Poxvirus-based vaccine platforms: getting at those hard-to-reach places

Abstract

Future VirologyVol. 3, No. 2 EditorialFree AccessPoxvirus-based vaccine platforms: getting at those hard-to-reach placesRodolfo Nino-Fong & James B JohnstonRodolfo Nino-FongInstitute for Nutrisciences & Health, National Research Council Canada, 550 University Avenue, Charlottetown, PE, C1A 4P3, Canada. Search for more papers by this authorEmail the corresponding author at rodolfo.nino-fong@nrc.ca & James B Johnston† Author for correspondenceInstitute for Nutrisciences & Health, National Research Council Canada, 550 University Avenue, Charlottetown, PE, C1A 4P3, Canada. Search for more papers by this authorEmail the corresponding author at james.johnston@nrc.caPublished Online:29 Feb 2008https://doi.org/10.2217/17460794.3.2.99AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit The poxviruses are a large family of dsDNA viruses that includes some of the most notorious and extensively researched pathogens, most notably Variola virus, the causative agent of smallpox, and Vaccinia virus (VV), the prototypical poxvirus. Poxviruses are also notable among viruses for their large virion and genome sizes, the ability to replicate autonomous of host cell nuclear machinery, and the apparent absence of a virus-specific surface moiety for cell entry [1]. Historically the subjects of extensive study because of their pathogenesis in humans and domestic animals, the eradication of smallpox as a human health concern in the 1980s greatly curtailed basic research involving poxviruses. In recent years, new avenues of biotherapeutic research, collectively known as virotherapeutics, have arisen to counter this trend, with the creation of numerous recombinant poxviruses for use as vaccine platforms, vectors for gene delivery and oncolytic agents in the treatment of cancer [2–4]. The prominence of poxviruses as candidate vaccine vectors completes a circle begun in the 18th century when Jenner first tested the theory of vaccination using Cowpox virus to inoculate against smallpox infection. Today, vaccination remains a critical intervention for preventing and limiting the spread of disease in the general population, as exemplified by the current campaign to vaccinate adolescent girls against human papilloma virus [5]. Despite many successes, effective vaccines for numerous prevalent conditions are lacking even as new infectious agents emerge and necessitate improved vaccination tools.The capacity to genetically engineer poxviruses to alter pathogenicity and express heterologous genes encoding foreign antigens was being demonstrated even as smallpox was being eradicated. This ability initiated the era of VV as a eukaryotic expression vector with broad potential as a vector-based vaccine candidate. The properties of poxviruses that make them amenable for use as immunizing agents are well documented [6,7]. From a practical perspective, poxvirus vectors are stable in lyophilized form and are comparatively cheap and easy to manufacture. They have the potential to be safely administered by multiple pathways and elicit both mucosal and systemic responses. Compared with smaller viral vectors, the poxvirus genome can accommodate large foreign DNA inserts without disrupting viral stability, supporting multivalent delivery systems targeting several antigens from a single pathogen or antigens from several different pathogens. The lack of a restrictive surface receptor for entry also increases the range of hosts and cell types against which poxviruses may be applied. The principal flaw inherent in poxviral vectors is the issue of safety in the general population. The same adverse complications associated with the Dryvax® vaccine used in the smallpox campaign also apply to vaccine vectors based on live VV recombinants. Attempts to address this concern include attenuated VV strains, such as modified vaccinia Ankara (MVA) and NYVAC, with improved safety potential due to the loss of key pathogenic genes [8,9]. Avipoxvirus vectors based on Canarypox virus (CPV) and Fowlpox virus (FPV), such as ALVAC and TROVAC, are also extremely attractive from a biosafety standpoint [10,11]. Like other poxviruses, Avipoxviruses can gain entry to a wide variety of cell types but infection is aborted in nonavian cells. In addition, Avipoxvirus vectors do not cross-react with VV and elicit weaker vector-directed immune responses in mammals, supporting a multiple boosting regimen of treatment. Similarly, vectors derived from other poxvirus genera may also offer safer alternatives to VV [12,13].Once their potential was recognized, numerous poxvirus vectors were engineered against diverse viral, bacterial and parasitic agents [14–16], as well as several cancerous states [17,18]. Theory is again becoming practice, as evidenced by human clinical trials [19–22] and the application of poxvirus-based vaccines in veterinary and agricultural sectors, especially in global rabies prevention programs [23]. Although there are currently no licensed vaccines for human parasitic diseases, VV vectors have been used to prevent cystic hydatid disease in sheep [24]. Protection against diverse animal viruses with economic implications has also been demonstrated. Within the swine industry, recombinant poxviruses have been used to immunize against the devastating effects of porcine reproductive and respiratory syndrome virus [25] and pseudorabies [26]. Recently, avian influenza vaccines for chickens that use live FPV recombinants expressing strain-specific antigens have been approved for use in several countries [27], joining the list of FPV- and CPV-based veterinary vaccines that are commercially available [28].Despite this progress, the 64 million dollar question remains – are poxviruses the Holy Grail in the fight against human diseases that have largely resisted concerted vaccine development efforts? To explore this question, we look at the role of poxvirus-based vaccines in two especially resistant conditions, malaria and HIV–AIDS. Despite overt dissimilarity in causative pathogens, both diseases are characterized by therapeutic stalemates in which interventions are able to reduce adverse effects but not eliminate the pathogen. The end goal in these conditions is not sterilizing immunity, but rather management of pathogen load during the critical early stages of infection in an effort to delay disease onset, reduce debilitating symptoms and limit transmission. To achieve this goal, vaccination strategies focus on restricting the spread of the pathogen as the host immune system reacts or boosting the initial responses to infection.The causative agent of malaria is a vector-borne, single-cell, eukaryotic parasite of the genus Plasmodium[29]. Vaccine development has been hampered by the complexity of the malarial parasite’s life cycle, which incorporates several different replicative stages and forms. The parasite also exhibits the ability to replicate in terminally differentiated erythrocytes lacking MHC-I expression, severely negating the impact of cell-mediated immune responses. Thus, acquired immunity develops slowly as the host attempts to mount a response against a constantly evolving target without utilizing its primary resources against intracellular pathogens. Owing to this complexity, multivalent subunit vaccines are the vaccine strategy of choice [30], but efforts in this area have been limited by the need to identify protective rather than immunizing antigens and the continuing slow rate of host immunity acquisition. Candidate antigens are also problematic as a group in that they are poorly immunogenic and possess complex structures that challenge stability and purification.Poxvirus-based vectors have the potential to alleviate many of these concerns. For example, poxvirus vectors have been shown to enhance the immunogenicity of recombinant protein-based vaccines, possibly through enhanced immune responses against the vector itself [31]. Poxviruses employ host protein production machinery to express the transgene product, thereby bypassing both the need for expensive production of purified protein and difficulties associated with retaining complex structures. Furthermore, the poxviral genome supports incorporation of multiple antigens from the different parasite forms within a single construct. This potential is best exemplified by NYVAC-Pf7, an attenuated VV-vector expressing seven different recombinant proteins, including the primary anti-invasive targets merozoite protein-1 and circumsporozoite protein (CSP) [32,33]. Clinical trials with NYVAC-pf7 demonstrated more effective immune responses than a comparable VV-based vector expressing only CSP and delayed onset of malaria symptoms, but did not provide complete protection. However, greater success with poxvirus vectors has been achieved using heterologous prime–boost regimens. For example, CD8+ T-cell responses capable of providing protection against sporozoite challenge were observed when a primary DNA vaccine against two antigens, CSP or trombospondin-related adhesive protein (TRAP), was followed by a poxvirus-based booster [34]. This finding translated into similar reduced parasite loads in subsequent human trials using FPV and MVA expressing TRAP and several other antigens [35]. Recently, Phase II trials have begun and interest in the potential inherent in co-administration of poxvirus vectors and DNA vaccines as a new protocol of immunization continues [36].Given the expense, poor accessibility and numerous adverse side effects associated with anti-HIV drug therapies, vaccines also represent the most cost-effective and practical control measure in HIV–AIDS. However, HIV and the malaria parasite share the ability to rapidly colonize host cells in a manner that dramatically reduces the host’s ability to mount an immune response against the pathogen. Analogous to the multiple forms of the plasmodium parasite, the HIV virion is also constantly mutating in response to immune pressure and inherent genetic variability, creating a moving target for the host immune system. Early proof-of-principle studies in both human and nonhuman primates suggested great promise in inducing an immune response against HIV with VV recombinants expressing relevant viral envelope antigens [37,38], but quickly led to clinical trials that failed to deliver on the promise of efficacy. However, these trials did reveal that a prime-boost regimen greatly improved the extent and duration of immune responses over virus-vectored antigen alone [39]. More recent studies using nonenvelope HIV antigens in combination with antiviral drugs or DNA vaccines have confirmed this finding and suggested the potential for therapeutic vaccination [40–42]. The scope and breadth of potential vaccine candidates developed and evaluated in the last few years are far too numerous for this editorial and have been reviewed elsewhere. However, among the more novel strategies being investigated is the incorporation of MVA–HIV envelope recombinants as orally available liposomal complexes. In mice, these complexes have been found to enhance envelope-specific cellular and humoral immune responses [43]. In addition, several cytokines, such as IL-15 and IFN-γ, have been incorporated into anti-HIV poxvirus vaccines in an attempt to promote Th1-specific responses and induce memory [44,45].Safety concerns, and the finding in the early HIV trials that pre-existing immunity to VV decreased the efficacy of VV-based vaccines for HIV [46], have focused recent efforts on the use of attenuated poxvirus species. Of note are the multisubunit MVA and NYVAC recombinants expressing HIV gag–pol–nef antigens in addition to the viral envelope genes that have been shown to consistently boost both CD4+ and CD8+ T-cell responses in HIV-1-infected patients [47,48]. In addition, novel inert poxvirus vectors have been developed in order to reduce the immune response against the vector itself, such as the highly attenuated VV substrain Dairen-I [49] and VV strains lacking the B5 ectodomain against which many host immune responses are directed [50].As described above, the poxvirus vector platform affords multiple vaccination strategies with diverse potential applications in human and animal disease. It can be argued that advances with recombinant poxvirus vector technologies continue to invigorate the next generation of vaccines, particularly in such areas as cancer immunotherapy [51]. The potential and excitement that accompanied the initial proposal in 1982 to use poxvirus-based vaccines has subsided to some extent, but the field continues to be one of extensive interest and research efforts. Successes within veterinary medicine have shown that the theory supporting the use of poxvirus vaccines is sound. As our understanding of the biology of poxviruses and the consequences of manipulating the poxviral genome expands, it seems logical that a human candidate vaccine is on the horizon. However, the biggest hurdle to overcome is likely never to be a scientific one. Rather, public perception and the fear of deliberately dosing oneself with a relative of an ancestral scourge will remain the greatest obstacle.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Bibliography1 Moss B: Poxviridae. In: The Virus and Their Replication. Knipe DM, Howley PM (Eds). 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(Basel)116,117–122 (2004).Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByImmunomodulatory Strategies for Parapoxvirus: Current Status and Future Approaches for the Development of Vaccines against Orf Virus Infection17 November 2021 | Vaccines, Vol. 9, No. 11 Vol. 3, No. 2 Follow us on social media for the latest updates Metrics History Published online 29 February 2008 Published in print March 2008 Information© Future Medicine LtdFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download