Only two adjuvants—alum and AS04—are used in commercially available vaccines in the United States. In 2013, the Food and Drug Administration approved the inclusion of another adjuvant, AS03, in the pandemic H5N1 influenza vaccine. Currently, this vaccine is included in the U.S. vaccine stockpile but is not commercially available. Additional adjuvants have been approved for use in Europe, and many others are being tested in clinical trials.
Some types of compounds being used or tested as adjuvants are highlighted below.
Naturally occurring parts of pathogens used as adjuvants can help trigger early non-specific, or innate, immune responses to vaccines. These adjuvants target various receptors inside or on the surface of innate immune cells. The innate immune system influences adaptive immune responses, which provide long-lasting protection against the pathogen that the vaccine targets. Examples of pathogen components tested and used as adjuvants include the following:
- Monophosphoryl Lipid A
Monophosphoryl lipid A (MPL) is an immune-stimulating lipid (fat). It has been combined with alum to produce the AS04 adjuvant used in the human papillomavirus vaccine Cervarix.
Poly(I:C) is synthetic double-stranded RNA that mimics a molecular pattern associated with viral infection. In rhesus monkeys, poly(I:C)-containing vaccines against SIV—a close relative of HIV that causes an AIDS-like disease in monkeys—have elicited protective immune responses.
- CpG DNA Adjuvants
CpG DNA adjuvants are short segments of DNA that include sequence motifs, or patterns, commonly found in bacterial DNA. Hepatitis B vaccines containing CpG-based adjuvants are being tested in clinical trials, and initial results suggest that the CpG-adjuvanted vaccines are safe and effective.
An emulsion is a blend of two liquids that are normally unmixable, such as water and oil. An oil-in-water emulsion called MF59 is used as an adjuvant in Fluad, an influenza vaccine available in Europe. MF59 helps recruit immune cells from the blood to the vaccine injection site. MF59 contains similar ingredients as AS03, which is part of the pandemic influenza vaccine in the U.S. vaccine stockpile.
Particulate adjuvants form very small particles that can stimulate the immune system and also may enhance delivery of antigen to immune cells. Examples of particulate adjuvants include the following:
Alum, the most commonly used vaccine adjuvant, consists of aluminum salts that are not soluble in water. Alum is included in numerous vaccines, including those that prevent hepatitis B and human papillomavirus. Scientists are beginning to understand how alum stimulates vaccine-induced immunity. Gaining information about the mechanisms that alum uses to activate the immune system will help increase understanding of adjuvant function and facilitate the design of new vaccine adjuvants.
Virosomes, particles that resemble viruses but are noninfectious, are included as adjuvants in the flu vaccine Inflexal and the hepatitis A vaccine Epaxal, both licensed in Europe. The virosomes incorporated into these vaccines have antigens and other viral proteins on their surfaces, but they cannot cause infection because they do not contain any viral genetic material. Certain immune cells recognize these virus-like particles and engulf them. These cells then present the antigen to adaptive immune cells, which mount a protective response.
Cytokines are small proteins that serve as chemical messengers of the immune system. Because of their role in coordinating immune responses, some cytokines have been evaluated as vaccine adjuvants. For example, scientists have conducted animal studies to evaluate interleukin 12 (IL-12) as an adjuvant in vaccines against various bacterial and viral infections. Results from these studies suggest that IL-12 may increase protective immunity to some respiratory pathogens.
Combinations of adjuvants, such as AS04, are of interest because of their ability to elicit multiple protective immune responses. Adjuvants that have a modest effect when used alone may induce a more potent immune response when used together.
Combination adjuvant research is in the early stages. Scientists must work to identify how adjuvants can be combined to elicit immune responses that are useful for a given antigen. NIAID is supporting research to identify and determine the function of novel adjuvant combinations. A long-range goal of this line of research is to develop a toolbox of adjuvants that can be combined in different ways to elicit a certain type of immune response.