review

Human Vaccines & Immunotherapeutics 8:10, 1492-1498; October 2012; © 2012 Landes Bioscience

Adjuvants for allergy vaccines

Philippe Moingeon
Research and Development; Stallergenes; Antony, France

Keywords: adjuvant, allergen vaccine, immunopotentiator, sublingual immunotherapy, vector system

with the aim to reduce the number of injections needed for sub-
Allergen-specific immunotherapy is currently performed via cutaneous desensitization.
either the subcutaneous or sublingual routes as a treatment
In the past 20 years, other routes of allergen administration

©2012 Landes Bioscience. Do not distribute

for type I (IgE dependent) allergies. Aluminum hydroxide
or calcium phosphate are broadly used as adjuvants for
(e.g., intranasal, oral, sublingual, intralymphatic, epicutaneous)
subcutaneous allergy vaccines, whereas commercial have been and are being explored as an alternative to SCIT.8 Most
sublingual vaccines rely upon high doses of aqueous allergen particularly, among non invasive routes, sublingual immunother-
extracts in the absence of any immunopotentiator. Adjuvants apy (SLIT) is now considered as a safe and efficacious alternative
to be included in the future in products for allergen specific to SCIT for respiratory allergies associated with either grass, tree
immunotherapy should ideally enhance Th1 and CD4+ pollens or house dust mites.9–11 Commercial sublingual vaccines
regulatory T cell responses. Imunomodulators impacting are based on aqueous allergen extracts presented either as drops
dendritic or T cell functions to induce IL10, IL12 and IFNγ or more recently as fast disolving tablets or lyocs. During SLIT,
production are being investigated in preclinical allergy models. high doses (usually 50- to 100-fold the doses used for SCIT) of
Such candidate adjuvants encompass synthetic or biological the allergen extract are kept under the tongue for 1 to 2 min
immunopotentiators such as glucocorticoids, 1,25-dihydroxy
prior to being swallowed, as per the so called sublingual-swallow
vitamin D3, selected probiotic strains (e.g., Lactobacillus and
Bifidobacterium species) as well as TLR2 (Pam3CSK4), TLR4
procedure. As of today, none of the commercially available sub-
(monophosphoryl lipid A, synthetic lipid A analogs) or TLR9 lingual vaccines contain any adjuvant.9
(CpGs) ligands. Furthermore, the use of vector systems such as Irrespective of the route of immunization used, current allergy
mucoadhesive particules, virus-like particles or liposomes are vaccines rely upon either natural or modified allergen extracts.
being considered to enhance allergen uptake by tolerogenic The latter can for example be obtained following treatment with
antigen presenting cells present in mucosal tissues. glutaraldehyde to form polymers with altered structure, thus pre-
cluding IgE recognition, as is the case for allergoids.3 New aller-
gen presentation platforms are needed to improve the efficacy of
such existing subcutaneous and sublingual allergy vaccines.12, 13
Introduction In addition, in the last few years, second generation treatments
based on recombinant allergens (in a natural or hypoallergenic
Current trends in allergen specific immunotherapy. Following conformation), fusions proteins, mix of peptides, plasmid DNA
the pioneer studies by Noon, Freeman et al.1,2 more than a cen- have raised considerable interest, even if none of those molecular
tury ago, allergen-specific immunotherapy (AIT) has been pro- allergens have reached commercialization.14–16 However, in con-
gressively established as a reference treatment for type I allergies, trast to natural extracts which often possess an intrinsic adju-
most particularly allergic rhinoconjunctivitis with or without vant activity (e.g., Th2-inducing activity ascribed to the Der p 1
moderate asthma induced by common respiratory allergens.3 In mite allergen, endotoxin, phytoprostanes),17,18 purified allergens
contrast to symptomatic treatments, AIT can be curative, due provided under such a well defined molecular form are usually
to its capacity to reorient inappropriate allergen-specific humoral poorly immunogenic. Thus, such second generation vaccines will
and cellular immune responses from a Th2 to a mixed Th1/T also require novel immunopotentiators and vector systems (col-
reg pattern.4 Allergen-specific immunotherapy is commonly per- lectively referred to as adjuvants in the present review).
formed via the subcutaneous route as a treatment for allergies to Like for any vaccines, adjuvants to be associated with aller-
grass and tree pollens, house dust mites, insect venoms, molds, gens are expected to allow simplifying immunization regimens,
dog and cat dander or even synthetic drugs.3,5 Subcutaneous and reaching efficacy faster and for a longer duration. Although
immunotherapy (SCIT) is performed with soluble allergens in allergy vaccines are usually well tolerated, an additional expected
North America, whereas allergen extracts are rather adsorbed benefit of adjuvants in this field is to help lowering the allergen
on aluminum hydroxide or calcium phosphate as adjuvants in dose, thus improving the safety profile with less local reactions
Europe.3,5,6 As will be reviewed below, numerous other candidate to the site of administration. Importantly, allergy vaccines are
adjuvants are being evaluated in preclinical models or in humans, therapeutic vaccines, used in patients prone to mounting Th2
responses. Thus, appropriate adjuvants should rather orient the
Correspondence to: Philippe Moingeon; immune response toward Th1 or regulatory mechanisms both
Email: pmoingeon@stallergenes.com known to downregulate Th2 cells.12
Submitted: 06/08/12; Revised: 07/11/12; Accepted: 08/01/12
http://dx.doi.org/10.4161/hv.21688

1492 Human Vaccines & Immunotherapeutics Volume 8 Issue 10

 review Special focus REVIEW

Immune mechanisms associated with allergen-specific example, the Th1 adjuvant MPL injected together with a grass pol-
immunotherapy. Our current understanding of immune mecha- len extract enhanced allergen-specific IgG1 and IgG4 responses,
nisms involved in allergen-specific immunotherapy emphasizes a raising the possibility to reduce the number of preseasonal injec-
prominent role for CD4 + T lymphocytes in controlling all effec- tions to control allergic symptoms.34,35 Also, a synthetic CpG oli-
tor immune mechanisms linked with allergic inflammation.4,19,20 gonucleotide acting as a Th1 adjuvant was chemically conjugated
Specifically, most allergic patients exhibit allergen-specific Th2 with the purified Amb a 1 allergen from short ragweed. This
responses associated with the secretion of IL-4, IL-5 and IL-13 vaccine was shown to improve rhinoconjunctivitis symptoms in
cytokines by CD4 + T cells. During subcutaneous or sublingual patients with allergy to ragweed pollen.36 The parallel use of oral
immunotherapy, such allergen-specific CD4 + T cell responses are steroids (prednisone) with or without Vitamin D3 (both of which
rather redirected toward both a Th1 type with an increased pro- were reported as potential inducers of regulatory T cells) during
duction of IFNγ (immunodeviation) as well as IL10-producing SCIT did not improve efficacy in asthmatic children allergic to
CD4 + regulatory T cells (immunosuppression).4,19,20 Such house dust mites.37

©2012 Landes Bioscience. Do not distribute

changes in the polarization of T cell responses have been docu- Vector systems. Various vector systems have also been used
mented both in peripheral blood and in respiratory mucosae21,22 successfully to formulate allergens administered via parenteral
As a consequence of such a change in the cytokine milieu, routes in animal models (Table 2). The latter include liposomes,
both SCIT and SLIT are associated with a decrease in seric aller- virosomes, D, L-lactic-co-glycolic acid (PLGA) or immunostim-
gen-specific IgEs, concomitantly with an upregulation of IgG1, ulating complexes (ISCOMS).38,39 Also, plasmid DNA or DNA
IgG4, IgA antibodies,4,20,23 some of which are thought to mediate absorbed on microparticules were shown to enhance systemic
a “blocking” anti-inflammatory activity.24 Successful immuno- and mucosal immune responses.40 Fusion proteins associating the
therapy also leads to a substantial decrease in the recruitment and Fel d 1 cat allergen and the Fcγ immunoglobulin fragment were
activation of proinflammatory cells, including basophils, mast also designed to co-crosslink FcεRI and FcγRII receptors, thus
cells and eosinophils in the skin, as well as nasal or bronchial downregulating immunoreactivity to Fel d 1.41 Another fusion
mucosae.25 protein combining the birch pollen Bet v 1 allergen to the bacte-
Based upon the above afore mentioned immune mechanisms rial S layer protein SbpA was shown to form particules facilitating
thought to be critical for tolerance induction during immuno- allergen uptake by dendritic cells, with subsequent induction of
therapy, adjuvants expected to enhance the efficacy of allergy Th1 and regulatory T cells.42 Fusing the allergen with the TLR5
vaccines include: ligand flagellin was also shown to reduce Th2 responses.43
(1) Synthetic or biological immunopotentiators capable to As of today, only a limited number of vector systems have been
reinforce allergen-specific Th1 and/or regulatory T cell responses evaluated in humans via parental routes. For example, non-rep-
(Table 1). These molecules could act directly on CD4 + T cells, licating virus-like particles (VLPs) obtained following assembly
but also on dendritic or even epithelial cells. of capsid proteins from the Qβ phage were coupled to peptides
(2) Vector systems facilitating allergen uptake by tolero- derived from the Der p 1 mite allergen. Those recombinant Der
genic APCs such as the dendritic cells found in oral tissues26,27 p 1 VLPs induce strong IgG responses after a single injection in
(Table 2). healthy volonteers.44 Conjugation of Fel d 1 to such VLPs was
shown to prevent IgE reactivity while enhancing IgG induction.45
Adjuvants for Allergy Vaccines Administered via the QβG10 VLPs containing a synthetic oligonucleotide as a Th1
Subcutaneous (and Other Parenteral) Route(s) adjuvant were also tested in mite allergic patients, leading in a sig-
nificant reduction of rhinoconjunctivitis and asthma symptoms
Immunopotentiators. Mineral adjuvant molecules such as after six weekly injections.46 More recently, a recombinant fusion
calcium phosphate or aluminum hydroxide are broadly used protein associating a peptide derived from the Phl p 1 grass pollen
in humans as adjuvants for subcutaneous allergic vaccines7, 12 allergen with a rhinovirus-derived VP1 protein was also proposed
(Table 1). Aluminum salts are commonly included in vaccines as a candidate vaccine for grass pollen allergies.47 Another fusion
against infectious pathogens with the aim to elicit proinflamma- protein associating the Fel d 1 allergen to a modular antigen
tory responses following activation of the inflammasome. In addi- transporter (MAT) was designed to facilitate capture, processing
tion however, those compounds also decrease established Th2 and efficient presentation of the allergen by APCs in association
responses.7 Beyond such mineral adjuvants, various immunopo- with MHC class II molecules.48 When administered in humans,
tentiators were shown in murine models to downregulate Th2 this vaccine elicited strong IgG4 responses to the allergen.
responses when administered via parenteral routes (Table 1). For
example, TLR ligands (e.g., monophosphoryl lipid A or MPL, Adjuvants for Allergy Vaccines Administered
imidazoquinolines, CpGs), living or heat-killed bacteria (e.g., via the Sublingual (and Other Mucosal) Route(s)
Lactobacillus plantarum, Lactococcus lactis, Mycobacterium vac-
cae), small molecules such as the active 1.25-dihydroxy Vitamin Immunopotentiators. Various mucosal immunopotentia-
D3 metabolite all contribute in decreasing airway inflammation tors have been tested in preclinical tolerance models. The lat-
in murine models of asthma, when used as adjuvants.28–33 ter include bacterial toxins, such as cholera toxin (CT) or E.
Several of those immunopotentiators impacting Th1 or Treg coli heat-labile enterotoxin (LT), (as well as genetically detoxi-
responses have been investigated in humans during SCIT. For fied forms or B-subunits without any ADP-ribosyl transferase

www.landesbioscience.com Human Vaccines & Immunotherapeutics 1493

Table 1. Immunopotentiators for allergy vaccines
Immunopotentiators Status Route Allergen Comments
Aluminum hydroxide and calcium phosphate are
commonly used for subcutaneous allergy vac-
Various com- cines in Europe. Mechanisms involved include
Mineral adjuvants Clinical Subcutaneous mercial vac- both a depot effect (ie slow release of the aller-
cines gen, formulation of the allergen as particles to
target APCs) as well as interaction with the innate
immune system (e.g., activation of the inflamma-
some).
Mucosal (ie intranasal or sublingual) administra-
tion of commensal bacteria such as Lactococcus
lactis, Lactobacillus plantarum or Bifidobacterium

©2012 Landes Bioscience. Do not distribute

Clinical bifidum in various murine models together with
(stand the allergen(s) induces Th1 and/or regulatory T
Probiotics alone) or Mucosal OVA, Bet v 1 cells as well as asthma improvement. Tolerogenic
preclinical IL10 inducing probiotics interact with DCSign3
(adjuvant) and exhibit specific forms of teichoid acids in
their wall composition. Selected probiotics used
as a stand alone therapy protect children against
eczema, following the induction of Th1 respons-
es. or asthma after intradermal administration.
In mice, heat-killed Mycobacterium vaccae
induces Treg cells secreting IL-10 and TGFβ, and
decreases airway inflammation. Genetically
Clinical detoxified cholera toxin (CT) and lymphotoxin
Attenuated (stand (LT) (or B subunits without ADP ribosyl trans-
Systemic / ferase activity) induce strong seric and mucosal
Mycobacteria, bac- alone) or Mite, grass pollen
mucosal IgAs responses. The allergen can be mixed, fused,
terial products preclinical
(adjuvant) or chemically conjuged with the toxin moiety.
Sublingual administration of the allergen con-
jugated to CTB enhances tolerance induction in
murine models. M vaccae and BCG exhibit some
clinical efficacy in children with atopic dermatitis
or asthma after intradermal administration.

Ligands for TLR2 (including lipopeptides,

Pam3Csk4), TLR4 (MPL, RC 529, OM294-BA-MP),
TLR7 (imidazoquinolines), TLR9 (CpGs) have some
efficacy in murine asthma models (decrease of
both airway inflammation and Th2 responses,
with induction of Th1 and/or T Reg responses).
Intradermal immunization with Amb a 1 fused to
Clinical CpG oligonucleotides prevents allergen-induced
(for CpGs Subcutaneous, hyperresponsiveness in mice.
OVA, Amb a 1, grass
TLR ligands and MPL), intradermal / A conjugate Amb a 1-CpG vaccine has been tested
pollen
preclinical sublingual in ragweed allergic humans through the subcutane-
(others) ous route, with some level of clinical efficacy, and
induction of Th1 responses and CD25+ T Reg cells.
In humans, the TLR4 ligand monophosphoryl lipid
A (MPL) with or without tyrosine-absorbed grass
pollen allergens induces a strong production of
IgG1 and IgG4 antibodies through the subcutane-
ous route. Following SLIT in grass pollen allergic
patients, MPL enhanced specific IgG responses and
decreased reactivity to nasal allergen challenge.

Dihydroxyvitamin D3 plus glucocorticoids, calci-

neurin inhibitors (cyclosporin A, FK 506), rapamy-
cin, aspirin and mycophenolate mofetil enhance
Clinical (flutica- IL10 production by CD4+ T cells. Dexamethasone
Small synthetic Systemic, OVA, grass pollen
sone), preclini- plus dihydroxy vit D3 enhance SLIT efficacy in a
molecules sublingual murine asthma model. No synergy between fluti-
cal (others)
casone and SLIT was observed in humans when
using distinct administration routes.

1494 Human Vaccines & Immunotherapeutics Volume 8 Issue 10

Table 2. Vector systems for allergy vaccines
Vectors/delivery
Status Route Allergen Comments
systems
Outer membrane protein A from Klebsiella
pneumoniae targeting CD11+c mucosal DCs through
Toll-like receptor 2. Adenylate cyclase (CyaA)
from Bordetella pertussis interacting with CD11b+
OVA, Fel d 1, DCs. Anti-DEC-205 antibodies and the B subunit
Preclinical,
DC targeting Bet v 1 of shiga toxin (STxB) also target DCs, leading to
except Fel d 1 Systemic, mucosal
vectors strong specific Th1 and humoral responses. Fusion
MAT (clinical)
proteins assembling allergens with Ig FcRs or with
S-layer bacterial product also enhance capture by
human dendritic cells. A Fel d 1-MAT fusion protein
elicited IgG4 in humans and protection against nasal

©2012 Landes Bioscience. Do not distribute

allergen challenge.
Plasmid DNA encoding allergens has shown efficacy
Systemic and in various preclinical models, both via parenteral and
Plasmid DNA Preclinical Fel d 1, peanut
mucosal mucosal routes, alone or adsorbed on microparticles
in various murine allergy models.
Lipid-based vehicles, with or without viral envelope
proteins (virosomes). Such particulate antigen
Liposomes, formulations increase the induction of specific IgG
Intradermal, Grass pollen,
virosomes Clinical and IgA antibodies. In humans, such liposomes
subcutaneous mite
encapsulating mite or grass pollen allergens are well
tolerated via the cutaneous route, but induce delayed
local reactions subcutaneously.
Formed by the spontaneous assembly of capsid
proteins. Elicit strong systemic and mucosal
responses in mice and in humans. VLPs can be based
on capsid proteins from the porcine parvovirus,
Norwalk virus, human papilloma viruses. VLPs based
Virus-like Der p 1, Fel d 1
Clinical Subcutaneous on Qβ phage protein alone, or associated with Der
particules Phl p 1
p 1 peptides have induced protection against nasal
allergen challenge. A recombinant fusion protein
combining a peptide from the Phl p 1 grass pollen
allergen with the rhinovirus VP1 proteins is being
tested in humans.
Nano or microparticles made of maltdextrin or
Mite, OVA, chitosan polymers improve in murine models
Carbohydrate- Intranasal, Bet v 1
Preclinical the uptake of the allergen by oral DCs, thereby
particles sublingual
enhancing tolerance induction during intranasal or
sublingual immunotherapy.
Spherical particles (30–100 nm diameter) comprising
the saponin-adjuvant Quil A, cholesterol, and
phospholipids. ISCOMs induce a strong systemic and
Other particles mucosal Th1 adjuvant activity.
Subcutaneaous
(ISCOMs, PLGA) Preclinical OVA, PLA2 Poly (D, L) lactic-co-glycolic acid forming nano
or microparticles, facilitating APC capture.
Subcutaneous administration of PLGA formulated
allergens (or encoding DNA) induces strong IgG2, Th1
and TReg responses in mice.

activity)49,50 (Table 1). These toxins were either co-administered, if immunomodulatory properties vary considerably depending
conjugated or fused with allergens.49, 50 TLR2 (e.g., Pam3CSK4) upon bacterial strains and growth conditions.56, 57 Bacteria selected
or TLR4 ligands (e.g., MPL and OM-294-BA-MP) were shown to specifically for their capacity to induce a strong production of
strengthen Th1 and T Reg responses when used as adjuvants via the IL10 and IL12 by mucosal DCs, such as Lactobacillus plantarum
nasal or sublingual routes.51–54 Similarly, dexamethasone associated or Bifidobacterium bifidum, were shown to enhance tolerance fol-
with 1.25-dihydroxy vitamin D3 enhanced the efficacy of SLIT lowing SLIT in mice with induced asthma to OVA, at least in part
in a murine asthma model following induction of interleukin 10 by strengthening allergen-specific Th1 and T Reg responses.58, 59
production by immune cells, including dendritic cells and CD4 + Interestingly, in preclinical models of SLIT, none of the pure Th1
T lymphocytes.55 Another emerging class of potential adjuvants for adjuvants (ie without any capacity to elicit IL10 production) had
the sublingual (and other mucosal) routes include probiotics, even any significant impact on tolerance induction.12

www.landesbioscience.com Human Vaccines & Immunotherapeutics 1495

 Two categories of immunopotentiators have been tested with they raised the interest of the vaccine industry.70–72 Noteworthy,
the aim to increase SLIT efficacy in allergic human patients. maltodextrin-based mucoadhesive nanoparticles have been used
High doses of the Th1 adjuvant MPL boosted allergen-specific to formulate an experimental flu vaccine, with evidence for the
IgG responses and reduced reactivity to a subsequent nasal aller- induction of strong mucosal IgA responses when administered
gen challenge in grass pollen allergic patients (Table 1).60 BCG intranasally to healthy volonteers.12
administered intradermally to children asthmatic to mite aller-
gens in parallel with SLIT had no impact on clinical outcome,61 Conclusion
possibly because the adjuvant and allergens were administered via
distinct routes. In addition, various lactic acid bacterial strains New adjuvants and vector systems are needed to improve the
are being considered to prevent or treat allergy in humans.57 efficacy of allergy vaccines, reduce the dose of allergens required
For example, oral administration of lactic acid bacteria reduces and simplify immunization schemes during desensitization. Our
atopic dermatitis in children with a positive family history of type current understanding of immune mechanisms supporting the

©2012 Landes Bioscience. Do not distribute

I allergy.62 Whereas such an observation suggests that selected induction and maintenance of antigen-specific immune toler-
probiotics could be used as adjuvants for mucosal vaccines, as of ance suggests an interest of adjuvants eliciting combined Th1
today probiotics have not yet been tested in combination with and regulatory CD4 + T cell responses. A variety of candidate
allergens in allergic patients. adjuvants (ie TLR ligands, bacterial toxins, probiotics) are effica-
Vector systems. The dual interest of vector systems for muco- cious in reducing allergic inflammation in murine models, when
sal vaccination is (1) to enhance the duration of contact of the used in combination with the allergen via either parenteral or
allergen with the mucosa, for example by using positively charged mucosal routes. Besides the commonly used mineral adjuvants
mucoadhesive polymers binding to epithelial cells, and further such as Alum and calcium phosphate, only a limited number of
(2) to target efficiently phagocytic APCs by presenting the aller- Th1 immunopotentiators (e.g., MPL, CpGs, lactic acid bacteria)
gen in a particulate form or by interacting with a specific surface have been tested in humans, but their impact on clinical efficacy
receptor expressed by dendritic cells12, 63 (Table 2). In this regard, remains to be fully investigated. Among available vector systems,
both nanoparticles made from polymerized maltodextrin or chi- virus like-particles represent a highly promising platform to pres-
tosan-based microparticles were shown to enhance the uptake of ent allergens and/or adjuvants to the immune-system. In this
allergens by oral dendritic cells, following sublingual administra- regard encouraging clinical efficacy results have been obtained
tion to asthmatic mice, thus resulting into a superior priming of during SCIT of mite allergic patients. Mucoadhesive particu-
allergen-specific Tr1 cells in draining cervical lymph nodes, and late vectors have not yet been tested in humans, but appear very
consequently in a stronger decrease in airway inflammation23,64 promising based on preclinical experiments to support the devel-
(Table 2). Still in murine models, conjugates with the outer opment of safer and more efficient mucosal allergy vaccines.
membrane protein A from Klebsiella pneumoniae (OmpA) as well Additional studies evaluating the long-term efficacy of such vec-
as the shiga toxin B subunit have been successfully used to target torized allergens in large cohorts of allergic patients are needed to
efficiently antigens/allergens to APCs65–67 (Table 2). Similarly, understand the true potential of those technologies in the field of
the adenylate cyclase protein from Bordetella pertussis fused to allergen-specific immunotherapy.
OVA enhanced tolerance induction via the sublingual route in
mice with OVA-induced asthma, following capture by CD11b + Disclosure of Potential Conflicts of Interest
tolerogenic myeloid DCs and macrophages.68,69 No potential conflicts of interest were disclosed.
As of today, none of those vector systems have been tested
in humans in the context of mucosal allergy vaccines, although

References 5. Joint Task Force on Practice Parameters; American 8. Mascarell L, Van Overtvelt L, Moingeon P. Novel ways
1. Noon L. Prophylactic inoculation against hay fever. Academy of Allergy, Asthma and Immunology; for immune intervention in immunotherapy: mucosal
Lancet 1911; 177:1572-3; http://dx.doi.org/10.1016/ American College of Allergy, Asthma and allergy vaccines. Immunol Allergy Clin North Am
S0140-6736(00)78276-6. Immunology; Joint Council of Allergy, Asthma and 2006; 26:283-306, vii-viii; PMID:16701145; http://
Immunology. Allergen immunotherapy: a practice dx.doi.org/10.1016/j.iac.2006.02.009.
2. Freeman J. Further observations on the treatment of
parameter second update. J Allergy Clin Immunol 9. Canonica GW, Bousquet J, Casale T, Lockey RF,
hay fever by hypodermic inoculations of pollen vaccine.
2007; 120(Suppl):S25-85.http://dx.doi.org/10.1016/j. Baena-Cagnani CE, Pawankar R, et al. Sub-lingual
Lancet 1911; 178:814-7; http://dx.doi.org/10.1016/
jaci.2007.06.019; PMID:17765078 immunotherapy: World Allergy Organization Position
S0140-6736(01)40417-X.
6. Bousquet J, Van Cauwenberge P, Khaltaev N; Aria Paper 2009. Allergy 2009; 64(Suppl 91):1-59;
3. Bousquet J, Lockey R, Malling HJ. Allergen
Workshop Group; World Health Organization. Allergic PMID:20041860; http://dx.doi.org/10.1111/j.1398-
immunotherapy: therapeutic vaccines for allergic
rhinitis and its impact on asthma. J Allergy Clin Immunol 9995.2009.02309.x.
diseases. A WHO position paper. J Allergy Clin
2001; 108(Suppl):S147-334; PMID:11707753; http:// 10. Wilson DR, Torres LI, Durham SR. Sublingual
Immunol 1998; 102:558-62; PMID:9802362; http://
dx.doi.org/10.1067/mai.2001.118891; http://dx.doi. immunotherapy for allergic rhinitis. Cochrane Database
dx.doi.org/10.1016/S0091-6749(98)70271-4.
org/10.1067/mai.2001.118891. Syst Rev 2003; CD002893; PMID:12804442.
4. Akdis CA, Akdis M. Mechanisms of allergen-specific
7. Wilcock LK, Francis JN, Durham SR. Aluminium 11. Passalacqua G, Lombardi C, Troise C, Canonica GW.
immunotherapy. J Allergy Clin Immunol 2011;
hydroxide down-regulates T helper 2 responses by Sublingual immunotherapy: certainties, unmet needs
127:18-27, quiz 28-9; PMID:21211639; http://dx.doi.
allergen-stimulated human peripheral blood mono- and future directions. Eur Ann Allergy Clin Immunol
org/10.1016/j.jaci.2010.11.030.
nuclear cells. Clin Exp Allergy 2004; 34:1373-8; 2009; 41:163-70; PMID:20128229.
PMID:15347369; http://dx.doi.org/10.1111/j.1365- 12. Moingeon P, Lombardi V, Saint-Lu N, Tourdot S,
2222.2004.02052.x. Bodo V, Mascarell L. Adjuvants and vector systems
for allergy vaccines. Immunol Allergy Clin North Am
2011; 31:407-19, xii; PMID:21530828; http://dx.doi.
org/10.1016/j.iac.2011.03.001.

1496 Human Vaccines & Immunotherapeutics Volume 8 Issue 10

13. Wheeler AW, Woroniecki SR. Immunological adjuvants 29. Akdis CA, Kussebi F, Pulendran B, Akdis M, Lauener 42. Gerstmayr M, Ilk N, Jahn-Schmid B, Sleytr UB, Bohle
in allergy vaccines: Past, present and future. Allergol Int RP, Schmidt-Weber CB, et al. Inhibition of T helper B. Natural self-assembly of allergen-S-layer fusion
2001; 50:295-301; http://dx.doi.org/10.1046/j.1440- 2-type responses, IgE production and eosinophilia by proteins is no prerequisite for reduced allergenicity and
1592.2001.00230.x. synthetic lipopeptides. Eur J Immunol 2003; 33:2717- T cell stimulatory capacity. Int Arch Allergy Immunol
14. Valenta R, Niederberger V. Recombinant aller- 26; PMID:14515255; http://dx.doi.org/10.1002/ 2009; 149:231-8; PMID:19218815; http://dx.doi.
gens for immunotherapy. J Allergy Clin Immunol eji.200323329. org/10.1159/000199718.
2007; 119:826-30; PMID:17335886; http://dx.doi. 30. Trujillo-Vargas CM, Mayer KD, Bickert T, Palmetshofer 43. Schülke S, Burggraf M, Waibler Z, Wangorsch A,
org/10.1016/j.jaci.2007.01.025. A, Grunewald S, Ramirez-Pineda JR, et al. Vaccinations Wolfheimer S, Kalinke U, et al. A fusion protein of
15. Crameri R, Rhyner C. Novel vaccines and adjuvants for with T-helper type 1 directing adjuvants have different flagellin and ovalbumin suppresses the TH2 response
allergen-specific immunotherapy. Curr Opin Immunol suppressive effects on the development of allergen- and prevents murine intestinal allergy. J Allergy Clin
2006; 18:761-8; PMID:17010585; http://dx.doi. induced T-helper type 2 responses. Clin Exp Allergy Immunol 2011; 128:1340-8, e12; PMID:21872305;
org/10.1016/j.coi.2006.09.001. 2005; 35:1003-13; PMID:16120081; http://dx.doi. http://dx.doi.org/10.1016/j.jaci.2011.07.036.
16. Vajdy M, Srivastava I, Polo J, Donnelly J, O’Hagan D, org/10.1111/j.1365-2222.2005.02287.x. 44. Kündig TM, Senti G, Schnetzler G, Wolf C, Prinz
Singh M. Mucosal adjuvants and delivery systems for 31. Santeliz JV, Van Nest G, Traquina P, Larsen E, Wills- Vavricka BM, Fulurija A, et al. Der p 1 peptide on
protein-, DNA- and RNA-based vaccines. Immunol Karp M. Amb a 1-linked CpG oligodeoxynucleotides virus-like particles is safe and highly immunogenic
Cell Biol 2004; 82:617-27; PMID:15550120; http:// reverse established airway hyperresponsiveness in a in healthy adults. J Allergy Clin Immunol 2006;
murine model of asthma. J Allergy Clin Immunol 117:1470-6; PMID:16751015; http://dx.doi.

©2012 Landes Bioscience. Do not distribute

dx.doi.org/10.1111/j.1440-1711.2004.01288.x.
17. Chapman MD, Wünschmann S, Pomés A. Proteases 2002; 109:455-62; PMID:11897991; http://dx.doi. org/10.1016/j.jaci.2006.01.040.
as Th2 adjuvants. Curr Allergy Asthma Rep 2007; org/10.1067/mai.2002.122156. 45. Schmitz N, Dietmeier K, Bauer M, Maudrich M,
7:363-7; PMID:17697645; http://dx.doi.org/10.1007/ 32. Johansen P, Senti G, Martinez Gomez JM, Storni T, von Utzinger S, Muntwiler S, et al. Displaying Fel d1
s11882-007-0055-6. Beust BR, Wüthrich B, et al. Toll-like receptor ligands on virus-like particles prevents reactogenicity
18. Trivedi B, Valerio C, Slater JE. Endotoxin content of as adjuvants in allergen-specific immunotherapy. Clin despite greatly enhanced immunogenicity: a novel
standardized allergen vaccines. J Allergy Clin Immunol Exp Allergy 2005; 35:1591-8; PMID:16393325; therapy for cat allergy. J Exp Med 2009; 206:1941-
2003; 111:777-83; PMID:12704357; http://dx.doi. http://dx.doi.org/10.1111/j.1365-2222.2005.02384.x. 55; PMID:19667059; http://dx.doi.org/10.1084/
org/10.1067/mai.2003.1338. 33. Taher YA, van Esch BC, Hofman GA, Henricks PA, jem.20090199.
19. Till SJ, Francis JN, Nouri-Aria K, Durham SR. van Oosterhout AJ. 1alpha,25-dihydroxyvitamin D3 46. Senti G, Johansen P, Haug S, Bull C, Gottschaller C,
Mechanisms of immunotherapy. J Allergy Clin Immunol potentiates the beneficial effects of allergen immuno- Müller P, et al. Use of A-type CpG oligodeoxynucleotides
2004; 113:1025-34, quiz 1035; PMID:15208578; therapy in a mouse model of allergic asthma: role for as an adjuvant in allergen-specific immunotherapy in
http://dx.doi.org/10.1016/j.jaci.2004.03.024. IL-10 and TGF-β. J Immunol 2008; 180:5211-21; humans: a phase I/IIa clinical trial. Clin Exp Allergy
20. Moingeon P, Batard T, Fadel R, Frati F, Sieber J, Van PMID:18390702. 2009; 39:562-70; PMID:19226280; http://dx.doi.
Overtvelt L. Immune mechanisms of allergen-specific 34. Drachenberg KJ, Wheeler AW, Stuebner P, Horak org/10.1111/j.1365-2222.2008.03191.x.
sublingual immunotherapy. Allergy 2006; 61:151-65; F. A well-tolerated grass pollen-specific allergy vac- 47. Edlmayr J, Niespodziana K, Linhart B, Focke-Tejkl M,
PMID:16409190; http://dx.doi.org/10.1111/j.1398- cine containing a novel adjuvant, monophosphoryl Westritschnig K, Scheiblhofer S, et al. A combination
9995.2006.01002.x. lipid A, reduces allergic symptoms after only four vaccine for allergy and rhinovirus infections based
21. Francis JN, Till SJ, Durham SR. Induction of preseasonal injections. Allergy 2001; 56:498-505; on rhinovirus-derived surface protein VP1 and a
IL-10+CD4+CD25+ T cells by grass pollen PMID:11421893; http://dx.doi.org/10.1034/j.1398- nonallergenic peptide of the major timothy grass
immunotherapy. J Allergy Clin Immunol 2003; 9995.2001.056006498.x. pollen allergen Phl p 1. J Immunol 2009; 182:6298-
111:1255-61; PMID:12789226; http://dx.doi. 35. Mothes N, Heinzkill M, Drachenberg KJ, Sperr WR, 306; PMID:19414783; http://dx.doi.org/10.4049/
org/10.1067/mai.2003.1570. Krauth MT, Majlesi Y, et al. Allergen-specific immu- jimmunol.0713622.
22. Durham SR, Ying S, Varney VA, Jacobson MR, notherapy with a monophosphoryl lipid A-adjuvanted 48. Crameri R, Kündig TM, Akdis CA. Modular antigen-
Sudderick RM, Mackay IS, et al. Grass pollen vaccine: reduced seasonally boosted immunoglobulin E translocation as a novel vaccine strategy for allergen-
immunotherapy inhibits allergen-induced infiltration production and inhibition of basophil histamine release specific immunotherapy. Curr Opin Allergy Clin
of CD4+ T lymphocytes and eosinophils in the nasal by therapy-induced blocking antibodies. Clin Exp Immunol 2009; 9:568-73; PMID:19680120; http://
mucosa and increases the number of cells expressing Allergy 2003; 33:1198-208; PMID:12956739; http:// dx.doi.org/10.1097/ACI.0b013e3283310fdf.
messenger RNA for interferon-gamma. J Allergy Clin dx.doi.org/10.1046/j.1365-2222.2003.01699.x. 49. Freytag LC, Clements JD. Mucosal adjuvants. Vaccine
Immunol 1996; 97:1356-65; PMID:8648033; http:// 36. Creticos PS, Schroeder JT, Hamilton RG, Balcer- 2005; 23:1804-13; PMID:15734046; http://dx.doi.
dx.doi.org/10.1016/S0091-6749(96)70205-1. Whaley SL, Khattignavong AP, Lindblad R, et al.; org/10.1016/j.vaccine.2004.11.010.
23. Razafindratsita A, Saint-Lu N, Mascarell L, Berjont N, Immune Tolerance Network Group. Immunotherapy 50. Pizza M, Giuliani MM, Fontana MR, Monaci E,
Bardon T, Betbeder D, et al. Improvement of sublingual with a ragweed-toll-like receptor 9 agonist vaccine Douce G, Dougan G, et al. Mucosal vaccines: non toxic
immunotherapy efficacy with a mucoadhesive allergen for allergic rhinitis. N Engl J Med 2006; 355:1445- derivatives of LT and CT as mucosal adjuvants. Vaccine
formulation. J Allergy Clin Immunol 2007; 120:278- 55; PMID:17021320; http://dx.doi.org/10.1056/ 2001; 19:2534-41; PMID:11257389; http://dx.doi.
85; PMID:17531296; http://dx.doi.org/10.1016/j. NEJMoa052916. org/10.1016/S0264-410X(00)00553-3.
jaci.2007.04.009. 37. Majak P, Rychlik B, Stelmach I. The effect of oral 51. Goldman M. Translational mini-review series on
24. Wachholz PA, Durham SR. Induction of ‘blocking’ steroids with and without vitamin D3 on early efficacy Toll-like receptors: Toll-like receptor ligands as novel
IgG antibodies during immunotherapy. Clin Exp of immunotherapy in asthmatic children. Clin Exp pharmaceuticals for allergic disorders. Clin Exp
Allergy 2003; 33:1171-4; PMID:12956735; http:// Allergy 2009; 39:1830-41; PMID:19817753; http:// Immunol 2007; 147:208-16; PMID:17223960; http://
dx.doi.org/10.1046/j.1365-2222.2003.01765.x. dx.doi.org/10.1111/j.1365-2222.2009.03357.x. dx.doi.org/10.1111/j.1365-2249.2006.03296.x.
25. Durham SR, Varney VA, Gaga M, Jacobson MR, 38. Schöll I, Weissenböck A, Förster-Waldl E, Untersmayr 52. Patel M, Xu D, Kewin P, Choo-Kang B, McSharry
Varga EM, Frew AJ, et al. Grass pollen immunotherapy E, Walter F, Willheim M, et al. Allergen-loaded biode- C, Thomson NC, et al. TLR2 agonist ameliorates
decreases the number of mast cells in the skin. Clin Exp gradable poly(D,L-lactic-co-glycolic) acid nanoparticles established allergic airway inflammation by promoting
Allergy 1999; 29:1490-6; PMID:10520076; http:// down-regulate an ongoing Th2 response in the BALB/c Th1 response and not via regulatory T cells. J Immunol
dx.doi.org/10.1046/j.1365-2222.1999.00678.x. mouse model. Clin Exp Allergy 2004; 34:315-21; 2005; 174:7558-63; PMID:15944255.
PMID:14987314; http://dx.doi.org/10.1111/j.1365- 53. Lombardi V, Van Overtvelt L, Horiot S, Moussu H,
26. Allam JP, Peng WM, Appel T, Wenghoefer M,
2222.2004.01884.x. Chabre H, Louise A, et al. Toll-like receptor 2 agonist
Niederhagen B, Bieber T, et al. Toll-like receptor 4
ligation enforces tolerogenic properties of oral mucosal 39. Sanders MT, Brown LE, Deliyannis G, Pearse MJ. Pam3CSK4 enhances the induction of antigen-specific
Langerhans cells. J Allergy Clin Immunol 2008; ISCOM-based vaccines: the second decade. Immunol tolerance via the sublingual route. Clin Exp Allergy
121:368-74, e1; PMID:18036651; http://dx.doi. Cell Biol 2005; 83:119-28; PMID:15748208; http:// 2008; 38:1819-29; PMID:18644025.
org/10.1016/j.jaci.2007.09.045. dx.doi.org/10.1111/j.1440-1711.2005.01319.x. 54. Mascarell L, Van Overtvelt L, Lombardi L.
27. Mascarell L, Lombardi V, Louise A, Saint-Lu N, 40. Kim N, Kwon SS, Lee J, Kim S, Yoo TJ. Protective Razafindratsita, Moussu H, Horiot S, Chabre H,
Chabre H, Moussu H, et al. Oral dendritic cells effect of the DNA vaccine encoding the major house Paccaud J-P, Limal D, Moutel S, Bauer J, Chiavaroli C,
mediate antigen-specific tolerance by stimulating TH1 dust mite allergens on allergic inflammation in the Moingeon P. A synthetic triacylated pseudodipeptide
and regulatory CD4+ T cells. J Allergy Clin Immunol murine model of house dust mite allergy. Clin Mol molecule promotes Th1/T Reg immune responses and
2008; 122:603-9, e5; PMID:18774396; http://dx.doi. Allergy 2006; 4:1-9; PMID:16478539; http://dx.doi. enhances tolerance induction via the sublingual route.
org/10.1016/j.jaci.2008.06.034. org/10.1186/1476-7961-4-4. Vaccine 2007; 26:108-18; PMID:18063445; http://
28. Zuany-Amorim C, Manlius C, Trifilieff A, Brunet LR, 41. Terada T. New therapeutic strategies: a chimeric dx.doi.org/10.1016/j.vaccine.2007.10.050.
Rook G, Bowen G, et al. Long-term protective and anti- human-cat fusion protein inhibits allergic reactiv-
gen-specific effect of heat-killed Mycobacterium vaccae ity. Clin Exp Allergy 2006; 6:96-100; http://dx.doi.
in a murine model of allergic pulmonary inflammation. org/10.1111/j.1365-2222.2006.00108.x.
J Immunol 2002; 169:1492-9; PMID:12133976.

www.landesbioscience.com Human Vaccines & Immunotherapeutics 1497

55. Van Overtvelt L, Lombardi V, Razafindratsita 62. Kalliomäki M, Salminen S, Poussa T, Arvilommi H, 68. El Azami El Idrissi M, Ladant D, Leclerc C. The
A, Saint-Lu N, Horiot S, Moussu H, et al. Isolauri E. Probiotics and prevention of atopic disease: adenylate cyclase of Bordetella pertussis: a vector to tar-
IL-10-inducing adjuvants enhance sublin- 4-year follow-up of a randomised placebo-controlled get antigen presenting cells. Toxicon 2002; 40:1661-5;
gual immunotherapy efficacy in a murine asth- trial. Lancet 2003; 361:1869-71; PMID:12788576; PMID:12457876; http://dx.doi.org/10.1016/S0041-
ma model. Int Arch Allergy Immunol 2008; http://dx.doi.org/10.1016/S0140-6736(03)13490-3. 0101(02)00205-2.
145:152-62; PMID:17848808; http://dx.doi. 63. De Souza Rebouças J, Esparza I, Ferrer M, Sanz ML, 69. Mascarell L, Saint-Lu N, Moussu H, Zimmer A,
org/10.1159/000108140. Irache JM, Gamazo C. Nanoparticulate adjuvants and Louise A, Lone Y, et al. Oral macrophage-like cells
56. de Roock S, van Elk M, van Dijk MEA, Timmerman delivery systems for allergen immunotherapy. J Biomed play a key role in tolerance induction following sub-
HM, Rijkers GT, Prakken BJ, et al. Lactic acid bac- Biotechnol 2012; 2012:474605; PMID:22496608; lingual immunotherapy of asthmatic mice. Mucosal
teria differ in their ability to induce functional regu- http://dx.doi.org/10.1155/2012/474605. Immunol 2011; 4:638-47; PMID:21775981; http://
latory T cells in humans. Clin Exp Allergy 2010; 64. Saint-Lu N, Tourdot S, Razafindratsita A, Mascarell dx.doi.org/10.1038/mi.2011.28.
40:103-10; PMID:19817754. L, Berjont N, Chabre H, et al. Targeting the aller- 70. Hobson P, Barnfield C, Barnes A, Klavinskis LS.
57. Vliagoftis H, Kouranos VD, Betsi GI, Falagas ME. gen to oral dendritic cells with mucoadhesive chito- Mucosal immunization with DNA vaccines. Methods
Probiotics for the treatment of allergic rhinitis san particles enhances tolerance induction. Allergy 2003; 31:217-24; PMID:14511954; http://dx.doi.
and asthma: systematic review of randomized 2009; 64:1003-13; PMID:19220212; http://dx.doi. org/10.1016/S1046-2023(03)00139-7.
controlled trials. Ann Allergy Asthma Immunol org/10.1111/j.1398-9995.2009.01945.x. 71. Broos S, Lundberg K, Akagi T, Kadowaki K, Akashi
2008; 101:570-9; PMID:19119700; http://dx.doi. M, Greiff L, et al. Immunomodulatory nanoparticles

©2012 Landes Bioscience. Do not distribute

65. Jeannin P, Renno T, Goetsch L, Miconnet I, Aubry
org/10.1016/S1081-1206(10)60219-0. JP, Delneste Y, et al. OmpA targets dendritic cells, as adjuvants and allergen-delivery system to human
58. Van Overtvelt L, Moussu H, Horiot S, Samson S, induces their maturation and delivers antigen into dendritic cells: Implications for specific immunotherapy.
Lombardi V, Mascarell L, et al. Lactic acid bacteria the MHC class I presentation pathway. Nat Immunol Vaccine 2010; 28:5075-85; PMID:20478343; http://
as adjuvants for sublingual allergy vaccines. Vaccine 2000; 1:502-9; PMID:11101872; http://dx.doi. dx.doi.org/10.1016/j.vaccine.2010.05.004.
2010; 28:2986-92; PMID:20175969; http://dx.doi. org/10.1038/82751. 72. Hu KF, Lövgren-Bengtsson K, Morein B.
org/10.1016/j.vaccine.2010.02.009. 66. Goetsch L, Gonzalez A, Plotnicky-Gilquin H, Immunostimulating complexes (ISCOMs) for nasal
59. Moussu H, Van Overtvelt L, Horiot S, Tourdot Haeuw JF, Aubry JP, Beck A, et al. Targeting of vaccination. Adv Drug Deliv Rev 2001; 51:149-59;
S, Airouche S, Zuercher A, et al. Bifidobacterium nasal mucosa-associated antigen-presenting cells in PMID:11516786; http://dx.doi.org/10.1016/S0169-
bifidum NCC 453 promotes tolerance vivo with an outer membrane protein A derived from 409X(01)00165-X.
induction in murine models of sublingual Klebsiella pneumoniae. Infect Immun 2001; 69:6434-
immunotherapy. Int Arch Allergy Immunol 2012; 44; PMID:11553588; http://dx.doi.org/10.1128/
158:35-42; PMID:22205338; http://dx.doi. IAI.69.10.6434-6444.2001.
org/10.1159/000330101. 67. Haicheur N, Benchetrit F, Amessou M, Leclerc C,
60. Pfaar O, Barth C, Jaschke C, Hörmann K, Klimek Falguières T, Fayolle C, et al. The B subunit of Shiga
L. Sublingual allergen-specific immunotherapy toxin coupled to full-size antigenic protein elicits
adjuvanted with monophosphoryl lipid A: a phase humoral and cell-mediated immune responses associ-
I/IIa study. Int Arch Allergy Immunol 2011; ated with a Th1-dominant polarization. Int Immunol
154:336-44; PMID:20975285; http://dx.doi. 2003; 15:1161-71; PMID:13679386; http://dx.doi.
org/10.1159/000321826. org/10.1093/intimm/dxg118.
61. Arikan C, Bahceciler NN, Deniz G, Akdis M,
Akkoc T, Akdis CA, et al. Bacillus Calmette-
Guérin-induced interleukin-12 did not additionally
improve clinical and immunologic parameters in
asthmatic children treated with sublingual immu-
notherapy. Clin Exp Allergy 2004; 34:398-405;
PMID:15005733; http://dx.doi.org/10.1111/
j.1365-2222.2004.01869.x.

1498 Human Vaccines & Immunotherapeutics Volume 8 Issue 10