Novel Recombinant Parapoxvirus Vectors Induce Protective Humoral and Cellular Immunity against Lethal Herpesvirus Challenge Infection in Mice

Abstract

Vaccines based on live virus are excellent inducers of longterm immunity by eliciting protective humoral and cell-mediated immune responses against the inserted antigen. To this end, poxviruses are one of the most versatile expression systems for foreign antigens and have been considered as vectors for human and veterinary live vaccines (37, 41). Long-term immunity induced by vaccinia virus (VACV) or other poxviruses, however, might result in unsuccessful revaccination or reduced protection against VACV-encoded foreign antigens (5, 23, 48). For safety reasons, different strategies are used to develop attenuated, host-restricted, or replication-deficient poxviruses, which retain their ability to activate the host's immune response (for review, see references 38 and 39). The host range-restricted attenuated VACV strain MVA (modified VACV Ankara) was found to induce lower levels of VACVneutralizing antibodies than wild-type VACV (45) and is currently widely used as a vector vaccine. It cannot grow in human cells (8) and is propagated on primary chicken embryo fibroblasts (CEFs). Avipoxvirus vectors, which show an abortive replication in mammalian cells, are also produced in CEFs (42). However, products from CEFs do not represent optimal safety profiles due to different adventitious contaminants, in contrast to production in permanent cell lines.Recently, the genus Parapoxvirus (PPV) of the family Poxviridae, and in particular the type species Orf virus (ORFV), has been proposed as candidate for novel vector vaccines. Arguments in favor of an ORFV vector include the very restricted host range (sheep and goats), its tropism restricted to the skin, the lack of systemic infection, a short-term vectorspecific protective immunity, and the exceptionally strong stimulation of fast innate cellular immune mechanisms at the site of infection (for review, see references 4 and 47). In addition to cytokines, chemokines, and alpha/beta interferon (IFN-␣/␤) as part of the host's inflammatory response against the infection, major histocompatibility complex class II-positive dendritic cells accumulate in the infected skin, which represent professional antigen-presenting cells for the subsequent induction of a specific immune response (4, 13). CD4 ϩ T cells dominate the local accumulation of B and T cells and were found to be of importance for the development of ORFV-specific antibodies (24). It is worthwhile to stress the short-lived duration of ORFV-specific immunity, which allows frequent reinfections (14). A most important feature of ORFV in the context with its use as a vaccine is the absence of systemic virus spread, even in immunocompromised individuals or after intravenous injection of high virus doses (4,18,47,59). Occasional transmission of wild-type ORFV to humans often remains unrecognized (4,14).A prime candidate for use as a recombinant vector is the highly attenuated, cell culture-adapted ORFV strain D1701, which is almost apathogenic in sheep (31). This attenuated

A New Rabies Vaccine Based on a Recombinant Orf Virus (Parapoxvirus) Expressing the Rabies Virus Glycoprotein

“…The ORFV recombinants were propagated, plaque purified, and titrated in Vero cells as described recently (44,49). Rabies challenge virus standard strain CVS-11 (Friedrich-Loeffler-Institut, Germany) was titrated by fluorescence focus assay.…”

“…The short-term vector-specific immunity and the lack of serum antibodies efficiently neutralizing ORFV (38,40) enable repeated immunizations with the same or with different ORFV recombinants. Unique immune-modulating properties of ORFV strongly stimulate the innate immunity (40)(41)(42)(43) and rapidly generate foreign antigen-specific immune responses (44)(45)(46)(47). The apathogenic, Vero cell culture-adapted ORFV strain D1701-V is used to generate recombinants by substituting the viral vegf-e gene with a foreign gene, which thereby removes an ORFV virulence gene and leads to further attenuation (38,44,48).…”

“…The apathogenic, Vero cell culture-adapted ORFV strain D1701-V is used to generate recombinants by substituting the viral vegf-e gene with a foreign gene, which thereby removes an ORFV virulence gene and leads to further attenuation (38,44,48). D1701-V recombinants have been reported to mediate protective immunity against a number of different viral infections, such as rabbit hemorrhagic disease virus (49), classical swine fever (50), Borna disease virus (51), or pseudorabies virus (44,52,53).…”

Viral vectors for use in the development of biodefense vaccines

“…In particular to biodefense, there have been several reports that have described the immunogenicity and efficacy of VVvectored vaccines against Lassa virus (LSV), Ebola hemorrhagic fever virus (EBOV), anthrax, VEEV, and Brucella abortus and one report of using raccoon poxvirus as the vector for a plague vaccine. Three other poxviruses, lumpy skin disease virus (Capripoxvirus genus) [18], Orf virus (Parapoxvirus genus) [19], and fowlpoxvirus (Avipoxvirus genus) [20], have been modified to express vaccine-related genes but have not yet been used to construct biodefense vaccines. Of interest is that the lumpy skin disease virus vector was designed as a replication-deficient vector whereas the Orf virus vector and the fowlpoxvirus vectors were both replication-competent.…”

Poxvirus-Based Vaccine Platforms: Getting at Those Hard-To-Reach Places

“…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].…”