Adjuvants, the neglected actors of vaccines

Yi Ni Ong

June 2020

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An adjuvant is a component in the formulation of vaccines which improves the immunogenicity and protective efficacy of the highly purified antigen (1). Adjuvants can act as antigen carriers, allowing the slow release of antigen in the blood over time, which stimulates the immune system to produce high-titre antibodies and long-lasting immunity. This effect contributes to reducing the dose of antigen required for effectiveness. In addition to facilitating the response of immune system cells to enhance vaccine efficacy, adjuvants can also activate macrophages and lymphocytes (2). Adjuvants are further employed as stabilizing agents, especially in veterinary vaccines (3).

There are several types of adjuvants currently used in vaccines and we will discuss three of the most important ones:

1.     Aluminium-based mineral salts

This is the most common class of adjuvants approved for human use. These include aluminium phosphate (AlPO4), aluminium hydroxide (Al(OH)3 and alum (KAl(SO4)2·12H2O) which can be found in various antiviral and antibacterial vaccines such as those against diphtheria, tetanus, pertussis, hepatitis A and B, rabies, anthrax, and others (4, 5). The mechanism of action of aluminium-based adjuvants is known to be associated with the enhancement of antibody production, which is achieved by the activation of dendritic cells and other immune cells. These secrete the so-called chemokines, mainly interleukin-1β (IL-1β), that are proinflammatory molecules with immunogenic action. Additionally, aluminium adjuvants can induce local inflammation at the injection site, which will attract immunocompetent cells and thereby form granulomas that contain antibody-producing plasma cells. There are two common methods to prepare aluminum-adjuvanted vaccines: in situ precipitation of aluminium compounds in the presence of antigen to form alum-precipitated vaccines, and adsorption of antigen onto pre-formed aluminium gel to form aluminium-adsorbed vaccines (6). The degree of adsorption of antigen on the adjuvant and the dose of adjuvant are the two main factors determining the immunogenicity of aluminium-adsorbed vaccines. Aluminium adjuvants have been used for more than six decades and are proven to be safe with very minor potential side effects. These comprise local reactions such as erythema, subcutaneous nodules, contact hypersensitivity and granulomatous inflammation (5).

2.     Oil-in-Water Emulsion

MF59 is an example of this class of adjuvants, appearing as a small, uniform oil droplet and is composed of squalene. MF59 has been used in influenza vaccine in Europe since 1997 and in the United States since 2016. Safety and immunogenicity studies in an elderly population demonstrated that the MF59-adjuvanted influenza vaccine was well-tolerated with a satisfactory safety profile (7, 8). The resulted vaccine, FLUAD®, was first licensed in Italy in 1997.2 Studies suggested that MF59 can function as an antigen delivery system, besides promoting antigen uptake by antigen-presenting cells. Furthermore, MF59 can activate monocytes, macrophages and granulocytes to produce chemokines. However, MF59 does not activate dendritic cells directly, but triggers the recruitment of dendritic cell precursors and their subsequent differentiation (9).

 3.     Toll-Like Receptor Agonists

Toll-like Receptors (TLRs) are cell surface pattern recognition receptors (PRRs), that recognise several pathogen-associated molecular patterns (PAMPs). Among TLRs, TLR4 is the receptor of bacterial lipopolysaccharide (LPS) and has been reported that TLR4 activation and subsequent cytokine production is one of the main mechanisms of adjuvancy (10). Monophosphoryl lipid A (MPL) is an example of non-toxic TLR4 activator (or agonist), which has been licensed in the development of vaccines for prevention of human papilloma virus (HPV) infection and hepatitis B. MPL is a detoxified form of the endotoxin LPS that is the natural agonist of TLR4 (11). It is typically used in combination with aluminium adjuvants to induce a transient localized innate immune response, leading to enhanced adaptive immunity, as well as promoting a Th1-type of helper T cell response (12).

In short, adjuvants play a fundamental role in the advancement of vaccine development. Our growing understanding on the mechanisms of action of adjuvants in facilitating innate immune response and thus potentiate downstream adaptive immune response enables us to rationalize the design and optimization of new vaccine adjuvants.

References

1.     A. D. Pasquale, S. Preiss, F. T. D. Silva and N. Garçon, Vaccines, 2015, 3, 320–343.

2.   British Society for Immunology, www.immunology.org/public-information/bitesized-immunology/vaccines-and-therapeutics/adjuvants (accessed May 2020).

3.     Benchmark Biolabs, https://web.archive.org/web/20120901084256/http://benchmarkbiolabs.com/resources/about- adjuvants/ (accessed May 2020).

4.     N. W. Baylor, W. Egan and P. Richman, Vaccine, 2002, 20, S18-S23.

5.     R. K. Gupta, B. E. Rost, E. Relyveld and G. R. Siber, in Vaccine Design: Pharmaceutical Biotechnology, ed. M. F. Powell and M. J. Newman, Springer, Boston, 1995, ch. 8, pp. 229–248.

6. R. Edelman, Rev. Infect. Dis., 1980, 2, 370-383.

7.       R. L. Atmar, W. A. Keitel, S. M. Patel, J. M. Katz, D. She, H. E Sahly, J. Pompey, T. R. Cate and R. B. Couch, Clin. Infect. Dis., 2006, 43, 1135-1142.

8.       P. Durando, G. Icardi and F. Ansaldi, Expert Opin Biol Ther, 2010, 10, 639–651.

9.       M. Dupuis, K. Denis-Mize, A. Labarbara, W. Peters, I. F. Charo, D. M. Mcdonald and G. Ott, Eur. J. Immunol., 2001, 31, 2910–2918.

10.   K. Takeda and S. Akira, International Immunology, 2005, 17, 1-14.

11.   C. R. Casella and T. C. Mitchell, Cell. Mol. Life Sci., 2008, 65, 3231–3240.

12.   A. M. Didierlaurent, S. Morel, L. Lockman, S. L. Giannini, M. Bisteau, H. Carlsen, A. Kielland, O. Vosters, N. Vandeheyde, F. Schiavetti, D. Larocque, M. V. Mechelen and N. Garçon, J. Immunol., 2009, 183, 6186-6197.

 

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