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IC31® and IC30, novel types of
vaccine adjuvant based on peptide
delivery systems
Karen Lingnau†, Karin Riedl and Alexander von Gabain
CONTENTS
Development of novel types
of adjuvants
Peptides IC30 & KLK as base
component for novel
vaccine adjuvants
Contribution of KLK & ODN1a
to the unique adjuvant
effects of IC31
IC31 adjuvant activities
Safety & activity of IC30 &
IC31 in humans
Expert commentary &
five-year view
Financial & competing
interests disclosure
Key issues
References
Affiliations
†
Author for correspondence
Intercell AG, Campus Vienna
Biocenter 6, 1030 Vienna, Austria
Tel.: +43 120 620 320
Fax: +43 120 620 805
[email protected]
KEYWORDS:
adjuvant, antibody, protection,
T cell, Toll-like receptor, vaccine
www.future-drugs.com
Toll-like receptor (TLR) agonists have a proven potential to become the adjuvants of the
next generation when admixed and formulated with all kinds of vaccine compositions. The
quality and magnitude of a vaccine-induced immune response is often strongly facilitated
by TLR agonists, with the result that protection is increased and expanded toward type 1driven immunity. DNA oligodeoxynucleotides bind to TLR9 and have been tested in a
variety of vaccine settings with encouraging results. Combining oligodeoxynucleotides
with poly-L-arginine (IC30) or certain artificial antimicrobial peptides dramatically
improves and synergizes with the adjuvant action of TLR9 agonists, a notion that has
prompted the development of IC31®, an adjuvant with a promising profile in both
preclinical and clinical trials.
Expert Rev. Vaccines 6(5), 741–746 (2007)
Development of novel types of adjuvants
The introduction of adjuvants into the vaccine
arena was an important step toward improving
the quality, efficacy and sustainability of the
immune response generated by vaccines. Until
approximately a decade ago, however, the only
adjuvant widely used in registered vaccines was
aluminum salts (alum). Although other types
of adjuvants with superior potency compared
with alum have been tested in the preclinical
setting, most of them are unacceptable for
medical use owing to toxic side effects (e.g.,
complete and incomplete Freund’s adjuvants).
The only other adjuvants that have entered the
medical arena in registered vaccines following
alum, are MF59 and virosomes [101,102]. A variety of novel adjuvants are currently being
tested in preclinical models and in the clinic,
although, the molecular mechanisms underpinning the action of the majority of these
adjuvants remain obscure.
The discovery of some of the key mechanisms of innate immunity has paved the way
for identification of novel and specific targets
for the induction of adaptive immunity. The
discovery of the Toll-like receptors (TLR) and
their natural ligands has opened a wide field to
search for novel substances that, as adjuvants,
10.1586/14760584.6.5.741
are able to improve the induction of adaptive
immune responses toward specific antigens.
Compared with many other novel vaccine
adjuvants, TLR agonists have the advantage
that their mode of action and the pathways
that they engage in the activation of the pivotal
dendritic cells (DCs) is becoming increasingly
understood [1]. In this regard, a number of
novel substances have entered the clinical
arena as vaccine adjuvants or are even used as
immune modulators in monotherapy:
• Monophosphoryl lipid A (MPL), a type of
detoxified version of a TLR4 agonist,
lipopolysaccharide (LPS);
• Imiquimod, a small molecule (1-isobutyl1H-imidazo[4,5-c]quinolin-4-amine),
acting as a TLR7 agonist;
• Unmethylated DNA oligonucleotides with
CpG motifs (CpG-oligodeoxynucleotides
[ODNs]) as TLR9 agonist;
• IC31® (Intercell AG, Vienna, Austria), comprising two synergizing components, a specific ODN as TLR9 agonist and an
antibacterial peptide.
IC31 is an adjuvant that belongs to the TLR9
agonists based on the immunostimulatory
ODN1a, a natural phosphodiester-backboned
© 2007 Future Drugs Ltd
ISSN 1476-0584
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Lingnau, Riedl & von Gabain
DNA, consisting of repeats of the dinucleotides deoxyinosine
and deoxycytosine. Its mode of action can be compared with the
well-known TLR9 activator, CpG-ODN [2]. On the other hand,
it contains a second component, the antibacterial peptide
KLKL5KLK (KLK), that has been derived from a previous adjuvant, poly-L-arginine, named IC30. IC30 alone has shown a
promising profile as adjuvant in clinical studies with a therapeutic HCV peptide vaccine. IC31 that combines the peptide KLK
with a specific ODN has disclosed a number of features that are,
in many regards, desirable for a next-generation adjuvant and
will be discussed, along with IC30, in this review.
Peptides IC30 & KLK as base component for novel
vaccine adjuvants
The potent function of polycationic peptides as cellular delivery systems has been recognized for several years. For example,
a complex with a transfering polycation was able to transport
bacterial DNA into cells [3]. Polycationic compounds have also
been used previously to transport proteins, such as heparin,
albumin or horseradish peroxidase, into cells [4,5]. These observations have prompted scientists at Intercell AG to identify, in
the context of vaccination, peptides capable of transporting
antigens into cells. Early studies indicated a potent role of polyL-arginine (IC30) in enhancing the uptake of peptide antigens
into antigen-presenting cells (APCs) [6]. In addition, IC30 also
exerts its adjuvant effects via the formation of a depot at the
injection site, leading to a sustained priming of specific T cells
and, in turn, prolonged immune responses [7].
Preclinical evaluations indicated the potency of IC30 to
induce specific (CD4+ and CD8+) T-cell responses against peptides derived from bacteria, viruses or tumors, characterized by
a typical type 1 phenotype (IFN-γ production and cytotoxic
T-lymphocyte [CTL] activity). On the basis of these properties,
IC30 was developed as an adjuvant for a therapeutic HCV vaccine, a fully synthetic vaccine based on peptides representing
conserved T-cell epitopes of HCV.
The discovery of natural cationic antimicrobial peptides
(CAMPs) has subsequently led to the development of artificial
CAMPs to treat infections. Recently, it was shown in preclinical
studies that the artificial CAMP KLK has the potential to induce
adaptive immune responses toward coinjected antigens [8]. Further analyses revealed that KLK constitutes a potent adjuvant,
inducing type 2 cellular and humoral immune responses.
Although the type of immune response induced is different to
that of IC30 (type 1), the modes of action of both compounds
seem to be similar. In addition, the adjuvant properties of KLK
are based on the induction of a depot formation at the injection
site and on the enhanced uptake of antigens into APCs. More
detailed analyses of the interaction of KLK with cell membranes
have revealed a KLK-induced change in membrane fluidity and
microviscosity [HENICS T, UNPUBLISHED DATA].
Recent data have indicated that TLR agonists have significant potential as vaccine adjuvants. TLR agonists represent
pathogen associated molecular patterns (PAMP), such as LPS,
lipoproteins, dsRNA, flagellin, or synthetic CpG-ODNs [9].
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CpG-ODNs activate the intracellularly localized TLR9, inducing type 1 immune responses [2]. Based on early findings that
cationic compounds can be used as transporter for bacterial
DNA into cells [3], the combination of IC30 with CpG-ODN
was tested for its potential as an adjuvant [10]. Compared with
the individual adjuvant components alone, the combination of
IC30 and CpG-ODN induced a stronger and remarkably prolonged antigen-specific type 1 immune response and also enabled a reduction in the CpG-ODN dose without any adjuvant
activity being lost. Thus, the combination of two adjuvants acting via different mechanisms represents a novel concept with
the potential of improving vaccines. This concept was followed
up by the development of the adjuvant IC31 by combining the
peptide KLK and a novel ODN.
Contribution of KLK & ODN1a to the unique adjuvant effects
of IC31
KLK: depot formation at the injection site
Antigen maintenance at the site of injection is thought to be a
prerequisite for eliciting an enhanced immune reaction and is
established effectively by oil-based adjuvants (e.g., complete and
incomplete Freund’s adjuvants) [11]. Using fluorescently labeled
vaccine compounds (antigen, ODN1a and KLK), it was demonstrated in mice that an important property of KLK is the
induction of a depot at the injection site, which was detectable
until day 58 (the latest time point analysed) following one single
subcutaneous immunization and retained not only the adjuvant
compounds, but also the antigen (FIGURE 1) [12]. Administration
of ODN1a without KLK leads to rapid clearance of ODN1a in
addition to the loss of its adjuvant effect.
The combination of the two components in IC31 forms a
stable complex via ionic and hydrophobic interactions, in
which not only the nuclease-sensitive ODN1a, but also the
antigen, are protected against degradation In that regard, the
described depot formation capacity of KLK is of great advantage since it favors continuous, long-term adjuvant and antigen
release in order to permanently stimulate the induction of specific immune responses. Possible granuloma formation due to
depot formation has not yet been observed in preclinical, as
well as toxicological studies.
ODN1a: involved signaling pathways
The molecular mechanisms through which IC31 is recognized by
immune cells leading to their subsequent stimulation are of significant interest. As mentioned earlier, cells of both the innate and
adaptive immune system express distinct TLRs, which are sensors
of PAMPs able to initiate host defense responses. In studies performed in TLR9- and myeloid differentiation factor 88 (MyD88)knockout mice, IC31 exerted an immunostimulatory effect via
the TLR9/MyD88 signaling pathway [11]. A similar mode of
action has been described for phosphorothioate-backboned DNA
molecules containing CpG-ODN [2], but also for phosphodiesterbackboned DNA without CpG motifs if translocated into the
endosome [13]. Hence, it is most likely that ODN1a, which is not
a CpG-ODN but a phophodiester-backboned DNA consisting of
Expert Rev. Vaccines 6(5), (2007)
IC31® and IC30 as vaccine adjuvant
repetitives of deoxyinosine/deoxycytosine, is responsible for that
effect. In this regard, the peptide KLK may serve as a gating molecule for the transport of ODN1a into the cytoplasm/endosome,
where it then gains access to TLR9. Efforts to evaluate this
hypothesis are being investigated.
In addition, investigation of the involvement of additional
molecules downstream of the TLR9/MyD88 pathway (e.g.,
MAPK and transcription factors) in IC31-induced immune
activation is a topic of current research. Signals from pattern
recognition receptors further cooperate with type I interferon
(IFN) in the induction of specific gene expression. Using
IFN-α receptor and signal transducers and activators of transcription (STAT)-1 knockout mice, type I IFN were shown to
be important mediators of IC31 adjuvant activity [DECKER TH,
PERSONAL COMMUNICATION].
IC31: activation of DCs
Among professional APCs, DCs are the most potent innate
immune cells for the induction of adaptive immunity. They
are highly specialized in capturing and presenting antigens
and, thus, have a central role in the determination of the specificity, magnitude and nature (type 1/type 2) of T-cell
responses. In this context, in vitro studies have demonstrated
direct effects of IC31 on the activation of different DC subsets. Both murine bone marrow-derived myeloid DCs
(CD11c+ CD11b+) and plasmacytoid DCs (CD11c+
CD11blow B220+ Gr-1low) are activated efficiently by IC31 in
terms of surface expression of costimulatory molecules including CD40, CD80 and CD86 [11]. Furthermore, such in vitro
IC31-stimulated and antigen-pulsed myeloid DCs are able to
prime naive CD4+ Th cells in an antigen-specific manner and
induce their in vitro proliferation and differentiation into a
mixture of IFN-γ-producing (Th1) and IL-4-producing (Th2)
cells. The stimulatory effect of IC31 on DCs is most probably
based on the ODN1a component; however, a role of KLK can
not be excluded absolutely at this timepoint.
In order to fully understand the mechanisms underlying priming of naive T-cell responses in the presence of IC31, we are in
the process of identifying the type of APCs involved in vivo for
initiating the respective type of immunity. Preliminary evidence
already suggests an involvement of murine plasmacytoid DCs in
the IC31-mediated immune activation. When isolated from
draining lymph nodes after immunization with IC31, these plasmacytoid DCs (PDCA-1+) exhibit a highly activated phenotype,
characterized by surface expression of costimulatory molecules.
The ability of in vivo IC31-activated plasmacytoid DCs to
secrete particular profiles of cytokines, as well as their impact on
T-cell responses, is currently under investigation. Analogous
experiments focus on different conventional DC subtypes that
are present upon IC31 immunization.
IC31 adjuvant activities
Induction of potent peptide- & protein-specific immune
responses in vivo
As outlined previously, the artificial antimicrobial peptide
KLK was shown to exhibit type 2-inducing capacities against
the model protein ovalbumin (OVA) [8]. Conversely, for
ODN1a, we have evidence that it is incapable of activating
the immune system by itself, most probably owing to a short
half-life caused by its phosphodiester backbone [UNPUBLISHED
DATA]. However, the combination of KLK and ODN1a triggered potent antigen-specific immune responses in the
murine system (FIGURE 2) [11]. IC31-mediated responses
against peptides (e.g., OVA257–264 and mTRP-2181–188) were
characterized by the induction of specific type 1 cellular
immune responses (IFN-γ production by splenocytes) with
no effect on type 2 responses (IL-4 production by splenocytes). CoadministraPotent and sustained
type 1/type 2 response
tion of IC31 with OVA protein was simiKLK
larly shown to provoke strong type 1• Type 2 induction
T cell
dominated cellular responses to both
• Depot formation at injection sites
• Delivery system: enhancement of antigen
MHC class I- and II-restricted epitopes.
and ODN1a uptake by APC
Thus, IC31 not only promotes the delivHLA-DR
ery of antigen into APCs, but also
CD40
potently enhances the processing and
cross-presentation of particular antigens
CD83
on MHC molecules. Since it is known
that KLK stimulates type 2 responses
B cell
CD86
upon coinjection with antigens, the addiCD80
tion of ODN1a is responsible for the
type 1 portion of the response. Mixed
ODN1a
type 1/type 2 (serum IgG2a and IgG1
• Type 1 induction
antibodies,
respectively)
humoral
• Activation of APC
immune responses are also obtained
• TLR9/MyD88-dependent signaling
upon immunization of IC31 and OVA,
indicating that there is potential for
Figure 1. IC31® mode of action.
IC31 to induce B-cell differentiation
APC: Antigen-presenting cell; KLK: KLKL5KLK; MyD88: Myeloid differentiation factor 88; ODN:
Oligodeoxynucleotides; TLR: Toll-like receptor.
into antibody-secreting plasma cells.
www.future-drugs.com
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Lingnau, Riedl & von Gabain
In addition to facilitating antigen-specific cytokine-producing cells, IC31-promoted antigen-specific CTL effector cells are
shown to have the unique lytic potential to kill target cells
in vivo in a highly specific manner, demonstrated by the lyses of
adoptively transferred, fluorescently labeled target cells pulsed
with the relevant antigen into vaccinated mice.
IC31 as a potent adjuvant for TB vaccines
The induction of a strong cell-mediated immune response is a
prerequisite for protection against TB. The currently used BCG
vaccine is a live vaccine that, when given to newborns, provides
good protection against TB for 10–15 years. However, when
the protective effect decreases, a booster BCG vaccination does
not provide sufficient protection. Thus, infections with TB continue to be a major global health problem. A third of the world’s
population is infected by the bacteria Mycobacterium tuberculosis
and the mortality rate is high (2–3 million deaths/year). The
weaknesses of the BCG vaccine have prompted the search for
more effective vaccines utilizing different strategies, such as liveattenuated vaccines, subunit vaccines and virally vectored vaccines. To be effective, subunit vaccines need the addition of
adjuvants. Based on its mode of action, the ability of IC31 to
augment immune responses, as well as protective efficacy of a
mycobacterial vaccine antigen, was evaluated in preclinical studies [14]. In the presence of IC31, the induction of antigen-specific CD4+ T-cells secreting high levels of IFN-γ was observed in
mice. In addition, coadministration of IC31 was found to provide efficient protection in both mouse and guinea pig models
of TB infection. The obtained promising preclinical data have
encouraged the conduction of clinical trials.
IC31 as a potent adjuvant to improve influenza vaccines
In addition to the suboptimal efficacy of current seasonal inactivated influenza vaccines, the risk of a new pandemic influenza underlines the urgent need for more potent influenza vaccine preparations. In that context, immunogenicity studies in
mice, using trivalent, subunit influenza vaccines and virosomebased influenza vaccines of different vaccination seasons and
product manufacturers, clearly demonstrate the powerful
immune adjuvant capacities of IC31 [RIEDL K, MANUSCRIPT IN
PREPARATION]. Compared with mice receiving the influenza
vaccine alone, the addition of IC31 increased serum neutralizing antihemagglutinin inhibition titers,
which mediate resistance to illness. Furthermore, upon coinjection of IC31, the
®
Novel vaccine adjuvant IC31 peptide + oligonucleotide
immune responses shifted towards type 1
humoral (IgG2a antibodies) and cellular
Antigen uptake by APCs
Formation of depot
responses (IFN-γ production by CD4+ Thelper cells), which are pivotal for viral
clearance and recovery from infection
[15–18]. Additionally, these IC31-mediated
immune responses were sustained up to
Long-lasting
200 days after a single immunization.
depot
Moreover, the combined administration
with IC31 enabled a decrease in the influenza vaccine antigen dose of at least tenfold without a loss of immunogenicity,
indicating that the number of available
vaccine doses could be considerably
increased by formulation with IC31.
Based on these findings in a murine
immunogenicity model, and supported by
the TB vaccine data already obtained in
humans, a Phase I clinical trial to demonAntibodies
APC
strate the ‘proof of concept’ for a superior
interpandemic vaccine formulated with
IC31 has been initiated recently.
Further efforts are underway to:
CTLs
• Evaluate the adjuvant activities of IC31
in neonatal and aged mice
• Identify the delivery activities of KLK as
component of IC31 in more detail
Humoral and
cellular response
Figure 2. The novel adjuvant IC31®.
APC: Antigen-presenting cell; CTL: Cytotoxic T-lymphocyte.
744
Maturation/activation
of APCs
• Preclinical proof of concept studies for
use of IC31 as an adjuvant in further
animal models
Expert Rev. Vaccines 6(5), (2007)
IC31® and IC30 as vaccine adjuvant
Safety & activity of IC30 & IC31 in humans
HCV is a major cause of chronic liver disease, including cirrhosis and liver cancer. The substantial unmet medical need is
underscored by the high number of deaths and liver transplants
due to HCV infection. Currently, there is no available vaccine
against HCV and the infection can only be treated with a combination of interferon and ribavirin, a long-term therapy with
limited efficacy and substantial side effects. Based on its promising adjuvant profile, the cationic peptide IC30 was evaluated
in clinical studies with a therapeutic HCV vaccine consisting of
a mixture of five peptides covering CD4+ and CD8+ T-cell
epitopes of HCV [19,20]. The evaluation of T-cell responses in
healthy individuals, as well as in chronic hepatitis C patients,
revealed the requirement of IC30 for the induction of a vaccine-specific type 1 immune response (Th1 and T cytotoxic 1).
Most importantly, its ability to induce T-cell responses even in
difficult settings, such as chronic HCV infections, while displaying an excellent safety profile reflects its promising potential as a cationic peptide adjuvant. The encouraging results
obtained so far with our therapeutic HCV peptide vaccine
adjuvanted with IC30 make it very tempting to continue the
development by replacing IC30 with IC31, since IC31 has
demonstrated to be superior in T-cell induction.
Preclinical studies in relevant animal models on immunogenicity and efficacy in regard to protection have encouraged
the use of IC31 as strong T-cell-inducing adjuvant with a subunit TB vaccine in clinical trials. Preliminary data evaluation of a
Phase I trial confirmed the potential of IC31 to induce strong
type 1 immunity in healthy individuals [21,22]. Furthermore, no
safety concerns were reported. Hence, further clinical trials will
follow in latent TB-infected or BCG-vaccinated individuals,
also in endemic countries.
As described in detail previously, IC31 has shown in preclinical studies to strongly improve seasonal influenza vaccines in
regard to increased hemaglutinin titers. Furthermore, the presence of IC31 induces very long-lasting and high levels of specific
T-cells, as well as type 1 antibody responses in mice, both markers for an immune response known to improve and broaden protection from influenza infections. Recently, a Phase I trial has
begun to evaluate the effect of IC31 on the immunogenicity of a
seasonal influenza vaccine in healthy individuals.
Considering the increasingly proven essential role of T-cell
immunity, IC31 will also find its way into clinical trials testing
therapeutic vaccines against latent viral infection and cancer.
Expert commentary & five-year view
IC30 and IC31 are both novel adjuvants based on peptides,
whose role is best characterized to help gating antigens and
ODNs into target cells. Both adjuvants form biodegradable
depots prolonging the duration of the antigen exposure to the
immune system at the injection site of the vaccine and show a
positive safety profile in clinical studies. A better understanding of the exact role and mechanisms of the peptides may
secure IC30 and KLK a place in vaccine formulations where a
gating function and a depot formation may suffice to build
www.future-drugs.com
up protective immunity. In addition, IC31 provokes a strong
induction of innate immunity via TLR9 activation in DCs.
Recent results from a Phase I trial testing a novel TB subunit
vaccine, have indicated that IC31 has enormous potential as a
vaccine adjuvant, particularly in vaccines where type 1-driven
immunity is pivotal. The development of novel adjuvants is
impeded by cost limitations, safety concerns and regulatory
hurdles. Thus, IC31, a simple combination of a peptide and
an ODN, with a known mode of action that is largely
explainable at molecular level, should have a good chance to
be positioned among the new TLR-activation adjuvants moving forward in clinical trials. Therefore, we would like to predict that IC31 will be available to the customers within the
next 5 years in a variety of prophylactic infectious disease vaccines, where its advantages will outweigh the risk to include a
novel adjuvant into the formulation.
Disclaimer
IC31® – CTM and US trademarks registered.
Financial & competing interests disclosure
Alexander von Gabain, Karin Riedl and Karen Lingnau are
employed by Intercell AG, the company developing IC30 and IC31
as commercial products for vaccine adjuvantation. Thus, they have
an interest to make the company to become successful. In their role
for the company, employees are bound to governance in communicating research results of the company to the public that are compliant with the legal rules in Europe and in the USA. Alexander von
Gabain, Karin Riedl and Karen Lingnau are holding shares and
options in the company that is publicly listed at the Austrian Stock
Exchange since 2005. The authors have 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 apart from
those disclosed.
No writing assistance was utilized in the production of this
manuscript.
Key issues
• Peptides, such as IC30 and KLKL5KLK (KLK), act as vaccine
adjuvants based on their action as immunostimulatory and
delivery-system agents.
• IC31® combines the unique activities of KLK and the novel
immunostimulatory oligodeoxynucleotide ODN1a as a
Toll-like receptor 9 agonist.
• Dendritic cells as key antigen-presenting cells are potently
activated by IC31.
• IC31-induced cellular and humoral immune responses are
prone toward type 1 immunity.
• First clinical data regarding IC30 and IC31 indicate that they
are safe and that they enhance the immunogenicity of
coadministered antigens.
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Lingnau, Riedl & von Gabain
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Websites
101
EMEA
www.emea.europa.eu
102
US FDA
www.fda.gov
Affiliations
•
Karen Lingnau, PhD
Head of Pharmacology & Toxicology,
Intercell AG, Campus Vienna Biocenter 6,
1030 Vienna, Austria
Tel.: +43 120 620 320
Fax: +43 120 620 805
[email protected]
•
Karin Riedl
Scientist of Pharmacology & Toxicology,
Intercell AG, Campus Vienna Biocenter 6,
1030 Vienna, Austria
Tel.: +43 120 620 147
Fax: +43 120 620 805
[email protected]
•
Alexander von Gabain, PhD
Professor, Intercell AG, Campus Vienna
Biocenter 6, 1030 Vienna, Austria
Tel.: +43 120 620 101
Fax: +43 120 620 800
[email protected]
Expert Rev. Vaccines 6(5), (2007)