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New Strategies for Vaccine Development
Liubov M. Lobanova
[email protected]
Program in Vaccinology and Immunotherapeutics
School of Public Health
and
Vaccine and Infectious Disease Organization
University of Saskatchewan
Saskatoon
Canada
For: Advanced Virology (VTMC 833)
© Liubov M. Lobanova
Abstract
Introduction
Reverse vaccinology approach
Virus-like particles
DNA vaccines
Improving immunogenicity through formulation
Improving immunogenicity by including immune modulatory adjuvants
Improving immunogenicity by using next-generation delivery strategies
Viral vectors
Prime-boost strategy
Conclusions
References
Abstract
Vaccination remains the most successful strategy for preventing and controlling infectious
diseases. In many cases, conventional vaccines, in particular live attenuated vaccines, inactivated
microorganisms and subunit vaccines have been successful at inducing protective immunity,
mainly humoral immunity, to disease-causing pathogens. However, it has become apparent that
certain highly dangerous pathogens, that resist the humoral immunity, are not readily controlled
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by conventional vaccination approaches. Recent knowledge of host-pathogen interactions,
received from fundamental research in immunology, molecular-cellular biology and vaccinology
provides understanding that the induction of T-cell immunity is required for optimal treatment
against pathogens causing chronic infections. Although conventional live attenuated vaccines
may induce cell-mediated immunity, there are serious safety issues regarding the application of
this strategy for the development of vaccines against highly dangerous pathogens, such as human
immunodeficiency virus (HIV). As a result of these problems, several new approaches to vaccine
development have emerged. These approaches are distinguished by having advantages over
conventional vaccine strategies. This review will focus on some of these new strategies
developed to promote potent cellular immunity, including (i) virus-like particles, (ii) plasmid
DNA vaccines, (iii) viral vectors, and (iv) prime-boost vaccination strategy. In addition, the
reverse vaccinology approach, which facilitates systematic identification of new potential
antigens of a pathogen, is discussed.
Introduction
The concept of vaccination was demonstrated over 200 years ago when Edward Jenner
showed that prior exposure to cowpox could prevent infection by smallpox. Over the last
century, the development and widespread use of vaccines against a variety of infectious agents
have been a great triumph of medical science. We have vaccines for nearly thirty out of the more
than seventy infectious diseases of humans. Among the greatest achievement of vaccination
remains the eradication of smallpox. Other achievements are: virtual disappearance of previously
disabling and lethal diseases such as diphtheria, tetanus, paralytic poliomyelitis, pertussis,
measles, mumps, rubella and invasive Haemophilus influenzae type B. Hepatitis A and B are
also being brought under control in an increasing number of countries.
Conventional approaches, in particular attenuation of the pathogen, inactivation of the
microorganism and creation of subunit preparations, have been very successful in the
development of vaccines against infectious agents. However, there are some diseases for which
attempts to develop vaccines using conventional approaches have failed. These include chronic
infectious diseases such as acquired immunodeficiency syndrome (AIDS) and hepatitis C
(HCV). Moreover, occasionally, a vaccine has to be withdrawn because of unexpected side
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effects. For instance, an inactivated vaccine against measles was withdrawn because it had
provoked atypical measles after natural infection (99). More recently, in October 1999, a simianhuman reassortant rotavirus vaccine was withdrawn due to intussusceptions and mortality of
vaccinated infants (117). Therefore, there is a constant interest in developing new approaches to
improve efficacy and safety of existing vaccines. There is also a continuous need for developing
new vaccines to newly emerging pathogens, such as the severe acute respiratory syndrome virus
(14) and hantavirus (26), as well as to pathogens for which no vaccines currently exist. Finally,
development of therapeutic vaccines and vaccines against allergic and autoimmune diseases
represents another new vaccine challenge. Achieving such ambitious goals certainly requires
new approaches in vaccine development.
This review explores some new approaches for vaccine development: reverse
vaccinology, virus-like particles (VLPs), ‘naked’ DNA plasmids, viral vectors, and heterologous
prime-boost strategy. Reverse vaccinology approach has emerged due to the need to identify
potential vaccine candidates providing new solutions for those vaccines which have been
difficult or impossible to develop, whereas the other approaches mentioned above have emerged
because it appears that protection against infection by many agents, particularly viruses, requires
generation of potent cell-mediated immunity (106). Successful vaccines are available for many
viruses, but almost exclusively ones that produce acute, self-limited infection (74). The most
important characteristic of these pathogens is that neutralizing antibodies protect against
infection or disease. Conventional approaches (e.g., live attenuated vaccines, inactivated
vaccines and subunit vaccines) have been employed successfully against these pathogens which
elicit protective immune responses with a bias towards the induction of humoral immunity. In
contrast, there are no successful vaccines available for viruses that cause chronic infections, such
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as HIV, HCV and herpes simplex virus. It has been shown that CD8+ T cells are especially
important for the control of HIV-1 and HCV infections (77, 106). In addition to CD8+ cell
responses, CD4+ T cells have been found to be critical in the maintenance of adequate CD8+ T
cell function and control of viremia in both HIV and HCV infection (64, 106). Live attenuated
vaccines have been the most successful in induction of efficient B- and T-cell responses (59).
However, there is much concern about the use of live attenuated vaccines against viruses that
cause chronic infection. Besides, such vaccines are unlikely to induce protection as the immune
response to the natural infection is not sufficient to eradicate the infection. Therefore, the
development of vaccines against such pathogens is more challenging, since they would have to
elicit more robust cytotoxic T lymphocyte (CTL) responses in addition to antibodies (71). This
review will cover the approaches are being studied today which are based on eliciting strong
cell-mediated immunity.
Reverse vaccinology approach:
The first revolution in vaccinology was the use of modern recombinant DNA technology to
produce subunit vaccines. This approach involves propagation of a pathogen in the laboratory
conditions, followed by identification of its components that are important in pathogenesis and
immunity. Then, identified protective antigens are produced in a system for large-scale
recombinant protein expression (Figure 1). While successful in some cases, for example the
subunit vaccines against hepatitis B (6) and Bordetella pertussis (65), this strategy is limited to
pathogens with known immunodominant protective antigens. The approach is time-consuming
and is amenable to only those antigens which can be purified in high quantities. However, in
some cases the most abundant proteins expressed by a pathogen are not suitable vaccine
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candidates and genetic tools required for identification of less abundant components may be
inadequate or not available. Moreover, this strategy is not applicable to non-cultivable
microorganisms.
Figure 1. Schematic representation of the conventional approach to vaccine
development. This approach requires the pathogen to be grown in laboratory
conditions, individual components to be identified and produced in a pure form,
either directly from the microorganism or through recombinant DNA technology and
then tested for their ability to induce immunity.
The second revolution in vaccine development took place at the end of 20th century as a result of
the use of the genomic technology. Currently, it became possible to determine the complete
genome sequence of any microorganism in a few months at a low cost. As a result, the sequences
of most of the pathogens are now available. This advantage is used by reverse vaccinology
approach (142) which is shown schematically in Figure 2. The strategy utilizes computer
analysis of available genome sequences to predict open reading frames (ORFs) as well as
localization and possible function of proteins encoded by these ORFs. Two-dimensional gel
electrophoresis together with mass spectrometry, DNA microarrays, in vivo expression
technology provide more information on these potential antigens. For example, microarray
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analysis is used to identify genes that are turned on during invasive infection (39), and thus, the
proteins encoded by these genes can be considered as potential targets for vaccine development
(156). It allows choosing, in a short period of time, many vaccine candidates including those
proteins which are expressed at very low levels during infection. Next step is a high throughput
expression of recombinant proteins and testing them in animal models. This approach reduces
the time of vaccine development to 1-2 years, whereas the development of vaccines by
conventional methods could take 5 or more years. An example of one of the first applications of
reverse vaccinology approach is the identification of vaccine candidates against Neisseria
meningitidis serogroup B (132). Potential antigens identified by computer programs were
expressed in Escherichia coli as recombinant fusion proteins, purified and used to immunize
animals. The resultant sera were examined for meningococcocidal activity in the presence of
complement (132). Among the proteins with bactericidal activity, a novel surface-exposed
oligomeric protein Neisseria adhesin A (NadA) was found to be present in most of the
meningococcus B strains. As NadA elicited production of bactericidal antibodies that correlated
with protection against the pathogen in the infant rat model it was considered as a promising
vaccine candidate (32). Moreover, immunization with a multicomponent vaccine containing
NadA and other protective antigens discovered by this approach, gave promising results in
clinical phase I and II trials (61). While the vaccine is in clinical development, research efforts
are focused on the structural characterization of the main vaccine antigens. For instance, a
truncated soluble variant of NadA was subjected to extensive physico-chemical characterization
in order to be formulated as part of the final drug product (97).
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Figure 2. The reverse vaccinology approach to vaccine development. This approach
utilizes available information about genomic sequences of pathogenic
microorganisms. With the use of computer software, ORFs and possible localization
and functions of proteins encoded by these ORFs are predicted. This is followed by a
high-throughput cloning and expression of identified ORFs. Expressed proteins
undergo screening in animal models to be tested for the immunogenicity and ability
to protect against challenge.
The success of the group B meningococcus paradigm facilitated the application of the
reverse vaccinology strategy for the identification of vaccine candidates against other bacterial
pathogens, such as Streptococcus pneumoniae (184), Porphyromonas gingivlis (150), Chlamydia
preumoniae (112), Staphylococcous aureus (46) as well as to protozoan pathogens (63).
However, in order to be successful against a more complex microorganism such as Streptococcus
agalactiae this approach had to evolve giving the beginning of pan-genome reverse vaccinology
and comparative reverse vaccinology (157). Pan-genome reverse analysis is focused on
comparing many pathogenic strains of a species in order to identify antigens that could provide
maximum coverage against different serotypes resulting in the development of a universal
vaccine. The identification of vaccine candidates against Streptococcus agalactiae, a group B
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streptococcus, is an example of successful application of multiple genomic approaches in
vaccine design (98). Comparative reverse vaccinology approach involves comparative analysis
of genomes of pathogenic and non-pathogenic strains of the same species with the goal of
finding pathogenicity markers (69). This strategy reduces the number of vaccine candidates to
express and test in the animal model and, consequently, reduces the time for the delivery of a
vaccine as genes conserved in both pathogenic and non-pathogenic strains are excluded from the
selection.
Thus, the reverse vaccinology approach is aimed at the identification of potential vaccine
candidates without the need for cultivating the pathogen, reducing the time and cost required for
the identification of new vaccine candidates. Although this approach has been predominantly
used for the development of vaccines against complex microorganisms, such as bacteria,
vaccines against viral pathogens (hepatitis C and HIV) are currently under development with use
of this approach (142). However, some limiting steps in reverse vaccinology include lack of
algorithms that can be used to make a good correlation between antigens and their likely
protective immune responses, and inability to identify non-protein antigens including
polysaccharides or CD1-restricted antigens such as glycolipids (142).
Virus-like particles:
Virus-like particles represent another promising and viable strategy to the production of vaccines
against many diseases. VLPs are a highly effective type of subunit vaccines that possess
characteristics that make them a safe and effective vaccine platform. “Virus-like particles are
highly organized spheres that self-assemble from virus-derived structural antigens” (93). VLPs
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preparations are all based on the observation that expression of the capsid proteins of many
viruses leads to the spontaneous assembly of particles that are structurally similar to authentic
virus (4, 76, 123). Immunological features of viruses, such as repetitive surfaces, particulate
structures and induction of innate immunity through activation of pathogen-associated
molecular-pattern recognition receptors, make VLPs very effective in inducing potent B- and Tcell responses. The critical role of innate immune response induced by virus in directing the
subsequent adaptive immune response of appropriate magnitude, quality and specificity has been
highlighted by Gaucher and coauthors (59). Besides, the authors demonstrated that the sum of all
immune arms is required for the long-lasting protection induced by yellow fever vaccine and
integrated immune response constitutes the correlates of protection. Moreover, unique features of
protective immune responses were identified, which can now be used as a basis for the
development of novel vaccines.
In practical terms, the fact that VLPs mimic the structure of virus particles usually means
that VLPs elicit strong humoral response as it allows the adaptive immune system rapidly detect
and respond to these repeated and ordered structures found on viral surfaces (11, 135).
Moreover, the dense, repetitive nature of VLPs makes them particularly effective in inducing
antibody responses, often without adjuvants (70). In addition, due to their structure and size
VLPs are capable of diffusing to lymph nodes from the site of injection where they can interact
directly with B-cells to trigger antibody responses (192).
In addition to B-cell responses, VLPs also induce strong CD4 proliferative and CTL
responses (116), which are the aim of current T-cell vaccine strategies. Features of VLPs, such as
preferential targeting of dendritic cells (DCs), efficient delivery to both MHC class I and II
molecules and the ability to directly activate the DC maturation, make them strong inducers of
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CTL responses. Due to their particulate structure exogenous VLPs are readily taken up by
antigen presenting cells (APCs), in particular by DCs, and presented effectively in the context of
MHC class II molecules as well as they can be cross-presented on MHC class I molecules,
thereby inducing a CTL response, which is essential for the clearance of intracellular pathogens
such as viruses (115). For example, it has been reported that human papillomavirus (HPV) VLPs
directly activate DCs leading to the expression of co-stimulatory molecules, cytokines necessary
for activation of CTLs (85). Furthermore, some VLPs that retain receptor binding regions of
cognate viruses can enter cells through their normal receptor and can be taken by DCs as
exogenous antigens for class I presentation (13). Importantly, DC maturation and migration,
essential for activating the innate and adaptive immune responses, are promoted by uptake of
VLPs (54). It was shown that the stimulation of DCs does not require the virus replication but it
requires an intact envelope of either an inactivated virus (50) or that of a VLP (13), or an intact
non-enveloped VLP (187). This feature gives advantages to VLPs over the cognate live viruses
for immune activation, because several viruses have an ability to interfere with the DC activation
(125). Moreover, the self-adjuvanting effect of VLPs to target DCs is an important advantage
over soluble antigens, which are less immunogenic and require the co-administration with
adjuvants in several booster injections. However, not all VLPs can skew the immune response
towards Th1, and the addition of innate immunity stimulators is required. This drawback can be
easily overcome as VLPs have the ability to encompass immune stimulating adjuvants, such as
Toll-like receptor (TLR) ligands, within their lumens. For instance, vaccination with CpG-loaded
VLPs derived from the hepatitis B core antigen or the bacteriophage Qbeta was able to induce
high frequencies of peptide-specific CD8+ T cells (164). TLR9 ligands have an adjuvant activity
that directly affects B-cells to undergo isotype switching to Th1 (79). Similarly, single-stranded
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RNA packaged within some VLPs can activate TLR7 present in B-cells and enhance B-cell
responses and class switching to Th1 (79).
Importantly, in addition to priming T-cell responses, CpG-loaded VLPs are capable of
boosting them without a change in carrier in contrast to heterologous prime-boost strategy (155).
Finally, in most of the cases VLPs lack the DNA or RNA viral genome, but have the authentic
conformation of viral capsid proteins seen with attenuated virus vaccines, thus they represent a
safer alternative to attenuated viruses. Therefore, all characteristics of VLPs described above
have made them attractive vaccine candidates for many viral diseases as well as carrier
molecules for epitopes for other pathogens (66) (Figure 3).
Figure 3. Features of virus-like particles. The ability of VLPs to self-assemble
allows incorporation of activators of innate immunity as well as plasmid DNA within
their lumen and makes them a promising vehicle for delivering immune stimulating
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adjuvants and genetic material into target cells. Due to their particulate structure
VLPs are readily taken up by APCs and presented effectively in the context of MHC
class I molecules, thereby inducing a CTL response. The dense, repetitive nature of
VLPs makes them particularly effective in inducing antibody responses.
Proteinaceous composition of VLPs permits chemical conjugation or genetic fusion,
thereby allowing them to serve as carrier molecules for other pathogens. Figure
created by using reference (129).
The most straightforward application of VLPs is to use them for vaccination against the
corresponding virus from which they are derived. Examples of such VLPs used for vaccines and
vaccine development are hepatitis B virus, HPV, hepatitis E virus, influenza, hepatitis C virus,
poliovirus, HIV, Ebola virus, Marburg virus, Norwalk virus, Rotavirus, SARS coronavirus VLPs
(66). Recently, VLP-based vaccines for HBV and HPV have been licensed commercially.
Recombivax (Merck & Co., Inc.) (104) and Engerix (GlaxoSmithKline (GSK)) (7), both were
approved in the USA in 1980s. Gardasil (Merck) was approved in 2006 (55). In addition, VLPs
can also be used to present foreign epitopes to the immune system. This can be achieved by
genetic fusion or chemical conjugation. Genetic fusion of the protein transduction domain of
HIV-1 Tat protein with the core gene of HBV provide an example of this approach (27).
Alternatively, foreign vaccine proteins may be chemically conjugated to pre-formed VLPs. For
example, this approach has been used in the production of HBV core antigen VLPs chemically
conjugated with M2 peptide of influenza A virus (51). Chemical conjugation also allows nonprotein targets, such as glycans or other small haptens to be attached to VLPs. One recent
example is the VLP-based vaccine against nicotine dependence. This vaccine was developed by
covalently coupling nicotine to the surface of VLPs (103). Therefore, the ability of VLPs to
serve as carriers of epitopes derived from either the parental virus or foreign sources has
enhanced and broadened their potential as prophylactic and therapeutic vaccines.
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This technological innovation, especially genetic fusion and chemical conjugation, has
given the beginning of numerous chimeric VLP-based vaccines. Chimeric VLPs can act as
carriers of immunologic epitopes derived from viral, microbial pathogens as well as they can be
used to induce autoantibodies to disease-associated self-molecules involved in chronic diseases.
For instance, VLPs derived from both double- and single-stranded DNA and RNA viruses
encompassing 14 different families have been used for the production of chimeras (134). Among
clinically tested vaccines based on VLPs carrying microbial epitopes are two anti-malaria
vaccines, Malarivax (Apovia) (118) and RTS,S (GSK) (67). VLP display of self-antigens is used
successfully to target molecules that are involved in the pathogenesis of a variety of chronic
diseases, including Alzheimer’s disease (190), hypertension (5, 172), obesity (53) and certain
cancers, specifically, epithelial cancers (58). Clinical proof of concept has been achieved with a
VLP-based anti-angiotensin II vaccine against hypertension. This vaccine known as AngQb has
been shown to reduce blood pressure in preclinical models of disease and in humans in a phase
IIa clinical trial (5, 172). Therefore, ability of VLPs to carry heterologous epitopes made it
possible to target antigens that were previously refractory to vaccine-based approaches.
Recently, VLPs have been explored for their ability to serve as delivery vehicles for plasmid
DNA (pDNA). The efficient packing of pDNA in VLPs derived from several viruses, such as
papillomavirus (PV) (173), polyomavirus (30) and hepatitis E virus (165) was demonstrated.
Touze and Coursaget showed higher gene transfer in diverse eukaryotic cell lines using
papillomavirus like particles for DNA delivery compared with DNA alone or delivered with
liposomes (173). Takamura et al. showed that VLPs derived from orally transmitted viruses, such
as hepatitis E, were especially suitable for the oral application of DNA vaccines (165). In a
mouse model, orally applied PV VLPs packed with pDNA encoding the HIV-1 Gag protein
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showed the ability to induce Gag-specific memory CTLs and the generation of Gag-specific
serum immunoglobulin G (IgG) and mucosal immunoglobulin A (IgA) antibodies (191). Thus,
virus-like particles are a very promising vehicle for delivering genetic material into target cells.
VLP technology has the potential for therapeutic vaccination as an economic and
effective treatment option for chronic diseases. However, one of the drawbacks that may delay
the application of this strategy is a low compositional and architectural consistency of VLPs
produced using existing manufacturing methods. This problem creates a demand for the
development of new large-scale bioprocesses having high yield, quick process time and reduced
total cost. Future directions in manufacturing may include an in vitro chemical self-assembly of
VLPs based on capsid components (66).
DNA vaccines:
Plasmid DNA vaccination was discovered over 10 years ago as a potent method to elicit humoral
and cellular immune responses to foreign antigens (169). The simplicity and attractiveness of
DNA vaccines were obvious, as they were represented by plasmid DNA which was easy to
produce in laboratory bacterial strains at comparatively low cost, as well as easy to store and
transport since plasmid DNA is chemically and biologically stable. Conventional plasmids used
for vaccination are double-stranded DNA molecules, which can be subdivided into two
functional units: an eukaryotic expression cassette (transcriptional unit) and a plasmid backbone
(68) (Figure 4). The transcription unit consists of regulatory elements: eukaryotic promoter,
enhancer and a polyadenylation signal required for the appropriate expression of the gene of
interest in the target cell. An additional expression cassette for genes of immunomodulatory
proteins may be inserted in order to enhance the immune response. The plasmid backbone
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includes elements, such as antibiotic resistance genes and an origin of replication required for the
production of plasmid DNA in bacterial cells. In addition, unmethylated CpG motifs, which
stimulate the immune response in the host, can be incorporated into this functional unit (Figure
4).
Figure 4. Schematic drawing of a plasmid DNA vector. The plasmid DNA can be
divided into a transcriptional unit and a bacterial backbone. The transcriptional unit
includes a promoter, which can drive high level of protein expression in eukaryotic
cells, an ORF for a vaccine antigen, and transcription/termination sequences (Poly
A). The bacterial backbone consists of a bacterial origin of replication and an
antibiotic resistance gene. Unmethylated CpG motifs can be incorporated into
plasmid DNA to stimulate immune responses in the host cell.
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Figure 5. Mechanisms of antigen presentation after DNA immunization. Application
of a plasmid DNA vaccine leads to: (A) Direct transfection of professional APCs
resulting in antigen presentation to T cells; (B) Cross-priming, when antigens
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generated by somatic cells can be taken up by professional APCs to prime T-cell
responses. Figure created by using reference (68).
The principle of DNA vaccination is based on the production of the antigen(s) of interest
in vivo by cells of the vaccinated person or animal, whereby pathogen-derived genetic
information combined with eukaryotic expression system is applied. It means that the in vivo
synthesized antigens retain their native structures, including post-translational modifications,
accurately mimicking their ‘natural’ counterpart. There are two main mechanisms by which the
antigen encoded by plasmid DNA is processed and presented to elicit an immune response:
direct transfection of professional APCs and cross-priming (68) (Figure 5A). When the gene of
interest is transfected directly into professional APCs and expressed after transfer into the
nucleus, the resulting protein is directed into the MHC class I pathway of antigen presentation.
On the other hand, if the antigen is first secreted or released following expression in myocytes
and then taken up by APCs, the protein is targeted to the MHC class II pathway of antigen
presentation, although such antigens may also be able to ‘cross-over’ into the MHC class I
pathway following internalization into APCs (cross-priming) (Figure 5B). In contrast to DNA
vaccines, exogenous delivery of killed or subunit vaccines leads preferentially to the Th2
immune response, since the antigens are taken up by APCs and targeted into the MHC class II
molecules. Therefore, the ability to present antigens through both MHC classes makes DNA
vaccines able to stimulate both arms of the immune system simultaneously (24).
Besides the intrinsic immunological advantages of DNA vaccines, there are other factors
making these vaccines attractive. As DNA vaccine plasmids are non-live, non-replicating and
non-spreading, there is little risk of either reversion to a disease-causing form or secondary
infection. Moreover, DNA vaccines are highly flexible, encoding several types of genes
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including viral or bacterial antigens, and immunological and biological proteins. In addition, the
use of DNA approach avoids the risks linked to the manufacture of killed vaccines, as
exemplified by the tainting of a polio vaccine with live polio virus owing to a production error
(122).
Due to their simplicity and versatility DNA vaccines became a promising strategy to
develop immunity against several infectious diseases including HIV, tuberculosis, malaria,
influenza and the newly emerging Ebola and SARS viruses (33, 42, 124, 141, 158). DNA
immunization was used in a wide variety of model systems (72, 177, 178). As a result, four
veterinary DNA vaccines have been approved for commercial sale by the respective regulatory
agencies in the USA and Canada. One against West Nile virus in horses (37), one against
infectious hematopoietic necrosis virus in schooled salmon (56), one for treatment of melanoma
in dogs (17) and the most recent licensure, growth hormone releasing hormone product for foetal
loss in swine (171). However, a much lower immunogenicity of DNA vaccines has been
observed in higher primates and clinical trials in humans and high doses and/or multiple
immunizations are required to induce protective immune responses (80, 90), which hampers the
practical application of DNA vaccines.
As a result of the limited immunogenicity of DNA vaccines, considerable efforts are
underway to solve this problem. There are several ways in which antigen expression and
immunogenicity can be improved for DNA vaccine platform: optimization of the transcriptional
elements in the plasmid backbone with the aim to improve antigen expression levels; strategies
to improve protein expression of the gene of interest, inclusion of adjuvants in the formulation or
as immune modulators, and the development of new delivery systems for specific targeting
and/or better DNA uptake (84). The latter two approaches influence the magnitude, the type of
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immune response as well as they can facilitate antigen entry into DCs. Approaches that are
aimed at targeting selected antigens to APCs, especially to DCs, have shown potential in
vaccinating against disease in animal models and humans as targeting vaccines to DC appears to
be essential for the induction and modulation of immune responses.
Improving immunogenicity through formulation
One current trend in DNA vaccine formulation is the use of biodegradable polymeric
microparticles and liposomes (121). Polymeric delivery systems and liposomal delivery systems
represent novel DNA delivery platforms that protect DNA from degradation and facilitate
targeting to specific tissues, thereby increasing the transfection efficacy of target cells. It has
been shown that microparticle constructs, such as poly (D,L-lactic-coglycolic acid) copolymers
(PLGA), can be easily phagocytosed by DCs in vitro or in vivo (120, 179) and this can stimulate
further DC maturation in the lymph node (139). The immune responses of DNA-loaded
microparticles were investigated in mice, non-human primates and humans (82, 111, 126, 127,
181). It was shown that the parenteral administration of PLGA encapsulated DNA induces a
significant CTL response (105). In addition, the oral administration of encapsulated DNA in
PLGA microparticles elicited systemic and mucosal immune responses upon challenge (81).
Moreover, polymeric matrices can be designed by the incorporation of ligands, such as folates,
transferrin, antibodies and sugars, to enhance tissue targeting (108). Similar to polymers,
liposomes are taken up by APCs and mediate MHC class I antigen presentation, and have been
shown to induce cellular and humoral immunity (180, 182). Furthermore, immunogenicity of
DNA vaccines can be improved by directly targeting the encoded vaccine protein to DCs in vivo.
Nchinda et al. demonstrated that the incorporation of antigens into an antibody against the DC
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endocytic receptor, DEC205, enhanced the antigen presentation by DCs in lymphoid tissues,
thereby improving the efficacy of DNA vaccines (119).
Improving immunogenicity by including immune modulatory adjuvants
The DNA itself has adjuvant properties through CpG motifs. For instance, synthetic
oligodeoxynucleotides containing unmethylated CpG motifs that are DNA specific sequences
recognized by TLR9 can act as immune adjuvants in mice, as they boost the humoral and cellular
responses to co-administered antigens (73). Moreover, the addition of many CpG motifs into a
plasmid backbone has improved the immunogenicity of DNA vaccines inducing Th1-biased
immune response (133). However, it has been recently shown that DNA vaccine immunogenicity
has been attributed to its double-stranded structure, which activates TANK-binding kinase 1dependent innate immune signaling pathway in the absence of TLRs (31).
In addition to self-adjuvanting effect of DNA, co-administration of genetic adjuvants
such as cytokines, chemokines or co-stimulatory molecules is a separate approach in which
genes are co-delivered in order to enhance the magnitude and type of desired immune responses
to DNA vaccines. For example, the employment of Th1-associated cytokines such as interleukin
(IL)-12 and IL-15 in non-human primates induced antigen specific cellular immune responses
(29, 151). DNA vaccines co-injected with plasmids encoding Th2-inducing cytokines such as IL4 augmented antigen-specific humoral immune responses (87). Furthermore, proinflammatory
cytokines have the ability to modulate immune responses to DNA vaccines. For instance, the
granulocyte-macrophage colony-stimulating factor (GM-CSF) is capable of enhancing humoral
and cellular immune responses (168). However, the timing of GM-CSF administration influences
the Th1/Th2 immune response (83). Chemokines can also modulate the immune response and
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protective immunity. Sin and colleagues observed that co-injection with IL-8 and RANTES
plasmid DNAs dramatically enhanced antigen-specific Th1 type cellular immune responses and
protection from lethal herpes simplex virus-2 challenge (159). In addition, co-delivery of the
costimulatory molecules CD86 during DNA vaccination enhanced both helper and cytotoxic Tcell responses (2).
Improving immunogenicity by using next-generation delivery strategies
The direct injection of plasmid DNA into muscle or skin is still the most widely used.
However, the biggest drawback of this delivery method is the low efficacy achieved in larger
animals and humans. Therefore, development of physical delivery methods to increase the
transfection efficiency of target cells has been a primary focus of research in more recent years.
Physical methods for pDNA transfection comprise electroporation, ballistic needle-free delivery
systems and microporation.
Microporation involves use of hundreds of microneedles that enable topical
immunization with naked plasmid DNA as they can bypass the stratum corneum, thereby
delivering plasmid DNA to APCs of the skin. This induces stronger and less variable immune
responses than via needle-based injections (109).
Another physical method widely employed in DNA vaccination is particle-mediated
epidermal delivery (PMED) also called the “gene gun”. In this procedure, DNA-coated
microparticles composed of gold are accelerated to high velocity to penetrate cell membranes in
the epidermis where a variety of cells, including the Langerhans cells, the APCs of the skin, can
be directly transfected (130). As a result, the gene gun immunization have 10-100-fold more
expression of the DNA-encoded protein than intramuscular vaccinations and 100-fold less DNA
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is required for the same level of expression (12). The gene gun technique has been used to
immunize nonhuman primates against a variety of diseases, including HIV, Ebola, Japanese
encephalitis, hepatitis E and B, influenza, smallpox etc (52). Thus, PMED can induce higher
antibody and /or CD8+ T cell responses in mice and monkeys with substantially lower doses of
DNA in comparison to needle-based approaches.
An alternative approach based on the use of electric pulses to transiently permeabilize
cell membranes, thus permitting cellular uptake of plasmid DNA, is electroporation. It has been
extensively studied in large animal species such as dogs, pigs, cattle and non-human primates to
deliver DNA vaccines (10, 75, 148, 176). The potential of electroporation for DNA vaccination
has been demonstrated by the increased protein expression and a robust stimulation of the
immune response. Electroporation might allow for less frequent immunizations with the DNA
vaccines, and can improve both cellular and humoral responses (149).
Currently, the DNA platform represents almost one quarter of all gene therapy vector
systems under clinical evaluation (84). The interest to further development of this vaccination
strategy is strengthened by recent licenses in the area of animal health and by the improvements
in immune potency reported in the non-human primate model systems.
Viral Vectors:
The idea of using viruses as gene-delivery systems to combat diseases stems from a documented
immunogenicity and safety profile of the majority of existing live-attenuated vaccines.
Attenuated live-virus vaccines appear to be the most effective immunogens that mimic natural
infection. Another important attribute of these vaccines is high cost efficiency for mass
22
vaccination as they are optimal for large-scale production. Recent developments in genetic
engineering coupled with the accumulated data on the nucleotide structure of viral genomes and
functions of viral genes allowed precise manipulations of viral genomes cloned as bacterial
plasmids (167) or bacterial artificial chromosomes (36). This set of diverse technologies is
applicable to the generation of recombinant DNA and RNA viruses and is based on reverse
genetics, which is the most powerful tool in modern virology and has the potential for a variety
of applications, from the basic understanding of virus biology to the development of genetically
engineered viral vaccines and therapeutic gene delivery systems. Reverse genetics approach can
be applied for the construction of genetically attenuated vaccine strains (100) or development of
live viral vectors that are engineered to induce immunity to an array of proteins encoded by
genes inserted into the vector (22). One of the first licensed recombinant virus vaccines was
represented by vaccinia virus carrying the gene encoding rabies virus glycoproteins. This vaccine
reduced the spread of rabies virus in wildlife populations and also reduced the spill-over of virus
infection from wildlife to domestic animals and humans (23, 96).
Reverse genetics approach led to the development of a wide range of different DNA (1,
163) and RNA (20, 131, 186) viruses as vectors for efficient delivery of vaccine antigens. This
strategy is especially attractive for the development of vaccines against highly dangerous
pathogens, such as HIV, for which even a short course of replication of an attenuated live virus
in the host is not acceptable due to the possibility of integration of vaccine genes or reversion of
the vaccine strain to wild-type. The appropriate balance between safety and immunogenicity is a
critical issue for the construction of any live attenuated vaccine. Inadequate safety is the main
reason for retaining of many replication-competent viral vectors from entry into human clinical
trials. In order to increase the safety of viral delivery vectors, the development of replication23
defective viruses produced in complementing cell systems was introduced (43). However, the
abrogation of the ability to replicate in the vaccinated host is commonly associated with lower
immune responses induced by replication-incompetent viral vectors. In this connection,
replication-competent viral vectors that originate from commercial live-attenuated vaccines seem
to be a promising perspective for the development of novel safe and immunogenic vaccines (20,
161).
Major concerns associated with viral vector vaccines include the potential risk of changes
in viral tropism induced by introduced modifications, and the presence of pre-existing antivector
host immunity. The latter drawback can be managed by certain approaches including engineering
of vaccine vectors from viral strains that have not circulated widely in host populations (101) or
by mutating viral surface proteins in order to evade host neutralizing antibodies (147). Additional
approach to circumvent the problem of pre-existing antivector immunity is to exploit the
asymmetry in induction of systemic and mucosal immune responses. Specifically, if the mucosal
immune system remains naïve after systemic immunization against certain virus, it might still be
amenable to immunization with recombinant viral vector based on the same or related virus. For
instance, mucosal administration of measles and measles-rubella vaccines was shown to be more
efficient than subcutaneous administration in pre-immunized humans (16, 41). On the contrary,
in the case of active mucosal immunity to a vector, subcutaneous vaccination may be an efficient
way to overcome pre-existing immunity (48). However, the pre-existing immunity is not
detrimental for some viral vectors, thus measles virus (MV) is able to induce cellular and
humoral immunity after re-vaccination (92).
24
Currently, a variety of recombinant viral vectors are either under preclinical or early
clinical investigation (89). Among the most promising viral vectors are adenovirus vectors (183,
189), adeno-associated virus (AAV) vectors (91), poxvirus vectors (62), alphavirus vectors (113,
145), MV (88), vesicular stomatitis virus (VSV) (78), poliovirus (35), and herpes virus (44).
Each of these vectors has unique properties that should be considered for the selection of the
optimal vector for the vaccination strategy of choice.
A high level of antigen expression and efficient targeted delivery are the main goals in
the process of the development of viral vector vaccines. Using the targeted vector delivery, the
antigen-coding gene can be directed to professional APCs or to a specific tissue. For example,
members of alphavirus genus and poxviruses are able to transduce DCs without inhibiting the
immunostimulatory function of these APCs (114, 174). The transduction of DCs may elicit direct
priming of an immune response. However, in the case of poxviruses it was shown that CTL
responses against modified vaccinia virus Ankara were dominated by cross-priming in vivo,
despite the ability of the virus to infect DCs (57).
Adenoviruses (9), MV (15) and poliovirus (34) infect predominantly via mucosal
surfaces. Vectors based on these viruses may therefore be effective for mucosal administration
and induction of mucosal immunity. In addition, it was shown that VSV recombinants
expressing the hemagglutinin protein of influenza virus (146) or the MV hemagglutinin (152)
were able to induce protective immune responses after intranasal immunization in rodents.
However, in the case of VSV as an intranasal vaccine vector potential neurotoxicity should be
taken into consideration (143). A positive characteristic of VSV as a vaccine vector is that no
proteins encoded by the VSV genome have the capacity to interfere with the host interferon
25
response (162). It seems likely that the cytokine response activated in target cells during the VSV
infection will possesses an adjuvant activity for antigen-specific responses to vaccine antigens.
Viral vectors are different in terms of their capacity for the insertion of foreign genetic
material. Thus, non-enveloped viruses such as poliovirus, adenovirus, and AAV have a rigid
capsid structure that does not allow incorporation of more genetic material than the size of wildtype virus genome. For example, adenoviral capsid can package ~105% of the adenovirus
genome size. It means that a transgene of 3-4 kilo base pairs (kbp) can be packaged by a
replication-competent E3-deleted adenovirus. Replication-defective vectors bearing additional
deletions of essential E1 region in their genomes are able to accommodate up to 7.5 kbp of
foreign DNA (140). Some viruses with larger genomes can tolerate larger insertions of foreign
genetic material, but vector construction may in turn be more laborious.
Viral vectors that replicate in the nucleus represent potential risk of incorporation of their
genes into the host genome. Thus, vectors with entirely cytoplasmic replication cycle, such as
poxviruses or MV, may be preferable to reduce the risk of integration. For some applications,
especially in gene replacement therapy, integrating vectors, such as retroviruses, could be
beneficial.
Another important characteristic of viral vaccine vectors is that some of them can induce
innate immune responses through pattern recognition receptors (PRRs), acting as adjuvants to
the delivered antigens. This adjuvant effects are mediated through type I interferon production
and an inflammatory response. It has been proposed that the more PRRs are activated, the more
robust the immune response induced by the vaccine (136). A group of membrane-bound
signaling PRRs is represented by an array of TLRs and the mannose receptor (8, 18). Each
26
member of the TLR family recognizes distinct pathogen-associated molecular pattern and
mediates the activation of NF-kB and over signaling pathways (166). TLRs recognize several
molecular patterns associated with viruses including surface glycoproteins (TLR1, 2 and 4) (19,
60) and nucleic acids (TLR3, 7, 8 and 9) (3, 40, 94, 175). TLR3 is a receptor for double-stranded
(ds) RNA that transmits signals that activate NF-kB and IFN-b promoter (102). The replication
cycle of many RNA viruses has a double-stranded RNA replication intermediate, which is able
to activate innate immune response through the TLR3 pathway (144). TLR3 signaling may be of
particular importance for the immune responses to viruses that do not directly infect DCs as it
was shown to promote cross-priming of CD8+ T cells in response to dsRNA (154).
The diversity of viruses and replication strategies employed by them creates unlimited
perspectives for their use as gene-delivery vehicles to combat diseases. Although many problems
associated with safety and efficient manufacturing of viral vectors remain to be addressed this
strategy is one of the most promising in respect of development of a cure against unconquerable
diseases, such as AIDS, malaria, tuberculosis, influenza, and various cancers.
Prime-boost strategy:
Commonly, schemes of vaccination include repeated administrations of the same vaccine
(homologous boosting) to achieve protective humoral immune responses. However, immunity
developed after the primary immunization by a vaccine antigen can impair effective antigen
presentation after subsequent injections. This is believed to be a reason for a low cellular
immune response induced by the use of homologous boosting. As a solution to this problem, the
27
sequential administration of a vaccine antigen using different antigen-delivery systems
(heterologous boosting) was proposed and referred to as ‘prime-boosting’. This strategy evolved
after the gene-based vaccines had emerged as promising alternatives to traditional vaccine
strategies. The basic prime-boost strategy involves priming the immune system to an antigen
delivered by one vector and then boosting this immunity by re-administration of the antigen in
the context of a distinct vector. This vaccination scheme induces synergistic enhancement of
immunity to the target antigen reflected in an increased number of antigen-specific T cells,
selective enrichment of high avidity T-cells and increased efficacy against pathogen challenge
(185). Recently, several studies have demonstrated the efficacy of prime-boost vaccination
strategies in generating cellular immunity to a variety of pathogens. These include,
Mycobacteriun tuberculosis (45, 137), HIV (21, 188) and simian immunodeficiency virus (153),
malaria (28, 170), Leishmania (25, 138), Ebola virus (107), hepatitis C virus (38, 128), herpes
simplex virus (49, 160), human papillomavirus (47, 95), hepatitis B virus (110), and Japanese
encephalitis virus (86). Thus, heterologous prime-boost vaccination strategies with use of DNA
vaccines and viral vectors generate high levels of both CD4+ and CD8+ T-cell mediated
immunity, which is currently viewed as crucial for protection against a variety of pathogens,
including HIV.
Conclusions:
Last decades have brought remarkable advances in the field of molecular biology and gene
sequencing that help to uncover the mechanisms of interactions between microorganisms and the
host immune system. This progress has significantly facilitated the development of rationally28
designed vaccines for both prophylaxis and therapy of a wide range of diseases. Currently, the
field of vaccine development has a set of novel powerful tools. This arsenal of tools includes
reverse vaccinology, which allows identification of potential vaccine antigens without the need
for cultivating the pathogen, as well as a wide variety of vectors that allow increase and
manipulation of the immune response towards the desired type of immunity. Some successful
steps have been made to solve the key problems associated with the relatively low
immunogenicity of DNA vaccines and pre-existing immunity to viral vectors. These steps
include development of a DNA prime and recombinant viral vector boost strategy, which may
help circumvent pre-existing immunity to the viral vector, and generation of different methods
that improve the antigen expression by vaccine vectors and presentation of expressed antigens to
the immune system. Some of these new vaccine strategies are being translated into clinical trials.
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