Trends in Vaccine Adjuvants

Virgil EJC Schijns; Ed C Lavelle

Disclosures

Expert Rev Vaccines. 2011;10(4):539-550. 

In This Article

Trends for Future Vaccine Adjuvants

Apart from the classical prophylactic antimicrobial disease vaccines, current vaccine strategies also target tumors, allergies and self-molecules involved in unwanted physiological conditions (e.g., aggression-associated hormones, harmful cytokines and β-amyloid in Alzheimer's disease); even nicotine is targeted to treat addiction to smoking. For these poorly immunogenic antigens there is an obvious need for suitable novel adjuvants. This is particularly evident for self-antigens that are used in anti-tumor vaccines where there is a need to break immunological tolerance.

Signal 1 Facilitators

Reverse Adjuvantology: Learning From the Mode of Action of Known Signal 1 Adjuvants For most signal 1 facilitators the critical features regarding antigen delivery in time, place and dose are far from understood. Many different formulations may be able to delay the release of proteinacious antigens from a depot type of formulation, but the required antigen release profile to evoke an amplified immune response is unknown. For example, certain depot adjuvants may protect the antigen from degradation by proteolytic enzymes, but on the other hand may only release amounts of antigen that are suboptimal for stimulation of an adaptive immune response. As mentioned previously, recent studies revealed that aluminum – as well as water-in-oil-based incomplete Freund's adjuvant formulations – are able to augment adaptive antibody responses in the absence of TLR signaling.[46] The studies question the requirement for TLR signaling in the induction of antibody responses by alum.[75]

Many attempts to develop improved adjuvants focus on steps to enhance uptake, processing and presentation of antigens by APCs. Strategies to target DCs in situ, by engineering the size, shape and surface characteristics of antigen-coated or antigen-encapsulating biomaterials,[76] or using specific DC-targeting molecules coupled to antigen illustrate this approach.[77] In addition, in recent years we have seen an explosion of logistically complex efforts in the field of tumor therapy based on loading of antigen onto ex vivo isolated autologous DCs that are subsequently exposed to maturation stimuli.[78] Hence, more knowledge on the requirements for antigen delivery (signal 1) in terms of timing, dosing and localization of antigen would substantially support rational vaccine design.

Other studies have aimed to decipher the key features underlying the in vivo activity of existing adjuvant formulations in order to design improved variants. This can be done by tracking of the antigen in time after injection and correlating the best kinetics profiles with effectiveness of the vaccine.[33,76,79]

In parallel to this approach it is possible to assess the immune response to signal 1 facilitators, which are identical in composition, except for certain components. Systematic in vivo assessment can dissect the contribution of these components to immune pathways[80] and consequently, cellular or even molecular events in the host in time after immunization have been determined.[33]

Signal 2 Facilitators

As mentioned previously, some well-known adjuvants, including MPL and mycobacterial components, are ligands for specific innate immune cell receptors. For these adjuvants the receptor is now determined, but the in vivo mode of action in terms of the role of specific cell types, kinetics of cellular influx and cellular function is not fully resolved. Investigations addressing these issues with identified immunostimulants may provide guidance regarding the choice of adjuvants and the design of alternative safer adjuvants with a similar immune response profile.

Another trend in adjuvant research is the specific targeting of key amplification steps within the immunological cascade. For example, PRRs, which upon stimulation may start an immunological cascade, are attractive targets for discovery of novel agonists. Consequently, one strategy comprises the search for new PAMP receptor agonists. This can be achieved by investigating various natural microbe-derived structures or purified molecules. Examples include cochleates, flagellin, lipoproteins, LPS derivatives and whole-killed microbial structures, including viruses and bacteria.

Apart from microbial agonists, synthetic chemical ligands for PRRs[81] are actively being searched for. Chemically defined PRR agonists may be identified by means of high-throughput screening and subsequent lead optimization of multiple chemical or virtual library compounds using one or more known receptors.[81] The use of a small molecule that acts as receptor ligand may circumvent the risk of immune responsiveness against the adjuvant itself and allows precise quality control of the adjuvant component.

In an alternative approach to the discovery of new molecular candidate signal 0 adjuvants, one may decide to mix two or more known PAMPs in order to achieve synergistic effects and find 'the golden combination'.[82] Although mixing is the easiest production and formulation method, physical linking of TLR agonists and antigens is an attractive option because both will be presented to the same APC, which may result in an enhanced response when compared with mixed administration. Examples include the coupling of antigens to the TLR-5 agonist flagellin[83] or the TLR-9 stimulus, CpG.[84]

In general, molecules on lymphoid cells that either activate or inhibit immune responses, particularly on innate immune cells, represent attractive and rational targets for immune modulation.[43] Obvious examples include the aforementioned agonists for PRRs, but also activating recombinant protein agonists, or activating antibodies specific for CD40 or CD28.

A complementary approach is the use of inhibitory antibodies for CTLA-4, programmed death-1 (PD-1), or functionally related blockers of immune system 'brakes'. This approach is currently being tested in vaccination strategies, especially for targeting chronic diseases or tumors. Cytokines, particularly IL-10[85,86] and TGF-β ,[87] can act on a range of target cells to suppress inflammatory responses and can also suppress effector T-cell responses. When using the strategy of blocking regulatory pathways, the risk of autoimmune reactions should be taken into account.

Obviously, all products of the aforementioned single approaches can be combined in novel formulations in order to generate more potent vaccines.

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