CORD-19-Sentences  

CORD-19:12fbecd4737a9af7b8fab5267094fdfa754f25fa JSONTXT 7 Projects

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Id Subject Object Predicate Lexical cue
TextSentencer_T1 0-181 Sentence denotes During the past decade, a dramatic shift has occurred in immunological theory, which has found its most practical application in the discovery and design of novel vaccine ADJUVANTS.
TextSentencer_T2 182-361 Sentence denotes This change in thinking has been driven by an increased appreciation that activation of the INNATE IMMUNE SYSTEM initiates, amplifies and drives antigen-specific immune responses.
TextSentencer_T3 362-642 Sentence denotes Moreover, the identification of discrete cell types, specific receptors and the signalling pathways involved in activation of innate immunity has provided a multitude of new targets for exploitation by the development of novel adjuvants (IMMUNE POTENTIATORS and DELIVERY SYSTEMS).
TextSentencer_T4 643-948 Sentence denotes Combined with these factors, there has been an increasing emphasis in the field of vaccines on the need for improved safety (for example, subunit vaccines), along with improved efficacy against particularly insidious pathogens (for example, human immunodeficiency virus (HIV) and hepatitis C virus (HCV)).
TextSentencer_T5 949-1061 Sentence denotes More recently, the threat of a bio-terrorist attack has added an even greater sense of urgency to these efforts.
TextSentencer_T6 1062-1307 Sentence denotes As a result, there has been a dramatic increase in efforts to target and manipulate the innate immune response with improved vaccine adjuvants, which has coincided with a greater mechanistic understanding of how this might be optimally achieved.
TextSentencer_T7 1308-1444 Sentence denotes Vaccination is considered by the World Health Organization to be the most cost-effective strategy for controlling infectious disease 1 .
TextSentencer_T8 1445-1601 Sentence denotes In terms of direct effects on public health, the development of the presently available vaccines is second only to the introduction of a clean water supply.
TextSentencer_T9 1602-1750 Sentence denotes Vaccination works by manipulating the body's immune system, preparing it for the rapid elimination of infectious agents and/or their toxic products.
TextSentencer_T10 1751-1953 Sentence denotes From a mechanistic perspective, vaccines select, activate and expand memory B and T cells of the immune system, which are then poised to respond rapidly and specifically to subsequent pathogen exposure.
TextSentencer_T11 1954-2238 Sentence denotes Since Edward Jenner's first successful vaccination against smallpox, which can be considered the birth of immunology as a scientific discipline, vaccine design and discovery has been dominated by pragmatic considerations -one uses what works, regardless of understanding why it works.
TextSentencer_T12 2239-2372 Sentence denotes In recent years, however, basic immunological research has started to make a greater contribution to the vaccine development process.
TextSentencer_T13 2373-2535 Sentence denotes There are many factors driving this re-invigorated search for the theoretical and mechanistic underpinnings of vaccination, including the need for the development
TextSentencer_T14 2536-2676 Sentence denotes Adjuvant design has historically had a touch of alchemy at its heart due to its reliance on the complex biology of innate immune activation.
TextSentencer_T15 2677-2860 Sentence denotes However, a new mechanistic understanding of innate immunity, combined with new adjuvant and delivery platforms for exploiting this knowledge, has led to significant advances recently.
TextSentencer_T16 2861-3072 Sentence denotes Although many challenges remain, the field is moving rapidly and the proper tools and methodologies are in place for the use of traditional drug discovery engines in guiding the development of vaccine adjuvants.
TextSentencer_T17 3073-3221 Sentence denotes In this review, we outline the current trends in immune potentiator, delivery system and adjuvant design that will shape the vaccines of the future.
TextSentencer_T18 3222-3346 Sentence denotes A vaccine formulation that localizes vaccine antigens and/or immune potentiators, and targets them to key immune cell types.
TextSentencer_T19 3347-3613 Sentence denotes The long-lived protective immunity elicited by vaccines and many naturally occurring infections, which is mediated by expanded populations of previously activated B and T cells selected for their expression of specific receptors for the antigens of a given pathogen.
TextSentencer_T20 3614-3621 Sentence denotes (TLRs).
TextSentencer_T21 3622-3906 Sentence denotes An evolutionarily conserved family of patternrecognition receptors that detect unique microbial products and allow rapid activation of innate immunity. response towards the cellular or humoural elements that are most appropriate for protection against the particular infectious agent.
TextSentencer_T22 3907-4144 Sentence denotes So, although the overall objective of vaccination is the activation of antigen-specific immunity, vaccines cannot optimally achieve this goal without effectively activating the pathogen-detection mechanisms of the innate immune response.
TextSentencer_T23 4145-4335 Sentence denotes Vaccine adjuvants are broadly defined by their functional ability to enhance in vivo immunogenicity (that is, antigen-specific responses) of the antigens with which they are co-administered.
TextSentencer_T24 4336-4551 Sentence denotes As such, adjuvants represent important components of most of the successful vaccines, particularly those based on subunits of pathogens, including isolated fractions of the killed pathogens, or recombinant antigens.
TextSentencer_T25 4552-4748 Sentence denotes However, as a consequence of the growing appreciation of innate immune mechanisms, and the details of antigen processing and presentation, more sophisticated definitions of adjuvants are required.
TextSentencer_T26 4749-4948 Sentence denotes Therefore, we have begun to separate both traditional and novel adjuvants into two main categories (immune potentiators and delivery systems) on the basis of their dominant mechanism(s) of action 2 .
TextSentencer_T27 4949-5199 Sentence denotes Whereas delivery systems mainly function to localize vaccine components and to target vaccines to antigen-presenting cells (APCs), immune potentiators directly activate these cells through specific receptors (for example, TOLL-LIKE RECEPTORS (TLRs)).
TextSentencer_T28 5200-5345 Sentence denotes So, delivery systems are used to promote the interaction of both antigens and immune potentiators with the key cells of the innate immune system.
TextSentencer_T29 5346-5522 Sentence denotes Immune potentiators provide the inflammatory context necessary for optimal antigen-specific immune activation by activating APCs and amplifying the innate immune response (FIG.
TextSentencer_T30 5523-5527 Sentence denotes 1) .
TextSentencer_T31 5528-5678 Sentence denotes Innate defence strategies are designed to detect broad and conserved patterns which differ between pathogenic organisms and their multicellular hosts.
TextSentencer_T32 5679-5828 Sentence denotes This non-antigen-specific detection strategy is mediated by diverse and evolutionarily conserved families of pattern-recognition receptors (PRRs) 3 .
TextSentencer_T33 5829-5979 Sentence denotes An increasing number of PRRs are being identified, with the ten recently discovered members of the TLR family attracting the most interest at present.
TextSentencer_T34 5980-6222 Sentence denotes The pathogen-associated molecular patterns (PAMPs) which they recognize are structurally and chemically diverse compounds, but they share the common feature of being highly conserved in pathogens and absent from multicellular organisms 4, 5 .
TextSentencer_T35 6223-6389 Sentence denotes This broad recognition strategy allows the innate immune system to respond rapidly to infection in advance of the more delayed activation of antigenspecific immunity.
TextSentencer_T36 6390-6696 Sentence denotes As such, the key advantage of an integrated system of pattern recognition and antigenspecific responses is that the immune system divides the responsibility of recognizing and eliminating infectious agents by fulfilling two mutually exclusive goals of the primary immune response: speed and specificity 6 .
TextSentencer_T37 6697-6939 Sentence denotes It is important to note that the optimal immune response required for long-term protective immunityimmunological memory -represents the merger of these two competing goals and that vaccination exploits this union with remarkable success (FIG.
TextSentencer_T38 6940-7172 Sentence denotes 2) . of safer, better defined and more effective vaccines against a number of important diseases for which vaccines do not presently exist (for example, HIV, HCV, Neisseria meningitides and severe acute respiratory syndrome (SARS)).
TextSentencer_T39 7173-7383 Sentence denotes Furthermore, recent breakthroughs in immunology have revealed numerous new targets and mechanisms of the innate arm of the immune system that can be manipulated by improved adjuvants to produce better vaccines.
TextSentencer_T40 7384-7571 Sentence denotes Protective immunity against pathogen exposure is achieved by the integration of two distinct arms of the immune response, the innate and antigen-specific (also called adaptive) responses.
TextSentencer_T41 7572-7700 Sentence denotes The innate response acts early after infection (within minutes), detecting and responding to broad cues from invading pathogens.
TextSentencer_T42 7701-7921 Sentence denotes By contrast, the adaptive response takes time (days to weeks) to become effective, but provides the fine antigenic specificity required for complete elimination of the pathogen and the generation of IMMUNOLOGICAL MEMORY.
TextSentencer_T43 7922-8558 Sentence denotes Antigen-independent recognition of pathogens by the innate immune system leads to the immediate mobilization of immune effector and regulatory mechanisms that provide the host with three crucial survival advantages: rapid initiation of the immune responses (both innate and adaptive) and creation of the inflammatory and co-stimulatory context for antigen recognition; establishment of a first line of defence, which holds the pathogen in check during the maturation of the adaptive response; and steering of the adaptive immune Antigens Adjuvants Delivery Immune potentiator Figure 1 | The three components of optimal subunit vaccines.
TextSentencer_T44 8559-8684 Sentence denotes It is well known that subunit vaccines elicit more potent and durable antigen-specific immunity if combined with an adjuvant.
TextSentencer_T45 8685-8792 Sentence denotes The in vivo adjuvant effect can be divided into two principal components: delivery and immune potentiation.
TextSentencer_T46 8793-8902 Sentence denotes Delivery systems localize antigens and target them to the appropriate cell types of the innate immune system.
TextSentencer_T47 8903-8967 Sentence denotes Delivery can also be optimized for immune potentiator targeting.
TextSentencer_T48 8968-9089 Sentence denotes Immune potentiators directly activate innate immune cells providing the pro-inflammatory context for antigen recognition.
TextSentencer_T49 9090-9192 Sentence denotes Antigens provide the specific pathogen epitopes necessary to generate long-lived immunological memory.
TextSentencer_T50 9193-9427 Sentence denotes These three components are intrinsic to naturally occurring infections and whole-cell vaccines, whereas they must be combined in subunit vaccine formulations. example, CD80/86) which induce full activation of antigen-specific T cells.
TextSentencer_T51 9428-9509 Sentence denotes In the absence of these proinflammatory cues, T-cell responses are shut down 10 .
TextSentencer_T52 9510-9758 Sentence denotes It is this better understanding of antigen presentation and APC biology that has provided opportunities for future improvements in vaccine development, as more selective and sophisticated immune potentiators and delivery systems are developed (FIG.
TextSentencer_T53 9759-9763 Sentence denotes 3) .
TextSentencer_T54 9764-9851 Sentence denotes Among other emerging targets of immune potentiators and delivery systems is the B cell.
TextSentencer_T55 9852-9951 Sentence denotes The direct adjuvant effects on B cells are particularly intriguing and seem to act at three levels.
TextSentencer_T56 9952-10159 Sentence denotes First, delivery systems, especially particulate ones, facilitate an ordered and repetitive array of B-cell epitopes, which results in more efficient B-cell activation through their antigen receptors 11, 12 .
TextSentencer_T57 10160-10439 Sentence denotes Second, although B cells are considered part of the antigen-specific immune system, they also express PRRs (for example, TLRs), and, therefore, can be activated by PAMPs or immune potentiators in ways that modify both the quantity and quality of their antibody responses 13, 14 .
TextSentencer_T58 10440-10486 Sentence denotes Last, B cells can also act as APCs, and B-cell
TextSentencer_T59 10487-10643 Sentence denotes Various cell types of the immune system are capable of presenting antigens to T cells, providing a crucial bridge between the innate and adaptive responses.
TextSentencer_T60 10644-10792 Sentence denotes Among these, dendritic cells (DCs) are considered 'professional APCs' because they are highly efficient and are specialized for this function 7, 8 .
TextSentencer_T61 10793-10942 Sentence denotes DCs and other APCs constantly sample their environment through pinocytosis and/or phagocytosis, and use their PRRs to 'screen' for infectious agents.
TextSentencer_T62 10943-11216 Sentence denotes This constitutive process is thought to provide the mechanism by which the immune system not only mobilizes both innate and antigen-specific defences to infection or following vaccination, but also maintains tolerance (non-responsiveness) to autologous or benign agents 9 .
TextSentencer_T63 11217-11419 Sentence denotes The dual activation/tolerization function of DCs is mediated by their capacity to change the context of antigen presentation and to communicate to T cells the nature of the antigens they are presenting.
TextSentencer_T64 11420-11735 Sentence denotes They do this by responding to PAMPs or synthetic immune potentiators, and producing pro-inflammatory cytokines and expressing co-stimulatory molecules (for immune responses on first encounter with a vaccine or infectious agent maximizes the two mutually exclusive priorities of host defence (speed and specificity).
TextSentencer_T65 11736-11859 Sentence denotes The equal importance of these competing goals can be seen when they are merged in the remarkably efficient memory response.
TextSentencer_T66 11860-11943 Sentence denotes Generating rapid, specific and durable memory responses is the goal of vaccination.
TextSentencer_T67 11944-12320 Sentence denotes In general, immune potentiators and delivery systems target the innate arm, whereas vaccine antigens drive pathogen-specific responses by B and T cells. b | The arrows indicate cytokine networks and cross-talk between regulatory cells of both innate and antigen-specific immune systems, which are central to the initiation and amplification of specific T-and B-cell responses.
TextSentencer_T68 12321-12718 Sentence denotes Key cytokines that both amplify and steer effector cell generation include interleukin-2 (IL-2), IL-4, IL-12, type I and II interferons (IFN) and other pro-inflammatory mediators (for example, tumour-necrosis factor (TNF)). c | In the effector and memory stages, the elicited cell-mediated and humoral mechanisms potently and specifically target the pathogen and/or infected cells for destruction.
TextSentencer_T69 12719-13161 Sentence denotes Abs, antibodies; ADCC, antibody-dependent cellmediated cytotoxicity; CTL, cytotoxic T lymphocyte; Imm-Pot, immune potentiator; mDC/pDC, myeloid/plasmacytoid dendritic cell; mono, monocyte; MΦ, macrophage; NC, natural cytotoxicity; NK, natural killer cell; NKT, natural killer T cell; Phag, phagocytosis; PMN, polymorphonuclear leukocyte (neutrophil); T H 1, helper T cell 1 (cell-mediated immunity); T H 2, helper T cell 2 (humoral immunity).
TextSentencer_T70 13162-13199 Sentence denotes infection or traditional vaccination.
TextSentencer_T71 13200-13373 Sentence denotes The immune potentiators and delivery systems used to improve the potency of subunit vaccines will need to be low cost, but more effective and safer than whole-cell vaccines.
TextSentencer_T72 13374-13710 Sentence denotes With the discovery of the TLR family of receptors, many pathogen products with known immunepotentiating activity (adjuvants) have now been shown to activate innate immunity via TLRs, or through an increasing number of non-TLR PRRs, including CD14, Dectin1, TREM1 and 2, RNA-dependent kinase (PKR) and CD91 (REFS 4, (15) (16) (17) (18) .
TextSentencer_T73 13711-14000 Sentence denotes For example, bacterial lipopolysaccharide (LPS), the epitome of a proinflammatory agent, is now known to interact specifically with TLR4, which acts together with other receptors (for example, CD14) found on LPS-responsive cell types (for example, monocytes, macrophages, DCs and B cells).
TextSentencer_T74 14001-14272 Sentence denotes Other examples of pathogen products with corresponding TLR-dependence include tri-acyl lipopeptides (TLR1); lipidated peptides, proteins and carbohydrates (TLR2); double-stranded RNA (Poly I:C) (TLR3); flagellin (TLR5); di-acyl lipopeptides (TLR6); and CpG DNA (TLR9) 4 .
TextSentencer_T75 14273-14387 Sentence denotes Of the ten TLR family members, only TLR7, 8 and 10 have yet to have a natural pathogen-derived product identified.
TextSentencer_T76 14388-14538 Sentence denotes Cooperation between individual TLRs and other PRRs also seems to be a general rule for natural infections and traditional whole-cell vaccines 19, 20 .
TextSentencer_T77 14539-14689 Sentence denotes Moreover, some TLRs seem to be highly promiscuous (for example, TLR2 and TLR4) and participate in responses to numerous and diverse pathogen products.
TextSentencer_T78 14690-14826 Sentence denotes Intriguingly, TLR2 and 4 have also been implicated in stress-induced responses to both pathogen-and host-derived heat-shock proteins 4 .
TextSentencer_T79 14827-15052 Sentence denotes These observations indicate that TLR2 and 4 play a more general role in initiation/amplification of the early immune response, whereas other TLR family members, and perhaps other PRRs, have evolved more specialized functions.
TextSentencer_T80 15053-15244 Sentence denotes Given the plethora of natural products capable of activating innate immune mechanisms, research and development efforts to exploit these immune potentiators as adjuvants have been aggressive.
TextSentencer_T81 15245-15491 Sentence denotes Although in vivo proof of concept has been established for the use of many natural PAMPs as adjuvants, and a number of these have been advanced into clinical trials, the trend for the future indicates an increased reliance on synthetic analogues.
TextSentencer_T82 15492-15648 Sentence denotes This is due mainly to the lower manufacturing and regulatory hurdles associated with synthetic immune potentiators that are highly defined and standardized.
TextSentencer_T83 15649-15817 Sentence denotes In addition, a synthetic platform allows for a more rational approach to the optimization of nextgeneration compounds possessing greater potency and decreased toxicity.
TextSentencer_T84 15818-15963 Sentence denotes From this perspective, perhaps the most promising adjuvant/immune potentiator platform recently identified is based on a small-molecule approach.
TextSentencer_T85 15964-16193 Sentence denotes The identification of imidizaquinolines as TLR7-and 8-dependent small-molecule immune potentiators (SMIPs) indicates that more traditional pharmaceutical-based or drug-like molecules can be exploited as vaccine adjuvants 21, 22 .
TextSentencer_T86 16194-16376 Sentence denotes Indeed, imidizaquinolines activation by antigen and immune potentiators enhances their efficiency of antigen presentation to T cells, as well as inducing the production of cytokines.
TextSentencer_T87 16377-16594 Sentence denotes Given that antibody responses are traditionally considered the correlate of protection for most vaccines, further efforts to selectively target B cells with immune potentiators and delivery systems hold great promise.
TextSentencer_T88 16595-16823 Sentence denotes It is important to keep in mind that infectious agents and most licensed vaccines, particularly live attenuated or killed whole-cell products, contain all of the components necessary for activating an integrated immune response.
TextSentencer_T89 16824-17018 Sentence denotes This is because the pathogens used in the vaccines possess all of the relevant antigens in a particulate form -a whole cell -which also contains many potent immune potentiators (that is, PAMPs).
TextSentencer_T90 17019-17207 Sentence denotes However, the trend in vaccine development is to move away from these whole-cell products towards safer and betterdefined subunit vaccines, produced as highly purified recombinant proteins.
TextSentencer_T91 17208-17337 Sentence denotes Unfortunately, these recombinant antigens are often poorly immunogenic, because they lack intrinsic immune-potentiating activity.
TextSentencer_T92 17338-17705 Sentence denotes So, the challenge in subunit vaccine development is to reintroduce selective signals for activation of the innate immune response, which will be sufficient to mimic natural The key interaction is driven by the recognition of antigenic peptide-major histocompatibility complex (MHC) dimers by T cells bearing T-cell receptors (TCRs) with high affinity for the complex.
TextSentencer_T93 17706-17813 Sentence denotes However, this signal alone is not sufficient for initiation and amplification of specific T-cell responses.
TextSentencer_T94 17814-18030 Sentence denotes Co-stimulatory signals (that is, CD28 recognition of CD80/CD86) and the production of pro-inflammatory cytokines, provide the 'infectious context' by which the full activation of antigen-specific T cells is achieved.
TextSentencer_T95 18031-18221 Sentence denotes The expression of co-stimulatory molecules and cytokines by APCs is tightly regulated and induced only when the APC encounters antigens associated with pathogenassociated molecular patterns.
TextSentencer_T96 18222-18296 Sentence denotes From the perspective of adjuvant design, the APC is a highpriority target.
TextSentencer_T97 18297-18421 Sentence denotes Delivery systems increase antigen uptake and presentation, and can also target immune potentiators more efficiently to APCs.
TextSentencer_T98 18422-18622 Sentence denotes Immune potentiators induce co-stimulatory signals and cytokine production, and the antigens select the highly specific T cells leading to the initiation and amplification of antigen-specific immunity.
TextSentencer_T99 18623-18642 Sentence denotes CD40L, CD40 ligand.
TextSentencer_T100 18643-18698 Sentence denotes the pathogens that the immune system evolved to combat.
TextSentencer_T101 18699-18838 Sentence denotes Therefore, these particulates are normally taken up efficiently by APCs and function mainly to deliver associated antigen into these cells.
TextSentencer_T102 18839-19053 Sentence denotes The main hurdle to the development of new and improved adjuvants has been safety, because vaccines that are to be used in healthy individuals will need to induce minimal adverse effects to prove acceptable for use.
TextSentencer_T103 19054-19284 Sentence denotes So, although many adjuvants have been extensively evaluated both preclinically and clinically, only aluminium salts (generically called 'alum') have been successfully licensed for use as vaccine adjuvants in North America 26, 27 .
TextSentencer_T104 19285-19366 Sentence denotes However, an alternative particulate delivery system, the microemulsion MF59 (REF.
TextSentencer_T105 19367-19503 Sentence denotes 28 ), was successfully introduced onto the market in Europe in 1997 to be used in conjunction with an influenza vaccine (Fluad; Chiron).
TextSentencer_T106 19504-19627 Sentence denotes MF59 seems to function as an adjuvant mainly through promoting the uptake of coadministered vaccine antigens into APCs 29 .
TextSentencer_T107 19628-19793 Sentence denotes Although MF59 has been shown to be safe and efficacious in a wide range of clinical trials 30 , its early clinical development yielded a number of important lessons.
TextSentencer_T108 19794-20013 Sentence denotes Originally, microemulsions such as MF59 were used as delivery systems for a potent adjuvant active molecule -a lipidated muramyl tripeptide (MTP-PE) -that was a novel synthetic derivative of mycobacterial cell wall 31 .
TextSentencer_T109 20014-20208 Sentence denotes However, the MF59/MTP-PE combination proved too reactogenic for routine clinical use, although MF59 alone was well-tolerated and had comparable immunogenicity to the MF59/MTP-PE combination 31 .
TextSentencer_T110 20209-20340 Sentence denotes Consequently, MF59 alone was used subsequently and proved sufficiently potent and safe to allow successful product development 32 .
TextSentencer_T111 20341-20487 Sentence denotes Our clinical experiences with microemulsions served to highlight the need for careful selection of immune potentiators to be included in vaccines.
TextSentencer_T112 20488-20638 Sentence denotes Overall, although MF59 is normally a more potent adjuvant than alum 32 , like alum, it cannot be expected to be appropriate for use with all vaccines.
TextSentencer_T113 20639-20741 Sentence denotes MF59 works well with a variety of antigens to enhance antibody and T-cell proliferative responses 32 .
TextSentencer_T114 20742-20965 Sentence denotes However, it is unable to induce potent T-cell responses of the T H 1 type, defined by the production of the cytokine interferon-γ, which might be required to provide protective immunity against some intracellular pathogens.
TextSentencer_T115 20966-21064 Sentence denotes So, it is clear that additional adjuvant and delivery approaches will be needed for some vaccines.
TextSentencer_T116 21065-21260 Sentence denotes In the recent past, we have focused on an alternative particulate delivery system for vaccines, comprising biodegradable microparticles prepared from the polymer POLY(LACTIDE CO-GLYCOLIDE) (PLG).
TextSentencer_T117 21261-21516 Sentence denotes Because PLG polymer has already been used for a variety of biomedical purposes, including the preparation of a controlledrelease delivery system for the therapeutic protein human growth hormone 33 , it was an excellent choice as a vaccine delivery system.
TextSentencer_T118 21517-21719 Sentence denotes In addition, microparticles of the appropriate size (~1 µm) have been shown to be taken up by APCs in vivo, which migrated to the T-cell area of local lymph nodes and differentiated into mature DCs 34 .
TextSentencer_T119 21720-21868 Sentence denotes Initial work focused on the use of microparticles for controlled release of trapped antigens, with the objective of making single-dose vaccines 35 .
TextSentencer_T120 21869-22018 Sentence denotes have been shown to enhance antigen-specific responses in mouse models and, therefore, have the potential to be developed as adjuvants for humans 23 .
TextSentencer_T121 22019-22142 Sentence denotes An SMIP-based platform for adjuvant design and discovery holds significant potential for the future of vaccine development.
TextSentencer_T122 22143-22355 Sentence denotes There are numerous advantages that can be realized throughout the vaccine R&D pipeline if SMIPs rather than other natural or synthetic immune potentiators are chosen for optimization and development as adjuvants.
TextSentencer_T123 22356-22682 Sentence denotes For discovery efforts, the incredible diversity of scaffolds generated through combinatorial chemistry, the ability to target with exceptional selectivity innate immune mechanisms, and the tried and tested drug discovery engines of highthroughput screening and hit-to-lead optimization can now be applied to vaccine adjuvants.
TextSentencer_T124 22683-22860 Sentence denotes Later in development and manufacturing, an SMIP-based adjuvant provides a low cost, highly pure and standardized alternative to all other existing candidate immune potentiators.
TextSentencer_T125 22861-23112 Sentence denotes Given these advantages, and the likelihood that more and diverse families of SMIPs will be discovered, it seems that the imidizaquinoline TL7/8 agonists represent only the first in a long line of future small-moleculebased vaccine adjuvant candidates.
TextSentencer_T126 23113-23401 Sentence denotes Although the terms 'adjuvant' and 'delivery system' have often been used interchangeably in relation to vaccines, a clear distinction can often be made and the respective roles of each can be more clearly differentiated, particularly when a delivery system is used for a vaccine adjuvant.
TextSentencer_T127 23402-23711 Sentence denotes Included in lists of vaccine adjuvants are a number of particulate delivery systems (for example, emulsions, liposomes, iscoms, virus-like particles and MICROPARTICLES), whose principal mode of action is to promote the uptake of antigens into the key APC responsible for the induction of immune responses 24 .
TextSentencer_T128 23712-23850 Sentence denotes However, the potency of these delivery systems can be significantly improved by the addition of a vaccine adjuvant, or immune potentiator.
TextSentencer_T129 23851-23976 Sentence denotes Adjuvants are included in delivery systems to focus their effects onto the APCs, and to minimize effects on non-immune cells.
TextSentencer_T130 23977-24048 Sentence denotes Hence, delivery systems can improve the therapeutic ratio of adjuvants.
TextSentencer_T131 24049-24258 Sentence denotes If the geographical concept of immune reactivity, in which antigens that do not reach local lymph nodes do not induce responses 25 , is accepted, then the role and importance of delivery systems becomes clear.
TextSentencer_T132 24259-24495 Sentence denotes Delivery systems serve to maximize the concentration of antigen in local lymph nodes either by directly promoting antigen uptake into lymphatics, or by promoting antigen uptake into motile APCs that will then migrate to the lymph nodes.
TextSentencer_T133 24496-24651 Sentence denotes As such, the role of a vaccine delivery system is to enhance the amount of antigen reaching the cells or tissues responsible for immune response induction.
TextSentencer_T134 24652-25033 Sentence denotes Particulate vaccine delivery systems (for example, emulsions, microparticles, iscoms, liposomes, virosomes and virus-like particles) have comparable dimensions to MICROPARTICLES Particulate carrier systems in the micron size range, normally prepared with synthetic polymers, which can be used as delivery systems for drugs or vaccines that are usually trapped within the particles.
TextSentencer_T135 25034-25176 Sentence denotes An oil-in-water microemulsion adjuvant which has been approved in Europe for use in combination with influenza vaccine in the elderly (Fluad).
TextSentencer_T136 25177-25210 Sentence denotes POLY(LACTIDE CO-GLYCOLIDE) (PLG).
TextSentencer_T137 25211-25431 Sentence denotes A biodegradable and biocompatible synthetic polymer that has been used to prepare a number of successfully marketed drug delivery systems. deliver adsorbed DNA into DCs, whereas naked DNA was unable to transfect DCs 41 .
TextSentencer_T138 25432-25628 Sentence denotes Similar cationic microparticles can also be used as delivery systems for adsorbed adjuvants, including CpG DNA, whereas anionic microparticles have been used for adsorbed protein vaccines 37, 42 .
TextSentencer_T139 25629-25798 Sentence denotes The potential of a broad range of particulate vaccine delivery systems to improve the potency of new generation vaccines has recently been reviewed in more detail 2,43 .
TextSentencer_T140 25799-26057 Sentence denotes Although the majority of vaccines have traditionally been administered by injection, mucosal administration of vaccines offers a number of important advantages, including easier administration, reduced adverse effects and the potential for frequent boosting.
TextSentencer_T141 26058-26170 Sentence denotes In addition, mucosal immunization induces local immunity at the sites where pathogens often establish infection.
TextSentencer_T142 26171-26306 Sentence denotes Oral immunization would be particularly advantageous in isolated communities, where access to health care professionals is problematic.
TextSentencer_T143 26307-26445 Sentence denotes Moreover, mucosal immunization would avoid the problem of infection due to the re-use of needles, which is common in the developing world.
TextSentencer_T144 26446-26579 Sentence denotes However, the difficulty of developing mucosal and particularly oral vaccines using nonliving approaches should not be underestimated.
TextSentencer_T145 26580-26757 Sentence denotes Protein, peptide, polysaccharide and DNA immunogens are extremely labile and will be extensively degraded and damaged during passage through the gut if not adequately protected.
TextSentencer_T146 26758-26991 Sentence denotes Intranasal immunization is an attractive approach, owing to the absence of acidity and secreted enzymes in the nasal cavity, but also because of the ease of access to the nasal cavity offered by simple commercially available devices.
TextSentencer_T147 26992-27121 Sentence denotes Nevertheless, potent adjuvants and delivery systems will be required to facilitate the development of effective mucosal vaccines.
TextSentencer_T148 27122-27284 Sentence denotes The most potent mucosal adjuvants available are the bacterial toxins secreted from Escherichia coli and Vibrio cholerae, called HEAT-LABILE ENTEROTOXIN (LT) (FIG.
TextSentencer_T149 27285-27325 Sentence denotes 5) and cholera toxin (CT), respectively.
TextSentencer_T150 27326-27514 Sentence denotes However, because these molecules are responsible for traveller's diarrhoea and cholera, respectively, the native molecules are clearly not appropriate for mucosal administration to humans.
TextSentencer_T151 27515-27626 Sentence denotes Therefore, these molecules have been manipulated to reduce toxicity, while retaining adjuvant activity 44 (FIG.
TextSentencer_T152 27627-27631 Sentence denotes 6) .
TextSentencer_T153 27632-27821 Sentence denotes One particular mutant of LT, LTK63, has recently been shown to be safe in a human clinical trial involving intranasal administration, following extensive preclinical toxicology testing 30 .
TextSentencer_T154 27822-28023 Sentence denotes In previous studies, we showed that the potency of LTK63 for intranasal administration could be enhanced by co-administration with bio-adhesive delivery systems in small 45 and large animal models 46 .
TextSentencer_T155 28024-28234 Sentence denotes The bio-adhesive delivery systems were designed to retain the vaccine formulation in the nasal cavity for extended periods and to promote the interaction of the antigen and adjuvant with the mucosal epithelium.
TextSentencer_T156 28235-28374 Sentence denotes Recent data indicate that LTK63 might prove sufficiently potent to allow the mucosal administration of paediatric combination vaccines 47 .
TextSentencer_T157 28375-28523 Sentence denotes However, problems arose as a consequence of the degradation of antigens following microencapsulation and during release from PLG microparticles 36 .
TextSentencer_T158 28524-28700 Sentence denotes We therefore adopted the novel approach of adsorbing antigens onto the surface of microparticles to avoid exposing them to damaging conditions during encapsulation and release.
TextSentencer_T159 28701-28858 Sentence denotes Adsorption was enhanced by using charged surfactants for microparticle preparation, which promoted antigen interaction with the surface of the particles 37 .
TextSentencer_T160 28859-29095 Sentence denotes Consequently, the microparticles were designed to perform as a delivery system to promote the uptake of antigen into APCs, thereby resulting in the induction of potent antibody and T-cell responses in mice 37 and non-human primates 38 .
TextSentencer_T161 29096-29260 Sentence denotes In addition, the adsorption of antigen on microparticles also serves to multimerize the antigens, and so facilitates direct recognition by B-cell antigen receptors.
TextSentencer_T162 29261-29471 Sentence denotes The approach of adsorbing antigens onto charged microparticles has proven sufficiently flexible to allow successful delivery of DNA vaccines, which are adsorbed onto the surface of cationic microparticles (FIG.
TextSentencer_T163 29472-29476 Sentence denotes 4) .
TextSentencer_T164 29477-29685 Sentence denotes Using cationic microparticles as a delivery system for DNA vaccines resulted in significantly enhanced immune responses in comparison with immunization using naked DNA in mice 39 and in nonhuman primates 40 .
TextSentencer_T165 29686-29799 Sentence denotes In mechanistic studies, we showed that the cationic PLG microparticles were able to HEAT-LABILE ENTEROTOXIN (LT).
TextSentencer_T166 29800-29980 Sentence denotes A bacterial toxin secreted from Escherichia coli which is potently immuno-stimulatory when applied to mucosal surfaces and can also act as an adjuvant for co-administered antigens.
TextSentencer_T167 29981-30205 Sentence denotes However, the molecule is also the causative agent of traveller's diarrhoea. of vaccinations that are administered to infants and toddlers, and it would be preferable if these could be administered without the use of needles.
TextSentencer_T168 30206-30327 Sentence denotes In addition, 'needle phobia' is a significant problem that makes it difficult to convince adults to receive vaccinations.
TextSentencer_T169 30328-30541 Sentence denotes This problem might become particularly acute in the future if it proves necessary to immunize large numbers of individuals in response to a pandemic strain of influenza, or to the threat of a bio-terrorism attack.
TextSentencer_T170 30542-30741 Sentence denotes The problems related to vaccination with needles are even greater in the developing world, where the re-use of needles often results in the transmission of blood-borne pathogens, such as HIV and HCV.
TextSentencer_T171 30742-30952 Sentence denotes Although this problem has been partly remedied through the development of single-use 'auto-disposable' syringes, needle-based injections still represent an infectious threat which must be disposed of carefully.
TextSentencer_T172 30953-31163 Sentence denotes One approach to obviate the problems associated with vaccines administered by needles involves a number of devices that are designed to deliver vaccines through or into the skin, but without the use of needles.
TextSentencer_T173 31164-31314 Sentence denotes Multiple-use jet injector devices that deliver liquid vaccines through the skin were widely used for mass immunization campaigns throughout the 1980s.
TextSentencer_T174 31315-31466 Sentence denotes However, these devices became discredited when it became apparent that they were capable of transmitting blood-borne pathogens such as hepatitis B 51 .
TextSentencer_T175 31467-31641 Sentence denotes More recently, single-dose jet injector devices have been developed, which are capable of delivering liquid 52 or dry powder vaccines 53 through the skin using high pressure.
TextSentencer_T176 31642-31756 Sentence denotes In addition, spring-powered liquid injection devices are available and have also been evaluated in the clinic 54 .
TextSentencer_T177 31757-31946 Sentence denotes However, none of these devices have yet attained broad acceptance in the medical community and their costs will make them difficult, if not impossible, to implement in the developing world.
TextSentencer_T178 31947-32175 Sentence denotes High-pressure-liquid, needlefree devices have also been used for the delivery of DNA vaccines in clinical trials 55 , as have new needle-free devices designed to deliver gold beads coated with DNA into the skin ('gene gun') 56 .
TextSentencer_T179 32176-32488 Sentence denotes An alternative needle-free approach to vaccine delivery, which could perhaps be described more accurately as 'needle-lite' , involves the use of microprojection arrays designed to painlessly disrupt the outer layers of the skin to allow the vaccine access to the epidermis and associated Langerhans cells 57,58 .
TextSentencer_T180 32489-32676 Sentence denotes Perhaps the most attractive needle-free approach to vaccine delivery being explored at present involves TRANSCUTANEOUS IMMUNIZATION through the topical application of vaccine patches 59 .
TextSentencer_T181 32677-32762 Sentence denotes This approach has recently provided promising observations in clinical trials 60,61 .
TextSentencer_T182 32763-33030 Sentence denotes In addition, the ability of a number of different adjuvants to function following topical application with vaccines is encouraging 62 , as is the ability of a topically applied 'immunostimulatory patch' to enhance the immunogenicity of a locally injected vaccine 63 .
TextSentencer_T183 33031-33244 Sentence denotes In addition to the mucosal immunization approaches discussed above, which clearly fall into the needle-free category, some vaccines might also be administered mucosally via aerosols, including measles vaccine 64 .
TextSentencer_T184 33245-33367 Sentence denotes However, the available devices need to be made more robust and reliable to be broadly accepted for vaccine administration.
TextSentencer_T185 33368-33557 Sentence denotes Although oral delivery of non-living vaccines remains extremely challenging, even with potent adjuvants, some success has been achieved in small animal models with non-toxic LT mutants 48 .
TextSentencer_T186 33558-33703 Sentence denotes Nevertheless, there is a requirement for the development of optimal delivery systems if successful oral vaccines are to be produced commercially.
TextSentencer_T187 33704-34025 Sentence denotes A variety of microparticle-based delivery systems can be designed to protect antigens against degradation in the gut, to promote interaction with the epithelium, or to be taken up by the mucosal-associated lymphoid tissues, and these offer significant promise as important components of oral vaccine delivery systems 49 .
TextSentencer_T188 34026-34250 Sentence denotes Recently, some success has been achieved in a human clinical trial with a vaccine trapped in PLG microparticles, but this approach is likely to require significant improvements to allow successful commercial development 50 .
TextSentencer_T189 34251-34455 Sentence denotes In its broadest sense, the concept of 'vaccine delivery systems' can be expanded to include a range of devices and physical delivery systems designed to allow immunization using novel non-invasive routes.
TextSentencer_T190 34456-34518 Sentence denotes Needle-free vaccination is attractive for a number of reasons.
TextSentencer_T191 34519-34805 Sentence denotes In the developed world, there are concerns about the number TRANSCUTANEOUS IMMUNIZATION Involves the topical application of vaccines, usually in a specially designed patch, and mediates effective immunization without penetrating the protective layer of the skin with a device or needle.
TextSentencer_T192 34806-35061 Sentence denotes The A1 subunit comprises a globular structure, which is enzymatically active and mediates ADP-ribosylation, resulting in permanent activation of adenylate cyclase, abnormal intracellular accumulation of cAMP and massive fluid loss, resulting in diarrhoea.
TextSentencer_T193 35062-35258 Sentence denotes The A1 subunit is linked to the B oligomer with the long helical A2 subunit, which must be proteolytically cleaved in addition to a disulphide being reduced to release and activate the A1 subunit.
TextSentencer_T194 35259-35390 Sentence denotes The ADP-ribosyltransferase activity of the A1 subunit is enhanced by interaction with intracellular ADP-ribosylation factors (ARF).
TextSentencer_T195 35391-35519 Sentence denotes Various groups have attempted to generate potent but safe mucosal adjuvants from LT, through a variety of genetic manipulations.
TextSentencer_T196 35520-35951 Sentence denotes Chiron scientists have focused on modifying or eliminating the enzymatic activity of LT (ADP-ribosylation) through single amino-acid substitutions in the active site of A1 (LTK63 and LTR72), while an alternative approach pursued by others was to modify the ability of the A1 subunit to be proteolytically cleaved from A2 by trypsin (LTR192G). allow vaccines to be used to treat chronic infectious diseases, autoimmunity and cancer.
TextSentencer_T197 35952-36106 Sentence denotes However, the potency of these adjuvants needs to be carefully balanced with their potential to overactivate the immune system, with damaging consequences.
TextSentencer_T198 36107-36263 Sentence denotes In this regard, vaccine and adjuvant delivery systems might have a role to play in limiting the systemic distribution of adjuvants following administration.
TextSentencer_T199 36264-36455 Sentence denotes Moreover, the main role of vaccine delivery systems is to ensure that the antigens and adjuvants interact optimally with the appropriate immunocompetent cells to induce the desired responses.
TextSentencer_T200 36456-36670 Sentence denotes Nevertheless, for adjuvants capable of initiating potent inflammatory responses, limiting their ability to act on a broad range of cells could prove to be as important as focusing their effects on key immune cells.
TextSentencer_T201 36671-36872 Sentence denotes Overall, it is clear that pharmaceutical scientists have a unique and important role to play in the development of optimal vaccine and adjuvant delivery systems for systemic and mucosal administration.
TextSentencer_T202 36873-37070 Sentence denotes We are entering an exciting and dynamic time in vaccine research in which the principles governing the successful induction of potent and protective immune responses are becoming better understood.
TextSentencer_T203 37071-37259 Sentence denotes At the forefront of this work are discoveries relating to the presence of receptors on innate immune cells, which recognize the characteristic patterns and components present on pathogens.
TextSentencer_T204 37260-37553 Sentence denotes Recognition of the importance of activation of the innate immune system to the eventual induction of antigen-specific immunity has fired enthusiasm to identify pathogen-based ligands for these receptors as potential new-generation adjuvants to be used in combination with recombinant proteins.
TextSentencer_T205 37554-37771 Sentence denotes A significant amount of work is underway in this area and will likely lead to the development of whole new classes of vaccine adjuvants that are able to control and manipulate the immune response in a variety of ways.
TextSentencer_T206 37772-38199 Sentence denotes It is likely that these adjuvants could prove to be sufficiently potent to In vitro toxicity on Y1 adrenal cells is shown for heat-labile enterotoxin (LT) wild type (LTwt), for the mutants generated by Chiron, which have modifications in the enzymatic active site of the A1 subunit (LTK63 and LTR72), and for an alternative mutant, LTR192G, which is modified in its ability to be enzymatically cleaved and activated by trypsin.
TextSentencer_T207 38200-38416 Sentence denotes LTK63 has no enzyme activity in the A1 subunit and shows no toxicity on Y1 cells, whereas LTR72 has residual enzyme activity (about 0.6% of LTwt) and shows residual toxicity, but is 100,000-fold less toxic than LTwt.
TextSentencer_T208 38417-38482 Sentence denotes By contrast, LTR192G shows only a marginal reduction in toxicity.
TextSentencer_T209 38483-38628 Sentence denotes Similar results were obtained for in vivo toxicity in the standard rabbit ileal loop model, which shows significant fluid accumulation with LTwt.
TextSentencer_T210 38629-38825 Sentence denotes In contrast, LTK63 shows no fluid accumulation, even at the highest dose tested (1 mg), whereas LTR72 shows reduced fluid accumulation and the requirement for a higher dose to trigger this effect.
TextSentencer_T211 38826-39019 Sentence denotes LTR192G shows high levels of fluid accumulation, even at low doses, similar to LTwt, probably because there are alternative enzymes present that can cleave the molecule, in addition to trypsin.
TextSentencer_T212 39020-39101 Sentence denotes For further details on experimental methodology for these studies see REFS 65,66.