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Adjuvants for foot-and-mouth disease virus vaccines: recent progress Expert Review of Vaccines Downloaded from informahealthcare.com by Korea University on 01/05/15 For personal use only.
Expert Rev. Vaccines 13(11), 1377–1385 (2014)
Yimei Cao State Key Laboratory of Veterinary Etiological Biology, OIE/National Foot-and-Mouth Disease Reference Laboratory of China, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Xujiaping No.1, Yanchangpu, Lanzhou, Gansu, 730046, China Tel.: +86 931 834 2667 Fax: +86 931 834 2052 [email protected]; [email protected]
Foot-and-mouth disease (FMD) is a highly contagious and rapidly spreading disease of cloven-hoofed animals. In most countries, animals are immunized with inactivated whole virus vaccines to control the spread of foot-and-mouth disease virus (FMDV); however, there are safety and efficacy (especially, cell-mediated immunity) concerns. Many efforts are currently devoted to the development of effective vaccines by combining the application of protective antigens together with the search for specific and targeting adjuvants that maximizes the immunogenicity with a desired immune response. In this review, we outline previous studies performed with both traditional adjuvants as well as the most promising new generation adjuvants such as ligands for Toll-like receptors (TLRs) or different cytokines, focusing mostly on their efficacy when used with FMD vaccine, and somewhat on mechanisms by which adjuvants mediate their effects. KEYWORDS: adjuvants • FMD • immunogenicity • mechanisms • vaccine
Foot-and-mouth disease (FMD) is a highly contagious and devastating disease affecting cloven-hoofed livestock worldwide. The disease is characterized by fever, lameness, lymphopenia and the appearance of vesicular lesions on the mouth, tongue, nose, feet and teats and is controlled by inhibition of susceptible animal movement, slaughter of infected animals and vaccination with an inactivated whole-virus vaccine. The commercially available vaccine is typically produced from BHK21 cell culture supernatants from foot-and-mouth disease virus (FMDV)-infected cells, chemically inactivated, partially purified and subsequently formulated with an adjuvant. This vaccine technology comes with the inherent risk of live virus release from production facilities or insufficient inactivation of the virus during vaccine preparation [1]. Thus, investigators have attempted to address these concerns by using new technologies to develop alternative vaccines, such as recombinant protein and peptide vaccines, empty capsid vaccines and genetically engineered inactivated vaccines [2–6]. Nonliving vaccine antigens, especially purified subunit vaccines, are often poorly immunogenic and require selected adjuvants to increase their immunogenicity and extend the
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10.1586/14760584.2014.963562
duration of effective protection [7]. In general, adjuvants are chemical substances that boost the immune response against the associated antigens. Moreover, the use of adjuvants may reduce the required amount of antigen or the multiple immunization protocol necessary to induce a protective immune response. Some types of immunity (e.g., Th1 cell vs Th2 cell, CD8+ vs CD4+ T cells, specific antibody isotypes) are not effectively achieved by the nonadjuvanted antigens [8]. Several kinds of vaccine adjuvants have been studied for their potency to promote immune response to FMDV vaccines. These adjuvants include mineral oil, saponins (Quil-A), Toll-like receptor (TLR) ligands, cytokines, liposomes and so on. Most of them have been developed empirically, without a clear understanding of their cellular and molecular mechanisms of action. This review outlines the action mechanisms and immunostimulatory effects of adjuvants both traditional and currently under development for FMD vaccines. Mineral oil
The efficacy of an oil adjuvant is attributed to depot formation at the site of injection, a vehicle for transport of the antigen throughout the
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lymphatic system and slow antigen release with the stimulation of antibody-producing cells. Montanide ISA-206, containing esters of octadecenoic acid and anhydromannitol in an oily solution, is a mineral oil-based adjuvant. This adjuvant renders a water-in-oil-in-water (w:o:w) emulsion and is presently used for formulating FMD vaccines in many Asian and South American countries. The traditional FMD inactivated whole virus vaccines are often formulated in aqueous Al(OH)3 and saponins or oil-based adjuvants. The Al(OH)3/saponin-based vaccines are not ideal for use in pigs as their protective efficacy is low in this species [9]. Currently, the double oil emulsion vaccines are preferred for FMD prevention as they can be used to protect all susceptible species and are ideal for emergency vaccination. Also, the oil-adjuvanted vaccines generate higher and longer lasting immune responses than the Al(OH)3-adjuvanted vaccines. FMDV-specific antibody responses were monitored for at least 92–120 days in cattle, 168 days in sheep and 141 days in pigs following a single intramuscular vaccination involving the use of Montanide ISA-206 oil adjuvant with an inactivated antigen, and protective immunity against disease could be maintained for at least 218 days in pigs using the oil adjuvant formulation [9–11]. Montanide ISA-201 is a newly developed mineral oil-based adjuvant by Seppic Inc., France (SEPPIC). This adjuvant retains the advantage of ISA-206 and adds some chemical components on the basis of ISA-206 to improve the cellular responses. Inactivated FMD vaccines formulated with the ISA-201 adjuvant induced earlier and higher neutralizing antibody responses, higher cellular immunity and protective efficacy in cattle, as compared to ISA-206 [12]. In our lab, we also compared both humoral immune responses and protection of two inactivated FMD vaccines formulated in Montanide ISA-201 or Montanide ISA-206 adjuvants in pigs, ISA-201-adjuvanted inactivated vaccines induced higher ELISA antibody titer and protective efficacy as compared to the ISA-206 adjuvant [13]. Presently, Montanide ISA-201 has been widely used in FMD marker vaccines and multiepitope protein vaccines in our lab [14,15]. Saponin-based adjuvants
The immunostimulating complexes (ISCOMs) are composed of saponin, cholesterol, phospholipid and immunogen. Saponin such as Quil-A has also been used as a component of ISCOMs. The use of saponin in ISCOMs-based vaccines retains the adjuvant activity of the saponin component but with a reduced toxicity. ISCOMs have been shown to elicit high-titer long-lasting antibodies and strong helper and cytotoxic T lymphocyte responses [16,17]. An influenza ISCOM vaccine for horses is licensed in Sweden [18]. ISCOMs enhance antigen uptake and prolong retention by dendritic cells (DCs) in draining lymph nodes, induce activation of DCs and lead to strong B- and Tcell responses [19]. They are potent enhancers of both Th1 and Th2 cells, enable substantial MHC class I presentation and induce both CD8+ and CD4+ T-cell responses to a variety of soluble protein antigens in man [20] and experimental animals. The most widely used saponin in adjuvant research is Quil-A 1378
and its derivatives, extracted from the bark of Quillaja saponaria, a tree of the rose family which is indigenous to South America. Quil-A is composed of a heterogeneous mixture of triterpene glycosides that vary in their adjuvant activity and toxicity. It has been widely used as an adjuvant in veterinary vaccines. However, its toxicity precludes expanded use in human vaccines. QS-21 is a purified component of Quil-A that demonstrates low toxicity and maximum adjuvant activity and is currently being tested in human studies with several vaccine candidates [8]. When used as an adjuvant for FMD vaccines, Quil-A and oil can synergistically enhance IgG and the subclass responses in mice and humoral immune responses in pigs [21]. The adjuvanticity of ISCOMs has been reported in the FMD recombinant protein (C-terminal half of the VP1 protein) vaccine; it was found that a combination of recombinant protein ISCOMs and Montanide ISA-206 could achieve early protective titers and longer lasting immunity in guinea pigs. The vaccine conferred protection against FMDV 105 days post-vaccination in 13 of 15 animals [22]. Recently, a study performed in mice showed that the ISCOMs could stimulate more strong cellular immunity responses than the complete Freund’s adjuvant/ incomplete Freund’s adjuvant to peptide antigens of FMDV [23]. While the studies in laboratory animals are encouraging, it remains to be seen whether FMD vaccines formulated in ISCOMs will be as successful in target species. Adjuvants targeting pattern recognition receptors
The discovery of innate signaling receptors and chemically defined ligands has given a new face to the adjuvant field, for many of the ligands serve as better adjuvants for cellular immunization relatively to the other adjuvants, such as alum. There are several classes of pattern recognition receptors such as the RIG-Ilike receptors, NOD-like receptors, C-type lectin receptors and TLRs. TLRs were the first to be identified and have been most thoroughly studied. To date, 15 mammalian TLRs have been described, of which 10 are found in humans (TLR1–TLR10) and 12 in mouse (TLR1–TLR9 and TLR11–TLR13) [24,25]. TLR1, TLR2, TLR4, TLR5, TLR6, TLR10 and TLR11 are expressed on the cell surface, whereas TLR3, TLR7, TLR8 and TLR9 are expressed intracellulary in endosomes. Natural or artificial ligands for most TLRs have been identified and presently are putative immunotherapeutics or candidate vaccine adjuvants. Polyriboinosinic acid-polyribocytidylic acid-TLR3 ligands
Polyriboinosinic acid-polyribocytidylic acid [poly(I:C)], a potent inducer of interferons, is a synthetic double-stranded RNA that is a viral mimic and activates multiple innate immune pathways through interaction with TLR3, retinoic acid-inducible gene1 and melanoma differentiation-associated gene-5 (MDA-5) [26]. After poly(I:C) activates TLR3 in endosomes, the TLR3 dimer recruits the adaptor molecule TIR domain containing adaptor inducing interferon-b and activates various transcription factors such as NF-kB and IFN-regulatory factor 3, resulting in the transcription of IFN-a and IFN-b, as well as proinflammatory Expert Rev. Vaccines 13(11), (2014)
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Adjuvants for FMDV vaccines
cytokines, such as IL-12 and IL-6, respectively. MDA-5 and RIG-I mediate their effects through the adaptor IFN-b promoter stimulatory-1 [27]. Stimulation of MDA-5 in the cytosol, most notably from nonhematopoietic cells [28,29], strongly enhances the production of type I interferons, and such type I interferons secretion is essential for NK cell activation, DC maturation and the elicitation of a strong CD4+ T-cell immunity [28,30]. Poly(I:C) activates both TLR3 and MDA-5 optimizing the magnitude and durability of Th1 cell immunity and CD8+ T-cell immunity compared to either pathway alone; this characteristic may make poly(I:C) an effective adjuvant. The adjuvanticity of poly(I:C) has been reported in some veterinary vaccines, for example, inactivated porcine reproductive and respiratory syndrome virus vaccines [31], Venezuelan equine encephalomyelitis virus vaccines [32], inactivated Newcastle disease virus vaccines [33] and transmissible gastroenteritis virus vaccines [34]. The adjuvanticity of poly (I:C) has also been reported in FMDV vaccines, poly(I:C) enhanced the early antibody production of swine to oil-emulsified FMDV vaccines, the immune response was potentiated tenfold when the emulsion contained poly(I:C) [35,36]. We had previously reported that poly(I:C) was an effective adjuvant for an FMD multiepitope protein vaccine; coadministration of poly(I:C) with FMD multiepitope protein in oil emulsion significantly increased the production of neutralizing antibodies against FMDV in mice [37] and vaccination of pigs with FMD multiepitope protein B4 incorporating poly(I:C) upregulated T-cell immunity and conferred complete protection against subsequent challenge with virulent FMDV [3]. Furthermore, vaccination of pigs with this vaccine formulation conferred cross-protection against three topotypes of FMDV serotype O [14]. Although poly(I:C) is the most widely used TLR3 agonist, higher doses of poly(I:C) may produce toxic side effects, including shock, renal failure, coagulopathies and hypersensitivity reactions and can be rapidly hydrolyzed in humans when used alone. poly-IC-poly-L-lysine (Poly ICLC), which is poly(I:C) stabilized with poly-L-lysine and carboxymethyl cellulose, has the same antiviral and adjuvant activity with poly(I:C) but minimizes observed deficiencies of poly(I:C) [38]. Pigs inoculated with 8 mg of poly ICLC were completely protected when challenged 24 h later with FMDV and the antiviral activity of poly ICLC is related to its ability to modulate the immune response by inducing the production of IFN-a, IFN-b and IFN-g in vivo [39]. Cytidine-phosphate-guanosine oligodeoxynucleotides-TLR9 ligands
Synthetic cytidine-phosphate-guanosine (CpG) oligodeoxynucleotides (ODNs), containing unmethylated CpG motifs that are commonly found in bacterial and viral DNA, act through TLR9 signaling via the MyD88-dependent pathway, leading to IRF7-mediated interferon production or proinflammatory responses such as production of TNF-a, IL-1, IL-6 and IL-12 via the triggering of NF-kB. TLR9 activation also leads to the production of the proinflammatory cytokines IFN-a, IFN-g and IL-12. CpGs are extremely efficient inducers of Th1 informahealthcare.com
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immunity and cytotoxic T lymphocyte responses and induce protection against infectious disease, allergy and cancer in mice and primate models [40,41]. CpG ODNs also improve the antigen presenting function of DCs, monocytes and macrophages, induce the proliferation of B cells and indirectly stimulate the immunoprotective activity of NK cells while recruiting T cells to the site of CpG ODNs administration. These diverse effects support the ability of CpG ODNs to act as vaccine adjuvants. The adjuvant properties of CpG ODNs have been assessed in a wide array of vaccine trials [42]. For prophylactic vaccines, pathogen-specific immunity is needed after exposure. In these situations, increasing the induction of protective immunity is critical. Several studies indicate that CpG ODNs speed up the development of vaccine-induced responses, enhance the antigen-specific antibody response and improve protection following challenge with virus [43–45]. Ongoing human clinical studies indicate that CpG ODNs have a good safety profile and increase the immunogenicity of coadministered vaccines [46,47]. Yet some studies note increased frequency of mild local reactions and systemic symptoms by CpG-adjuvanted vaccines compared to nonadjuvanted vaccines. Most of the adverse events reported in clinical studies were mild to moderate, appeared within 24 h of dosing and persisted only for a few days [42]. The adjuvant effects of CpG ODNs on FMD vaccines were also evaluated. The studies demonstrated that a combination of CpG ODNs with ISA-206 could facilitate a recombinant FMDV vaccine A7 (containing multiple B- and T-cell epitopes) to induce a vigorous and long-lasting specific antibody response in mice and cattle. The peak antibody level of mice induced by A7 plus ISA-206 and CpG ODN was sustained until 175 days post-immunization. The anti-FMDV antibody induced by A7+ISA-206+CpG ODN was 1.9-fold higher than that induced by A7+ISA-206 on day 175 post-immunization (p < 0.01). In cattle, on day 84, the anti-FMDV antibody induced by A7+ISA-206+CpG ODN was 4.3- and 2.1-fold higher than those induced by A7+ISA-206 (p < 0.01) and inactivated vaccine (p < 0.01), respectively. After FMDV challenge, the protection rate of cattle vaccinated with CpG-adjuvanted A7 vaccine was higher compared to nonadjuvanted vaccines and conventional inactivated FMDV vaccines [48]. In our lab, we compared CpG with poly(I:C) for their ability to act as an adjuvant on FMD multiepitope protein B4 vaccines. Mice and pigs immunized with B4+CpG+ISA-201 showed significantly higher (p < 0.05) FMDV-specific antibody titers than those immunized with B4+poly(I:C)+ISA-201. In addition, challenging immunized pigs with a high dose of virulent FMDV resulted in a higher 50% protective dose (PD50) value for B4 +CpG+ISA-201 compared to B4+poly(I:C)+ISA-201. We concluded that CpG was superior to poly(I:C) as an adjuvant for FMD multiepitope protein B4 vaccines in pigs [YIMEI CAO, ET AL. UNPUBLISHED DATA]. Also, treatment of mice with CpG ODNs significantly reduced viremia, disease and death in five of six FMDV serotypes, when compared to no treatment or treatment with control ODNs. The effect was observed when 1379
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ODNs were administered simultaneously with, or up to 12 h after, infection with FMDV, and lasted for 14 days post treatment [49]. However, the employment of CpG as emergency vaccination to promote early protection against FMDV challenge in pigs has failed. CpG combined with an FMD inactivated vaccine did not promote protection [50]. Although CpG ODNs are relatively safe and effective when administered as a vaccine adjuvant, the biological instability of CpG and its resulting short half-life should be considered. There are several approaches used to enhance its biostability. Replacement of the CpG phosphodiester bonds with phosphorothioate bonds enhances the stability and activity of this oligonucleotide and is the lead CpG candidate. Other stabilizing approaches involve complexing to cationic peptides or cationic carriers, conjugating to the vaccine antigen or incorporating CpG into nucleic acids that form double-stranded hairpin loops. Imidazoquinolines-TLR7/TLR8 ligands
The imidazoquinoline compounds imiquimod (R-837) and resiquimod (R-848) are fully synthetic small molecules that are recognized by TLR7 and TLR7/TLR8, respectively. TLR7 and TLR8 are expressed in endosomes but not on the cell surface, and both mediate their effects through MyD88-dependent signaling [51]. On ligation, NF-kB-mediated induction of proinflammatory cytokines combined with enhanced antigenpresenting capacity of matured DCs promotes Th1-biased humoral and cellular immunity [52]. Imiquimod, the first synthetic imidazoquinoline, is licensed for the topical treatment of genital warts, skin cancer, superficial basal cell carcinoma and actinic keratosis [53]. A bispecific TLR7/TLR8 agonist may be more effective than a monospecific agonist by activating multiple DC subsets and B cells to induce cytokines optimal for Th1 cell immunity, cross-presentation and antibody production. R-848 induces more pronounced APC activation, enhancement of cellular immunity and cytokine production compared to imiquimod [54]. Both R-837 and R-848 have been evaluated in various animal models as vaccine adjuvants. Studies indicated that these molecules have the ability to activate APCs, induce immune modulatory cytokines and activate Band T-cell responses [55–57]. A study from our lab indicated that the R-848 and poly(I: C) together with Al(OH)3 enhanced humoral and cellular immune responses to immunization with 146S FMDV antigens in mice. Particular application was demonstrated for inducing a high amount of IgG antibody and Th1-biased immune responses [58]. However, to date, no published data are available to determine vaccine adjuvant activity of imidazoquinolines on FMD vaccines in natural hosts. Flagellin-TLR5 agonist
Flagellin, the principal constituent of bacterial flagellum, is a potent activator of the NF-kB signaling pathway through TLR5. It has been reported to be an effective adjuvant inducing robust and broad-spectrum immune responses against pathogens [59]. The adjuvant effects of flagellin have been determined in many 1380
vaccines, such as influenza viruses, human immunodeficiency virus and Yersinia pestis [60–62]. A recent study investigated the adjuvant effect of flagellin to inactivated FMDV antigens in guinea pig model. Coadministration of flagellin with inactivated FMDV antigens through the intradermal route induced earlier and higher anti-FMDV neutralizing antibodies, enhanced IgG1 and IgG2 responses and protection in guinea pigs against live virus challenge as compared to FMDV antigens alone [63]. Although flagellin itself can be an adjuvant when mixed with antigens, current application is primarily by generation of fusion proteins of recombinant vaccine antigens and flagellin [64]. Unlike many other TLR ligands, flagellin tends to produce both Th1 and Th2 cell responses rather than strongly polarized Th1 cell patterns [64]. Cytokines
Cytokines are low-molecular-weight soluble proteins that play key roles in the regulation of innate and adaptive immunity. Cytokines are included in the modern classification of adjuvants. Cytokines including IFN-a, IFN-g, IL-1, IL-2, IL-15, IL-18 and GM-CSF have been reported to exhibit adjuvant activity in vaccination with candidate FMD vaccines based on DNA and recombinant virus vectors as well as traditional vaccines. For example, IL-1 and IL-2 have been reported to improve the humoral immune response to inactivated FMD vaccines in a mouse model [65,66]. Porcine IFN-a is a powerful adjuvant for recombinant protein and multiple-epitope vaccines against FMDV in swine, and both FMDV-specific humoral and cell-mediated immune responses as well as protection were increased when IFN-a was included [67,68]. It was found that the inclusion of the gene for porcine granulocyte-macrophage colony-stimulating factor with a DNA empty capsid vaccine resulted in a significant increase in antibody levels against FMDV and some improvement in protection from FMD challenge [69,70]. Studies have shown that recombinant fowlpox virus or plasmids coexpressing IL-18 with P12A and 3C of FMDV could result in improvement in humoral and cellular immune responses and some improvement in protection against FMD challenge [71,72]. However, in these studies, two or three inoculations were given prior to challenge. Ultimately, to be successful, any new vaccine must provide protection after a single inoculation, since in an outbreak there will presumably be no time or sufficient logistical support for multiple vaccinations. Previous experiments have shown that, in addition to inducing a rapid antiviral response, IFN-a can function as an adjuvant and enhance the long-term (at least 42 days) protective response of the Ad5-A24 vaccine in pigs after a single inoculation [73]. Although these cytokines are effective adjuvants for FMD vaccines in various animal models, the relatively short serum half-life of certain cytokines may contribute to a less than optimal adjuvant activity, and a number of approaches have been adopted to overcome these difficulties. These include incorporation of cytokines into liposomes, coadministration of cytokine expression vectors together with DNA vaccines and coexpression of cytokines and immunogens in the same vectors. In addition, Expert Rev. Vaccines 13(11), (2014)
Adjuvants for FMDV vaccines
systemic administration of high doses of certain cytokines including IL-2, IL-12, IFN-a and IFN-g is associated with significant toxicity, which would limit their use as vaccine adjuvants at such doses.
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Bacterial toxins
Bacterial toxins such as cholera toxin (CT) and heat-labile enterotoxin (LT) of Escherichia coli are powerful mucosal adjuvants. CT and LT consist of a homopentamer of B subunit that binds to GM1 receptors and an enzymatically active A subunit that is responsible for the toxicity. They strongly potentiate the immunogenicity of soluble antigens by inducing enhanced antigen presentation by dendritic cells, macrophages and B cells. However, their use is limited by their high toxicity. To overcome the toxicity problem, recombinantly produced derivatives with no or reduced toxicity have been developed such as the nontoxic B subunits of CT (CTB) and LT (LTB). Even though both CTB and LTB are poor adjuvants in animals when coadministered with non-coupled antigens by the oral route, both CTB and LTB have significant adjuvanticity via the nasal route [74]. CTB is used to enhance the immune response in a licensed whole-cell orally delivered cholera vaccine [75]. CTB is also a useful mucosal adjuvant to elicit protective immune responses against FMDV [76,77]. The LTK63 and LTR72 mutants of LT have been generated with reduced toxicity while maintaining the adjuvanticity of LT and have been successfully used to immunize a variety of animal species with various vaccine antigens [78–80]. The oral and respiratory mucosae are the main ports of entry of FMDV, so the stimulation of local immunity in these tissues may help prevent initial infection and viral spread. A recently performed study has shown that Ad5 vectors encoding the mucosal adjuvant LTR72 (Ad5-LTR72) could be used as an important tool to enhance mucosal and systemic immunity against FMDV. Mice receiving Ad5-A24 plus Ad5-LTR72 had higher levels of mucosal and systemic neutralizing antibodies than those receiving Ad5-A24 alone or Ad5-A24 plus Ad5-LTB. The vaccine plus Ad5-LTR72 group also demonstrated 100% survival after intradermal challenge with a lethal dose of homologous FMDV serotype A24 [81].
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adjuvants for T-cell immunization. In fact, any single immunostimulant or delivery system will be insufficient to induce strong and long-lasting humoral and cellular immunity that is required for new vaccines. Effective adjuvant systems are likely to require synergy between one or more immunostimulants and a carrier or a delivery system. For instance, addition of TLR ligands to oil-based adjuvants could contribute to a synergistic immunostimulatory effect. Thus, further effort will be made to identify optimal combinations of immune modulators. As vaccine development is a highly empirical process, and different types of response are required to protect against FMDV, there is little justification for concluding that one particular adjuvant will be significantly more useful than other available alternatives. In addition to efficacy, source, cost and safety should be taken into account in adjuvant selection. Five-year view
New knowledge of innate immunity has brought a wider interest in understanding how existing adjuvants work and how they might be improved. Understanding the mechanisms of action of adjuvants will provide critical information on how innate immunity influences the development of adaptive immunity and help in rational design of vaccine formulations against FMDV. In future FMD vaccine adjuvant research, further effort should be made to clarify action mechanisms of new or existing adjuvants and determine optimal combinations of multiple compounds to achieve the desired immunological enhancement. On the other hand, FMDV is a mucosal pathogen with its primary route of entry through the oro- or nasopharyngeal route, with virus replication taking place initially in epithelial or lymphoid cells. The establishment of local mucosal immunity in these primary sites of entry of FMDV could block the invading virus, thereby preventing or limiting replication, reducing viral load as well as dissemination to other tissues during the initial stage of infection. Adjuvants are presumably an essential element for the development of effective mucosal vaccines that could induce protective immunity at mucosal and systemic compartments. Thus, the development of effective, safe adjuvants and formulations inducing mucosal immunity to prevent the development of carrier animals of FMDV would be an important future goal.
Expert commentary
Today, most researchers working on FMD vaccines are not only focusing on the antigen but also on adjuvant technology. Development of safe and effective adjuvants may also have important implications for the improvement of efficacy and safety of new/ existing vaccines. Increasing importance is now being placed on the development of new or existing adjuvants to enhance not only humoral but also cell-mediated immune responses to FMDV antigens. Well-defined ligands for TLRs have attracted most of the attention, many of the ligands serving as nice
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Financial & competing interests disclosure
This research was supported by a grant from the National Natural Science Foundation of China (31372422). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
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Key issues • Foot-and-mouth disease is a devastating disease of livestock that has had a significant impact on world economies and public health. Vaccination was used to control the spread of infection in many countries. • Although the traditional inactivated vaccine is effective, there are some concerns with its use. These include potential virus escape from the production facility, the inability of inoculation with this vaccine to block the development of the carrier state and so on. • Many efforts are currently devoted to the development of effective foot-and-mouth disease virus (FMDV) vaccines by combining the application of protective antigens together with the search for specific and targeting adjuvants that maximizes the immunogenicity with a desired immune response. • Ligands of Toll-like receptors activate multiple innate immune pathways and stimulate the production of proinflammatory cytokines/ chemokines and type I interferons. This innate immune response also supports the subsequent development of adaptive immunity, and Expert Review of Vaccines Downloaded from informahealthcare.com by Korea University on 01/05/15 For personal use only.
thus can be used as adjuvants to accelerate and enhance the induction of FMDV-specific responses. • Combinations of multiple compounds have a synergistic effect when used as adjuvants. New adjuvant development should identify novel combinations of adjuvants and formulations capable of inducing stronger and longer-lasting humoral and cellular immune responses. • New vaccines combined with ligands of Toll-like receptors that provide immunity more rapidly and/or can be produced without the need for production of a great quantity of infectious virus required for manufacture of the traditional vaccine are being developed and may provide alternative tools to control foot-and-mouth disease. • Mucosal adjuvants are essential for the induction of effective mucosal immunity, which may be the effective way to prevent the development of carrier animals of FMDV.
differentiating infected from vaccinated animals. J Virol 2012;86:11675-85
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Adjuvants for FMDV vaccines
Alejo DM, Moraes MP, Liao XF, et al. An adenovirus vectored mucosal adjuvant augments protection of mice immunized intranasally with an adenovirus-vectored
foot-and-mouth disease virus subunit vaccine. Vaccine 2013;31:2302-9 •
important tool to enhance mucosal and systemic immunity against FMDV.
This work suggests that Ad5-LTR72 could be used as an
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Expert Rev. Vaccines 13(11), 1377–1385 (2014)
Yimei Cao State Key Laboratory of Veterinary Etiological Biology, OIE/National Foot-and-Mouth Disease Reference Laboratory of China, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Xujiaping No.1, Yanchangpu, Lanzhou, Gansu, 730046, China Tel.: +86 931 834 2667 Fax: +86 931 834 2052 [email protected]; [email protected]
Foot-and-mouth disease (FMD) is a highly contagious and rapidly spreading disease of cloven-hoofed animals. In most countries, animals are immunized with inactivated whole virus vaccines to control the spread of foot-and-mouth disease virus (FMDV); however, there are safety and efficacy (especially, cell-mediated immunity) concerns. Many efforts are currently devoted to the development of effective vaccines by combining the application of protective antigens together with the search for specific and targeting adjuvants that maximizes the immunogenicity with a desired immune response. In this review, we outline previous studies performed with both traditional adjuvants as well as the most promising new generation adjuvants such as ligands for Toll-like receptors (TLRs) or different cytokines, focusing mostly on their efficacy when used with FMD vaccine, and somewhat on mechanisms by which adjuvants mediate their effects. KEYWORDS: adjuvants • FMD • immunogenicity • mechanisms • vaccine
Foot-and-mouth disease (FMD) is a highly contagious and devastating disease affecting cloven-hoofed livestock worldwide. The disease is characterized by fever, lameness, lymphopenia and the appearance of vesicular lesions on the mouth, tongue, nose, feet and teats and is controlled by inhibition of susceptible animal movement, slaughter of infected animals and vaccination with an inactivated whole-virus vaccine. The commercially available vaccine is typically produced from BHK21 cell culture supernatants from foot-and-mouth disease virus (FMDV)-infected cells, chemically inactivated, partially purified and subsequently formulated with an adjuvant. This vaccine technology comes with the inherent risk of live virus release from production facilities or insufficient inactivation of the virus during vaccine preparation [1]. Thus, investigators have attempted to address these concerns by using new technologies to develop alternative vaccines, such as recombinant protein and peptide vaccines, empty capsid vaccines and genetically engineered inactivated vaccines [2–6]. Nonliving vaccine antigens, especially purified subunit vaccines, are often poorly immunogenic and require selected adjuvants to increase their immunogenicity and extend the
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10.1586/14760584.2014.963562
duration of effective protection [7]. In general, adjuvants are chemical substances that boost the immune response against the associated antigens. Moreover, the use of adjuvants may reduce the required amount of antigen or the multiple immunization protocol necessary to induce a protective immune response. Some types of immunity (e.g., Th1 cell vs Th2 cell, CD8+ vs CD4+ T cells, specific antibody isotypes) are not effectively achieved by the nonadjuvanted antigens [8]. Several kinds of vaccine adjuvants have been studied for their potency to promote immune response to FMDV vaccines. These adjuvants include mineral oil, saponins (Quil-A), Toll-like receptor (TLR) ligands, cytokines, liposomes and so on. Most of them have been developed empirically, without a clear understanding of their cellular and molecular mechanisms of action. This review outlines the action mechanisms and immunostimulatory effects of adjuvants both traditional and currently under development for FMD vaccines. Mineral oil
The efficacy of an oil adjuvant is attributed to depot formation at the site of injection, a vehicle for transport of the antigen throughout the
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ISSN 1476-0584
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lymphatic system and slow antigen release with the stimulation of antibody-producing cells. Montanide ISA-206, containing esters of octadecenoic acid and anhydromannitol in an oily solution, is a mineral oil-based adjuvant. This adjuvant renders a water-in-oil-in-water (w:o:w) emulsion and is presently used for formulating FMD vaccines in many Asian and South American countries. The traditional FMD inactivated whole virus vaccines are often formulated in aqueous Al(OH)3 and saponins or oil-based adjuvants. The Al(OH)3/saponin-based vaccines are not ideal for use in pigs as their protective efficacy is low in this species [9]. Currently, the double oil emulsion vaccines are preferred for FMD prevention as they can be used to protect all susceptible species and are ideal for emergency vaccination. Also, the oil-adjuvanted vaccines generate higher and longer lasting immune responses than the Al(OH)3-adjuvanted vaccines. FMDV-specific antibody responses were monitored for at least 92–120 days in cattle, 168 days in sheep and 141 days in pigs following a single intramuscular vaccination involving the use of Montanide ISA-206 oil adjuvant with an inactivated antigen, and protective immunity against disease could be maintained for at least 218 days in pigs using the oil adjuvant formulation [9–11]. Montanide ISA-201 is a newly developed mineral oil-based adjuvant by Seppic Inc., France (SEPPIC). This adjuvant retains the advantage of ISA-206 and adds some chemical components on the basis of ISA-206 to improve the cellular responses. Inactivated FMD vaccines formulated with the ISA-201 adjuvant induced earlier and higher neutralizing antibody responses, higher cellular immunity and protective efficacy in cattle, as compared to ISA-206 [12]. In our lab, we also compared both humoral immune responses and protection of two inactivated FMD vaccines formulated in Montanide ISA-201 or Montanide ISA-206 adjuvants in pigs, ISA-201-adjuvanted inactivated vaccines induced higher ELISA antibody titer and protective efficacy as compared to the ISA-206 adjuvant [13]. Presently, Montanide ISA-201 has been widely used in FMD marker vaccines and multiepitope protein vaccines in our lab [14,15]. Saponin-based adjuvants
The immunostimulating complexes (ISCOMs) are composed of saponin, cholesterol, phospholipid and immunogen. Saponin such as Quil-A has also been used as a component of ISCOMs. The use of saponin in ISCOMs-based vaccines retains the adjuvant activity of the saponin component but with a reduced toxicity. ISCOMs have been shown to elicit high-titer long-lasting antibodies and strong helper and cytotoxic T lymphocyte responses [16,17]. An influenza ISCOM vaccine for horses is licensed in Sweden [18]. ISCOMs enhance antigen uptake and prolong retention by dendritic cells (DCs) in draining lymph nodes, induce activation of DCs and lead to strong B- and Tcell responses [19]. They are potent enhancers of both Th1 and Th2 cells, enable substantial MHC class I presentation and induce both CD8+ and CD4+ T-cell responses to a variety of soluble protein antigens in man [20] and experimental animals. The most widely used saponin in adjuvant research is Quil-A 1378
and its derivatives, extracted from the bark of Quillaja saponaria, a tree of the rose family which is indigenous to South America. Quil-A is composed of a heterogeneous mixture of triterpene glycosides that vary in their adjuvant activity and toxicity. It has been widely used as an adjuvant in veterinary vaccines. However, its toxicity precludes expanded use in human vaccines. QS-21 is a purified component of Quil-A that demonstrates low toxicity and maximum adjuvant activity and is currently being tested in human studies with several vaccine candidates [8]. When used as an adjuvant for FMD vaccines, Quil-A and oil can synergistically enhance IgG and the subclass responses in mice and humoral immune responses in pigs [21]. The adjuvanticity of ISCOMs has been reported in the FMD recombinant protein (C-terminal half of the VP1 protein) vaccine; it was found that a combination of recombinant protein ISCOMs and Montanide ISA-206 could achieve early protective titers and longer lasting immunity in guinea pigs. The vaccine conferred protection against FMDV 105 days post-vaccination in 13 of 15 animals [22]. Recently, a study performed in mice showed that the ISCOMs could stimulate more strong cellular immunity responses than the complete Freund’s adjuvant/ incomplete Freund’s adjuvant to peptide antigens of FMDV [23]. While the studies in laboratory animals are encouraging, it remains to be seen whether FMD vaccines formulated in ISCOMs will be as successful in target species. Adjuvants targeting pattern recognition receptors
The discovery of innate signaling receptors and chemically defined ligands has given a new face to the adjuvant field, for many of the ligands serve as better adjuvants for cellular immunization relatively to the other adjuvants, such as alum. There are several classes of pattern recognition receptors such as the RIG-Ilike receptors, NOD-like receptors, C-type lectin receptors and TLRs. TLRs were the first to be identified and have been most thoroughly studied. To date, 15 mammalian TLRs have been described, of which 10 are found in humans (TLR1–TLR10) and 12 in mouse (TLR1–TLR9 and TLR11–TLR13) [24,25]. TLR1, TLR2, TLR4, TLR5, TLR6, TLR10 and TLR11 are expressed on the cell surface, whereas TLR3, TLR7, TLR8 and TLR9 are expressed intracellulary in endosomes. Natural or artificial ligands for most TLRs have been identified and presently are putative immunotherapeutics or candidate vaccine adjuvants. Polyriboinosinic acid-polyribocytidylic acid-TLR3 ligands
Polyriboinosinic acid-polyribocytidylic acid [poly(I:C)], a potent inducer of interferons, is a synthetic double-stranded RNA that is a viral mimic and activates multiple innate immune pathways through interaction with TLR3, retinoic acid-inducible gene1 and melanoma differentiation-associated gene-5 (MDA-5) [26]. After poly(I:C) activates TLR3 in endosomes, the TLR3 dimer recruits the adaptor molecule TIR domain containing adaptor inducing interferon-b and activates various transcription factors such as NF-kB and IFN-regulatory factor 3, resulting in the transcription of IFN-a and IFN-b, as well as proinflammatory Expert Rev. Vaccines 13(11), (2014)
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Adjuvants for FMDV vaccines
cytokines, such as IL-12 and IL-6, respectively. MDA-5 and RIG-I mediate their effects through the adaptor IFN-b promoter stimulatory-1 [27]. Stimulation of MDA-5 in the cytosol, most notably from nonhematopoietic cells [28,29], strongly enhances the production of type I interferons, and such type I interferons secretion is essential for NK cell activation, DC maturation and the elicitation of a strong CD4+ T-cell immunity [28,30]. Poly(I:C) activates both TLR3 and MDA-5 optimizing the magnitude and durability of Th1 cell immunity and CD8+ T-cell immunity compared to either pathway alone; this characteristic may make poly(I:C) an effective adjuvant. The adjuvanticity of poly(I:C) has been reported in some veterinary vaccines, for example, inactivated porcine reproductive and respiratory syndrome virus vaccines [31], Venezuelan equine encephalomyelitis virus vaccines [32], inactivated Newcastle disease virus vaccines [33] and transmissible gastroenteritis virus vaccines [34]. The adjuvanticity of poly (I:C) has also been reported in FMDV vaccines, poly(I:C) enhanced the early antibody production of swine to oil-emulsified FMDV vaccines, the immune response was potentiated tenfold when the emulsion contained poly(I:C) [35,36]. We had previously reported that poly(I:C) was an effective adjuvant for an FMD multiepitope protein vaccine; coadministration of poly(I:C) with FMD multiepitope protein in oil emulsion significantly increased the production of neutralizing antibodies against FMDV in mice [37] and vaccination of pigs with FMD multiepitope protein B4 incorporating poly(I:C) upregulated T-cell immunity and conferred complete protection against subsequent challenge with virulent FMDV [3]. Furthermore, vaccination of pigs with this vaccine formulation conferred cross-protection against three topotypes of FMDV serotype O [14]. Although poly(I:C) is the most widely used TLR3 agonist, higher doses of poly(I:C) may produce toxic side effects, including shock, renal failure, coagulopathies and hypersensitivity reactions and can be rapidly hydrolyzed in humans when used alone. poly-IC-poly-L-lysine (Poly ICLC), which is poly(I:C) stabilized with poly-L-lysine and carboxymethyl cellulose, has the same antiviral and adjuvant activity with poly(I:C) but minimizes observed deficiencies of poly(I:C) [38]. Pigs inoculated with 8 mg of poly ICLC were completely protected when challenged 24 h later with FMDV and the antiviral activity of poly ICLC is related to its ability to modulate the immune response by inducing the production of IFN-a, IFN-b and IFN-g in vivo [39]. Cytidine-phosphate-guanosine oligodeoxynucleotides-TLR9 ligands
Synthetic cytidine-phosphate-guanosine (CpG) oligodeoxynucleotides (ODNs), containing unmethylated CpG motifs that are commonly found in bacterial and viral DNA, act through TLR9 signaling via the MyD88-dependent pathway, leading to IRF7-mediated interferon production or proinflammatory responses such as production of TNF-a, IL-1, IL-6 and IL-12 via the triggering of NF-kB. TLR9 activation also leads to the production of the proinflammatory cytokines IFN-a, IFN-g and IL-12. CpGs are extremely efficient inducers of Th1 informahealthcare.com
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immunity and cytotoxic T lymphocyte responses and induce protection against infectious disease, allergy and cancer in mice and primate models [40,41]. CpG ODNs also improve the antigen presenting function of DCs, monocytes and macrophages, induce the proliferation of B cells and indirectly stimulate the immunoprotective activity of NK cells while recruiting T cells to the site of CpG ODNs administration. These diverse effects support the ability of CpG ODNs to act as vaccine adjuvants. The adjuvant properties of CpG ODNs have been assessed in a wide array of vaccine trials [42]. For prophylactic vaccines, pathogen-specific immunity is needed after exposure. In these situations, increasing the induction of protective immunity is critical. Several studies indicate that CpG ODNs speed up the development of vaccine-induced responses, enhance the antigen-specific antibody response and improve protection following challenge with virus [43–45]. Ongoing human clinical studies indicate that CpG ODNs have a good safety profile and increase the immunogenicity of coadministered vaccines [46,47]. Yet some studies note increased frequency of mild local reactions and systemic symptoms by CpG-adjuvanted vaccines compared to nonadjuvanted vaccines. Most of the adverse events reported in clinical studies were mild to moderate, appeared within 24 h of dosing and persisted only for a few days [42]. The adjuvant effects of CpG ODNs on FMD vaccines were also evaluated. The studies demonstrated that a combination of CpG ODNs with ISA-206 could facilitate a recombinant FMDV vaccine A7 (containing multiple B- and T-cell epitopes) to induce a vigorous and long-lasting specific antibody response in mice and cattle. The peak antibody level of mice induced by A7 plus ISA-206 and CpG ODN was sustained until 175 days post-immunization. The anti-FMDV antibody induced by A7+ISA-206+CpG ODN was 1.9-fold higher than that induced by A7+ISA-206 on day 175 post-immunization (p < 0.01). In cattle, on day 84, the anti-FMDV antibody induced by A7+ISA-206+CpG ODN was 4.3- and 2.1-fold higher than those induced by A7+ISA-206 (p < 0.01) and inactivated vaccine (p < 0.01), respectively. After FMDV challenge, the protection rate of cattle vaccinated with CpG-adjuvanted A7 vaccine was higher compared to nonadjuvanted vaccines and conventional inactivated FMDV vaccines [48]. In our lab, we compared CpG with poly(I:C) for their ability to act as an adjuvant on FMD multiepitope protein B4 vaccines. Mice and pigs immunized with B4+CpG+ISA-201 showed significantly higher (p < 0.05) FMDV-specific antibody titers than those immunized with B4+poly(I:C)+ISA-201. In addition, challenging immunized pigs with a high dose of virulent FMDV resulted in a higher 50% protective dose (PD50) value for B4 +CpG+ISA-201 compared to B4+poly(I:C)+ISA-201. We concluded that CpG was superior to poly(I:C) as an adjuvant for FMD multiepitope protein B4 vaccines in pigs [YIMEI CAO, ET AL. UNPUBLISHED DATA]. Also, treatment of mice with CpG ODNs significantly reduced viremia, disease and death in five of six FMDV serotypes, when compared to no treatment or treatment with control ODNs. The effect was observed when 1379
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ODNs were administered simultaneously with, or up to 12 h after, infection with FMDV, and lasted for 14 days post treatment [49]. However, the employment of CpG as emergency vaccination to promote early protection against FMDV challenge in pigs has failed. CpG combined with an FMD inactivated vaccine did not promote protection [50]. Although CpG ODNs are relatively safe and effective when administered as a vaccine adjuvant, the biological instability of CpG and its resulting short half-life should be considered. There are several approaches used to enhance its biostability. Replacement of the CpG phosphodiester bonds with phosphorothioate bonds enhances the stability and activity of this oligonucleotide and is the lead CpG candidate. Other stabilizing approaches involve complexing to cationic peptides or cationic carriers, conjugating to the vaccine antigen or incorporating CpG into nucleic acids that form double-stranded hairpin loops. Imidazoquinolines-TLR7/TLR8 ligands
The imidazoquinoline compounds imiquimod (R-837) and resiquimod (R-848) are fully synthetic small molecules that are recognized by TLR7 and TLR7/TLR8, respectively. TLR7 and TLR8 are expressed in endosomes but not on the cell surface, and both mediate their effects through MyD88-dependent signaling [51]. On ligation, NF-kB-mediated induction of proinflammatory cytokines combined with enhanced antigenpresenting capacity of matured DCs promotes Th1-biased humoral and cellular immunity [52]. Imiquimod, the first synthetic imidazoquinoline, is licensed for the topical treatment of genital warts, skin cancer, superficial basal cell carcinoma and actinic keratosis [53]. A bispecific TLR7/TLR8 agonist may be more effective than a monospecific agonist by activating multiple DC subsets and B cells to induce cytokines optimal for Th1 cell immunity, cross-presentation and antibody production. R-848 induces more pronounced APC activation, enhancement of cellular immunity and cytokine production compared to imiquimod [54]. Both R-837 and R-848 have been evaluated in various animal models as vaccine adjuvants. Studies indicated that these molecules have the ability to activate APCs, induce immune modulatory cytokines and activate Band T-cell responses [55–57]. A study from our lab indicated that the R-848 and poly(I: C) together with Al(OH)3 enhanced humoral and cellular immune responses to immunization with 146S FMDV antigens in mice. Particular application was demonstrated for inducing a high amount of IgG antibody and Th1-biased immune responses [58]. However, to date, no published data are available to determine vaccine adjuvant activity of imidazoquinolines on FMD vaccines in natural hosts. Flagellin-TLR5 agonist
Flagellin, the principal constituent of bacterial flagellum, is a potent activator of the NF-kB signaling pathway through TLR5. It has been reported to be an effective adjuvant inducing robust and broad-spectrum immune responses against pathogens [59]. The adjuvant effects of flagellin have been determined in many 1380
vaccines, such as influenza viruses, human immunodeficiency virus and Yersinia pestis [60–62]. A recent study investigated the adjuvant effect of flagellin to inactivated FMDV antigens in guinea pig model. Coadministration of flagellin with inactivated FMDV antigens through the intradermal route induced earlier and higher anti-FMDV neutralizing antibodies, enhanced IgG1 and IgG2 responses and protection in guinea pigs against live virus challenge as compared to FMDV antigens alone [63]. Although flagellin itself can be an adjuvant when mixed with antigens, current application is primarily by generation of fusion proteins of recombinant vaccine antigens and flagellin [64]. Unlike many other TLR ligands, flagellin tends to produce both Th1 and Th2 cell responses rather than strongly polarized Th1 cell patterns [64]. Cytokines
Cytokines are low-molecular-weight soluble proteins that play key roles in the regulation of innate and adaptive immunity. Cytokines are included in the modern classification of adjuvants. Cytokines including IFN-a, IFN-g, IL-1, IL-2, IL-15, IL-18 and GM-CSF have been reported to exhibit adjuvant activity in vaccination with candidate FMD vaccines based on DNA and recombinant virus vectors as well as traditional vaccines. For example, IL-1 and IL-2 have been reported to improve the humoral immune response to inactivated FMD vaccines in a mouse model [65,66]. Porcine IFN-a is a powerful adjuvant for recombinant protein and multiple-epitope vaccines against FMDV in swine, and both FMDV-specific humoral and cell-mediated immune responses as well as protection were increased when IFN-a was included [67,68]. It was found that the inclusion of the gene for porcine granulocyte-macrophage colony-stimulating factor with a DNA empty capsid vaccine resulted in a significant increase in antibody levels against FMDV and some improvement in protection from FMD challenge [69,70]. Studies have shown that recombinant fowlpox virus or plasmids coexpressing IL-18 with P12A and 3C of FMDV could result in improvement in humoral and cellular immune responses and some improvement in protection against FMD challenge [71,72]. However, in these studies, two or three inoculations were given prior to challenge. Ultimately, to be successful, any new vaccine must provide protection after a single inoculation, since in an outbreak there will presumably be no time or sufficient logistical support for multiple vaccinations. Previous experiments have shown that, in addition to inducing a rapid antiviral response, IFN-a can function as an adjuvant and enhance the long-term (at least 42 days) protective response of the Ad5-A24 vaccine in pigs after a single inoculation [73]. Although these cytokines are effective adjuvants for FMD vaccines in various animal models, the relatively short serum half-life of certain cytokines may contribute to a less than optimal adjuvant activity, and a number of approaches have been adopted to overcome these difficulties. These include incorporation of cytokines into liposomes, coadministration of cytokine expression vectors together with DNA vaccines and coexpression of cytokines and immunogens in the same vectors. In addition, Expert Rev. Vaccines 13(11), (2014)
Adjuvants for FMDV vaccines
systemic administration of high doses of certain cytokines including IL-2, IL-12, IFN-a and IFN-g is associated with significant toxicity, which would limit their use as vaccine adjuvants at such doses.
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Bacterial toxins
Bacterial toxins such as cholera toxin (CT) and heat-labile enterotoxin (LT) of Escherichia coli are powerful mucosal adjuvants. CT and LT consist of a homopentamer of B subunit that binds to GM1 receptors and an enzymatically active A subunit that is responsible for the toxicity. They strongly potentiate the immunogenicity of soluble antigens by inducing enhanced antigen presentation by dendritic cells, macrophages and B cells. However, their use is limited by their high toxicity. To overcome the toxicity problem, recombinantly produced derivatives with no or reduced toxicity have been developed such as the nontoxic B subunits of CT (CTB) and LT (LTB). Even though both CTB and LTB are poor adjuvants in animals when coadministered with non-coupled antigens by the oral route, both CTB and LTB have significant adjuvanticity via the nasal route [74]. CTB is used to enhance the immune response in a licensed whole-cell orally delivered cholera vaccine [75]. CTB is also a useful mucosal adjuvant to elicit protective immune responses against FMDV [76,77]. The LTK63 and LTR72 mutants of LT have been generated with reduced toxicity while maintaining the adjuvanticity of LT and have been successfully used to immunize a variety of animal species with various vaccine antigens [78–80]. The oral and respiratory mucosae are the main ports of entry of FMDV, so the stimulation of local immunity in these tissues may help prevent initial infection and viral spread. A recently performed study has shown that Ad5 vectors encoding the mucosal adjuvant LTR72 (Ad5-LTR72) could be used as an important tool to enhance mucosal and systemic immunity against FMDV. Mice receiving Ad5-A24 plus Ad5-LTR72 had higher levels of mucosal and systemic neutralizing antibodies than those receiving Ad5-A24 alone or Ad5-A24 plus Ad5-LTB. The vaccine plus Ad5-LTR72 group also demonstrated 100% survival after intradermal challenge with a lethal dose of homologous FMDV serotype A24 [81].
Review
adjuvants for T-cell immunization. In fact, any single immunostimulant or delivery system will be insufficient to induce strong and long-lasting humoral and cellular immunity that is required for new vaccines. Effective adjuvant systems are likely to require synergy between one or more immunostimulants and a carrier or a delivery system. For instance, addition of TLR ligands to oil-based adjuvants could contribute to a synergistic immunostimulatory effect. Thus, further effort will be made to identify optimal combinations of immune modulators. As vaccine development is a highly empirical process, and different types of response are required to protect against FMDV, there is little justification for concluding that one particular adjuvant will be significantly more useful than other available alternatives. In addition to efficacy, source, cost and safety should be taken into account in adjuvant selection. Five-year view
New knowledge of innate immunity has brought a wider interest in understanding how existing adjuvants work and how they might be improved. Understanding the mechanisms of action of adjuvants will provide critical information on how innate immunity influences the development of adaptive immunity and help in rational design of vaccine formulations against FMDV. In future FMD vaccine adjuvant research, further effort should be made to clarify action mechanisms of new or existing adjuvants and determine optimal combinations of multiple compounds to achieve the desired immunological enhancement. On the other hand, FMDV is a mucosal pathogen with its primary route of entry through the oro- or nasopharyngeal route, with virus replication taking place initially in epithelial or lymphoid cells. The establishment of local mucosal immunity in these primary sites of entry of FMDV could block the invading virus, thereby preventing or limiting replication, reducing viral load as well as dissemination to other tissues during the initial stage of infection. Adjuvants are presumably an essential element for the development of effective mucosal vaccines that could induce protective immunity at mucosal and systemic compartments. Thus, the development of effective, safe adjuvants and formulations inducing mucosal immunity to prevent the development of carrier animals of FMDV would be an important future goal.
Expert commentary
Today, most researchers working on FMD vaccines are not only focusing on the antigen but also on adjuvant technology. Development of safe and effective adjuvants may also have important implications for the improvement of efficacy and safety of new/ existing vaccines. Increasing importance is now being placed on the development of new or existing adjuvants to enhance not only humoral but also cell-mediated immune responses to FMDV antigens. Well-defined ligands for TLRs have attracted most of the attention, many of the ligands serving as nice
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Financial & competing interests disclosure
This research was supported by a grant from the National Natural Science Foundation of China (31372422). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
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Key issues • Foot-and-mouth disease is a devastating disease of livestock that has had a significant impact on world economies and public health. Vaccination was used to control the spread of infection in many countries. • Although the traditional inactivated vaccine is effective, there are some concerns with its use. These include potential virus escape from the production facility, the inability of inoculation with this vaccine to block the development of the carrier state and so on. • Many efforts are currently devoted to the development of effective foot-and-mouth disease virus (FMDV) vaccines by combining the application of protective antigens together with the search for specific and targeting adjuvants that maximizes the immunogenicity with a desired immune response. • Ligands of Toll-like receptors activate multiple innate immune pathways and stimulate the production of proinflammatory cytokines/ chemokines and type I interferons. This innate immune response also supports the subsequent development of adaptive immunity, and Expert Review of Vaccines Downloaded from informahealthcare.com by Korea University on 01/05/15 For personal use only.
thus can be used as adjuvants to accelerate and enhance the induction of FMDV-specific responses. • Combinations of multiple compounds have a synergistic effect when used as adjuvants. New adjuvant development should identify novel combinations of adjuvants and formulations capable of inducing stronger and longer-lasting humoral and cellular immune responses. • New vaccines combined with ligands of Toll-like receptors that provide immunity more rapidly and/or can be produced without the need for production of a great quantity of infectious virus required for manufacture of the traditional vaccine are being developed and may provide alternative tools to control foot-and-mouth disease. • Mucosal adjuvants are essential for the induction of effective mucosal immunity, which may be the effective way to prevent the development of carrier animals of FMDV.
differentiating infected from vaccinated animals. J Virol 2012;86:11675-85
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Alejo DM, Moraes MP, Liao XF, et al. An adenovirus vectored mucosal adjuvant augments protection of mice immunized intranasally with an adenovirus-vectored
foot-and-mouth disease virus subunit vaccine. Vaccine 2013;31:2302-9 •
important tool to enhance mucosal and systemic immunity against FMDV.
This work suggests that Ad5-LTR72 could be used as an
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