well as in the approved malaria vaccine Mosquirix.
The adjuvant Matrix-M is an immune stimulating complex consisting of nanospheres made of QS-21, cholesterol and phospholipids. It is used in the approved Novavax Covid-19 vaccine and in the malaria vaccine R21/Matrix-M.
Several unmethylated cytosine phosphoguanosine oligonucleotides activate the TLR9 receptor that is present in a number of cell types of the immune system. The adjuvant CpG 1018 is used in an approved Hepatitis B vaccine.

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:
This process carried out by both dendritic cells 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.
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.
  • 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 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, 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 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 that are expressed on the membranes of leukocytes including dendritic cells, macrophages, natural killer cells, cells of the adaptive immunity and non-immune cells.
The binding of ligandseither in the form of adjuvant used in vaccinations or in the form of invasive moieties during times of natural infection to TLRs mark the key molecular events that ultimately lead to innate immune responses and the development of antigen-specific acquired immunity.
As of 2016, several TLR ligands were in clinical development or being tested in animal models as potential adjuvants.