Trends in adjuvant development for vaccines: DAMPs and PAMPs as potential new adjuvants

Aluminum salts have been widely used in vaccine formulations and, after their introduction more than 80 years ago, only few vaccine formulations using new adjuvants were developed in the last two decades. Recent advances in the understanding of how innate mechanisms influence the adaptive immunity opened up the possibility for the development of new adjuvants in a more rational design. The purpose of this review is to discuss the recent advances in this field regarding the attempts to determine the molecular basis and the general mechanisms underlying the development of new adjuvants, with particular emphasis on the activation of receptors of innate immune recognition. One can anticipate that the use of these novel adjuvants will also provide a window of opportunities for the development of new vaccines.

Adjuvant; Vaccine; Innate immunity; DAMP; PAMP

Authorship

E.N. Miyaji

Instituto Butantan, Centro de Biotecnologia , São Paulo, São Paulo, BrazilInstituto ButantanBrazilSão Paulo, São Paulo, BrazilInstituto Butantan, Centro de Biotecnologia , São Paulo, São Paulo, Brazil

E. Carvalho

M.L.S. Oliveira

I. Raw

P.L. Ho

SCIMAGO INSTITUTIONS RANKINGS

Figures | Tables

Figures (4)
Tables (2)

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Figure 1.
Schematic representation of the major classes of pattern recognition receptors (PRRs) of the innate immune system. Members of the Toll-like receptors (TLRs) can be found on the cell surface membrane (TLR1/2/4/5/6/10) as well as in the membrane of endosomes (TLR3/7/8/9); C-type lectins can be of type I or type II. Type I C-type lectins have an N-terminal domain displayed in the extracellular portion of the molecule, containing a cysteine-rich repeat (S-S), a fibronectin type II repeat (FN) and 8-10 carbohydrate recognition domains (CRDs), which bind ligands in a Ca²⁺-dependent manner. Type II C-type lectins contain only one CRD at their carboxy-terminal extracellular domain. Nucleotide-binding oligomerization domain (NOD) leucine-rich repeat (LRR)-containing receptors (NLRs) are cytoplasmic PRR receptors and the central components of the inflammasomes; the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are also cytoplasmic PRR receptors. Retinoic acid-inducible protein I (RIG-I) is an interferon-inducible protein containing a caspase recruitment domain (CARD) and a DExD/H box helicase domain and has been described as a cytoplasmic dsRNA sensor and considered to be the prototype of this family of PRRs. Other miscellaneous PRRs are also shown (DNA sensors DAI and AIM2). The different kinds of motifs, domains, repeats, and features that compose modularly the PRRs are also shown. AIM2 = absent in melanoma 2; CLEC-1 = C-type lectin receptor 1; DAI = DNA-dependent activator of interferon-regulatory factors; DCIR = dendritic cell immunoreceptor; DC-SIGN = dendritic-cell specific ICAM-3 grabbing non-integrin; DEC-205 = dendritic cell receptor for endocytosis 205; DLEC = dendritic cell lectin; IPAF = ice protease-activating factor; ITAM = immunoreceptor tyrosine-based activation motif; ITIM = immunoreceptor tyrosine-based inhibitory motif; LGP2 = laboratory of genetics and physiology 2; MDA5 = melanoma differentiation-associated gene 5; MMR = macrophage mannose receptor; NLRP1/3 = nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 1/3; PKR = double-stranded RNA activated protein kinase; PYD = Pyrin domains; TIR = Toll/interleukin-1 receptor homology domain. Based on Refs. 10 and 32.

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Figure 2.
Schematic representation of some possible Toll-like receptor (TLR) signaling events stimulated during the infection by bacteria and viruses. Some ligands for specific TLRs are indicated. TLRs and IL-1R share common signaling events in general. Following ligand binding, TLRs dimerize to form homo- or heterodimers (depending on the type of TLR) and undergo conformational changes that recruit Toll/interleukin-1 receptor (TIR) homology domain-containing adaptor molecules. MyD88 was the first adaptor molecule identified and is involved in signaling induced by all TLRs, with the exception of TLR3. Depending on the TLR, another MyD88-independent pathway may exist, as in the cases of TLR3/4. An MyD88-dependent pathway triggers a cascade of events leading to the activation of IRAK kinase enzymes, which trigger NFκB transcription factor activation and pro-inflammatory cytokine gene expression. Depending on the TLR stimulation, the MyD88-dependent pathway can also activate the interferon regulatory factor (IRF) family of transcription factors IRF1, IRF5 or IRF7 by phosphorylation mechanisms, resulting in homo- or heterodimers, their translocation to the nucleus and, in association with transcriptional co-activators, binding to target interferon-stimulated response elements (ISREs). The MyD88-independent pathway activates the transcription factor IRF3 through the TRIF adaptor that stimulates the expression of interferon-β. IRF1, IRF3 and IRF7 are involved in the transcription control of type I interferons, whereas IRF5 is involved in the transcription of pro-inflammatory cytokines by all TLRs tested so far. AP-1 = activator protein 1; CD14 = cluster of differentiation 14; CpG DNA = C-phosphate-G DNA; ds RNA = double-stranded RNA; IFN = interferon; IKKs = I kappa B kinases; IKKε = I kappa B kinase epsilon; IL = interleukin; IRAK = interleukin-1 receptor associated kinase; JNK p38 = c-Jun N-terminal kinase and p38 mitogen-activated protein kinase; LPS = lipopolysaccharide; MD-2 = myeloid differentiation factor 2; MyD88 = myeloid differentiation primary response gene 88; NF-κB = nuclear factor-kappa B; ssRNA = single-stranded RNA; TAK = TGF-β activated kinase; TBK-1 = TANK-binding kinase 1; TANK = TRAF family member-associated NF-κB activator; TIRAP = Toll-interleukin-1 receptor domain containing adaptor protein; TNF = tumor necrosis factor; TRAF = TNF receptor associated factor; TRAM = Toll-receptor-associated molecule; TRIF = TIR domain-containing adapter inducing IFN-β. Based on Refs. 21 and 32.

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Figure 3.
Schematic representation of inflammasome activation. Nucleotide-binding domain, leucine-rich repeat (NBD-LRR) proteins (NLRs) are comprised by 22 human genes. NLRs are activated by host/environment-derived molecules (DAMPs) or by pathogen-associated molecular patterns (PAMPs). NLRP3 is one member of these NLR proteins. NLRP3 can be activated by ATP and K⁺ efflux, triggering a P2X7-dependent pore formation by the pannexin-1 hemichannel from where small PAMPs and DAMPs can reach the cytosol to activate NLRP3 resulting in the inflammasome formation. Alternatively, NLRP3 can be activated by crystalline/particulate ligands, which can lead to lysosomal rupture and cathepsin B leakage, activating the NLRP3 inflammasome in the cytosol. Generation of reactive oxygen species (ROS) by PAMPs and DAMPs can also activate the inflammasome. Activation of the inflammasome involves the formation of an oligomeric complex composed of activated NLRP3, ASC and Procaspase 1, primarily through the CARD and Pyrin (PYD) domains, resulting in the formation of penta- or heptameric inflammasome structures. Procaspases 1 undergo autoactivation in the inflammasomes to active caspases 1, leading to the processing and maturation of the pro-inflammatory IL-1β and IL-18 to mature IL-1β and IL-18. Several pattern recognition receptor (PRR) activations such as those induced by TLR ligands, induce the expression of pro-inflammatory cytokines, among them pro-IL-1β, that will be substrates of caspases 1, therefore connecting and potentiating these two (TLRs and NLRs) innate immune responses. ASC = apoptosis-associated speck-like protein containing a caspase recruitment domain; ATP = adenosine triphosphate; CARD = caspase recruitment domain; DAMPs = danger-associated molecular patterns; IL = interleukin; IRAK = interleukin-1 receptor associated kinase; NF-κB = nuclear factor-kappa B; NLRP3 = nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3; NOD = nucleotide-binding oligomerization domain; P2X7 = P2X purinoreceptor 7; TLR = Toll-like receptor. Based on Refs. 24 and 26.

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Figure 4.
General view of the stimulation and differentiation of CD4⁺ T lymphocytes by dendritic cells after pathogen or antigen encounter. The pathogen or antigen is processed and the resulting antigenic peptides are presented to CD4⁺T cells by the MHC II molecules (signal 1) in a true immunological synapse. Co-receptors, co-stimulatory molecules (signal 2) and cytokines (for instance, IL-4, IL-12 for Th2 differentiation) are important to drive the CD4⁺T cells to their final differentiation to Th2, Th1 or other population subset of cells. The antigen presentation environmental context is seminal to define this differentiation and this is dictated by the pattern recognition receptors (PRRs) and their ligands, showing the importance of the innate immune response in the modulation of the acquired immunity by the adaptive immune system, interconnecting both branches of the immune response of an organism. Therefore, modulation of the immune response to a vaccine antigen can be achieved using appropriate adjuvants, based on PAMP and DAMP agonists of PRRs. CD = cluster of differentiation; IFN-γ = interferon gamma; IL = interleukin; iTreg = inducible T regulatory cells; MHC = major histocompatibility complex; NKT = natural killer T cells; TCR = T cell receptor; Tfh = T follicular helper cells; TGF-β = transforming growth factor beta; Th = T-helper cell; TNF-α = tumor necrosis factor alpha. Based on Ref. 35.

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Table 1.
Pattern-recognition receptors (PRRs).

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Table 2.
Licensed adjuvants.

Figure 1. Schematic representation of the major classes of pattern recognition receptors (PRRs) of the innate immune system. Members of the Toll-like receptors (TLRs) can be found on the cell surface membrane (TLR1/2/4/5/6/10) as well as in the membrane of endosomes (TLR3/7/8/9); C-type lectins can be of type I or type II. Type I C-type lectins have an N-terminal domain displayed in the extracellular portion of the molecule, containing a cysteine-rich repeat (S-S), a fibronectin type II repeat (FN) and 8-10 carbohydrate recognition domains (CRDs), which bind ligands in a Ca²⁺-dependent manner. Type II C-type lectins contain only one CRD at their carboxy-terminal extracellular domain. Nucleotide-binding oligomerization domain (NOD) leucine-rich repeat (LRR)-containing receptors (NLRs) are cytoplasmic PRR receptors and the central components of the inflammasomes; the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are also cytoplasmic PRR receptors. Retinoic acid-inducible protein I (RIG-I) is an interferon-inducible protein containing a caspase recruitment domain (CARD) and a DExD/H box helicase domain and has been described as a cytoplasmic dsRNA sensor and considered to be the prototype of this family of PRRs. Other miscellaneous PRRs are also shown (DNA sensors DAI and AIM2). The different kinds of motifs, domains, repeats, and features that compose modularly the PRRs are also shown. AIM2 = absent in melanoma 2; CLEC-1 = C-type lectin receptor 1; DAI = DNA-dependent activator of interferon-regulatory factors; DCIR = dendritic cell immunoreceptor; DC-SIGN = dendritic-cell specific ICAM-3 grabbing non-integrin; DEC-205 = dendritic cell receptor for endocytosis 205; DLEC = dendritic cell lectin; IPAF = ice protease-activating factor; ITAM = immunoreceptor tyrosine-based activation motif; ITIM = immunoreceptor tyrosine-based inhibitory motif; LGP2 = laboratory of genetics and physiology 2; MDA5 = melanoma differentiation-associated gene 5; MMR = macrophage mannose receptor; NLRP1/3 = nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 1/3; PKR = double-stranded RNA activated protein kinase; PYD = Pyrin domains; TIR = Toll/interleukin-1 receptor homology domain. Based on Refs. 10 and 32.

Figure 2. Schematic representation of some possible Toll-like receptor (TLR) signaling events stimulated during the infection by bacteria and viruses. Some ligands for specific TLRs are indicated. TLRs and IL-1R share common signaling events in general. Following ligand binding, TLRs dimerize to form homo- or heterodimers (depending on the type of TLR) and undergo conformational changes that recruit Toll/interleukin-1 receptor (TIR) homology domain-containing adaptor molecules. MyD88 was the first adaptor molecule identified and is involved in signaling induced by all TLRs, with the exception of TLR3. Depending on the TLR, another MyD88-independent pathway may exist, as in the cases of TLR3/4. An MyD88-dependent pathway triggers a cascade of events leading to the activation of IRAK kinase enzymes, which trigger NFκB transcription factor activation and pro-inflammatory cytokine gene expression. Depending on the TLR stimulation, the MyD88-dependent pathway can also activate the interferon regulatory factor (IRF) family of transcription factors IRF1, IRF5 or IRF7 by phosphorylation mechanisms, resulting in homo- or heterodimers, their translocation to the nucleus and, in association with transcriptional co-activators, binding to target interferon-stimulated response elements (ISREs). The MyD88-independent pathway activates the transcription factor IRF3 through the TRIF adaptor that stimulates the expression of interferon-β. IRF1, IRF3 and IRF7 are involved in the transcription control of type I interferons, whereas IRF5 is involved in the transcription of pro-inflammatory cytokines by all TLRs tested so far. AP-1 = activator protein 1; CD14 = cluster of differentiation 14; CpG DNA = C-phosphate-G DNA; ds RNA = double-stranded RNA; IFN = interferon; IKKs = I kappa B kinases; IKKε = I kappa B kinase epsilon; IL = interleukin; IRAK = interleukin-1 receptor associated kinase; JNK p38 = c-Jun N-terminal kinase and p38 mitogen-activated protein kinase; LPS = lipopolysaccharide; MD-2 = myeloid differentiation factor 2; MyD88 = myeloid differentiation primary response gene 88; NF-κB = nuclear factor-kappa B; ssRNA = single-stranded RNA; TAK = TGF-β activated kinase; TBK-1 = TANK-binding kinase 1; TANK = TRAF family member-associated NF-κB activator; TIRAP = Toll-interleukin-1 receptor domain containing adaptor protein; TNF = tumor necrosis factor; TRAF = TNF receptor associated factor; TRAM = Toll-receptor-associated molecule; TRIF = TIR domain-containing adapter inducing IFN-β. Based on Refs. 21 and 32.

Figure 3. Schematic representation of inflammasome activation. Nucleotide-binding domain, leucine-rich repeat (NBD-LRR) proteins (NLRs) are comprised by 22 human genes. NLRs are activated by host/environment-derived molecules (DAMPs) or by pathogen-associated molecular patterns (PAMPs). NLRP3 is one member of these NLR proteins. NLRP3 can be activated by ATP and K⁺ efflux, triggering a P2X7-dependent pore formation by the pannexin-1 hemichannel from where small PAMPs and DAMPs can reach the cytosol to activate NLRP3 resulting in the inflammasome formation. Alternatively, NLRP3 can be activated by crystalline/particulate ligands, which can lead to lysosomal rupture and cathepsin B leakage, activating the NLRP3 inflammasome in the cytosol. Generation of reactive oxygen species (ROS) by PAMPs and DAMPs can also activate the inflammasome. Activation of the inflammasome involves the formation of an oligomeric complex composed of activated NLRP3, ASC and Procaspase 1, primarily through the CARD and Pyrin (PYD) domains, resulting in the formation of penta- or heptameric inflammasome structures. Procaspases 1 undergo autoactivation in the inflammasomes to active caspases 1, leading to the processing and maturation of the pro-inflammatory IL-1β and IL-18 to mature IL-1β and IL-18. Several pattern recognition receptor (PRR) activations such as those induced by TLR ligands, induce the expression of pro-inflammatory cytokines, among them pro-IL-1β, that will be substrates of caspases 1, therefore connecting and potentiating these two (TLRs and NLRs) innate immune responses. ASC = apoptosis-associated speck-like protein containing a caspase recruitment domain; ATP = adenosine triphosphate; CARD = caspase recruitment domain; DAMPs = danger-associated molecular patterns; IL = interleukin; IRAK = interleukin-1 receptor associated kinase; NF-κB = nuclear factor-kappa B; NLRP3 = nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3; NOD = nucleotide-binding oligomerization domain; P2X7 = P2X purinoreceptor 7; TLR = Toll-like receptor. Based on Refs. 24 and 26.

Figure 4. General view of the stimulation and differentiation of CD4⁺ T lymphocytes by dendritic cells after pathogen or antigen encounter. The pathogen or antigen is processed and the resulting antigenic peptides are presented to CD4⁺T cells by the MHC II molecules (signal 1) in a true immunological synapse. Co-receptors, co-stimulatory molecules (signal 2) and cytokines (for instance, IL-4, IL-12 for Th2 differentiation) are important to drive the CD4⁺T cells to their final differentiation to Th2, Th1 or other population subset of cells. The antigen presentation environmental context is seminal to define this differentiation and this is dictated by the pattern recognition receptors (PRRs) and their ligands, showing the importance of the innate immune response in the modulation of the acquired immunity by the adaptive immune system, interconnecting both branches of the immune response of an organism. Therefore, modulation of the immune response to a vaccine antigen can be achieved using appropriate adjuvants, based on PAMP and DAMP agonists of PRRs. CD = cluster of differentiation; IFN-γ = interferon gamma; IL = interleukin; iTreg = inducible T regulatory cells; MHC = major histocompatibility complex; NKT = natural killer T cells; TCR = T cell receptor; Tfh = T follicular helper cells; TGF-β = transforming growth factor beta; Th = T-helper cell; TNF-α = tumor necrosis factor alpha. Based on Ref. 35.

Table 1. Pattern-recognition receptors (PRRs).

Table 2. Licensed adjuvants.

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Trends in adjuvant development for vaccines: DAMPs and PAMPs as potential new adjuvants

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