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Recombinant viruses as vaccines and immunological tools
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Recombinant viruses as vaccines and immunological tools Michael S Rolph* and lan A Ramshawt Recombinant viruses have been investigated as candidate vaccines, and have also been used extensively as immunological tools. Recent advances in this area include the following: the construction and testing of a recombinant simian immunodeficiency virus encoding human interferon-T; the development of new vectors such as recombinant poliovirus; and the generation of polyepitope vaccines. Basic immunological research has benefited from the use of recombinant viruses to further understand the role of molecules such as CD40 ligand, nitric oxide and interleukin-4.
Addresses *Department of Immunology, Max Planck Institute for Infection Biology, Monbijoustrasse 2, D-10117 Berlin, Germany; e-mail: [email protected] ~'Division of Immunology and Cell Biology, John Curtin School of Medical Research, Australian National University, PO Box 334, Canberra, ACT 2601, Australia; e-mail: [email protected] Current Opinion in Immunology 1997, 9:517-524
http://biomednet.com/elecref/0952791500900517 © Current Biology Ltd ISSN 0952-7915 Abbreviations CTL cytotoxic T lymphocyte E early HA haemagglutinin IFN interferon iNOS inducible nitric oxide synthase L ligand MVA modified VV Ankara strain r recombinant VV vaccinia virus
Introduction Recombinant viruses represent a particularly promising avenue of vaccine research, both for improving existing vaccines and for developing new ones. In addition, recombinant viruses are valuable tools for the experimental immunologist. Expression of antigens or immunomodulators by virus vectors has proven to be a productive approach for studying in vitro and in vivo immune responses. This review focuses on recent developments in the field of recombinant viruses as vaccines and immunological tools, with an emphasis on their use in understanding/treating infectious disease. Recombinant viruses for cancer immunotherapy (reviewed in [1]) and gene therapy [2] are beyond the scope of this review.
Recombinant viruses as vaccines A wide range of viruses has been investigated as potential recombinant vaccines. Although each viral vector has its own unique characteristics, an important feature of almost all recombinant viruses is the ability to induce not just humoral, but also cell-mediated immunity. For example,
recombinant viral vectors have received considerable attention as candidate HIV vaccines due to their capacity to stimulate cell-mediated immunity. This may be a very important component of a successful HIV vaccine [3]. PoxvJruses
T h e prototype for all recombinant viruses remains vaccinia virus (VV). Due to safety concerns over their use in humans, standard recombinant (r)VVs are being investigated principally as veterinary vaccines. Indeed, one of the major achievements in this area has been the use of r W expressing rabies surface glycoprotein as a live vaccine in bait for controlling rabies in fox populations (reviewed in [4°]). Due to the relatively high complication rate of vaccination with rVV, and the increasing number of immunodeficient people, highly attenuated rVV have been favoured as potential vaccines for human populations. One such virus, NYVAC, was constructed by the deletion of 18 VV open-reading frames [5,6]. This virus is highly attenuated in vivo, but still induces an effective immune response not substantially inferior to that seen for standard r W [5]. NYVAC vectors encoding a wide range of pathogen-derived molecules have been constructed. For example, NYVAC recombinants have recently been used as candidate malaria vaccines [7,8"]. Recombinant viral vectors represent an attractive approach for malaria vaccines as it is becoming increasingly apparent that CD8 ÷ T cells constitute all important protective mechanism against malaria infection [7]. Mice were immunized with an NYVAC encoding Plasmodium berghei circumsporozoite protein. This resulted in a high level of CD8 ÷ T cell mediated protection against subsequent challenge with P berghei [7]. An NYVAC has also been constructed that expresses seven different P. falcipantm antigens, derived from various stages of the parasite life cycle [8°]. This virus induces Plasmodium-specific antibody responses in rhesus macaques, and it will be interesting to see whether the vaccine induces T cell responses such as cytotoxic T lymphocytes (CTLs), and whether similar responses can be induced in humans. Recombinant viruses have also been constructed from the modified VV Ankara strain (MVA). This virus was generated by repeated passage in chick embryo fibroblasts, and is replication deficient in mammalian cells [9]. During the smallpox eradication programme, MVA was used extensively to vaccinate individuals at risk from standard vaccinia vaccines, such as those with impaired immune systems. Recombinant MVAs expressing influenza haemagglutinin and nucleoprotein genes were shown to protect mice from influenza virus challenge [10,11"]. Solid mucosal immunity was induced following
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oral immunisation of mice with this MVA recombinant [11"]. Furthermore, animals vaccinated with an MVA encoding simian immunodeficiency virus (SIV) gag-pol and env sequences, followed by inactivated SIV, showed restricted SIV replication on subsequent challenge with SIV [12]. Due to the safety concerns associated with replicationcompetent recombinant viruses, avipoxviruses have been examined as potential vaccines. These viruses abortively infect mammalian cells, while maintaining the capacity to present antigens to the immune system. Thus, these viruses provide a level of safety not obtainable with replication-competent viruses. Canarypoxvirus has received the most attention as a candidate recombinant vaccine, as it more efficiently induces immunity than other avipoxviruses [13]. Immunisation with recombinant avipoxviruses encoding foreign glycoproteins has been shown to induce both humoral and cellular immunity against determinants from a number of pathogens, including influenza virus [14], Japanese encephalitis virus [15], rabies [16], canine distemper virus [17] and HIV [18-20]. Adenovirus Some of the advantages of adenovirus vaccines include: they are not particularly pathogenic in humans; they can be administered orally; live adenoviral vaccines have been used previously in humans; their genome is well characterised; and techniques are well established for the construction of adenoviral recombinants. Depending on the area of the genome into which foreign DNA is inserted, recombinant adenoviruses are either replication competent or replication deficient (reviewed in [21]). Most vaccine studies have used replication-competent viruses. Replication-deficient viruses are preferable from a safety viewpoint and are also able to induce effective immunity [22-24,25"]. Indeed, several reports have suggested that replication-deficient adenoviruses may be as good as, or even superior, to rVV vectors [25°,26]. Particularly impressive results were obtained when the foreign gene was placed under the control of a cytomegalovirus promoter [25"]. T h e major disadvantage of adenoviruses is their limited cloning capacity as compared with other vectors such as poxviruses. Classically, adenoviruses with deletions in the early (E)I or E3 genomic regions have been used, but more recent studies have demonstrated the viability of using even larger deletions in E3 and E4, thereby leading to an increase in cloning capacity (reviewed in [21]). A number of antigens have been encoded within recombinant adenoviruses, including bovine herpes virus type 1 glycoprotein gD [27], HIV [28], hepatitis C [22], measles virus nucleocapsid [24] and rabies glycoprotein [25",29]. Humoral [24,25",27], cell-mediated [24,25°,30] and mucosal immunity [27,30] can be induced by recombinant adenoviruses.
Other viruses
A number of other viruses have been investigated as potential recombinant vaccines (Table 1). Recent attention has focused on recombinant polioviruses as potential vaccine vectors. Attenuated polioviruses are already known to be safe and to induce long-lasting immunity. T h e virus can be given orally and induces both systemic and mucosal immunity. Development of recombinant polioviruses as vaccines is at an early stage, and a number of different strategies are being investigated for the construction of recombinants [31,32",33,34,35°,36]. Genetic stability of these vectors remains a concern. Nonetheless, recombinants expressing genes from SIV [35°,37], HIV [31,33,34,38] and hepatitis B [32"] have all been reported. Furthermore, some of these recombinants have been tested in vivo and shown to be immunogenic [32",35",38]. A number of other viruses have been tested as recombinant vaccines, some of which are listed in Table 1. T h e technology is available for the genetic manipulation of many other viruses and, for some, efforts are underway to construct vectors for vaccine testing. This should prove to be an intriguing area of research in the next few years. M i n i g e n e s and p o l y e p i t o p e s Increasing recognition of the potential importance of C T L s in vaccination, a view driven especially by HIV research, has recently focused attention on the expression of minimal C T L epitopes in recombinant viruses. Due to the small insert size, this approach is especially attractive for use with vectors, such as poliovirus, which have a limited capacity to accept foreign DNA. Conceivably, a very large number of individual epitopes could be encoded in a single vaccine, allowing immunisation against a wide range of pathogens, or against a pathogen, such as HIV, which has the capacity to vary its antigenic make-up. This strategy has been adopted in several studies [39",40,41",42]. Recombinant VV vectors were constructed encoding several contiguous minimal C T L epitopes. All C T L epitopes were appropriately presented, and when tested in vivo were shown to induce protective C T L responses [39",41"]. Furthermore, minimal B cell and T helper cell epitopes were also successfully encoded within the C T L epitope insert and in vivo could induce B cell and T helper cell responsiveness respectively [41"]. Two potential problems for linked minigene constructs have been proposed. First, that natural flanking sequences may be required for efficient proteolytic processing of the encoded epitopes and second, that peptide competition and immunodominance between the epitopes may interfere with their presentation. T h e above studies provide evidence that neither may present an insurmountable obstacle [39",40,41",42]. Another concern over the use of minigenes in vaccines is the potential for the generation of escape mutants, in which a single amino acid mutation in
Recombinant viruses as vaccines and immunological tools Rolph and Ramshaw
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Table 1 Some candidate recombinantviral vaccines. Type of immunity Virus type
Ab
CMI
Muc
Vaccinia
+
+
+
Prototype for all recombinant viruses. Can induce a wide range of immune responses, and very large amounts of foreign DNA can be incorporated into the vector. Used as a smallpox vaccine, and thus has been thoroughly tested in humans. Highly attenuated forms have been constructed.
[6,7,11",75,76]
Avipox
+
+
+
Undergoes abortive replication in mammalian cells, providing a high degree of biosafety, while maintaining the capacity to express foreign antigens.
[6,14,18,48]
Adenovirus
+
+
+
Can be administered orally, and can induce a wide range of immune responses. Replication-deficient adenoviruses can be constructed which still induce strong immune responses. Cloning capacity is not as great as for pox'viruses.
[91,24,25°,27]
Polio
+
+
Can be given orally and induces a strong mucosal response. Attenuated poliovirus vaccines have already been extensively tested in humans. Limited cloning capacity as compared with pox'viruses.
[31,32°,35",38]
Mengo
+
+
Limited cloning capacity.
[77,78]
SFV
+
+
Can be engineered either as recombinant infectious RNA, expressing additional subgenomic RNAs, or as 'replicons' in which structural genes are replaced with foreign DNA. Replicons require helper RNA or packaging cell lines for production.
[79-81]
Sindbis
+
+
Similar characteristics to SFV. Genetic stability of a recombinant expressing immunogenic proteins from Japanese encephalitis virus was low.
[80,82]
VEE
+
+
There is little or no pre-existing immunity to this vector in human populations.
Influenza
+
+
+
General comments
Induction of strong mucosal immunity. Pre-existing vector-specific immunity could potentially be avoided by using vectors belonging to different influenza virus subtypes.
References
[83] [84,85]
This table is a non-exhaustive list of types of recombinant viruses that have been tested as vaccines, showing the classes of immune response that have so far been demonstrated for each type. Ab, antibody; CMI, cell-mediated immunity; Muc, mucosal immunity; SFV, Semliki Forest virus; VEE, Venezuelan equine encephalitis.
a key epitope might be sufficient for a pathogen to escape vaccine induced immunity. This was addressed in one study, using an rVV encoding a C T L epitope from ListeHa monotytogenes. Immunisation with this virus protected mice against subsequent challenge with L. monocytogenes. Polymerase chain reaction analysis of colonies derived from the spleens of the vaccinated mice six days after infection with L. monocytogenes provided no evidence for the generation of C T L escape mutants [43].
Vector-specific i m m u n i t y Vector-specific immunity may present an obstacle to the use of some recombinant viral vectors. Early clinical trials of rVV encoding HIV gpl60 found that the immune response of vaccinia-naive subjects was superior to that of vaccinia-immune subjects [44]. Vector-specific immunity may also interfere with the immune response to booster immunisations. T h e problem of vector-specific immunity may not be as great with replication-deficient, as compared with replication-competent, recombinant vaccines. Previous immunity to canarypox virus or VV, did not substantially affect the immune response to a subsequent challenge
with a canarypox virus recombinant [45]. Similarly, a strong booster effect was seen at the second and third immunisation with a recombinant canarypoxvirus expressing rabies glycoprotein, despite the induction of a canarypoxvirus specific IgG response [16]. Prior immunisation with a replication-competent adenovirus had little or no effect on the response to subsequent immunisation with a replication-deficient adenovirus encoding rabies glycoprotein [25°]. Another study, however, found that a course of four immunisations with a replication-deficient adenovirus encoding I]-galactosidase did not give a better immune response than a single immunisation with the same virus. A strong adenovirus neutralising antibody response was detected after the second immunisation and may have been responsible for the lack of a booster effect [23].
P r i m e - b o o s t protocols Strategies involving priming with a recombinant viral vector, followed by boosting with the corresponding recombinant protein ('prime-boost'), have been used to circumvent the problems associated with vector-specific immunity, as well as being used to induce a broad immune response. Initial studies with rVV encoding HIV gpl60
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in humans reported rather poor HIV-specific immune responses [44]. When a prime-boost protocol was used, involving boosting with recombinant gpl60, the HIV-specific immune response was increased, and neutralising antibody and C T L activity were also detected [46,47]. A large number of the studies using prime-boost protocols have been directed towards HIV/SIV vaccination [12,18-20,48-52]. In addition to avoiding problems with vector-specific immunity, prime-boost protocols are attractive for HIV vaccines due to their capacity to induce humoral and cell-mediated immunity, both of which may be necessary for an efficacious HIV vaccine. In one study [49], poxviruses encoding HIV-1 sequences were used in a prime-boost protocol to immunise rhesus macaques against HIV-1. This protocol induced humoral and cellular immune responses, and protected against subsequent challenge with HIV-2 [49]. This demonstration that cross-protection between HIV-1 and HIV-2 can occur raises our hopes that the substantial genetic variability observed for HIV may not be an insurmountable barrier to effective vaccination [49]. An alternative prime-boost protocol has been used, involving priming with a DNA vaccine encoding influenza haemagglutinin (HA), followed by boosting with a recombinant fowlpoxvirus encoding influenza HA. This strategy induced particularly high HA-specific antibody levels, and resulted in strong resistance to subsequent influenza challenge [53].
Clinical trials Several clinical trials of recombinant viral vaccines have been reported in the past two years. Mostly these studies have used recombinant canarypox vectors due to their enhanced safety characteristics. A prime-boost protocol employing two immunisations with a recombinant canarypoxvirus expressing HIV gpl60, followed by a recombinant gpl60 boost, was shown to be safe in HIV-seronegative volunteers in a phase I trial [20]. Neutralising antibodies were induced in a majority of subjects. This approach also resulted in induction of gpl60-specific cytotoxicity, mainly class I restricted CD8 ÷ T cells, in 39% of subjects [20,48]. A similar study also induced gpl60-specific C T L activity, but in only 2 out of 12 volunteers, that is 17% [19]. I m m u n o m o d u l a t o r s as vaccines and immunological tools Since the early studies of Ramshaw et al. [54] and Flexner etal. [55], a large number of recombinant viruses encoding immunomodulatory agents such as cytokines has been constructed. T h e use of such immunomodulators has been investigated as a means of attenuating vaccines (resulting in greater biosafety) and enhancing vaccine-induced immune responses. Furthermore, such viruses have been useful as immunological tools for dissecting the in vivo function of virus-encoded molecules.
We have recently described an rVV encoding murine IL-4 [56"], the virulence of which, in mice, is enhanced as compared with a control rVV. Virus-encoded IL-4 downregulated antivirai C T L activity, suggesting that IL-4 can potentially play a role in downregulating an antiviral immune response, and that high levels of IL-4 production may be deleterious during virus infection. This finding is particularly interesting in relation to the hypothesis that progression to AIDS is associated with the development of a type 2 (IL-4, IL-5) cytokine response [57]. A recombinant adenovirus encoding the p35 and p40 subunits of murine IL-12 was used as a vector to investigate the role of IL-12 during infection of mice with Klebsiellapneumoniae. Intratracheal infection with the IL-12 expressing adenovirus resulted in 45% of the mice surviving a subsequent intratracheal K. pneumoniae infection, as compared with a 0% survival rate in K. pneumoniae-infected mice receiving a control adenovirus [58]. Thus, localised IL-12 production can exert considerable antimicrobial activity during K. pneumoniae infection. Studies with an rVV encoding murine IL-12, have demonstrated that this cytokine has considerable antiviral activity, as well as the capacity to inhibit pulmonary allergic airways disease (SP Hogan, PS Foster, X Tan, AJ Ramsay, personal communication). T h e directed delivery of cytokines by virus vectors to cytokine gene knockout mice has proved to be a powerful technique for investigating the role of cytokines in immune regulation. For example, mucosal IgA responses were found to be grossly deficient in IL-6 knockout mice [59]. T h e IgA response could be completely restored by the administration of an rVV encoding the gene for IL-6, but not by rVVs encoding IL-2, IL-4 or IL-5 [59]. Similarly, in a mouse model of asthma, IL-5 knockout mice were shown to be immune to airways damage [60"]. T h e full pathological response, characterised by eosinophilia and airways hyper-reactivity, was restored following intranasal treatment with an rVV encoding IL-5, thus confirming the crucial role in this model of IL-5 in the development of airways dysfunction [60"]. We, and others, have constructed rVVs encoding inducible nitric oxide synthase (iNOS), as a means of investigating the role of N O during VV infection. Such studies were important in view of the finding that inhibition of NO production during VV infection had no effect on the course of virus infection in mice [61]. iNOS-encoding VVs were, however, attenuated both in vitro [62",63] and in vivo [62"] indicating that NO has the potential to exert considerable antiviral activity in vivo. An interesting approach was taken by Wrighton et al. [64] who encoded the specific NF-~B inhibitor, I~¢Ba, in a recombinant adenovirus. Infection of endothelial cells with this virus resulted in the decreased expression of a number of factors associated with activation, such as vascular cell
Recombinant viruses as vaccines and immunological tools Rolph and Ramshaw
adhesion molecule 1, IL-1, IL-6 and IL-8, suggesting that targeting NF-~rB may be a possible immunosuppressive strategy. This type of approach has considerable potential for investigating the role of transcription factors in vivo. Another strategy for suppressing an inflammatory response is to encode molecules that can block the effects of endogenously produced inflammatory mediators. For example, an adenovirus was constructed to encode a chimeric protein capable of binding and blocking the activity of tumor necrosis factor o: and 13 (lymphotoxin) [65]. Mice treated with this virus showed a considerably reduced capacity to control infection with Pseuclomonas aeruginosa, but were protected against a lethal dose of lipopolysaccharide, showing the dual role of tumor necrosis factor in host defense and endotoxic shock [65]. Cell-surface ligands have also been encoded in rVV. In the case of the CD40 ligand (CD40L), infection of mice with an r W encoding this molecule revealed an unexpected role for CD40L: it can exert potent antiviral activity, as demonstrated by the reduced virulence of the recombinant virus in vivo [66]. An rVV encoding Fas ligand (FasL) was constructed to investigate the role of FasL in the regulation of C T L responses during virus infection. Thus, virus-infected cells expressed viral antigenic determinants and FasL. No effect of FasL on C T L activity was detected, arguing against a role for FasL in the regulation of C T L responses during W infection [67]. T h e role of chemokines in immunological processes represents a rapidly expanding field of research. Intratracheal administration of adenoviruses encoding macrophage inflammatory protein-2 [68] and regulated on activation normal T cell expressed and secreted (RANTES) [69] induced accumulation of polymorphs and monocytes respectively in the lung. Such constructs should prove invaluable for investigating in vivo chemokine function. Cytokine-expressing recombinant viruses have also been constructed with the aim of modulating the immune response to virus-encoded molecules, or of attenuating vaccine vectors. For example, the construction and testing of an attenuated (nefregion deleted) SIV encoding human interferon (IFN)-y has recently been reported [70,71°°]. Immunisation of macaques with the recombinant SIV expressing I F N - y resulted in lower virus titres following a subsequent challenge with virulent SIV, as compared with macaques immunised with a control nef-deleted SIV. This reduction in virus titres occurred despite the fact that the I F N - y expressing virus replicated less than the control virus, and despite the genetic instability of the IFN-y insert [71"]. Although nef-deleted SIV are safe for use in adult macaques, they are pathogenic in neonates [72]. Therefore, it is particularly encouraging that the IFN-y expressing SIV was not pathogenic in neonatal macaques, and was cleared within six weeks of challenge (T Yilma, personal communication). In contrast, an IL-2 expressing SIV replicated marginally more than the control
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virus and had little or no effect on antibody titres, T cell proliferation or C T L activity [73]. Other examples of cytokine modulation of vaccine responses include an avipoxvirus encoding influenza HA and IL-6 [14]. Virus-encoded IL-6 considerably enhanced the primary systemic and mucosal antibody responses to HA, and primed for enhanced recall responses when compared to a control virus [14]. Similarly, humotal and C T L responses were considerably augmented in an adenovirus encoding hepatitis B surface antigen (HBsAg) and human B7-1, as compared with an adenovirus encoding HBsAg only [74].
Conclusions Recombinant viral vectors hold considerable promise as candidate vaccines. Many different viruses are being investigated as potential vaccines, each with its own advantages and disadvantages. Important considerations for recombinant viral vaccines include biosafety, cloning capacity and the type of immunity that can be induced. Recombinant viruses are also important tools for the experimental immunologist and continue to provide novel insights into all aspects of immunobiology.
Acknowledgements The authors wish to thank T Yilma, B Moss and K Uberla for providing unpublished data and G Karupiah, (; Ada, B Coupar and A Suhrbier for their critical reading of the manuscript.
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•
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microbes, induces appropriate responses in vivo and confers protection against more than one pathogen. J Viro11997, 71:2292-2302. Along with [39"], this paper demonstrates the potential utility of recombinant viruses presenting multiple minimal immunogenic epitopes. Each epitope was processed and presented effectively and, where tested, induced protective immune responses. 42.
43.
56. •
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Kent SJ, Hu S-L, Corey L, Morton WR, Greenberg PD: Detection of simian immunodeficiency virus (SIV)-specific CD8 + T cells in macaques protected from SIV challenge by prior SIV subunit vaccination. J Virol 1996, 70:4941-4947.
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Foster PS, Hogan SP, Ramsay AJ, Matthaei KI, Young IG: Interleukin 5 deficiency abolishes eosinophUia, airways hyperreactivity, and lung damage in a mouse asthma model. J Exp Med 1996, 183:195-201. See annotation [62"]. Rolph MS, Ramshaw IA, Rockett KA, Ruby J, Cowden WB: Nitric oxide production is increased during murine vaccinia virus infection, but may not be essential for virus clearance. Virology 1996, 217:470-477
Rolph MS, Cowden WB, Medveczky CJ, Ramshaw IA: A recombinant vaccinia virus encoding inducible nitric oxide synthase is attenuated in vivo. J Viro11996, 70:7676-7685. This paper, along with [56",60"], demonstrates the utility of recombinant viruses expressing immunoactive molecules as tools for basic immunological research.
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Giavedoni L, Ahmad S, Jones L, Yilma T: Expression of gamma interferon by simian immunodeficiency virus increases attenuation and reduces postchallenge virus load in vaccinated rhesus macaques. J Virol 1997, 71:866-872. Expression of IFN-y in a recombinant nef-deleted SIV was shown to result in increased virus attenuation. Following challenge with virulent SIV, virus titres were lower in macaques that had previously received the IFN-y expressing SIV than in those that had received the control nef-deleted SIV. 72.
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Recombinant viruses as vaccines and immunological tools Michael S Rolph* and lan A Ramshawt Recombinant viruses have been investigated as candidate vaccines, and have also been used extensively as immunological tools. Recent advances in this area include the following: the construction and testing of a recombinant simian immunodeficiency virus encoding human interferon-T; the development of new vectors such as recombinant poliovirus; and the generation of polyepitope vaccines. Basic immunological research has benefited from the use of recombinant viruses to further understand the role of molecules such as CD40 ligand, nitric oxide and interleukin-4.
Addresses *Department of Immunology, Max Planck Institute for Infection Biology, Monbijoustrasse 2, D-10117 Berlin, Germany; e-mail: [email protected] ~'Division of Immunology and Cell Biology, John Curtin School of Medical Research, Australian National University, PO Box 334, Canberra, ACT 2601, Australia; e-mail: [email protected] Current Opinion in Immunology 1997, 9:517-524
http://biomednet.com/elecref/0952791500900517 © Current Biology Ltd ISSN 0952-7915 Abbreviations CTL cytotoxic T lymphocyte E early HA haemagglutinin IFN interferon iNOS inducible nitric oxide synthase L ligand MVA modified VV Ankara strain r recombinant VV vaccinia virus
Introduction Recombinant viruses represent a particularly promising avenue of vaccine research, both for improving existing vaccines and for developing new ones. In addition, recombinant viruses are valuable tools for the experimental immunologist. Expression of antigens or immunomodulators by virus vectors has proven to be a productive approach for studying in vitro and in vivo immune responses. This review focuses on recent developments in the field of recombinant viruses as vaccines and immunological tools, with an emphasis on their use in understanding/treating infectious disease. Recombinant viruses for cancer immunotherapy (reviewed in [1]) and gene therapy [2] are beyond the scope of this review.
Recombinant viruses as vaccines A wide range of viruses has been investigated as potential recombinant vaccines. Although each viral vector has its own unique characteristics, an important feature of almost all recombinant viruses is the ability to induce not just humoral, but also cell-mediated immunity. For example,
recombinant viral vectors have received considerable attention as candidate HIV vaccines due to their capacity to stimulate cell-mediated immunity. This may be a very important component of a successful HIV vaccine [3]. PoxvJruses
T h e prototype for all recombinant viruses remains vaccinia virus (VV). Due to safety concerns over their use in humans, standard recombinant (r)VVs are being investigated principally as veterinary vaccines. Indeed, one of the major achievements in this area has been the use of r W expressing rabies surface glycoprotein as a live vaccine in bait for controlling rabies in fox populations (reviewed in [4°]). Due to the relatively high complication rate of vaccination with rVV, and the increasing number of immunodeficient people, highly attenuated rVV have been favoured as potential vaccines for human populations. One such virus, NYVAC, was constructed by the deletion of 18 VV open-reading frames [5,6]. This virus is highly attenuated in vivo, but still induces an effective immune response not substantially inferior to that seen for standard r W [5]. NYVAC vectors encoding a wide range of pathogen-derived molecules have been constructed. For example, NYVAC recombinants have recently been used as candidate malaria vaccines [7,8"]. Recombinant viral vectors represent an attractive approach for malaria vaccines as it is becoming increasingly apparent that CD8 ÷ T cells constitute all important protective mechanism against malaria infection [7]. Mice were immunized with an NYVAC encoding Plasmodium berghei circumsporozoite protein. This resulted in a high level of CD8 ÷ T cell mediated protection against subsequent challenge with P berghei [7]. An NYVAC has also been constructed that expresses seven different P. falcipantm antigens, derived from various stages of the parasite life cycle [8°]. This virus induces Plasmodium-specific antibody responses in rhesus macaques, and it will be interesting to see whether the vaccine induces T cell responses such as cytotoxic T lymphocytes (CTLs), and whether similar responses can be induced in humans. Recombinant viruses have also been constructed from the modified VV Ankara strain (MVA). This virus was generated by repeated passage in chick embryo fibroblasts, and is replication deficient in mammalian cells [9]. During the smallpox eradication programme, MVA was used extensively to vaccinate individuals at risk from standard vaccinia vaccines, such as those with impaired immune systems. Recombinant MVAs expressing influenza haemagglutinin and nucleoprotein genes were shown to protect mice from influenza virus challenge [10,11"]. Solid mucosal immunity was induced following
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oral immunisation of mice with this MVA recombinant [11"]. Furthermore, animals vaccinated with an MVA encoding simian immunodeficiency virus (SIV) gag-pol and env sequences, followed by inactivated SIV, showed restricted SIV replication on subsequent challenge with SIV [12]. Due to the safety concerns associated with replicationcompetent recombinant viruses, avipoxviruses have been examined as potential vaccines. These viruses abortively infect mammalian cells, while maintaining the capacity to present antigens to the immune system. Thus, these viruses provide a level of safety not obtainable with replication-competent viruses. Canarypoxvirus has received the most attention as a candidate recombinant vaccine, as it more efficiently induces immunity than other avipoxviruses [13]. Immunisation with recombinant avipoxviruses encoding foreign glycoproteins has been shown to induce both humoral and cellular immunity against determinants from a number of pathogens, including influenza virus [14], Japanese encephalitis virus [15], rabies [16], canine distemper virus [17] and HIV [18-20]. Adenovirus Some of the advantages of adenovirus vaccines include: they are not particularly pathogenic in humans; they can be administered orally; live adenoviral vaccines have been used previously in humans; their genome is well characterised; and techniques are well established for the construction of adenoviral recombinants. Depending on the area of the genome into which foreign DNA is inserted, recombinant adenoviruses are either replication competent or replication deficient (reviewed in [21]). Most vaccine studies have used replication-competent viruses. Replication-deficient viruses are preferable from a safety viewpoint and are also able to induce effective immunity [22-24,25"]. Indeed, several reports have suggested that replication-deficient adenoviruses may be as good as, or even superior, to rVV vectors [25°,26]. Particularly impressive results were obtained when the foreign gene was placed under the control of a cytomegalovirus promoter [25"]. T h e major disadvantage of adenoviruses is their limited cloning capacity as compared with other vectors such as poxviruses. Classically, adenoviruses with deletions in the early (E)I or E3 genomic regions have been used, but more recent studies have demonstrated the viability of using even larger deletions in E3 and E4, thereby leading to an increase in cloning capacity (reviewed in [21]). A number of antigens have been encoded within recombinant adenoviruses, including bovine herpes virus type 1 glycoprotein gD [27], HIV [28], hepatitis C [22], measles virus nucleocapsid [24] and rabies glycoprotein [25",29]. Humoral [24,25",27], cell-mediated [24,25°,30] and mucosal immunity [27,30] can be induced by recombinant adenoviruses.
Other viruses
A number of other viruses have been investigated as potential recombinant vaccines (Table 1). Recent attention has focused on recombinant polioviruses as potential vaccine vectors. Attenuated polioviruses are already known to be safe and to induce long-lasting immunity. T h e virus can be given orally and induces both systemic and mucosal immunity. Development of recombinant polioviruses as vaccines is at an early stage, and a number of different strategies are being investigated for the construction of recombinants [31,32",33,34,35°,36]. Genetic stability of these vectors remains a concern. Nonetheless, recombinants expressing genes from SIV [35°,37], HIV [31,33,34,38] and hepatitis B [32"] have all been reported. Furthermore, some of these recombinants have been tested in vivo and shown to be immunogenic [32",35",38]. A number of other viruses have been tested as recombinant vaccines, some of which are listed in Table 1. T h e technology is available for the genetic manipulation of many other viruses and, for some, efforts are underway to construct vectors for vaccine testing. This should prove to be an intriguing area of research in the next few years. M i n i g e n e s and p o l y e p i t o p e s Increasing recognition of the potential importance of C T L s in vaccination, a view driven especially by HIV research, has recently focused attention on the expression of minimal C T L epitopes in recombinant viruses. Due to the small insert size, this approach is especially attractive for use with vectors, such as poliovirus, which have a limited capacity to accept foreign DNA. Conceivably, a very large number of individual epitopes could be encoded in a single vaccine, allowing immunisation against a wide range of pathogens, or against a pathogen, such as HIV, which has the capacity to vary its antigenic make-up. This strategy has been adopted in several studies [39",40,41",42]. Recombinant VV vectors were constructed encoding several contiguous minimal C T L epitopes. All C T L epitopes were appropriately presented, and when tested in vivo were shown to induce protective C T L responses [39",41"]. Furthermore, minimal B cell and T helper cell epitopes were also successfully encoded within the C T L epitope insert and in vivo could induce B cell and T helper cell responsiveness respectively [41"]. Two potential problems for linked minigene constructs have been proposed. First, that natural flanking sequences may be required for efficient proteolytic processing of the encoded epitopes and second, that peptide competition and immunodominance between the epitopes may interfere with their presentation. T h e above studies provide evidence that neither may present an insurmountable obstacle [39",40,41",42]. Another concern over the use of minigenes in vaccines is the potential for the generation of escape mutants, in which a single amino acid mutation in
Recombinant viruses as vaccines and immunological tools Rolph and Ramshaw
519
Table 1 Some candidate recombinantviral vaccines. Type of immunity Virus type
Ab
CMI
Muc
Vaccinia
+
+
+
Prototype for all recombinant viruses. Can induce a wide range of immune responses, and very large amounts of foreign DNA can be incorporated into the vector. Used as a smallpox vaccine, and thus has been thoroughly tested in humans. Highly attenuated forms have been constructed.
[6,7,11",75,76]
Avipox
+
+
+
Undergoes abortive replication in mammalian cells, providing a high degree of biosafety, while maintaining the capacity to express foreign antigens.
[6,14,18,48]
Adenovirus
+
+
+
Can be administered orally, and can induce a wide range of immune responses. Replication-deficient adenoviruses can be constructed which still induce strong immune responses. Cloning capacity is not as great as for pox'viruses.
[91,24,25°,27]
Polio
+
+
Can be given orally and induces a strong mucosal response. Attenuated poliovirus vaccines have already been extensively tested in humans. Limited cloning capacity as compared with pox'viruses.
[31,32°,35",38]
Mengo
+
+
Limited cloning capacity.
[77,78]
SFV
+
+
Can be engineered either as recombinant infectious RNA, expressing additional subgenomic RNAs, or as 'replicons' in which structural genes are replaced with foreign DNA. Replicons require helper RNA or packaging cell lines for production.
[79-81]
Sindbis
+
+
Similar characteristics to SFV. Genetic stability of a recombinant expressing immunogenic proteins from Japanese encephalitis virus was low.
[80,82]
VEE
+
+
There is little or no pre-existing immunity to this vector in human populations.
Influenza
+
+
+
General comments
Induction of strong mucosal immunity. Pre-existing vector-specific immunity could potentially be avoided by using vectors belonging to different influenza virus subtypes.
References
[83] [84,85]
This table is a non-exhaustive list of types of recombinant viruses that have been tested as vaccines, showing the classes of immune response that have so far been demonstrated for each type. Ab, antibody; CMI, cell-mediated immunity; Muc, mucosal immunity; SFV, Semliki Forest virus; VEE, Venezuelan equine encephalitis.
a key epitope might be sufficient for a pathogen to escape vaccine induced immunity. This was addressed in one study, using an rVV encoding a C T L epitope from ListeHa monotytogenes. Immunisation with this virus protected mice against subsequent challenge with L. monocytogenes. Polymerase chain reaction analysis of colonies derived from the spleens of the vaccinated mice six days after infection with L. monocytogenes provided no evidence for the generation of C T L escape mutants [43].
Vector-specific i m m u n i t y Vector-specific immunity may present an obstacle to the use of some recombinant viral vectors. Early clinical trials of rVV encoding HIV gpl60 found that the immune response of vaccinia-naive subjects was superior to that of vaccinia-immune subjects [44]. Vector-specific immunity may also interfere with the immune response to booster immunisations. T h e problem of vector-specific immunity may not be as great with replication-deficient, as compared with replication-competent, recombinant vaccines. Previous immunity to canarypox virus or VV, did not substantially affect the immune response to a subsequent challenge
with a canarypox virus recombinant [45]. Similarly, a strong booster effect was seen at the second and third immunisation with a recombinant canarypoxvirus expressing rabies glycoprotein, despite the induction of a canarypoxvirus specific IgG response [16]. Prior immunisation with a replication-competent adenovirus had little or no effect on the response to subsequent immunisation with a replication-deficient adenovirus encoding rabies glycoprotein [25°]. Another study, however, found that a course of four immunisations with a replication-deficient adenovirus encoding I]-galactosidase did not give a better immune response than a single immunisation with the same virus. A strong adenovirus neutralising antibody response was detected after the second immunisation and may have been responsible for the lack of a booster effect [23].
P r i m e - b o o s t protocols Strategies involving priming with a recombinant viral vector, followed by boosting with the corresponding recombinant protein ('prime-boost'), have been used to circumvent the problems associated with vector-specific immunity, as well as being used to induce a broad immune response. Initial studies with rVV encoding HIV gpl60
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in humans reported rather poor HIV-specific immune responses [44]. When a prime-boost protocol was used, involving boosting with recombinant gpl60, the HIV-specific immune response was increased, and neutralising antibody and C T L activity were also detected [46,47]. A large number of the studies using prime-boost protocols have been directed towards HIV/SIV vaccination [12,18-20,48-52]. In addition to avoiding problems with vector-specific immunity, prime-boost protocols are attractive for HIV vaccines due to their capacity to induce humoral and cell-mediated immunity, both of which may be necessary for an efficacious HIV vaccine. In one study [49], poxviruses encoding HIV-1 sequences were used in a prime-boost protocol to immunise rhesus macaques against HIV-1. This protocol induced humoral and cellular immune responses, and protected against subsequent challenge with HIV-2 [49]. This demonstration that cross-protection between HIV-1 and HIV-2 can occur raises our hopes that the substantial genetic variability observed for HIV may not be an insurmountable barrier to effective vaccination [49]. An alternative prime-boost protocol has been used, involving priming with a DNA vaccine encoding influenza haemagglutinin (HA), followed by boosting with a recombinant fowlpoxvirus encoding influenza HA. This strategy induced particularly high HA-specific antibody levels, and resulted in strong resistance to subsequent influenza challenge [53].
Clinical trials Several clinical trials of recombinant viral vaccines have been reported in the past two years. Mostly these studies have used recombinant canarypox vectors due to their enhanced safety characteristics. A prime-boost protocol employing two immunisations with a recombinant canarypoxvirus expressing HIV gpl60, followed by a recombinant gpl60 boost, was shown to be safe in HIV-seronegative volunteers in a phase I trial [20]. Neutralising antibodies were induced in a majority of subjects. This approach also resulted in induction of gpl60-specific cytotoxicity, mainly class I restricted CD8 ÷ T cells, in 39% of subjects [20,48]. A similar study also induced gpl60-specific C T L activity, but in only 2 out of 12 volunteers, that is 17% [19]. I m m u n o m o d u l a t o r s as vaccines and immunological tools Since the early studies of Ramshaw et al. [54] and Flexner etal. [55], a large number of recombinant viruses encoding immunomodulatory agents such as cytokines has been constructed. T h e use of such immunomodulators has been investigated as a means of attenuating vaccines (resulting in greater biosafety) and enhancing vaccine-induced immune responses. Furthermore, such viruses have been useful as immunological tools for dissecting the in vivo function of virus-encoded molecules.
We have recently described an rVV encoding murine IL-4 [56"], the virulence of which, in mice, is enhanced as compared with a control rVV. Virus-encoded IL-4 downregulated antivirai C T L activity, suggesting that IL-4 can potentially play a role in downregulating an antiviral immune response, and that high levels of IL-4 production may be deleterious during virus infection. This finding is particularly interesting in relation to the hypothesis that progression to AIDS is associated with the development of a type 2 (IL-4, IL-5) cytokine response [57]. A recombinant adenovirus encoding the p35 and p40 subunits of murine IL-12 was used as a vector to investigate the role of IL-12 during infection of mice with Klebsiellapneumoniae. Intratracheal infection with the IL-12 expressing adenovirus resulted in 45% of the mice surviving a subsequent intratracheal K. pneumoniae infection, as compared with a 0% survival rate in K. pneumoniae-infected mice receiving a control adenovirus [58]. Thus, localised IL-12 production can exert considerable antimicrobial activity during K. pneumoniae infection. Studies with an rVV encoding murine IL-12, have demonstrated that this cytokine has considerable antiviral activity, as well as the capacity to inhibit pulmonary allergic airways disease (SP Hogan, PS Foster, X Tan, AJ Ramsay, personal communication). T h e directed delivery of cytokines by virus vectors to cytokine gene knockout mice has proved to be a powerful technique for investigating the role of cytokines in immune regulation. For example, mucosal IgA responses were found to be grossly deficient in IL-6 knockout mice [59]. T h e IgA response could be completely restored by the administration of an rVV encoding the gene for IL-6, but not by rVVs encoding IL-2, IL-4 or IL-5 [59]. Similarly, in a mouse model of asthma, IL-5 knockout mice were shown to be immune to airways damage [60"]. T h e full pathological response, characterised by eosinophilia and airways hyper-reactivity, was restored following intranasal treatment with an rVV encoding IL-5, thus confirming the crucial role in this model of IL-5 in the development of airways dysfunction [60"]. We, and others, have constructed rVVs encoding inducible nitric oxide synthase (iNOS), as a means of investigating the role of N O during VV infection. Such studies were important in view of the finding that inhibition of NO production during VV infection had no effect on the course of virus infection in mice [61]. iNOS-encoding VVs were, however, attenuated both in vitro [62",63] and in vivo [62"] indicating that NO has the potential to exert considerable antiviral activity in vivo. An interesting approach was taken by Wrighton et al. [64] who encoded the specific NF-~B inhibitor, I~¢Ba, in a recombinant adenovirus. Infection of endothelial cells with this virus resulted in the decreased expression of a number of factors associated with activation, such as vascular cell
Recombinant viruses as vaccines and immunological tools Rolph and Ramshaw
adhesion molecule 1, IL-1, IL-6 and IL-8, suggesting that targeting NF-~rB may be a possible immunosuppressive strategy. This type of approach has considerable potential for investigating the role of transcription factors in vivo. Another strategy for suppressing an inflammatory response is to encode molecules that can block the effects of endogenously produced inflammatory mediators. For example, an adenovirus was constructed to encode a chimeric protein capable of binding and blocking the activity of tumor necrosis factor o: and 13 (lymphotoxin) [65]. Mice treated with this virus showed a considerably reduced capacity to control infection with Pseuclomonas aeruginosa, but were protected against a lethal dose of lipopolysaccharide, showing the dual role of tumor necrosis factor in host defense and endotoxic shock [65]. Cell-surface ligands have also been encoded in rVV. In the case of the CD40 ligand (CD40L), infection of mice with an r W encoding this molecule revealed an unexpected role for CD40L: it can exert potent antiviral activity, as demonstrated by the reduced virulence of the recombinant virus in vivo [66]. An rVV encoding Fas ligand (FasL) was constructed to investigate the role of FasL in the regulation of C T L responses during virus infection. Thus, virus-infected cells expressed viral antigenic determinants and FasL. No effect of FasL on C T L activity was detected, arguing against a role for FasL in the regulation of C T L responses during W infection [67]. T h e role of chemokines in immunological processes represents a rapidly expanding field of research. Intratracheal administration of adenoviruses encoding macrophage inflammatory protein-2 [68] and regulated on activation normal T cell expressed and secreted (RANTES) [69] induced accumulation of polymorphs and monocytes respectively in the lung. Such constructs should prove invaluable for investigating in vivo chemokine function. Cytokine-expressing recombinant viruses have also been constructed with the aim of modulating the immune response to virus-encoded molecules, or of attenuating vaccine vectors. For example, the construction and testing of an attenuated (nefregion deleted) SIV encoding human interferon (IFN)-y has recently been reported [70,71°°]. Immunisation of macaques with the recombinant SIV expressing I F N - y resulted in lower virus titres following a subsequent challenge with virulent SIV, as compared with macaques immunised with a control nef-deleted SIV. This reduction in virus titres occurred despite the fact that the I F N - y expressing virus replicated less than the control virus, and despite the genetic instability of the IFN-y insert [71"]. Although nef-deleted SIV are safe for use in adult macaques, they are pathogenic in neonates [72]. Therefore, it is particularly encouraging that the IFN-y expressing SIV was not pathogenic in neonatal macaques, and was cleared within six weeks of challenge (T Yilma, personal communication). In contrast, an IL-2 expressing SIV replicated marginally more than the control
521
virus and had little or no effect on antibody titres, T cell proliferation or C T L activity [73]. Other examples of cytokine modulation of vaccine responses include an avipoxvirus encoding influenza HA and IL-6 [14]. Virus-encoded IL-6 considerably enhanced the primary systemic and mucosal antibody responses to HA, and primed for enhanced recall responses when compared to a control virus [14]. Similarly, humotal and C T L responses were considerably augmented in an adenovirus encoding hepatitis B surface antigen (HBsAg) and human B7-1, as compared with an adenovirus encoding HBsAg only [74].
Conclusions Recombinant viral vectors hold considerable promise as candidate vaccines. Many different viruses are being investigated as potential vaccines, each with its own advantages and disadvantages. Important considerations for recombinant viral vaccines include biosafety, cloning capacity and the type of immunity that can be induced. Recombinant viruses are also important tools for the experimental immunologist and continue to provide novel insights into all aspects of immunobiology.
Acknowledgements The authors wish to thank T Yilma, B Moss and K Uberla for providing unpublished data and G Karupiah, (; Ada, B Coupar and A Suhrbier for their critical reading of the manuscript.
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