Over the last century the approach to vaccine design has moved from vaccines (many of them still available today) that were developed empirically to the development of vaccines with higher specificity, better activation of relevant immunological mechanisms, lower reactogenicity, and better safety profiles. With these advances, a major challenge emerged; in comparison to whole inactivated microorganisms or less purified vaccines highly purified and defined antigens can have the unwanted consequence of impaired immunogenicity . While live attenuated or killed whole organisms contain a multitude of antigenic structures that can act as “intrinsic adjuvants” [ 1] to enhance their immunogenicity, this quality often is lost with the purification process of subunit vaccines. In order to conserve the advantages of subunit vaccines it was necessary to develop tools, i.e., adjuvants that support a sufficient activation of the immune system (Table 1 ).

Table1. Adjuvants potentiate vaccine -induced immune response s

Traditional vaccine adjuvants include aluminum salts, emulsions, and liposomes [ 1 ]. Aluminum salts have been used widely as adjuvants in human vaccines for more than 80 years [ 2 ]. It is now known that aluminum salts (and other adjuvants) are able to provide proinflammatory or immunostimulatory effects as well as pro long the persistence of vaccine antigens by slowing down antigen degradation. However, it has also been demonstrated that aluminum salts primarily promote antibody responses, with little or no effect on T-helper 1 and cytotoxic T cell immune response s, which are key for protection against many pathogens [ 3 ]. Oil-in-water (O/W) emulsions have a good safety profile and are capable of eliciting a strong humoral response. An example is MF59™, which is composed of stable droplets of the metabolizable oil squalene, and two surfactants, polyoxyethylene sorbitan monooleate (Tween 80) and sorbitan trioleate (Span-85). Enhancement of the immune response generated by MF59 ^TM appears to be limited to antibody responses [ 4 ].

Especially for vaccines designed to induce a cytotoxic T cell- mediated immune response s, aluminum salts have been found to be inadequate to imitate the required protection. This is essentially due to a lack of “intrinsic immune defense triggers” usually provided by the pathogen , such as pathogen-associated molecular pattern s (PAMPs) [ 3 ]. Naturally available PAMPs may be reduced or even become lost during the selection process for relevant vaccine antigens or in the course of the purification process. PAMPs represent conserved “danger signals” that are recognized by pattern recognition receptors (PRRs), mainly of the innate immune system and to some degree also on B and T cells, including so-called Toll- like receptors (TLRs). The targeting of PRRs by PAMPs delivers an important early activation signal that can alert and potentiate multiple aspects of the adaptive immune responses, i.e., type, magnitude, and quality of specific B and T cell activation, and immune memory induction. Hence, it is by the recognition of particular PAMPs the innate immune system can create different immunological environments that can shape the type of protective adaptive immune responses. It was a logical step in vaccine development to target the “danger-sensing” PRRs in order to improve the quality and persistence of vaccine-related immune responses. A variety of TLR agonists have also been identified as potential vaccine immunomodulators, including deacylated monophosphoryl lipid A (MPL) [ 5], a purified, detoxified derivative of the lipopolysaccharide (LPS) molecule of the bacterial wall of Salmonella minnesota [ 6 ]. Like LPS, MPL acts through binding to TLRs, stimulating upregulation of co-stimulatory molecules and cytokine release, inducing a strong humoral and cellular response, depending on the antigen considered [ 7 ]. Most recently, the improved understanding of TLR signaling has led to the recognition of a role for immunostimulatory DNA, such as CpG [ 8], and other TLR agonists, such as messenger RNA molecules as vaccine adjuvants.

Other molecules besides TLR agonists have also been identified as immunomodulators and are currently investigated as vaccine adjuvants. For example, QS-21 is a highly purified immunostimulant extracted from the bark of the South American tree Quillaja saponaria [ 9 ]. It has the ability to optimize antigen presentation to antigen-presenting cells and stimulate both humoral and cellular responses. Importantly, the adjuvant properties of MPL and QS-21 appear synergistic. MPL and QS-21 have been studied in combination and have been shown to enhance Th1 and cytotoxic T cell responses against exogenous protein in mice.

Liposomes are synthetic nanospheres consisting of lipid layers that can encapsulate antigens and act as both a vaccine delivery vehicle and an adjuvant [ 10 ]. Liposomes promote humoral and cell-mediated immune response s to a wide range of bacterial and viral antigens as well as tumor cell antigens. Vaccines containing liposomes are available against hepatitis A and influenza [ 11 ].

Adjuvant research has demonstrated that with the right selection of antigens together with new adjuvants the immune response elicited by vaccines can be adapted to the pathogens and targeted populations. Recognizing that this cannot always be achieved with only one adjuvant type led to investigation of adjuvant systems, which combine classical adjuvants (aluminum salts, o/w emulsion, and liposomes) and immunomodulatory molecules, such as MPL and Q-S21. This concept has allowed the development of vaccines tailored to the antigen and target population, such as the HPV vaccine with adjuvant system AS04 and a malaria vaccine with adjuvant system AS02.

References

---------------

[1] Leroux-Roels G (2010) Unmet needs in modern vaccinology: adjuvants to improve the immune response. Vaccine 28 Suppl 3:C25–C36

[2] Brewer JM (2006) (How) do aluminium adju vants work? Immunol Lett 102:10–15

[3] Moser M, Leo O (2010) Key concepts in immunology. Vaccine 28 Suppl 3:C2–C13

[4] Fraser A, Goldberg E, Acosta CJ et al (2007) Vaccines for preventing typhoid fever. Cochrane Database Syst Rev 3, CD001261

[5] Garçon N, Van Mechelen M, Wettendorff M (2006) Development and evaluation of AS04, a novel and improved immunological adjuvant system containing MPL and aluminium salt. In: Schijns V, O’Hagan D (eds) Immunopotentiators in modern vaccines. Elsevier Academic Press, London, pp 161–177

[6] Alderson MR, McGowan P, Baldridge JR et al (2006) TLR4 agonists as immunomodulatory agents. J Endotoxin Res 12:313–319

[7] Evans JT, Cluff CW, Johnson DA, Lacy MJ, Persing DH, Baldridge JR. Enhancement of antigen-specific immunity via the TLR4 ligands MPL adjuvant and Ribi.529. Expert Rev Vaccines. 2003 Apr;2(2):219–29

[8] Higgins D, Marshall JD, Traquina P et al (2007) Immunostimulatory DNA as a vaccine adjuvant. Expert Rev Vaccines 6:747–759

[9] Garçon N, Van Mechelen M (2011) Recent clinical experience with vaccines using MPL- and QS-21-containing adjuvant systems. Expert Rev Vaccines 10:471–486

 [10] Aguilar JC, Rodríguez EG (2007) Vaccine adjuvants revisited. Vaccine 25:3752–3762

[11] Schwendener RA (2014) Liposomes as vaccine delivery systems: a review of the recent advances. Ther Adv Vaccines 2:159–182

مواضيع ذات صلة

Pan-Genomic Analysis

Reverse Vaccinology

Selecting Vaccine Antigens

Principles of Vaccine Development

A Brief History of Vaccination

Development of Vaccines for Tuberculosis and Meningitis

Development of Vaccines for Viral Hepatitis, Coronavirus, and Norovirus

Development of Powerful Influenza Vaccines

Vaccines for HIV and Ebola Virus

Vaccines for Diseases Associated with Urban Areas in the Developing Countries

HIV Vaccine

Yellow Fever Vaccine