Understanding Vaccine Adjuvants

How are vaccine immune responses strengthened?

Vaccines work by stimulating the immune system to produce antibodies and immune cells that recognize the antigens—foreign proteins—in the vaccine. These antigens are normally found in harmful pathogens (viruses and bacteria) which cause disease. The idea is to prepare the immune system so that if a person is exposed to the pathogen later, the immune system can respond and prevent an illness from developing.

The immune system has two separate arms (see March 2004 Primer on Understanding the Immune System, Part II). One arm is responsible for the cell-mediated response. In this arm, certain kinds of immune cells called killer T cells are produced that can destroy infected cells. These killer T cells are sometimes called CD8+ T cells. Another kind of immune cell is the helper T cell, and these cells help coordinate the other parts of the immune response. Helper T cells are sometimes called CD4+ T cells and are what are measured when people refer to "CD4 cell counts" in HIV infection.

The second arm of the immune response is called the antibody or humoral response. Here, B cells recognize the antigen and produce antibodies that can attach to it. When these antibodies attach to the antigen on the pathogen they "neutralize" it. This means that the pathogen can no longer infect cells and cause infection.

Once T or B cells have been exposed to a foreign antigen, they produce memory cells that remember that antigen (see February 2004 Primer on Understanding the Immune System, Part I). If the pathogen with that antigen enters the body at a later time, these memory cells can respond quickly and strongly to stop any infection and disease. So, for example, if someone who has been vaccinated against measles is exposed to the measles virus, his or her body will immediately recognize the virus and will destroy it.

Helping hand

But most antigens in vaccines do not stimulate the immune system enough on their own, they need a helping hand. This extra help can be provided by compounds called adjuvants. Different adjuvants can increase the strength of the immune response in a number of different ways. After a vaccine is injected, over time it is cleared away by the body. Some adjuvants can increase the amount of time that the vaccine antigen remains at the injection site, allowing the immune system to respond for longer and more strongly. It is a type of sustained-release mechanism, a so-called "depot effect."

Other adjuvants can cause helper T cells and other immune cells to become active by "showing" (or presenting) the vaccine antigen in a better way. Since helper T cells help coordinate many other parts of the immune response, adjuvants that work this way can strengthen killer T cell and antibody responses to the vaccine antigen. Other adjuvants work by causing a granuloma to form. This is a mass of cells loaded with other immune cells called macrophages. Macrophages work by presenting foreign antigens to other immune cells so that they can recognize it and make an immune response. In addition, some adjuvants can stimulate immune cells to produce factors called cytokines. These cytokines can then act on a variety of immune cells to produce more antibody or stronger immune cell responses.

Adjuvants and AIDS vaccines

Although scientists do not know if an AIDS vaccine will need an adjuvant, it is likely that it will. Some licensed vaccines against other diseases contain whole viruses or whole bacteria in them. But the kinds of vaccines that will be used against HIV will contain only portions of HIV’s genetic material, to ensure that it is safe (see September 2004Primer on Understanding Viral Vectors). These portions will probably not be as good at causing an immune response as the whole intact virus would be. Because of that, AIDS vaccines will likely need adjuvants to help make the immune response stronger.

The most commonly used adjuvants are aluminum (alum) based compounds—for example aluminum hydroxide. This has been used in billions of doses of vaccines for other diseases and is effective at increasing the length of time an antigen is present, from days to as much as weeks. Recent studies on aluminum hydroxide adjuvant show that it stimulates the production of specific types of immune cells called antigen presenting cells (APCs). These APCs pick up the antigen and present it to T cells.

Various adjuvants are now being tested or considered for use with candidate AIDS vaccines. These range from adjuvants designed to act on specific parts of the immune response to bacterial protein adjuvants which will stimulate immune cells more generally.

Mixtures of adjuvant compounds are becoming increasingly popular. Among these is a mixture of MPL (monophosphoryl lipid A) plus alum, called AS04. It is now being tested in Phase III clinical trials, the large clinical trials that test the safety and effectiveness of a vaccine. AS02 is an adjuvant that contains an oil-in-water mix and MPL plus saponin, a plant extract. A malaria vaccine with AS02 has demonstrated promise in a recent efficacy trial, a study which showed actual protection against disease.

Toll-like receptors (TLRs) are areas on various immune cells that "sense" the initial presence of pathogens by attaching to it. Once TLRs have attached to a pathogen a whole range of inflammatory and immune responses involving many cells are set in motion. New adjuvants are being developed that target different TLRs and will activate only certain parts of the immune response.

Because AIDS vaccines will be unlike most other vaccines that have been licensed, specifically targeted adjuvants may lead them to produce a stronger, longer-lasting immunity.