British Medical Bulletin 62:29-44 (2002)
© 2002 Oxford University Press
Delivery technologies for human vaccines
Philippe Moingeon,
Charles de Taisne and
Jeffrey Almond
Aventis Pasteur SA, Research and Development, Marcy l'Etoile, France
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Abstract
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There is currently intense research activity aimed at the development
of new delivery systems for vaccines. The goal is to identify
optimal methods for presenting target antigens to the immune
system in a manner that will elicit immune responses appropriate
for protection against, or treatment of, a specific disease.
Several different approaches to this general goal have been
developed, some are empirical and remain poorly understood,
others are more rational, being based, for example, on mimicking
natural infections
in vivo or on targeting particular features
of the immune system. This article will review three categories
of delivery systems: (i) adjuvants and formulations; (ii) antigen
vectors, including live attenuated micro-organisms and synthetic
vectors; and (iii) novel devices for vaccine administration.
The review will be restricted to late stage developments in
the field of human vaccination.
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Why do we need innovative delivery technologies?
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There are currently several factors that are creating pressure
to improve delivery systems for vaccines. First, in the current
regulatory environment, there is a growing requirement to develop
vaccines that are very well defined in molecular terms. Thus,
as opposed to using whole-inactivated pathogens presenting a
complex range of antigens, most newly developed vaccines are
rather based on selected target antigens. In some cases these
may be single molecules, or even fragments thereof, derived
from an infectious micro-organism, a tumour cell, an allergen
or an auto-antigen. The target molecule may be administered
as a purified protein or as a peptide(s), or may be expressed
from plasmid DNA or a recombinant virus. Often, such molecular
vaccines are poorly immunogenic, implying a need for an adjuvant,
a specific formulation or a vector system of enhanced immunogenicity
1
.
Second, although in the past most vaccines have been designed
to stimulate antibody responses against surface molecules of
bacteria or viruses, new generation vaccines are increasingly
designed to elicit cellular immune responses, especially of
the Th1 type. Such responses are considered paramount for targeting
chronic infectious diseases that may have an intracellular stage
(associated for example with HIV1, herpes viruses, hepatitis
C virus,
Helicobacter pylori,
Plasmodium falciparum,
Mycobacterium tuberculosis), but also for the development of therapeutic vaccines
against cancer, autoimmune diseases or allergies
2. New vaccines
are also being developed to elicit mucosal immune responses
in humans, for example to protect against pathogens such as
influenza virus, HIV1, HSV or human oncogenic or wart-associated
papilloma viruses. Unlike most of the traditional vaccines,
these efforts require the recruitment of cellular or mucosal
immune effector mechanisms and necessitate the exploration of
new routes of administration, new formulations, and new adjuvant
systems
3. Third, improving vaccine administration generally,
either for the physician, or more importantly for the customer,
towards pain-free and safe needle-less devices is likely to
represent a major driver in the future vaccine market.
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Adjuvant and formulation systems
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Main adjuvant categories
Adjuvants encompass a highly heterogeneous group of substances
capable of increasing or modulating humoral and/or cellular
immune responses. They include mineral compounds (
e.g. aluminium
hydroxide or aluminium phosphate), water-in-oil or oil-in-water
emulsions (
e.g. incomplete Freund's adjuvant [IFA] or MF59,
respectively), chemically or genetically detoxified bacterial
toxins, such as the cholera toxin (CT) or lymphotoxin (LT) from
Escherichia coli, saponins (QuilA, QS21), muramyl di- or tripeptides
and derivatives (MTP-PE), copolymers, ISCOMS, cytokines, CpG
oligonucleotides, and combinations thereof (
Table 1)
1,4–6.
Some of these adjuvants may facilitate long-term persistence
of the antigen at the injection site (the so-called ‘depot’
effect). Others may target antigen presenting cells (APCs) by
presenting antigens in a particulate state, or may specifically
elicit the production of a pattern of cytokines relevant to
the induction of a Th1 or Th2 response
1,4.
Efficient enhancement of antibody responses has been possible
in humans for many decades through the use of aluminium salts
4.
By contrast, enhancement of the magnitude and duration of cellular
(Th1) immune responses has been more difficult to achieve, even
if some lymphoproliferative and, to a much lower extent, cytotoxic
T-cell responses have been observed with selected antigen-adjuvant
combinations (
Table 1)
6–11. To elicit mucosal immunity,
many approaches have exploited soluble holotoxins mixed with
antigen, such as the holotoxin from
Vibrio cholerae (CT), from
E. coli (heat labile LT), or
Bordetella pertussis (PT). In humans,
CT is highly toxic, therefore attempts have focused on the use
of the CTB subunit, which can bind to the widely expressed GM1
ganglioside, but lacks the toxic ADP-ribosyltransferase activity
associated with the A subunit. More recently, genetically detoxified
toxins, which lack the ADP ribosyltransferase activity but retain
most of their adjuvant properties have been developed
5.
Cytokines such as IL-2, GM-CSF, IL-12 and accessory molecules such as B7.1 have also been tested as immunoadjuvants in humans, mostly in cancer patients, with mixed results, both in terms of safety and immunogenicity (Table 1).
Antigen particulate formulations
Apart from simply admixing the antigen with the adjuvant, formulation strategies may aim to facilitate the capture and the entry of the antigen into antigen presenting cells. For example, formulating T-cell antigens, expressed as peptides, proteins, plasmid DNA or even RNA into cationic liposomes appears to increase CTL responses in vivo in animal models12,13. Liposomes are artificial, spherical, closed vesicles which consist of one or more lipid bilayers. Liposome-encapsulated antigens are delivered more efficiently to the cytoplasm of APCs, presumably as a result of membrane fusion. Usually, liposomes are made from ester phospholipids. More recently, polar phospholipids from archebacteriae have also been used, leading to so-called ‘archeosomes’14. The latter are based on regularly branched phytanyl chains, with 20 or 40 carbon length. Archeosomes demonstrate better stabilities to high temperature, alkaline pH, serum proteins, when compared with conventional liposomes. Other formulations being explored include spherulites (multilamellar vesicles made of biocompatible amphiphiles) and transfersomes (highly deformable vesicles which can deliver small molecules non-invasively through the skin)13,15. One liposome-based approach has proven successful in humans: in this approach, antigens derived from the hepatitis A or influenza virus have been incorporated into a mixture of natural and synthetic phospholipids, called virosomes (Table 1). Such vaccines were shown to be well tolerated and to induce both a 100% seroconversion rate and high antibody titres within 2 weeks10.
Other exploratory approaches consist of attaching the antigen to small particles. Non-ionic block co-polymers synthesized from ethylene oxide and propylene oxide can be produced, with varying surfactant characteristics. Other antigen formulations, based on poly-(L)-lactide or alginate microspheres, appear, in animal models, to enhance immune responses (both antibody and T-cell lymphoproliferative, and mucosal immunity)12. Such formulations also facilitate phagocytosis and fluid phase internalization of the antigen by macrophages and dendritic cells, with subsequent transfer into the class I and class II presentation pathways, with up to a 1000–10,000-fold increased efficiency as compared to soluble antigen12. Microparticulate antigen presentation systems, when given orally, deliver the antigen to the mucosal surface, where they are captured by specialized microfold or M cells, prior to transfer to Peyer's patches, thereby inducing mucosal immunity3. In addition, injectable microsphere formulations containing the target antigen(s) create a controlled-release mechanism allowing the possibility of providing disease protection after a single inoculation.
Towards the rational design of adjuvants and formulations
In the absence of a detailed understanding of their modes of action, the development of adjuvants and formulations has, in the past, been largely empirical. Recent advances in our understanding of the physiology of immune responses, however, promises to pave the way to a more ‘rational’ design of adjuvants and formulations, most particularly with the aim of eliciting Th1 immune responses1,2,6. Notwithstanding a potential direct effect on T lymphocytes, the central target for Th1 adjuvants/formulations is the APC. Theoretically, Th1 adjuvants and formulations of the future should have the following properties:
- Attract APCs, for example by providing molecular cues mimicking the natural ‘danger’ signals that seem to be a feature of bacteria and viruses. A range of molecular stimuli providing ‘danger signals’ to the immune system has recently been identified. These include, double stranded (ds) RNA, LPS, and unmethylated CpG dinucleotides flanked by two 5' purines and two 3' pyrimidines, either from bacteria or of synthetic origin1,6. Most of these molecules appear to function as ligands for Toll-like receptors (TLR3, TLR4 and TLR9, respectively), and can rapidly stimulate immune cells (T-cells, B-cells, NK-cells and macrophages) to produce pro-inflammatory cytokines, including IL-1, IL-6, IL-12, IL-18, TNF-
and IFN-
.
- Target antigen presenting cells. Formulating antigens to better target antigen presenting cells might be facilitated by the recent identification of a variety of surface receptors expressed preferentially by APCs1. These include the high affinity receptor for IgGs (FcRI, CD64), mannose/fucose receptors, certain chemokine receptors, scavenger receptors, molecules capable of binding and capturing heat shock proteins, apoptotic bodies and apoptotic cells (e.g. CD14, Vß5, CD36) or endocytic receptors such as the C-type lectin termed langerin. There is now clear evidence that targeting the antigen to such surface receptors allows antigen internalization, and presentation to T-cells in an MHC class I restricted manner (cross-priming)12.
- Induce dendritic cell maturation. Maturation or ‘conditioning’ of APCs can be achieved by cross-linking CD40 molecules with CD40L or anti-CD40 antibodies. This leads to enhancement of antigen-presenting functions presumably by mimicking signals associated with T-cell help1.
Collectively, the recent insights into pro-inflammatory signals have opened the way to a more rational design of immuno-adjuvants, most particularly of Th1 adjuvants1,2,6. Improved knowledge on the biology of dendritic cells and antigen trafficking and processing also provide clues for designing new formulations. Considering the complex and orchestrated series of events leading to an antigen-specific activation of the immune system, it is very unlikely that a single molecule or component will suffice as a Th1 adjuvant. Rather, it appears important to combine various molecules in order to achieve both recruitment, targeting, and activation/conditioning of APCs in the presence of the desired antigen1.
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Vectors
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Viral vectors
Based on the observation that viral infection results in the
presentation of virus-specific peptides in association with
both MHC class I and MHC class II on the surface of infected
cells, strategies have been designed to use viruses as immunization
vehicles to elicit antigen-specific immune responses. In such
approaches, cDNAs encoding one or several antigens, which may
be whole or truncated, are inserted into the viral vector. The
resulting recombinant viruses are used to infect the vaccinee,
with the aim of causing the expression of the selected antigen(s)
de novo and their subsequent presentation to the immune system.
For vaccination purposes, the ideal viral vector should be safe with respect to disease-causing potential, transmissibility and long-term persistence in the host. It should enable efficient presentation of expressed antigens to the immune system while preferably exhibiting low intrinsic immunogenicity so that it can be administered repeatedly to boost relevant specific immune responses. Indeed, the strong immunogenicity of adenoviral vectors has been a limiting factor for their use in gene therapy of cancer as well as in vaccination protocols requiring repeated administrations of the immunogen. The vector system must also meet criteria that enable its large scale industrialization. These include; efficient growth on a cell substrate acceptable to regulatory authorities; total genetic stability with respect to attenuation and presence of the foreign gene(s), scalability to tens of millions of doses; easy purification of the vector virus away from cellular debris, and stability in the final formulation15.
A large number of RNA and DNA viruses have been developed experimentally as vectors although their flexibility and utility varies greatly (Table 2). Several have been based on attenuated virus strains that have themselves been used as vaccines (e.g. vaccinia virus, polio virus, yellow fever virus), whereas others have been specifically manipulated to minimize disease-causing potential while maximizing immunogenic potential15. Some viral vector systems take advantage of natural host restriction. For example, avipox virus-derived vectors which replicate in avian cells are unable to complete a full round of replication in human cells and are, therefore, apathogenic and unable to transmit person-to-person. They are, however, capable of infecting human cells and express the incorporated antigen gene. On the same concept, other viral vectors such as those based on alphaviruses, adeno-associated viruses and some herpes simplex viruses, have been engineered to remove critical genes required for generating completely infectious particles in humans cells15. These vectors require helper systems for their propagation in the laboratory. It may be, for vaccination purposes, an advantage for viral vectors to be able to infect human APCs, such as dendritic cells or macrophages. Cytopathic viral vectors can still induce immune responses following infection of APCs, suggesting that these cells retain their capacity to initiate immune responses, at least during the early phase of the infectious cycle. It may be that apoptotic bodies containing antigens and produced as a result of viral infection can be captured by uninfected APCs.
Recently, a category of new potential vectors has emerged, based
on viral-like particles (VLPs)
16,17. These vectors consist of
capsid protein(s) capable of self-assembly into non-infectious
viral particles. Heterologous genes can be inserted, usually
as fusion protein with capsid proteins. VLPs based on capsid
proteins from human papilloma viruses (HPV), parvovirus or rotavirus,
have been produced and tested successfully in animal models
(
Table 2)
16,17. Another potentially useful viral vector for
vaccination purposes, which can accommodate a large nucleic
acid insert, is based on coronavirus. This virus is responsible
for respiratory (
i.e. common cold) and also enteric diseases
in humans and can be used specifically as a vector to elicit
immune responses at mucosal surfaces. Given, however, that virtually
all humans have developed antibodies to these viruses in prior
exposure, the interest of coronavirus as a vector in humans
remains to be demonstrated.
Bacterial vectors
In addition to viral vectors, live bacteria are also being tested as carrier systems for DNA vaccines. In this approach, attenuated or mutant strains of both Gram-positive or Gram-negative intracellular bacteria can be used to administer DNA vaccines via mucosal surfaces, or as a direct delivery systems to target APCs18. In this regard, BCG, Listeria monocytogenes, Salmonella typhi, S. typhimurium, or Shigella flexnerii can be considered as vectors. After being phagocytosed by APCs, such bacteria can survive inside the cell, by either preventing the fusion of the phagolysosome with lysosomes, or by exiting from the phagosome into the cytosol where they can release the DNA18. Such DNA can subsequently enter the nucleus and express the encoded antigen, which can be presented by the APC in association with both MHC class I and class II molecules. Importantly, live, but not heat-inactivated, intracellular bacteria also exhibit a capacity to induce a potent maturation of dendritic cells, thereby optimizing the presentation of heterologous antigens19. When used as vectors in vivo to immunize mice, live intracellular bacteria have been shown to elicit both humoral and cellular responses against heterologous bacterial, viral and tumoural antigens, leading to protection against infectious or tumour challenge. Several Gram-negative bacteria were also found to deliver plasmid DNA to human dendritic cells in vitro18. As an alternative to using whole bacteria, attempts are being made to use bacterial proteins and lipoproteins as carriers for T-cell epitopes20: with this aim, outer membrane proteins (e.g. OmpA from Klebsiella pneumoniae, or Opr1 from Pseudomonas aeruginosa) and bacterial toxins (e.g. the adenylate cyclase toxin from Bordetella pertussis) have been successfully engineered to accommodate peptides representing heterologous T-cell epitopes20,21. These bacterial proteins have the capacity to target the antigens to dendritic cells and to elicit, at least in murine models, strong CTL responses. The utilization of bacterial proteins as carriers for capsular polysaccharides as antigens has also been very successful (see article by Finn elsewhere in this issue).
Other vectors
Plasmid DNA
Vaccines based on plasmid DNA elicit strong antibody and T-cell responses in animal models, including mice and non-human primates. In contrast, when used in humans to immunize against HIV1 or P. falciparum antigens, these vaccines failed to elicit antibodies, even if cellular immune responses (CTLs) were detected when using milligram quantities of the vaccine22,23. Currently, attempts to further enhance immune responses elicited by DNA vaccines are focusing on codon optimization in order to enhance expression in eukaryotic cells, formulation with cationic lipids to improve targeting of APCs and cell entry, and design of DNA vaccines co-expressing the antigen with an immunostimulatory cytokine gene2. These approaches, which have given some encouraging results in terms of improvement of immunogenicity in animal models, are still unproven in humans. In another approach, microscopic particles have been coated with a plasmid encoding the hepatitis B surface antigen, and administered to seronegative human volunteers through the skin using the Powderject XR1 particle accelerator. The vaccine was well tolerated, but it failed to induce primary antibody responses24. Another trend today is to associate DNA with other vectors, as part of mixed (prime-boost) immunization regimens: associations for example between DNA and poxviruses, including vaccinia or the canarypox ALVAC, appear to be promising in order to induce both antibody and cellular responses in animals, and are now being tested in humans2.
Plant-based edible vaccines
New developments in molecular plant virology, including for example Agrobacterium tumefaciens-mediated gene transfer, have helped to generate plant-based systems as a means to produce vaccine antigens or even as an immunization vehicle25,26. Antigens such as the hepatitis B surface antigen, the E. coli heat-labile enterotoxin, or the rabies virus glycoprotein have been produced in such plant-based systems and shown to elicit antibodies (including in some systems mucosal IgAs) when fed orally to mice. In humans, feeding of transgenic lettuce expressing HbsAg or of transgenic potatoes expressing E. coli LT or the Newcastle virus capsid protein also elicited significant levels of antigen-specific antibodies25. Plants represent cost-effective expression systems to produce large amounts of recombinant proteins. Such expression systems, however, might not be suitable when the vaccine antigen is a glycoprotein. In addition, vaccination through the oral route usually does not elicit strong systemic immune responses in humans.
Dendritic cells and exosomes
Dendritic cells (DCs) are currently being used as an antigen presentation platform for vaccination in cancer patients27. In this approach, DCs are traditionally expanded in vitro from monocyte-derived progenitors, and subsequently loaded with tumour-associated antigens in the form of peptides, proteins, recombinant viruses, plasmid DNA, RNA formulated with cationic lipids, or tumour lysates. DC-based cellular vaccines have been tested thus far in humans against the following cancers (and target antigens): B-cell lymphoma (Ig idiotypes), melanoma (MAGE1, MAGE3, MART1, tyrosinase, tumour lysates), bladder cancer (MAGE3), colorectal cancer (CEA), and prostate cancer (PSM-P1, PSM-P2, PSA, PAP)27. Collectively, these vaccines were very well tolerated, and elicited some level of antitumour CTL responses. Partial remissions and disease stabilization were observed in at least a fraction (usually in the range of 10–30%) of the vaccinees. Despite such encouraging results, procedures to prepare and load DCs with antigens remain expensive and cumbersome, making it difficult to apply on a large scale to current clinical practice. One alternative being explored in humans consists in isolating exosomes (subcellular organelles containing both MHC class I and II and T-cell co-stimulatory molecules) from DCs as a basis for a cell-free vaccine28. In animal models, exosomes isolated from tumour peptide-pulsed DCs could prime efficiently in vivo cytotoxic T lymphocytes capable of eradicating or suppressing growth of established tumours.
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Devices
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A number of new needle-free or modified needle devices, which
carry potentially a number of advantages over conventional needle
injection, are being developed for vaccine administration
29–31.
Such advantages include increased safety, acceptability and,
therefore, treatment compliance, as well as potentially increased
efficacy linked to a broader, or modified, tissue distribution
of the antigen, ease of use leading to self-administration,
administration of smaller doses of the antigen and adjuvants,
as well as delivery via either the mucosal (nasal or oral),
subcutaneous or intradermal route
29,30.
Table 3 summarizes devices which have been (or are being tested in humans). The Macroflux microneedle system allows administration of the antigen dry-coated onto microneedles. When pressed onto the skin, the microprojections create mechanical pathways through the superficial skin, allowing intracutaneous delivery of the antigen to an average depth of 100 µm. The antigen dose administered can be controlled by the formulation, wearing time, and system size. The largest experience in the field of needle-free delivery to humans has been gained with a variety of jet-injectors able to deliver vaccines by the subcutaneous route32,33. These devices use forces derived from two sources of power, either a spring or compressed gas, to propel the vaccine through the skin. Needle-free injection was found to increase immune responses to both conventional and DNA-based vaccines: for example, seroconversion rates as well as antibody titres elicited in humans by a hepatitis A vaccine or a trivalent influenza vaccine were found to be increased by at least 10% when using needle-free injections, as opposed to needle and syringe administration34. Further work is required, however, to control the consistency of the pressure of injection to ensure proper delivery of vaccine to various types of skin. Also, the greater depth of administration, the greater discomfort. An advantage of spring-powered devices is that they are usually lighter and smaller than gas-powered devices. They are also more durable and inexpensive. Coiled springs, however, provide only a limited pressure. In contrast, gas-operated devices are more powerful. As such, they allow the administration of larger volumes through both the subcutaneous and intramuscular route. The gas cartridge needs, however, to be replaced regularly, making these usually large devices more costly than systems operated with a coiled spring. With both systems, the antigen can be administered either in a liquid form, or as a powder (e.g. adsorbed onto a microscopic gold particle, as in the Powderject system). Both single-dose injectors, but also high-speed multidose injector systems (allowing mass immunization) are being developed.
Recently, transcutaneous immunization strategies have been introduced
as an alternative non-invasive administration route
35. In this
approach, the antigen is topically applied to intact skin, thereby
targeting the antigen to Langerhans cells, which will subsequently
migrate through the skin into draining lymph nodes to initiate
the immune response. Adjuvants usually associated with the antigen
include the CT and LT toxins derived from
V. cholera and
E. coli, respectively
35. When applied to the rehydrated skin of
human volunteers using a patch, such vaccines were shown to
be well tolerated, and to elicit strong antibody and lymphoproliferative
responses against the antigen, such as LT or the CS6 antigen
from enterotoxigenic
E. coli.
Lastly, attempts are being made to develop aerosol delivery of powder vaccine formulations, using a nebulizer36. Advantages would include ease of use, increased safety, dry powder formulation (which would reduce refrigeration requirements), and potential enhanced mucosal immunity.
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Key points for clinical practice
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- New delivery systems for human vaccines are being developed to enhance cellular and mucosal immunity, as well as ease of use
- There is as of today no Th1 adjuvant efficient in humans. Such adjuvants are needed to develop powerful therapeutic vaccines against cancer or chronic infectious diseases
- Needle-less injection systems being developed include spring or gas-powered devices, transdermal patches, as well as aerosols for delivery of powder vaccines
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Footnotes
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Correspondence to: Dr Philippe Moingeon, Aventis Pasteur SA,
Campus Mérieux, 1541 Avenue Marcel Mérieux, 69280
Marcy l'Etoile, France
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