- Review Article
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The perfect mix: recent progress in adjuvant research
Nature Reviews Microbiologyvolume 5, pages396–397 (2007)Cite this article
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Key Points
New vaccines are often less immunogenic than previous vaccines, and adjuvants are therefore required to assist in the induction of potent and persistent immune responses, to reduce the amount of antigen and limit the number of injections.
Some new vaccines also need adjuvants that are capable of inducing potent cell-mediated immunity in addition to an antibody response, such as T helper (TH) 1 responses and cytotoxic T lymphocyte (CTL) responses.
Recent advances in basic immunology have demonstrated the crucial role of some innate immune signals in modulating — both quantitatively and qualitatively — the subsequent adaptive response. Among these, some agonists of Toll-like receptors (TLRs) would in theory constitute promising adjuvants.
Vaccine research can take advantage of these discoveries to design and develop more focused and efficient adjuvants, such as new synthetic agonists of TLRs.
Moreover, new formulations can combine different immunostimulants, including TLR agonists and non-TLR 'classical' adjuvants. These compounds can act in synergy, and targeting them towards antigen-presenting cells could further increase and focus their action.
In parallel, new biochemical and immunological tools and assays have been developed to characterize and evaluate these new adjuvants, bothin vitro andin vivo. The combination of information obtained in several assays, for example in animal models and human primary or transformed cells, can provide more accurate information on the potency and safety of these new adjuvants before use on humans.
Vaccine research scientists can now chose between a larger panel of compounds and technologies to design and develop the formulation that would drive the most efficient and safest response with respect to each considered pathogen, keeping in mind that each antigen–adjuvant couple is unique.
Abstract
Developing efficient and safe adjuvants for use in human vaccines remains both a challenge and a necessity. Past approaches have been largely empirical and generally used a single type of adjuvant, such as aluminium salts or emulsions. However, new vaccine targets often require the induction of well-defined cell-mediated responses in addition to antibodies, and thus new immunostimulants are required. Recent advances in basic immunology have elucidated how early innate immune signals can shape subsequent adaptive responses and this, coupled with improvements in biochemical techniques, has led to the design and development of more specific and focused adjuvants. In this Review, I discuss the research that has made it possible for vaccinologists to now be able to choose between a large panel of adjuvants, which potentially can act synergistically, and combine them in formulations that are specifically adapted to each target and to the relevant correlate(s) of protection.
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“World in motion” – emulsion adjuvants rising to meet the pandemic challenges
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Acknowledgements
I wish to acknowledge J. Almond, N. Burdin, P. Chaux, F. Dalençon, J. Haensler and E. Trannoy for their support, discussions and critical reading of the manuscript. They synergized efficiently to help me formulate my work and target it in the right direction. Innate immunity and adjuvants are large fields and I apologize for not having mentioned numerous important works because of space constraints.
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Research Department, sanofi pasteur, Campus Merieux, Marcy l'Etoile, 69280, France
Bruno Guy
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Glossary
- T helper cell
(TH cell). A T cell that has cell-surface antigen receptors that bind fragments of antigens displayed by MHC class II molecules, which are expressed at the surface of antigen-presenting cells. Activated TH cells express cytokines and membrane-associated co-stimulatory molecules that help other immune cells carry out their specific functions. TH cells can be divided into subsets according to their cytokine-secretion profiles.
- Dendritic cell
(DC). 'Professional' antigen-presenting cells that are found in the T-cell areas of lymphoid tissues and as minor cellular components in most tissues. They have a branched or dendritic morphology and are the most potent stimulators of naive T-cell responses.
- CD4+ T cell
A subpopulation of T cells that express the CD4 receptor. These cells aid in immune responses and are therefore referred to as T helper cells.
- CD8+ T cell
A subpopulation of T cells that express the CD8 receptor. CD8+ T cells recognize antigens that are presented on the surface of host cells by MHC class I molecules, leading to their destruction, and are therefore also known as cytotoxic T lymphocytes.
- Regulatory T (TReg) cell
A population of CD4+ T cells that naturally express high levels of CD25 (the interleukin-2 receptor a-chain) and the transcription factor forkhead box P3 (Foxp3), and that have suppressive regulatory activity towards effector T cells and other immune cells.
- TH1 cell
(T helper 1 cell). A type of activated TH cell that promotes responses associated with the production of a particular set of cytokines, including interleukin (IL)-2, interferon (IFN)-γ and tumour-necrosis factor (TNF), the main function of which is to stimulate phagocytosis-mediated defences against intracellular pathogens.
- TH2 cell
(T helper 2 cell). A type of activated TH cell that participates in phagocytosis-independent responses and downregulates pro-inflammatory responses that are induced by TH1 cells. TH2 cells secrete interleukin (IL)-4, IL-5 and IL-6.
- Pattern-recognition receptor
(PRR). A host receptor (such as Toll-like receptors (TLRs) or NOD-like receptors (NLRs)) that can sense pathogen-associated molecular patterns and initiate signalling cascades that lead to an innate immune response. These can be membrane bound (such as TLRs) or soluble cytoplasmic receptors (such as NLRs).
- Pathogen-associated molecular pattern
(PAMP). A molecular pattern that is found in microorganisms but not mammalian cells. Examples include bacterial lipopolysaccharides, hypomethylated DNA, flagellin and double-stranded RNA.
- Tolerance
Immunological tolerance (central or peripheral) results from different mechanisms preventing the immune system mounting responses against (self) antigens. Peripheral tolerance occurs when mature lymphocytes encounter antigens and undergo anergy, deletion or suppression. In particular, T-cell anergy is defined by defective proliferation by previously primed T cells following restimulation, reflecting a selective defect in the activation of some TCR-induced signalling pathways.
- Natural killer T cells
(NKT cells). A subpopulation of T cells that expresses both NK-cell and T-cell markers.
- γδ T cells
A minor population of T cells that express the γδ T-cell receptor (TCR), and that are more abundant in epithelial-rich tissues such as the skin, gut and reproductive tract. Like NKT cells, γδ T cells can be cytolytic and produce high levels of cytokines and chemokines.
- M cells
(Microfold cells). Specialized epithelial cells that deliver antigens by transepithelial vesicular transport from the gut lumen directly to intraepithelial lymphocytes and to subepithelial lymphoid tissues.
- Langerhans cell
Dendritic, antigen-presenting cells that contain characteristic racquet-shaped granules, known as Birbeck granules, and which express the CD1a antigen. Principally found in the stratified squamous epithelium.
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Guy, B. The perfect mix: recent progress in adjuvant research.Nat Rev Microbiol5, 396–397 (2007). https://doi.org/10.1038/nrmicro1681
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