Review

RNA-based viral vectors

Expert Rev. Vaccines Early online, 1–30 (2014)

Mark A Mogler1 and The advent of reverse genetic approaches to manipulate the genomes of both positive (+) and Kurt I Kamrud*2 negative (-) sense RNA viruses allowed researchers to harness these genomes for basic research. Manipulation of positive sense RNA virus genomes occurred first largely because infectious RNA 1Harrisvaccines, Inc., 1102 Southern Hills Drive, Suite 101, Ames, IA 50010, could be transcribed directly from cDNA versions of the RNA genomes. Manipulation of USA negative strand RNA virus genomes rapidly followed as more sophisticated approaches to 2Synthetic Genomics Vaccines, Inc., provide RNA-dependent RNA polymerase complexes coupled with negative-strand RNA 11149 North Torrey Pines, La Jolla, CA templates were developed. These advances have driven an explosion of RNA virus vaccine vector 90237, USA *Author for correspondence: development. That is, development of approaches to exploit the basic replication and expression [email protected] strategies of RNA viruses to produce vaccine antigens that have been engineered into their genomes. This study has led to significant preclinical testing of many RNA virus vectors against a wide range of pathogens as well as cancer targets. Multiple RNA virus vectors have advanced through preclinical testing to human clinical evaluation. This review will focus on RNA virus vectors designed to express heterologous genes that are packaged into viral particles and have progressed to clinical testing.

KEYWORDS: alphavirus • flavivirus • orthomyxovirus • paramyxovirus • reverse genetics • rhabdovirus • RNA virus vector

This review will describe RNA virus vector nsP3 and nsP4) are translated from the genomic development and the reverse genetics approaches RNA. The nsP2 is a viral protease that processes used to support the development for five RNA the nonstructural polyprotein into its individual virus families: Togaviridae, Flaviviridae, Ortho- subunits that function to transcribe negative-

For personal use only. myxoviridae, Rhabdoviridae and Paramyxoviri- sense as well as new positive-sense viral RNA. dae. The RNA vector system(s) designed for The negative-sense replicative intermediate each will be described and a summary of preclin- RNA codes for a subgenomic promoter (26S ical work that has supported advanced testing promoter) that is recognized by the nonstruc- and human clinical evaluation will also be dis- tural proteins and is used to generate a subge- cussed. Although some systems have developed nomic mRNA that represents the 3´ one-third DNA-based vectors, only RNA particle-based of the genome; the viral structural proteins are systems will be discussed in this review. Reverse translated from this subgenomic mRNA. Repli- genetics systems for the generation of viruses in cation occurs completely in the cytoplasm of the Arenaviridae family have been described, but cells and progeny viruses bud at the plasma these RNA vectors are still in very early develop- membrane as virus capsid protein encapsidates Expert Review of Vaccines Downloaded from informahealthcare.com by 174.97.229.189 on 11/08/14 ment and therefore will not be examined in this genomic RNA and associates with the envelope review. Finally, reverse genetics approaches to glycoproteins that accumulate on the membrane develop Lentivirus vectors are well established of infected cells [2,3]. but will not be covered here as they have recently Because alphaviruses are positive-sense RNA been reviewed elsewhere [1]. viruses, full-length cDNA clones of their genomes can be used to generate RNA transcripts Togaviridae that, when introduced into susceptible cells, will Genus: Alphavirus initiate a complete virus replication cycle and Alphaviruses have a single-strand, positive-sense generate infectious virus. Manipulation of alpha- RNA genome that carries a 5´ 7-mG cap and a virus genomes is possible through introduction of 3´ polyadenylated region. The alphavirus non- mutations/modifications to the cDNA of their structural proteins are coded for in the 5´ two- respective clones. Two types of alphavirus vectors thirds of the genome and the structural proteins have been developed to express heterologous are coded for in the 3´ one-third of the genome. genes: propagation-competent vectors where a The nonstructural proteins (termed nsP1, nsP2, 26S promoter region is duplicated, either

informahealthcare.com 10.1586/14760584.2015.979798 2014 Informa UK Ltd ISSN 1476-0584 1 Review Mogler & Kamrud

upstream or downstream of a complete structural gene region, that intravenously has been described and preliminary data have drives expression of a foreign gene or propagation-defective repli- been provided that indicate this formulation (1 Â 108 or con vectors where a foreign gene is inserted in place of the struc- 5 Â 109 particles/m2 body surface) was well tolerated and that tural protein gene region [4,5]. The replicon RNA can be packaged a transient increase (five- to tenfold) in IL-12 serum levels was into virus replicon particles (VRP) by supplying the structural pro- detected within the first 3–4 days after injection [16–18]. tein genes in trans. Replicon RNA is packaged into VRP when cells A complete summary of the clinical outcomes of this clinical are cotransfected with helper RNA which encode the full comple- trial has not yet been published. A study protocol for a ment of structural proteins. A split helper system that provides the Phase I/II clinical trial using continuous intratumoral infusion structural proteins on separate helper RNAs greatly reduces the of LSFV-IL12 in recurrent glioblastoma multiforme patients chance of an intact genome being regenerated by RNA–RNA has been described, but no data are available on the status of recombination. Thus, the VRP are defective, in that they can infect this clinical trial [18]. target cells in culture or in vivo and can express the foreign gene at high levels, but they lack critical portions of the genome (i.e., the Venezuelan equine encephalitis vectors structural protein genes) necessary to produce virus particles which Development of VEEV VRP for human clinical evaluation has could spread to other cells [4,5]. Chimeric alphavirus vectors have occurred in both an infectious disease and cancer setting [20–23]. also been developed where the structural region of one alphavirus VEEV VRP vaccines have been tested preclinically against a is exchanged for a different alphavirus structural region; the result- large range of pathogens (TABLE 1), of which only a few have pro- ing chimeric alphavirus is usually attenuated in nature [6–10]. gressed into human clinical evaluation. Some notable VEEV Alphavirus replicon vectors have been developed from a VRP preclinical testing examples include successful vaccines number of viruses within the Togaviridae family; these viruses developed against Ebola virus (EBOV), Marburg virus, Lassa consist of Salmonid alphavirus, Chikungunya virus (CHIKV), virus, Smallpox virus, equine encephalitis viruses, Clostridium Sindbis-like XJ-160, Venezuelan equine encephalitis virus botulinum neurotoxins and anthrax [24–30]; detailed descriptions (VEEV), Sindbis and Semliki forest virus (SFV), with the of these studies are not provided here in order to focus on majority of vaccine development having been conducted with those VEEV VRP vaccines that have progressed into human VEEV, Sindbis and SFV [4,11–15]. clinical evaluation. Alphavirus vectors have been developed against a large num- The initial human evaluation of a VEEV VRP vaccine was ber of pathogens. A representative list of the many alphavirus with a replicon expressing an HIV antigen carried out by vector particle-based vaccines developed and tested preclinically AlphaVax, Inc. The sequence of an HIV-1 Clade C gag gene is presented in TABLE 1. This review will focus on alphavirus vec- was identified based on a prevalent virus circulating in South For personal use only. tor particle vaccines that have reached human clinical testing or Africa, where one arm of the clinical trial would take have achieved regulatory approval/licensure to highlight how place [31,32]. This first-in-man testing of the VEEV-gag VRP far this vaccine platform has progressed. Clinical evaluation of (AVX101) vaccine demonstrated that the vaccine was safe and VRP vaccines has occurred for a number of infectious diseases well tolerated, but unlike the robust immune responses noted and cancer indications using the VEEV and SFV VRP systems. in preclinical testing of AVX101, anti-Gag immune responses in humans were limited [23]. The AVX101 vaccine expressed a Semliki forest virus vectors nonmyristoylated HIV gag gene and it is known that myristoy- To the best of our knowledge, SFV vectors have only been lation of the Gag protein is important in the production of examined clinically in a cancer setting and with the gene of Gag-derived virus-like particles (VLP) [33,34]. Furthermore, a interest being a cytokine (IL-12). Preclinical studies for the VEEV-gag VRP expressing a myristoylated version of the gag oncolytic nature of SFV supported its use in this setting [16–19]. gene was preliminarily reported to be more immunogenic in Expert Review of Vaccines Downloaded from informahealthcare.com by 174.97.229.189 on 11/08/14 A SFV replicon vector expressing murine IL-12 genes was nonhuman primates than the AVX101 VRP, suggesting that shown to have oncogenic activity when injected directly into the Gag myristoylation mutation (inhibiting Gag-VLP forma- established B16 murine melanoma and P815 mastocytoma tion) may be related to the diminished immune responses tumors to provide support for further development of a SFV noted in the trial [23]. replicon expressing the human cytokine counterpart [16–19]. AlphaVax also developed VEEV VRP vaccines against sea- Ren et al. (2003) encapsulated SFV-IL12 particles in cationic sonal influenza virus and tested them clinically [35,36]. The liposomes (LSFV-IL12) to reduce the possibility of antivector VEEV VRP vaccine for influenza virus was based on a replicon immunity and serum components from negatively affecting vector expressing the A/Wyoming/03/2003 Hemagglutinin antitumor efficacy by inactivating the VRP [18]. The LSFV- (HA) gene that demonstrated promising immunogenicity and IL12 particles injected intraperitoneally in mice implanted sub- protection results from extensive preclinical studies in animal cutaneously with pancreatic cancer cells resulted in reduction of models [37]. The vaccine (AVX502) was tested initially in tumor size if vaccinations were initiated either immediately healthy young adults aged 18–40 years and then in the elderly after tumor implantation or up to 3 weeks after implan- (>65 years); the results of these clinical trials have not yet been tation [18]. A Phase I human clinical trial in kidney car- formally published, but a preliminary summary of the studies cinoma and melanoma patients using LSFV-IL12 delivered is provided [OLMSTEAD R, PERS.COMM.].

doi: 10.1586/14760584.2015.979798 Expert Rev. Vaccines RNA-based viral vectors Review

Table 1. Selected RNA virus vector vaccine references. Virus family Subfamily Genus Virus (strain Gene of interest Ref. or modification) Togaviridae Alphavirus SFV HIV gp160 [345] LIV prME and NS1 [346] Influenza A NP and HA [347] HPV16 E6 and E7 [348] proteins HCV core or E2 [349] SIV env, gag-pol, nef, [350] rev and tat HCV nsP3 [351] SINV Plasmodium yoelli CS [352] HTNV, SEOLV S and M [353] HPV 16 E7, fusion E7/ [354] HSP70 RVFV Gn, Gc, nsM [355] HCV C, E1 and E2 [356] VEEV MARV GP, NP, VP40, [25] VP35, VP30 or VP24 BoNT C, MARV GP, [27] Anthrax PA Anthrax PA [28]

For personal use only. Lassa and EBOV GP [29] Influenza A HA [37] VACV, A27L, B5R, [26] A33R, L1R EBOV GP [24] Rhesus [357] lymphocrypticvirus gp350, EBNA-3A, EBNA-3B BVDV E2 [358] Expert Review of Vaccines Downloaded from informahealthcare.com by 174.97.229.189 on 11/08/14 EBOV GP [24] Swine influenza A HA, NP [359] VEEV GP, WEEV GP, [30] EEEV GP ANDV: Andes virus; b/hPIV3: Bovine-human parainfluenza virus 3; BoNT-A: Botulinum neurotoxin type A; bPIV3: Bovine parainfluenza virus 3; bRSV: Bovine respira- tory syncytial virus; BVDV: Bovine viral diarrhea virus; CAT: Chloramphenicol acetyltransferase; CEA: Carcinoembryonic antigen; CHIKV: Chikungunya virus; CS: Cir- cumsporozoite; CSFV: Classical swine fever virus; CTL: Cytotoxic T lymphocyte; DEN1, DEN2, DEN3, DEN4: Dengue virus serotypes 1–4; DENV: Dengue virus; EAV: Equine arteritis virus; EBOV: Ebola virus; F: Fusion; G: Attachment glycoprotein; GFP: Green fluorescent protein; GP: Glycoprotein; GPC: Surface glycoprotein precur- sor; HA: Hemagglutinin; hMPV: Human metapneumovirus; HN: Hemagglutinin neuraminidase; hPIV1: Human parainfluenza virus 1; hPIV3: Human parainfluenza virus 3; HPV: Human papilloma virus; hRSV: Human respiratory syncytial virus; HSP70: Heat shock protein 70; HTNV: Hantaan virus; IAV: Influenza A virus; IRES: Internal ribosomal entry site; KUN: Kunjin virus; JEV: Japanese encephalitis virus; LGT: Langat virus; LIV: Louping ill virus; M: Membrane; MARV: Marburg virus; MeV: Measles virus; MS: Middle envelope surface protein; MuV: Mumps virus; MVEV: Murray Valley encephalitis virus; N: Nucleoprotein; NA: Neuraminidase; NDV: Newcastle disease virus; NiV: Nipah virus; NP: Nucleoprotein; P: Phosphoprotein; prME: Pre-membrane-envelope; RABV: Rabies virus; rB/HPIV3: Recombinant bovine- human parainfluenza virus 3; RSV: Respiratory syncytial virus; RVFV: Rift Valley fever virus; S: Spike; sAg: Surface antigen; SARS-CoV: Severe acute respiratory syn- drome coronavirus; SCFV: Single-cycle flavivirus; SEOLV: Seoul virus; SeV: Sendai virus; SFV: Semliki forest virus; SH: Small hydrophobic protein; SHIV: Simian human immunodeficiency virus; SINV: Sindbis virus; SIV: Simian immunodeficiency virus; SLEV: St Louis encephalitis virus; SV5: Simian virus 5; TBEV: Tick-borne encephalitis virus; VACV: Vaccinia virus; VEEV: Venezuelan equine encephalitis virus; VHSV: Viral hemorrhagic septicemia virus; VSV: Vesicular stomatitis virus;WNV:WestNile virus; YFV: Yellow fever virus.

informahealthcare.com doi: 10.1586/14760584.2015.979798 Review Mogler & Kamrud

Table 1. Selected RNA virus vector vaccine references (cont.). Virus family Subfamily Genus Virus (strain Gene of interest Ref. or modification) Flaviviridae Flavivirus YFV (17D) JEV prME [45] DEN1–4 prME [49] WNV prME [55] DEN4 (814669 TBEV prME [64] and derivatives) LGT prME [65] SLEV prME [63] WNV prME [70] DEN2 prME [62] DEN2 (PDK-53) DEN1, 3, 4 prME [73] KUN EBOV GP [85] HIV-1 Gag [360] JEV (SA14-14-2) WNV prME [361] DENV prME [87] MVEV (IRES IFN-b [88] attenuated) WNV (SCFV) DENV prME [78] TBEV prME [83] Pestivirus BVDV (CP7) CSFV E2 [91] CSFV E1/E2 [97] For personal use only. BDV E2 [98] BVDV (SD1) GFP [100] BVDV (NADL) Heterologous Erns [101] CSFV BVDV Erns or E2 [105] JEV E(truncated) [104] Orthomyxoviridae Influenzavirus Influenza A Circumsporozoite (CS) [119] protein of P. yoelii CS protein of P. [118]

Expert Review of Vaccines Downloaded from informahealthcare.com by 174.97.229.189 on 11/08/14 falciparum HIV gp41 [122] HIV gp41 [120] HIV GAG [123] ANDV: Andes virus; b/hPIV3: Bovine-human parainfluenza virus 3; BoNT-A: Botulinum neurotoxin type A; bPIV3: Bovine parainfluenza virus 3; bRSV: Bovine respira- tory syncytial virus; BVDV: Bovine viral diarrhea virus; CAT: Chloramphenicol acetyltransferase; CEA: Carcinoembryonic antigen; CHIKV: Chikungunya virus; CS: Cir- cumsporozoite; CSFV: Classical swine fever virus; CTL: Cytotoxic T lymphocyte; DEN1, DEN2, DEN3, DEN4: Dengue virus serotypes 1–4; DENV: Dengue virus; EAV: Equine arteritis virus; EBOV: Ebola virus; F: Fusion; G: Attachment glycoprotein; GFP: Green fluorescent protein; GP: Glycoprotein; GPC: Surface glycoprotein precur- sor; HA: Hemagglutinin; hMPV: Human metapneumovirus; HN: Hemagglutinin neuraminidase; hPIV1: Human parainfluenza virus 1; hPIV3: Human parainfluenza virus 3; HPV: Human papilloma virus; hRSV: Human respiratory syncytial virus; HSP70: Heat shock protein 70; HTNV: Hantaan virus; IAV: Influenza A virus; IRES: Internal ribosomal entry site; KUN: Kunjin virus; JEV: Japanese encephalitis virus; LGT: Langat virus; LIV: Louping ill virus; M: Membrane; MARV: Marburg virus; MeV: Measles virus; MS: Middle envelope surface protein; MuV: Mumps virus; MVEV: Murray Valley encephalitis virus; N: Nucleoprotein; NA: Neuraminidase; NDV: Newcastle disease virus; NiV: Nipah virus; NP: Nucleoprotein; P: Phosphoprotein; prME: Pre-membrane-envelope; RABV: Rabies virus; rB/HPIV3: Recombinant bovine- human parainfluenza virus 3; RSV: Respiratory syncytial virus; RVFV: Rift Valley fever virus; S: Spike; sAg: Surface antigen; SARS-CoV: Severe acute respiratory syn- drome coronavirus; SCFV: Single-cycle flavivirus; SEOLV: Seoul virus; SeV: Sendai virus; SFV: Semliki forest virus; SH: Small hydrophobic protein; SHIV: Simian human immunodeficiency virus; SINV: Sindbis virus; SIV: Simian immunodeficiency virus; SLEV: St Louis encephalitis virus; SV5: Simian virus 5; TBEV: Tick-borne encephalitis virus; VACV: Vaccinia virus; VEEV: Venezuelan equine encephalitis virus; VHSV: Viral hemorrhagic septicemia virus; VSV: Vesicular stomatitis virus;WNV:WestNile virus; YFV: Yellow fever virus.

doi: 10.1586/14760584.2015.979798 Expert Rev. Vaccines RNA-based viral vectors Review

Table 1. Selected RNA virus vector vaccine references (cont.). Virus family Subfamily Genus Virus (strain Gene of interest Ref. or modification) HIV gp160 and Gag [121] hPIV HN [124] RSV F [125] Rhabdoviridae Lyssavirus RABV HCV E2 [149] Botulinum neurotoxin [148] SARS-CoV N or S [150] HIV-1 gp160 [153] HIV-1 Gag [154] IL-2 and IL-4 [157] IFN-b [156] SHIV Env and SIV Gag [362] SIV Gag-Pol [158] Vesiculovirus VSV HIV-1 gp120 [164] IAV(H1N1) HA or NA [165] IAV(H5N1) HA [169] HBV MS [171] ANDV GPC [175] HCV C/E1/E2 [176] RSV G or F [174]

For personal use only. Yersinia pestis LcrV [177] Various filovirus GP Reviewed in [180] CD4 [166] CD4 and CXCR4 [167] CHIKV E1/E2 [181] SIV Gag and Env [182] HIV-1 Gag and Env [183] VSV for oncolytic virotherapy Various genes Reviewed in [192]

Expert Review of Vaccines Downloaded from informahealthcare.com by 174.97.229.189 on 11/08/14 Novirhabdovirus VHSV WNV E [194] Paramyxoviridae Pneumovirinae Pneumovirus hRSV hRSV G (subgroup B) [338] (subgroup A) bRSV hRSV F and/or G [363] ANDV: Andes virus; b/hPIV3: Bovine-human parainfluenza virus 3; BoNT-A: Botulinum neurotoxin type A; bPIV3: Bovine parainfluenza virus 3; bRSV: Bovine respira- tory syncytial virus; BVDV: Bovine viral diarrhea virus; CAT: Chloramphenicol acetyltransferase; CEA: Carcinoembryonic antigen; CHIKV: Chikungunya virus; CS: Cir- cumsporozoite; CSFV: Classical swine fever virus; CTL: Cytotoxic T lymphocyte; DEN1, DEN2, DEN3, DEN4: Dengue virus serotypes 1–4; DENV: Dengue virus; EAV: Equine arteritis virus; EBOV: Ebola virus; F: Fusion; G: Attachment glycoprotein; GFP: Green fluorescent protein; GP: Glycoprotein; GPC: Surface glycoprotein precur- sor; HA: Hemagglutinin; hMPV: Human metapneumovirus; HN: Hemagglutinin neuraminidase; hPIV1: Human parainfluenza virus 1; hPIV3: Human parainfluenza virus 3; HPV: Human papilloma virus; hRSV: Human respiratory syncytial virus; HSP70: Heat shock protein 70; HTNV: Hantaan virus; IAV: Influenza A virus; IRES: Internal ribosomal entry site; KUN: Kunjin virus; JEV: Japanese encephalitis virus; LGT: Langat virus; LIV: Louping ill virus; M: Membrane; MARV: Marburg virus; MeV: Measles virus; MS: Middle envelope surface protein; MuV: Mumps virus; MVEV: Murray Valley encephalitis virus; N: Nucleoprotein; NA: Neuraminidase; NDV: Newcastle disease virus; NiV: Nipah virus; NP: Nucleoprotein; P: Phosphoprotein; prME: Pre-membrane-envelope; RABV: Rabies virus; rB/HPIV3: Recombinant bovine- human parainfluenza virus 3; RSV: Respiratory syncytial virus; RVFV: Rift Valley fever virus; S: Spike; sAg: Surface antigen; SARS-CoV: Severe acute respiratory syn- drome coronavirus; SCFV: Single-cycle flavivirus; SEOLV: Seoul virus; SeV: Sendai virus; SFV: Semliki forest virus; SH: Small hydrophobic protein; SHIV: Simian human immunodeficiency virus; SINV: Sindbis virus; SIV: Simian immunodeficiency virus; SLEV: St Louis encephalitis virus; SV5: Simian virus 5; TBEV: Tick-borne encephalitis virus; VACV: Vaccinia virus; VEEV: Venezuelan equine encephalitis virus; VHSV: Viral hemorrhagic septicemia virus; VSV: Vesicular stomatitis virus;WNV:WestNile virus; YFV: Yellow fever virus.

informahealthcare.com doi: 10.1586/14760584.2015.979798 Review Mogler & Kamrud

Table 1. Selected RNA virus vector vaccine references (cont.). Virus family Subfamily Genus Virus (strain Gene of interest Ref. or modification) Metapneumovirus hMPV aMPV N or P [319] Paramyxovirinae Respirovirus hPIV3 bPIV3 N [206] hPIV1 HN and F [205] hPIV2 HN and F [205] MeV HA [364] hPIV1 HN and hPIV2 [365] HN and MeV HA Ebo GP [366] bPIV3 N [207] hPIV3/DF-HN Ebo GP [367] hPIV1 hMPV F or G or SH [368] rB/HPIV3 RSV F or RSV G [215] subgroup A RSV F or RSV G [216] subgroup A and B hPIV3 F and HN [207] bPIV3 hPIV3 F and HN [212] (generating b/hPIV3) hPIV3 F and HN [213] (generating rB/HPIV3) b/hPIV3 hPIV3 F and HN [214] For personal use only. RSV F or RSV G or [217] hMPV F hRSV F or soluble [369] hRSV F hMPV F [370] RSV F [371] SeV RSV G [232] RSV F [233] HIV GAG [245] Expert Review of Vaccines Downloaded from informahealthcare.com by 174.97.229.189 on 11/08/14 hPIV2 F or hPIV2 HN [228] or HPIV3 HN or RSV F RSV F [229] HIV Env [246] ANDV: Andes virus; b/hPIV3: Bovine-human parainfluenza virus 3; BoNT-A: Botulinum neurotoxin type A; bPIV3: Bovine parainfluenza virus 3; bRSV: Bovine respira- tory syncytial virus; BVDV: Bovine viral diarrhea virus; CAT: Chloramphenicol acetyltransferase; CEA: Carcinoembryonic antigen; CHIKV: Chikungunya virus; CS: Cir- cumsporozoite; CSFV: Classical swine fever virus; CTL: Cytotoxic T lymphocyte; DEN1, DEN2, DEN3, DEN4: Dengue virus serotypes 1–4; DENV: Dengue virus; EAV: Equine arteritis virus; EBOV: Ebola virus; F: Fusion; G: Attachment glycoprotein; GFP: Green fluorescent protein; GP: Glycoprotein; GPC: Surface glycoprotein precur- sor; HA: Hemagglutinin; hMPV: Human metapneumovirus; HN: Hemagglutinin neuraminidase; hPIV1: Human parainfluenza virus 1; hPIV3: Human parainfluenza virus 3; HPV: Human papilloma virus; hRSV: Human respiratory syncytial virus; HSP70: Heat shock protein 70; HTNV: Hantaan virus; IAV: Influenza A virus; IRES: Internal ribosomal entry site; KUN: Kunjin virus; JEV: Japanese encephalitis virus; LGT: Langat virus; LIV: Louping ill virus; M: Membrane; MARV: Marburg virus; MeV: Measles virus; MS: Middle envelope surface protein; MuV: Mumps virus; MVEV: Murray Valley encephalitis virus; N: Nucleoprotein; NA: Neuraminidase; NDV: Newcastle disease virus; NiV: Nipah virus; NP: Nucleoprotein; P: Phosphoprotein; prME: Pre-membrane-envelope; RABV: Rabies virus; rB/HPIV3: Recombinant bovine- human parainfluenza virus 3; RSV: Respiratory syncytial virus; RVFV: Rift Valley fever virus; S: Spike; sAg: Surface antigen; SARS-CoV: Severe acute respiratory syn- drome coronavirus; SCFV: Single-cycle flavivirus; SEOLV: Seoul virus; SeV: Sendai virus; SFV: Semliki forest virus; SH: Small hydrophobic protein; SHIV: Simian human immunodeficiency virus; SINV: Sindbis virus; SIV: Simian immunodeficiency virus; SLEV: St Louis encephalitis virus; SV5: Simian virus 5; TBEV: Tick-borne encephalitis virus; VACV: Vaccinia virus; VEEV: Venezuelan equine encephalitis virus; VHSV: Viral hemorrhagic septicemia virus; VSV: Vesicular stomatitis virus;WNV:WestNile virus; YFV: Yellow fever virus.

doi: 10.1586/14760584.2015.979798 Expert Rev. Vaccines RNA-based viral vectors Review

Table 1. Selected RNA virus vector vaccine references (cont.). Virus family Subfamily Genus Virus (strain Gene of interest Ref. or modification) hPIV3 HN [236] Human fibroblast [249] growth factor-2 (FGF- 2) HIV GAG [247] Avulavirus NDV hPIV3 HN [372] hPIV3 or SARS-CoV S [334] Ebo GP [332] Rubulavirus MuV HIV Gag [300] SV5 GFP [299] Morbilivirus MeV MuV HN, F SIV Env, [294] Gag, Pol GFP [253] HIV Env [290] HIV gp140 [289] WNV prM-E or HIV [288] gp140 SIV Gag, Env, Pol/Env, [296] GFP, Lac-Z, CAT WNV prM-E [373] CEA [374] For personal use only. HIV Gag and/or Env [286] CEA [268] H. pylori neutrophil- [375] activating protein HIV p17, p24, RT and [291] Nef fusion HIV p17, p24, RT and [292] Nef fusion RSV F or EBV gp350 [254] Expert Review of Vaccines Downloaded from informahealthcare.com by 174.97.229.189 on 11/08/14 HIV Env [295] HIV p17, p24, RT and [293] Nef fusion ANDV: Andes virus; b/hPIV3: Bovine-human parainfluenza virus 3; BoNT-A: Botulinum neurotoxin type A; bPIV3: Bovine parainfluenza virus 3; bRSV: Bovine respira- tory syncytial virus; BVDV: Bovine viral diarrhea virus; CAT: Chloramphenicol acetyltransferase; CEA: Carcinoembryonic antigen; CHIKV: Chikungunya virus; CS: Cir- cumsporozoite; CSFV: Classical swine fever virus; CTL: Cytotoxic T lymphocyte; DEN1, DEN2, DEN3, DEN4: Dengue virus serotypes 1–4; DENV: Dengue virus; EAV: Equine arteritis virus; EBOV: Ebola virus; F: Fusion; G: Attachment glycoprotein; GFP: Green fluorescent protein; GP: Glycoprotein; GPC: Surface glycoprotein precur- sor; HA: Hemagglutinin; hMPV: Human metapneumovirus; HN: Hemagglutinin neuraminidase; hPIV1: Human parainfluenza virus 1; hPIV3: Human parainfluenza virus 3; HPV: Human papilloma virus; hRSV: Human respiratory syncytial virus; HSP70: Heat shock protein 70; HTNV: Hantaan virus; IAV: Influenza A virus; IRES: Internal ribosomal entry site; KUN: Kunjin virus; JEV: Japanese encephalitis virus; LGT: Langat virus; LIV: Louping ill virus; M: Membrane; MARV: Marburg virus; MeV: Measles virus; MS: Middle envelope surface protein; MuV: Mumps virus; MVEV: Murray Valley encephalitis virus; N: Nucleoprotein; NA: Neuraminidase; NDV: Newcastle disease virus; NiV: Nipah virus; NP: Nucleoprotein; P: Phosphoprotein; prME: Pre-membrane-envelope; RABV: Rabies virus; rB/HPIV3: Recombinant bovine- human parainfluenza virus 3; RSV: Respiratory syncytial virus; RVFV: Rift Valley fever virus; S: Spike; sAg: Surface antigen; SARS-CoV: Severe acute respiratory syn- drome coronavirus; SCFV: Single-cycle flavivirus; SEOLV: Seoul virus; SeV: Sendai virus; SFV: Semliki forest virus; SH: Small hydrophobic protein; SHIV: Simian human immunodeficiency virus; SINV: Sindbis virus; SIV: Simian immunodeficiency virus; SLEV: St Louis encephalitis virus; SV5: Simian virus 5; TBEV: Tick-borne encephalitis virus; VACV: Vaccinia virus; VEEV: Venezuelan equine encephalitis virus; VHSV: Viral hemorrhagic septicemia virus; VSV: Vesicular stomatitis virus;WNV:WestNile virus; YFV: Yellow fever virus.

informahealthcare.com doi: 10.1586/14760584.2015.979798 Review Mogler & Kamrud

The first clinical trial was a placebo-controlled, randomized, and high-dose groups remained neutralizing antibody positive, double-blind study in 216 healthy volunteers (aged 18–40 years), respectively [20]. which evaluated the safety and humoral and cellular immune A Phase I/II study (open-label, dose-escalation study) was responses after one or two inoculations [35]. AVX502 was admin- conducted to evaluate the safety and immunogenicity of carci- istered either subcutaneously or intramuscularly at two dosage noembryonic antigen (CEA(6D))-expressing VRP vaccine levels and was found to be safe and well tolerated irrespective of (AVX701) in patients with CEA-expressing malignancies [21]. the route or the dose given. Both antibody and T-cell responses The subjects with advanced or metastatic (stage IV) CEA- were efficiently stimulated and persisted for the duration expressing malignancies were treated with one of the three esca- of the 4-month study. Among volunteers with prevaccination lating doses of CEA-expressing VRP. In these subjects, influenza antibody titers (measured by hemagglutination inhibi- AVX701 was administered by intramuscular injection every tion assay) that were below levels thought to be protective, 3 weeks for a minimum of four immunizations, with additional 77 and 80% of these individuals receiving a single low or high doses in patients without progressive disease every 3 months. dose, respectively, responded with protective HAI antibody titers. A total of 28 subjects were treated in the dose-ranging part of A second immunization in these individuals increased seroprotec- the study (dose range: 4 Â 107 IU to 4 Â 108 IU) and no tive responses to 86% for both dosage levels. A rapid and safety or toxicity issues were identified. Following repeated dose-dependent T-cell response (measured by antigen-specific administration, AVX701 was shown to be effective in eliciting IFN-g ELISPOT assay) was also observed and remained signifi- CEA-specific T-cell and antibody response even in the presence cantly elevated for at least 4 months. A second immunization of antivector neutralizing antibodies and elevated Treg levels. extended the duration, but not the magnitude, of these T-cell The study results also suggested that patients with CEA-specific responses. For both antibody and cellular responses, there was T-cell responses exhibited longer overall survival [21]. no significant difference observed between subcutaneous and A VEEV VRP expressing the prostate-specific membrane intramuscular vaccinations. antigen (PSMA) gene was evaluated in a Phase I clinical trial The same VEEV VRP vaccine (AVX502) was also tested in for patients with castration-resistant metastatic prostate can- a Phase I trial involving 28 healthy adults aged 65 years or cer [22]. Two VRP doses (given up to five-times) were tested in older. The trial was a placebo-controlled, randomized, double- patients; the PSMA-VRP was well tolerated at both doses blind study that evaluated responses after administration of tested (9 Â 106 IU or 3.6 Â 107 IU). There did not appear to two doses of vaccine given at a single dosage level. The vac- be clinical benefit at the two PSMA-VRP doses studied sug- cine was safe and well tolerated in this group of healthy, gesting that dosing was suboptimal. This is supported by the ambulatory elderly subjects, paralleling the experience in young positive responses demonstrated with the CEA-VRP vaccine For personal use only. adults. At 4 weeks after the second dose, ten of 20 vaccine described above; the lowest CEA-VRP dose tested was equiva- recipients had a fourfold or greater rise in HAI antibody titer lent to the highest PSMA-VRP dose tested in this study [21,22]. compared to baseline. A significant increase in T-cell responses Two additional cancer trials using VEEV VRP vaccines are was also observed in those receiving vaccine at this time point. currently recruiting patients. A Phase I study using CEA-VRP None of the eight placebo subjects had measurable increases in (AVX701) in patients with stage III colon cancer is now antibody or T-cell responses. The HAI antibody responses recruiting as an extension of the clinical trial already completed measured in the subjects receiving the vaccine exceeded the with this vaccine [40]. Development and testing of a VRP vac- current regulatory approval guidelines for seroconversion in cine for treatment of HER2-neu positive cancers has taken this age group. place [41]. Preclinical testing of neu-VRP in neu transgenic mice A VEEV VRP vaccine expressing human CMV (hCMV) induced robust CD8+, antigen-specific, T cells and tolerance to antigens has been tested in preclinical studies that induced both neu was broken in these animals resulting in the absence or Expert Review of Vaccines Downloaded from informahealthcare.com by 174.97.229.189 on 11/08/14 humoral and cellular immune responses to the expressed anti- inhibition of tumor growth in these animals [41]. Based on gens [38,39]. A combination of VRP expressing the extracellular these promising results, a Phase I trial is recruiting patients domain of hCMV glycoprotein B (gB) or a pp65/IE1 fusion with advanced or metastatic HER2-neu (HER2) expressing protein was chosen for human clinical evaluation [39]. Healthy malignancies for treatment with a VRP expressing the extracel- young adults aged 18–45 years were immunized with two dos- lular domain and the transmembrane region of the HER2 gene ages of the vaccine (1 Â 107 or 1 Â 108 infectious units) at 0, (AVX901, [42]). 8 and 24 weeks in a randomized, double-blind Phase I clinical trial [20]. The combination vaccine (AVX601) was well tolerated Licensed veterinary VEEV VRP and all vaccinated individuals developed cellular immune In addition to human clinical testing of VRP vaccines, the responses (by IFN-g ELISPOT) to CMV antigens and poly- VEEV replicon has recently achieved USDA/CVB approval functional CD4+ and CD8+ T cells were detected by polychro- and licensure for veterinary vaccine development. The first matic flow cytometry. After the third dose, 93% of individuals VEEV (strain TC-83) VRP vaccine (expressing the influenza in the low-dose group and all of the individuals in the high- HA gene) against H3N2 swine influenza virus was fully dose group demonstrated CMV neutralizing antibody response; licensed in 2012. Licensure of the H3-VRP vaccine was sup- 6 months after the third dose, 53 and 75% of the low-dose ported by significant safety and efficacy data as well as

doi: 10.1586/14760584.2015.979798 Expert Rev. Vaccines RNA-based viral vectors Review

demonstration of USDA/CVB compliant manufacture of the fever or dengue shock syndrome). Enhancement of dengue vaccine [43]. In addition, conditional licensure of a porcine epi- disease is associated with incomplete protection against one or demic diarrhea virus VRP vaccine as well as an autogenous more serotypes, further complicating dengue vaccine develop- rotavirus C VRP vaccine have been granted in 2014. ment efforts. The results of the first Phase III clinical trial of the CYD-TDV vaccine were reported in mid-2014 [53] [54]. Flaviviridae The vaccine had statistically significant efficacy against three Genus: Flavivirus serotypes, but not against serotype 2. Despite the relatively Viruses in the genus Flavivirus have nonsegmented, ssRNA(+) poor efficacy against serotype 2, the safety profile of the vac- genomes of approximately 10–12 kb contained within an cine was acceptable and is a promising advance in the field of enveloped, icosahedral nucleocapsid. The genome organization dengue vaccine development. Additional clinical trial results of the flaviviruses is characterized by 5´ and 3´ noncoding are expected in late 2014. regions and a single polyprotein open reading frame. The 5’ The development, safety and preclinical efficacy of a 17D- portion of the polyprotein consists of the three structural pro- based West Nile virus (WNV) vaccine (ChimeriVax-WN02) teins: capsid (C), pre-membrane (prM) and envelope (E), and were recently reviewed [55]. This chimeric virus differs from an the 3´ portion encodes seven nonstructural proteins. The poly- earlier version (ChimeriVax-WN01) by several mutations in protein is co- and post-translationally cleaved into its constitu- the E sequence (L07F, A316V and K440R) that improved ent parts by viral and cellular factors. safety outcomes in neurovirulence studies. The original chimera The Flavivirus genus contains a number of important human has been licensed for use in horses as both a live attenuated and animal pathogens, and vaccine development in this area vaccine and a formalin-inactivated vaccine [55]. has drawn significant attention over the years. Both traditional While most applications of the 17D platform to date have inactivated virus and attenuated virus vaccines have been pro- relied on expression of heterologous prM-E sequence, the duced, with varying degrees of success. Molecular cloning of incorporation of nonflaviviral sequences would potentially allow several flavivirus genomes has enabled the production of recom- for broader applicability of the vaccine platform. Stable incor- binant, chimeric viruses that encode heterologous sequences. In poration of heterologous sequence (e.g., eGFP) between the E most cases, this is accomplished by replacing the backbone and the NS1 sequence has proven to be particularly useful [56]. virus sequence with an orthologous sequence from another fla- Other insertion sites allow for small (~40 codon) insertions vivirus. However, there are some instances where unrelated between the NS2B-NS3 sequences, which enable delivery of T- sequences have been successfully incorporated into functional cell epitopes by this vector [57,58]. flavivirus genomes. The ability to manipulate the genomes of For personal use only. these viruses has proven to be a powerful tool for investigating Dengue virus vectors the biology of both viruses and their hosts. This section will The attenuated Dengue 4 (DEN4) strain 814669 infectious focus on the use of flaviviruses as vaccine platforms for both clone has provided a platform for the creation of numerous related and unrelated viruses. chimeric DEN viruses. The C-prM-E or prM-E sequences derived from Dengue 1 (DEN1), Dengue 2 (DEN2) and Den- Yellow fever virus vectors gue 3 (DEN3) viruses have been used to replace the analogous A system to produce infectious YF-17D virus from in vitro sequence on the DEN4 backbone [59,60]. Further attenuation RNA transcripts has enabled the production of chimeric viruses (in rhesus monkeys and humans) of this and other DENV has that take advantage of the attractive manufacturing and safety been accomplished by deletions in the 3´ UTR as well as other characteristics of the backbone virus [44]. The first chimeric mutations [61,62]. virus based on the 17D backbone replaced the yellow fever The DEN4 backbone containing the prM-E sequence of Expert Review of Vaccines Downloaded from informahealthcare.com by 174.97.229.189 on 11/08/14 virus (YFV) prM-E sequence with that of Japanese encephalitis Saint Louis Encephalitis virus (SLEV) demonstrated protective virus (JEV) [45–47]. Clinical development of this vaccine (first immunity in monkeys [63]. This DEN4 platform has also been ChimeriVax-JE; now IMOJEV) has been recently used to express the C-prM-E or prM-E sequence derived from reviewed [48]. tick-borne encephalitis virus (TBEV) and Langat virus Preclinical development of a tetravalent Dengue vaccine (LGT) [64,65]. A Phase I clinical trial of a chimeric LGT/ based on the 17D backbone (ChimeriVax-DEN) demon- DEN4 vaccine resulted in 80% seroconversion to LGT, but strated promising safety and efficacy profiles in nonhuman poor cross-reactivity with wild-type TBEV [66,67]. primates and mice [49]. This vaccine has progressed to human The DEN4 backbone containing the prM-E sequence of clinical trials under the name ‘CYD-TDV’ and is nearing final SLEV demonstrated protective immunity in monkeys [63]. The regulatory approval [50]. A recently completed Phase IIb clini- prM-E of WNV in the DEN4 backbone demonstrated efficacy cal trial showed efficacy against DENV serotypes 1, 3 and against challenge in several preclinical studies [68]. Initial clinical 4 but not against serotype 2 (ClinicalTrials.gov Identi- trials of the ‘WN/DEN4D30’ vaccine candidate induced sero- fier: [51]) [52]. The vaccine itself was well tolerated, and there conversion in 55–75% of vaccinates with a single dose and was no indication that vaccination increased risk for antibody- 89% after two doses [69,70]. The DEN4D30 backbone contains dependent enhancement of infection (dengue hemorrhagic a 30-nucleotide deletion in the 3´ UTR.

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A DEN2/DEN4 chimera is advancing through clinical trials protective responses in mice, and protected monkeys from chal- as part of the TV003 tetravalent dengue vaccine [62]. Clinical lenge in the case of the chimeric DENV. Another strategy trials have demonstrated good safety and immunogenicity, with involves the attenuation of Murray Valley encephalitis virus 90% of participants seroconverting to at least three dengue (MVEV) by inserting an internal ribosomal entry site between serotypes after a single vaccination [71,72]. the C and PrM sequences [88]. Insertion of sequence encoding Similarly, a backbone based on DEN2 attenuated strain IFN-b downstream of and in frame with the MVEV capsid PDK-53 has been modified to incorporate prM-E sequences sequence was stable using this genome design, and the resulting from DEN1, DEN3 and DEN4 viruses [73]. The four resulting virus exhibited attenuation and immunogenicity in mice. viruses have been evaluated for preclinical safety and efficacy and are advancing as a tetravalent clinical candidate Genus: Pestivirus ‘DENvax’ [74]. A recently completed Phase I clinical trial The pestivirus genome is approximately 12.3 kb of non- showed acceptable safety and immunogenicity, with 62 and segmented ssRNA(+), and the viral particles are enveloped with 96% of participants seroconverting to four or three serotypes, an icosahedral nucleocapsid. The 5´ and 3´ ends of the genome respectively [75,76]. are noncoding, and there is a single open reading frame encod- ing the polyprotein precursor. A 5´ internal ribosomal entry Replication-defective flavivirus vectors site initiates polyprotein translation, which begins with Npro In contrast to use of replication-competent, chimeric flavivi- (a nonstructural autoprotease), followed by the structural ruses as vaccine vectors, single-cycle flavivirus (SCFV) vectors proteins C, Erns, E1, E2 and finally the remaining nonstruc- have been developed [77–79]. These SCFV are rendered tural proteins p7, NS2–3, NS4A, NS4B, NS5A and NS5B. As replication-defective by an internal deletion in the capsid with the flaviviruses, the polyprotein is co- and post- sequence, which requires trans-complementation with C to translationally cleaved, leading to cytoplasmic replication and recover functional particles. The risk of recombination events eventual virus assembly and release. leading to replication-competent virus was reduced by altera- Viruses of the genus Pestivirus primarily infect ruminants and tions to the cyclization sequence of the trans-complemented C swine, and pestivirus diseases cause significant disruptions to ani- sequence. In the host, SCFV expresses subviral particles com- mal agriculture. The type species of the genus, bovine viral diar- posed of the prM-E products, which induce immunity without rhea virus (BVDV), is endemic in many cattle-producing cell-to-cell spread of the vector. The SCFV approach to vaccine regions around the world. Classical swine fever virus (CSFV) is design also allows for substitution of prM-E sequences on a endemic in many countries throughout Asia and South America, common vector backbone. but has been controlled or eradicated from North America and For personal use only. Preclinical efficacy of SCFV vaccines has been demonstrated western Europe. Efficacious vaccines against CSFV and BVDV for WNV, DENV, YFV, JEV and TBEV challenge, and a vari- are currently available, but new vaccines that allow differentia- ety of safety studies have been completed [77,78,80–83]. tion of infected and vaccinated animals (DIVA) are desirable as An alternate approach to the development of replication- a means to improve control and eradication efforts [89]. This sec- defective flaviviruses was demonstrated by the packaging of tion will focus primarily on efforts to develop chimeric pestivirus Kunjin virus replicons [84]. In this approach, the sequences vaccines for the prevention of classical swine fever. encoding most of C, and all of prME, are deleted. The repli- con RNA can be modified to accept transgenes in place of the Bovine viral diarrhea virus vectors deleted sequence, and packaging is accomplished by providing Successful recovery of virus from a full-length cDNA clone of the Kunjin virus structural proteins in trans. This system has BVDV isolate CP7 was reported in 1996 [90]. This backbone shown preclinical efficacy in guinea pigs against EBOV chal- was developed as a chimeric vaccine candidate by replacing the Expert Review of Vaccines Downloaded from informahealthcare.com by 174.97.229.189 on 11/08/14 lenge and immunogenicity against HIV-1 Gag in mice [85]. E2 sequence of BVDV with the corresponding E2 sequence A method for the production of recombinant YFV using a from CSFV strain Alfort 187 [91]. The resulting chimeric virus, two-component genome strategy has also been developed [86]. CP7_E2alf, has been developed as a potential vaccine allowing This method utilizes intact nonstructural coding sequences for DIVA, with several successful efficacy and safety trials in swine both genomes, but deletes either C or prME. The two genomes vaccination models [92–96]. Another version of this approach is only produce pseuodinfectious particles if both genomes are the CP7_E1E2alf chimeric virus, which has both E1 and present in an infected cell, and can be modified to include E2 sequences derived from CSFV [97]. transgenes (e.g., GFP). Infection of a cell with a single particle Serological cross-reactivity between some pestivirus species will produce subviral particles, transgene products and non- has been exploited to develop novel marker vaccines. The chi- structural proteins but the infection will not propagate. meric pestivirus CP7_E2gif was generated by replacing the BVDV strain CP7 E2 sequence with an analogous E2 sequence Other flavivirus-based vaccine vectors from border disease virus strain Gifhorn [98]. The resultant chi- Recently, the attenuated JEV strain SA14-14-2 was used to meric virus contains no sequence derived from CSFV, but still develop a chimeric virus expressing prME sequences derived induced a protective immune response against CSFV challenge from WNV or DENV [87]. These chimeric vaccines induced and allowed for DIVA serology [98,99].

doi: 10.1586/14760584.2015.979798 Expert Rev. Vaccines RNA-based viral vectors Review

The BVDV genome has also been shown to accept the inser- plasmid DNA engineered to code for a modified influenza A tion of a heterologous gene between the Npro and C sequen- NS segment; the chloramphenicol acetyltransferase (CAT) gene ces. A gene construct encoding green fluorescent protein and was inserted in place of the NS gene and flanked by the wild the 2A protease from foot and mouth disease virus were type 5´ and 3´ noncoding regions. RNA of the engineered inserted in-frame with the polyprotein sequence [100]. Growth CAT segment was produced by in vitro transcription and the kinetics and protein expression were only mildly impacted by RNA was complexed with purified influenza virus polymerase the inserted sequence, suggesting that other heterologous genes complex to form a CAT-RNP. Transfection of the CAT-RNP may be compatible with pestivirus vectors. No in vivo experi- into cells followed by infection with influenza helper virus mentation with this vector design has been reported. resulted in CAT expression in the transfected cells and release Traditional attenuated or inactivated vaccines for BVDV are of influenza virus that had incorporated the CAT RNA seg- not compatible with DIVA serological assays that measure anti- ment. CAT expression was still evident after several passages of body against the Erns antigen. Heterologous pestivirus Erns the modified influenza virus demonstrating that the CAT seg- sequence was used to replace the wild-type Erns sequence in a ment was truly packaged into particles [107]. Enami et al. BVDV backbone [101]. The Erns sequence of giraffe pestivirus, (1990) extended this work by replacing the wild-type influenza reindeer pestivirus and pronghorn antelope pestivirus were A/WSN/33 (WSN) NA gene segment with one containing compatible with the BVDV backbone and produced infectious engineered point mutations by using a WSN helper virus lack- chimeric virus. However, only the pronghorn antelope pestivi- ing a wild-type NA segment, demonstrating the ability to engi- rus/BVDV chimera proved to be distinguishable from BVDV neer the genome of an influenza virus [108]. A rapid expansion infection by anti-Erns serology after vaccination. This approach of methods to produce influenza VLP and to rescue influenza may provide a method to develop DIVA-compatible BVDV from cDNA followed these early successes [109–117]. The culmi- vaccines. nation of the efforts resulted in construction of plasmids con- taining promoter elements to generate both viral RNA (vRNA) Classical swine fever virus vectors transcripts for incorporation into RNP and replication and Deletion of Erns, E2 or partial E2 sequence from a CSFV mRNA transcripts for influenza protein expression to support infectious clone, followed by trans-complementation with the polymerase complex formation and structural protein synthe- missing/defective glycoprotein, allows for recovery of nontrans- sis [111,113,115]. Generation of vRNA with precise 5´ and 3´ ends missible replicon particles [102,103]. These CSFV replicons was accomplished by putting the influenza genome regions induce a protective response in some cases and are compatible under the control of DNA-dependent RNA polymerase I (pol with a DIVA approach to serology. Additionally, E2-deleted I) promoter elements; these RNAs were compatible with RNP For personal use only. CSFV replicons with an inserted sequence derived from JEV formation and replication [115]. Flanking the pol I promoter (truncated E protein) induced immune responses to both elements with DNA-dependent RNA polymerase II promoter CSFV and JEV in both mouse and pig models [104]. elements to produce mRNA for translation supported influenza Chimeric viruses with BVDV Erns or E2 sequence replacing virus protein expression allowing for rescue of recombinant that of CSFV have been shown to protect vaccinated pigs from influenza viruses using only an eight plasmid system [113]. lethal CSFV challenge while maintaining DIVA serological compatibility [93,94,105]. Influenzavirus A vectors With methods in place to manipulate the influenza genome Orthomyxoviridae segments, vaccine antigens were introduced into the vectors for Genus: Influenzavirus a number of targets. A representative list of vaccine targets can Viruses in the Orthomyxoviridae family are negative-sense, sin- be found in TABLE 1. Briefly, influenza vectors have been modi- Expert Review of Vaccines Downloaded from informahealthcare.com by 174.97.229.189 on 11/08/14 gle-strand, RNA viruses with eight genome segments (PB2, fied to express circumsporozoite protein B- and T-cell epito- PB1, PA, HA, NP, NA, M and NS). The eight genome seg- pes [118,119], HIV and SIV antigens [120–123], respiratory virus ments express ten viral proteins; M and NS each code for two pathogen antigens [124,125] and tumor-associated antigens [126]. proteins generated through differential splicing of the respective In all cases, antigen-specific immune responses were detected in primary transcripts. As is true for viruses in the Paramyxoviri- animal models, demonstrating the potential of influenza virus dae and Rhabdoviridae families, naked genomic RNA is not vectors in a preclinical setting. infectious; only genomic RNA encapsidated with the polymer- Perhaps the most effective use of influenza reverse genetics ase complex (PB1, PB2, PA and NP) to form a ribonucleopro- capabilities has been the development of live attenuated influ- tein (RNP) is able to initiate a replication and transcription enza vaccines used in seasonal influenza vaccination. MedI- cycle. Viral replication takes place in the nucleus of cells and mmune produced the first cold-adapted live attenuated progeny virus buds from the plasma membrane of infected cells influenza vaccine (termed FluMist in the USA) to be US (reviewed in [106]). FDA licensed for seasonal influenza in 2003 [127]. The reverse The first successful reverse genetics manipulation of any genetically engineered influenza viruses combine attenuating negative-strand RNA virus genome was demonstrated with mutations, cold-adaption and temperature sensitivity character- influenza virus [107]. This was accomplished by generating a istics to restrict vaccine virus replication to the nasopharynx of

informahealthcare.com doi: 10.1586/14760584.2015.979798 Review Mogler & Kamrud

immunized individuals. Each new seasonal influenza vaccine is increasing the length of the helical nucleoprotein/RNA generated by swapping out relevant HA and NA segments in complex. the context of the attenuated, cold-adapted and temperature- sensitive background influenza segments. FluMist is now Development of reverse genetics systems for approved for seasonal influenza vaccination in persons aged single-strand, negative-sense RNA viruses 2–49 years [128]. Similar to the segmented Orthomyxoviridae viruses, wild-type, The reverse genetics approach to rescue influenza virus pro- naked, negative-sense rhabdovirus RNA is not infectious; rather vides the promise of unprecedented response times to the infectious RNA consists of an RNP complex containing N, P appearance of pandemic influenza virus outbreaks [129]. Advan- and L proteins. Early studies using viral functions expressed ces in synthetic biology have reduced the time required to syn- from plasmid constructs or provided by homologous virus thesize DNA from weeks to hours from receipt of a infected cells resulted in successful encapsidation of small engi- nucleotide sequence [130]. Recently, Dormitzer et al. (2013) neered RNAs or cDNA copies of naturally occurring defective completed a proof-of-concept study to demonstrate the speed interfering RNAs [133–136]. These studies helped define the 3´ with which synthetic seed influenza viruses could be rescued and 5´ minimal terminal sequence requirements for replication completely from cDNA in Madin Darby Canine Kidney of viral RNA. cells [129]. Seed viruses are the source material for amplification Understanding that an RNP complex is required for RNA of traditional inactivated influenza vaccines, so they represent a replication was the key to developing reverse genetics systems for key component in the vaccine production process. rhabdoviruses as well as paramyxoviruses. The basic approach to Dormitzer et al. demonstrated that 4 days and 6.5 h after HA generate recombinant viruses from cDNA for viruses in the and NA sequences were provided to initiate DNA synthesis, Rhabdoviridae and Paramyxoviridae families involved devising synthetic seed viruses could be produced for a putative ways to introduce viral genome (or antigenome) RNA to cells H7N9 pandemic influenza virus [129]. Furthermore, a deriva- that were also expressing the structural proteins N, P and L to tion of the H7N9 synthetic seed virus has been used to manu- reconstitute the active RNP replication complex. This was ini- facture a vaccine suitable for clinical evaluation. A Phase I tially accomplished with the help of a recombinant vaccinia virus clinical trial using the H7N9, MF59 adjuvanted, influenza expressing the bacteriophage T7 DNA-dependent RNA vaccine has been reported (Bart 2014). Eighty-five percent of polymerase [137–142]. Plasmid DNAs coding for a virus genome immunized subjects were immunologically protected (micro- or antigenome and plasmids coding for the N, P and L genes all neutralization titer >1:40) after receiving a second dose of the under the control of a T7 promoter were transfected into cells. MF59 adjuvanted H7N9 inactivated vaccine (Bart 2014) [131]. The transfected cells were then infected with the recombinant For personal use only. The results of this study demonstrate that recombinant influ- T7 expressing vaccinia virus, and a combination of enza virus vaccines represent a powerful tool to rapidly design, T7 transcription terminator sequences and ribozyme elements manufacture and test vaccines in response to a pandemic incorporated into the plasmid DNA constructs resulted in the influenza outbreak. production of authentic or near-authentic viral genome RNAs along with mRNA for each of the critical viral proteins. The Rhabdoviridae T7 transcribed genomic or antigenomic RNA was then recog- Viruses of the family Rhabdoviridae are characteristically rod- nized by the expressed N, P and L proteins to form replication or bullet-shaped enveloped viruses containing a linear, nonseg- complexes and viral replication was initiated resulting in rescue mented, negative-sense ssRNA genome. This section will of viruses completely from cDNA [137–142]. The reverse genetics describe vaccine vector development efforts utilizing rabies virus system was further refined to reduce variables introduced by the (RABV) and vesicular stomatitis virus (VSV). The viral particle vaccinia T7 expressing helper virus as it became known that vac- Expert Review of Vaccines Downloaded from informahealthcare.com by 174.97.229.189 on 11/08/14 derives its shape from the helical nucleocapsid protein com- cinia virus enhanced recombination events between genome plexed with genomic RNA. The genome organization of VSV, templates and nonstructural protein helper plasmid con- from 3´ to 5´, consists of nucleocapsid (N), phosphoprotein structs [138]. One approach to reduce this confounding effect was (P), matrix (M), glycoprotein (G) and an RNA-dependent to render the recombinant vaccinia virus incapable of a complete RNA polymerase (L). In the RABV genome, the P protein replication cycle (by UV inactivation) yet allow it to retain ortholog is referred to as NS. Following infection of the host expression of the T7 polymerase [143]. Another approach was to cell, the viral transcriptase complex directs the synthesis of sub- develop continuous cell lines that express the T7 polymerase to genomic mRNAs, pausing at intergenic regions. The transcrip- drive the relevant viral genomes and proteins involved in replica- tase does not proceed in all cases, which manifests as a tion [140,144]. Yet another approach to reduce cell toxicity issues decreasing relative abundance of subgenomic mRNA by gene related to vaccinia helper virus could be attained through addi- position (3´ to 5´) [132]. This characteristic allows for modula- tion of cytosine arabinoside and rifampicin to cell culture during tion of transgene expression by altering the insertion site. The infection [145]. With development of reverse genetics systems genomes of VSV and RABV are amenable to insertion of het- firmly in place, the basics of single-strand, negative-sense RNA erologous genes without drastic impacts on viral replication, virus replication could be explored and these viruses could now and viral particles accommodate the extra genome size by be examined as vaccine vectors.

doi: 10.1586/14760584.2015.979798 Expert Rev. Vaccines RNA-based viral vectors Review

Genus: Lyssavirus vectors undergo a single round of replication, but budded prog- Rabies virus vectors eny lack the ability to infect cells [159]. Single-cycle RABV vec- Rabies virus is classified in the genus Lyssavirus and has a tors show great promise as a safe platform for vaccine genome size of approximately 12 kb. The first successful recov- development. Various G-deleted RABV vectors are also being ery of an infectious negative-strand RNA virus entirely from a exploited as tools for the dissection of neuronal function, complete cDNA genome was achieved with RABV [141,146]. although these applications are outside the scope of this Prevalence of antibodies directed against RABV is low among review [152,160]. the human population, except for those who are prophylacti- cally vaccinated due to occupational hazards. Vaccination of Genus: Vesiculovirus companion animals (e.g., dogs) and wildlife for RABV is com- Vesicular stomatitis virus vectors mon, which may limit the utility of these vectors in VSV is an arthropod-borne virus that causes periodic epizootics such applications. among domestic livestock. Humans are rarely affected by VSV One strategy for immunization with recombinant RABV and infections are typically asymptomatic. Antibodies to VSV involves the use of inactivated virions that have transgene prod- are uncommon, outside of high-exposure populations (e.g., vet- ucts incorporated into the viral particle. This strategy has been erinarians), making it likely that VSV-based vaccines would used to induce immune responses against hepatitis C virus have little interference from preexisting antivector immunity. E2 glycoprotein and Clostridium botulinum neurotoxin, among A method for producing recombinant VSV (rVSV) was others [147–149]. The E2 glycoprotein of hepatitis C virus was developed shortly after the first infectious clone of RABV was also immunogenic when expressed by replication-competent reported [139,161–163]. Early development efforts demonstrated RABV vectors [149]. The severe acute respiratory syndrome that foreign antigens, such as the envelope protein of HIV-1 or coronavirus (SARS-CoV) nucleocapsid protein or spike glyco- hemagglutinin of influenza virus, could be expressed from protein genes were inserted between the G and L genes of a rVSV vectors [164–167]. Mice were protected from influenza chal- RABV-based vector [150]. Following a single intramuscular lenge following intraperitoneal or intranasal immunization with immunization with the vector expressing spike glycoprotein, rVSV-HA [168]. To reduce vector-associated pathogenesis, two mice developed high levels of SARS-CoV-neutralizing antibod- rVSV vectors were developed with either a C-terminal trun- ies. The use of replication-competent RABV vectors presum- cated G protein or a deleted G protein [161]. The G-deleted ably would be compatible with oral administration, since vector (rVSVDG) protected mice from influenza challenge attenuated RABV vaccines have been used in this manner [151]. without inducing VSV-neutralizing antibodies, but required The development of vaccines targeting HIV-1 has been an two administrations to induce influenza virus-neutralizing anti- For personal use only. active area of RABV vector research [152]. Expression of bodies. In contrast, durable protection of mice against HIV-1 gp160 envelope protein by replication-competent H5N1 influenza challenge was seen even in mice that received RABV induced neutralizing antibodies in mice [153]. Another a single dose of rVSVDG-HA [169]. Further development of the report demonstrated that cytotoxic T lymphocyte (CTL) rVSVDG platform would potentially allow for repeated immu- responses were also primed by this approach [154]. Building on nizations without degrading vaccine vector efficacy [170]. this result, RABV vectors expressing HIV-1 Gag protein were The rVSV platform has demonstrated preclinical efficacy also shown to induce specific CTL responses [155]. Modifica- against a wide range of pathogens, including hepatitis B virus, tions of the RABV G protein, intended to improve safety, did measles virus, sudden acute respiratory syndrome (SARS), respi- not harm the vector’s ability to induce these responses. Rabies ratory syncytial virus (RSV), Andes virus, hepatitis C virus, vectors expressing HIV-1 proteins have also been modified to Nipah virus and Yersinia pestis [171–179]. To our knowledge, simultaneously express cytokines, such as IL-2, IL-4 and none of these vaccine candidates have advanced to human Expert Review of Vaccines Downloaded from informahealthcare.com by 174.97.229.189 on 11/08/14 IFN-b [156–158]. Of these trials, IL-2 improved antibody clinical trials at this time. These varied antigens and disease responses slightly, while IFN-b increased CTL responses in models demonstrate the flexibility and potential of VSV as a mice. Simian immunodeficiency virus (SIV) Env and Gag or vaccine platform. Gag-Pol proteins, when expressed by RABV vectors, induced The rVSVDG platform has shown particular utility against neutralizing antibodies and CTL responses in macaques [158]. filoviruses, such as EBOV or Marburg virus (reviewed in [180]). These animals, when challenged with virulent SIV, were pro- Recombinant VSV expressing filovirus glycoprotein have dem- tected from clinical disease. onstrated preventive efficacy in a number of studies in nonhu- Ultimately, the use of RABV-based vectored vaccines in man primates. As a post-exposure therapy, vaccination has humans will depend on the development of constructs with shown mixed results, ranging from 33–100% survival. Certain acceptable safety profiles, particularly neurovirulence. aspects of the laboratory model likely contribute to this vari- Replication-defective and highly attenuated variants are being ability, such as challenge dose or route of exposure. developed, primarily by the deletion of the viral P or M Coincorporation of heterologous proteins into the VSV genes [152]. These viruses have severely reduced fitness and are envelope provide a means to alter the tissue tropism of the primarily of interest as rabies vaccines. However, single-cycle virus, as was demonstrated by incorporation of CD4 and RABV can be produced by deletion of the viral G gene. Such CXCR4 for targeting of HIV-infected cells [166,167]. Expression

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of CHIKV envelope glycoproteins in place of VSV G, and disease burden falls on young children and the elderly as well without trans-complementation with G, resulted in VSV par- as the immunocompromised. RSV, human metapneumovirus ticles that incorporated CHIKV E1/E2 into the envelope [181]. (hMNV) and human paramyxovirus (hPIV) 1–3 are responsi- This vector induced immune responses specific to CHIKV and ble for a majority of this disease [195–200]. Although live attenu- protected vaccinated mice from challenge. ated vaccines exist for measles virus and mumps virus (also Multiple immunizations of nonhuman primates with rVSV members of the Paramyxoviridae family), RSV, hMNV and expressing Gag and Env protected animals from AIDS follow- hPIV-1–3 have been refractory and no licensed vaccines ing challenge with virulent SIV [182]. Boosting in this study was are available. accomplished by exchanging the serotype of the rVSV G pro- Paramyxoviridae family viruses have a single-strand, negative- tein. Expression of HIV-1 Gag and Env from rVSV stimulated sense RNA genome (ranging from ~13 to 19 kb in size) sur- cytotoxic T-cell responses in mice, consistent with SIV experi- rounded by a lipid envelope; the viruses replicate solely in the ence [183]. Additional trials have supported the use of rVSV vec- cytoplasm of infected cells. All paramyxoviruses code for six tors for the control of HIV in humans [184,185]. Vaccine common genes in their genome; the genes are entitled matrix regimens that utilize rVSV and another vector system in a (M), fusion (F), hemagglutinin neuraminidase (HN; sometimes prime-boost model have also been developed for HIV [186,187]. referred to as G or H), nucleoprotein (NP or N), phosphopro- The first human clinical trial of an rVSV-based vaccine was tein (P) and the large polymerase protein (L). In addition to conducted using a construct encoding HIV-1 Gag [188]. The the six proteins found in all paramyxoviruses, some members dose-escalation study revealed acceptable safety profile, although code for additional proteins. Each gene has precise transcription Gag-specific CD4+ and CD8+ T-cell stimulation was low [189]. initiation and termination signals such that a gradient of The clinical trial is still ongoing at the time of this writing. mRNAs is produced. This occurs because the RNA-dependent The only other report of rVSV use in humans was that of an RNA polymerase pauses as it completes a new mRNA before emergency post-exposure vaccination following a laboratory engaging a new intergenic sequence. If it dissociates from the accident. A laboratory worker was potentially exposed to Zaire genomic RNA before engaging the next start signal, then it ebolavirus (ZEBOV) by accidental needlestick and received must reinitiate at the leader sequence found at the 3´ end of research-grade rVSV expressing the ZEBOV glycoprotein [190]. the genome again. This phenomenon results in those genes at No severe adverse reaction was observed, and the patient the 5´ end of the genome being transcribed into mRNA less showed no signs of ZEBOV infection. Antibodies to VSV and frequently than those at the 3´ end of the genome [133]. ZEBOV were present after vaccination, consistent with the pre- Although not required for efficient replication of all paramyxo- clinical experience with that vector. A Phase I clinical trial of virus RNA templates, the finding that RNA templates with a For personal use only. rVSV expressing ZEBOV glycoprotein is currently recruiting nucleotide length divisible by six (the rule of six) assisted the participants [191]. development of the reverse genetics systems and helped explain The development of rVSV for use in oncolytic virotherapy why natural defective interfering genomes as well as full-length was recently reviewed [192]. The first Phase I clinical trial of viral genomes are generally divisible by a factor of six [200]. rVSV for oncolytic virotherapy has been initiated for treatment The focus of the following section will be on the use of par- of hepatocellular carcinoma [193]. In this case, the virus amyxoviruses as vectors to express heterologous genes that are expresses IFN-b to enhance the safety and efficacy following not naturally associated with the virus that the system is based intratumoral injection. on. This may be a subtle distinction in some of the examples where the heterologous gene is an ortholog of a gene from Genus: Novirhabdovirus another paramyxovirus, but these examples are consistent with Viral hemorrhagic septicemia virus vectors the use of these powerful systems as vectors to express genes Expert Review of Vaccines Downloaded from informahealthcare.com by 174.97.229.189 on 11/08/14 Another approach to rhabdovirus-based vaccine development is not naturally associated with the base vector system employed. the use of viruses that do not naturally infect mammals as anti- There are examples of reverse genetically derived paramyxovi- gen presentation vehicles. Viral hemorrhagic septicemia virus, a ruses developed as live attenuated viruses but without engineer- member of the genus Novirhabdovirus, does not replicate at ing expression of heterologous genes; these examples will not temperatures above 20˚C, making it naturally inactivated in be specifically reviewed here. A description of paramyxovirus mammals. Expression of WNV E protein domains by a recom- vector development is subdivided into the genus that the spe- binant viral hemorrhagic septicemia virus resulted in incorpo- cific virus falls into phylogenetically with a general focus on ration of WNV antigen into the viral particles, which were those paramyxovirus vectors that have advanced into human used to immunize mice [194]. Mice challenged with WNV were clinical evaluation. only partially protected, despite the presence of anti-WNV antibodies. Genus: Respirovirus Human parainfluenza virus vectors Paramyxoviridae Recovery of hPIV-1, hPIV-2 and hPIV-3 infectious viruses Viruses in the Paramyxoviridae family are responsible for a sig- completely from cDNA, using either genomic or antigenomic nificant number of respiratory diseases in humans; most of the templates, has been accomplished [201–204]. Soon after the reverse

doi: 10.1586/14760584.2015.979798 Expert Rev. Vaccines RNA-based viral vectors Review

genetics systems were developed, efforts to generate chimeric par- positions affected recombinant virus growth or heterologous ainfluenza viruses began; Tao et al. (1998) replaced the wild-type gene expression [217]. Placement of heterologous genes in the F and HN hPIV-3 genes with those of hPIV-1 to generate a second position was generally superior to the first position [217]. chimeric rPIV3-1 virus [205]. The rPIV3-1 virus demonstrated a The b/hPIV-3 RSV and hMPV recombinant viruses were both mixture of hPIV-3 and hPIV-1 biological characteristics in cell shown to be immunogenic and protective in animal mod- culture. Other chimeric hPIV-3 viruses were generated by els [200]. The b/hPIV-3 RSV F virus (now referred to as replacement of the wild-type hPIV-3 N gene with the N gene MEDI-534) was further developed and tested clinically in from two different strains of bPIV-3 (rHPIV3-NB). The chime- healthy adults, seropositive children aged 1 to 9 years and RSV ric rHPIV3-NB viruses demonstrated restricted replication in and hPIV-3 seronegative children aged 6 to 23 months. Sero- nonhuman primates yet induced robust anti-hPIV-3 immune conversion to RSV and hPIV-3 occurred in 67 and 100% of [206] [200] responses . The rHPIV3-NB chimeric was clinically tested in vaccinated children, respectively . adults and young children as a live attenuated vaccine for hPIV-3; the vaccine was well tolerated and demonstrated Sendai virus vectors restricted replication characteristics similar to those noted in Sendai virus (SeV), also known as murine parainfluenza virus nonhuman primates [207]. type 1, has structural and sequence similarity to hPIV-1 [218,219] and has been shown to be antigenically similar as well [220–222]. Bovine parainfluenza virus vectors For this reason, SeV has been tested as a xenotropic vaccine for Bovine parainfluenza 3 (bPIV-3) has been shown to be antigen- hPIV-1 clinically and has been shown to be well tolerated and ically similar to hPIV-3 and to induce hPIV-3 cross-reactive safe in adults [200]. Recruitment of children and toddlers for and protective immune responses in nonhuman primates [208]. clinical evaluation of SeV (as a vaccine against hPIV-1) in these A bPIV-3 virus (strain Kansas/15626/84) was shown to be well age groups is occurring now [223]. Supported by the clinical tolerated clinically as a live attenuated vaccine for hPIV-3 in safety demonstrated by wild-type SeV it has become the focus children and infants [209–211]. Because of the species-restricted of vaccine vector development. replication noted with bPIV-3 and the clinical safety demon- Garcin et al. (1995) were the first to rescue infectious SeV strated by the live bPIV-3 virus in humans, recombinant from cDNA using vaccinia T7 expressing helper virus and plas- bPIV-3 vectors were developed [212,213]. Haller et al. (2000) mids providing the NP, P and L genes along with the SeV generated a bPIV-3 vector where the F and HN wild-type genome as described above [138]. This was followed closely by genes were replaced with hPIV-3 F and HN genes and the chi- another group in 1996 [145].Inadditiontoreplication- meric was termed b/hPIV3 [212]. A similar bPIV-3-based vector competent SeV vectors, versions modified by deletion of the F For personal use only. was generated by Schmidt et al. (2000) and it was termed gene have been developed that are not transmissible [224].The rBPIV3-FHHNH, where the human PIV-3 F and HN genes SeV-DF vector must be produced in cells that provide F in trans were used to replace the bovine PIV-3 orthologs [213]. This to make particles. These particles are able to infect cells in a [225,226] group also constructed a reciprocal vector, rHPIV3-FBHNB, similar manner to replication-competent SeV and express using hPIV-3 as the base vector modified to contain the bovine heterologous genes but cannot spread to other cells [224,225].Ini- F and HN gene PIV-3 orthologs [213]. tial recombinant SeV viruses expressed reporter genes, but Both the b/hPIV3 and rBPIV-FHHNH (also known as rB/ researchers rapidly began to introduce a host of additional HPIV3) viruses demonstrated replication in vitro that was genes [226,227]. Although SeV has been used to develop vaccines nearly identical to hPIV-3 but reduced replication in vivo in against a large range of pathogens (see TABLE 1), two major areas hamsters and nonhuman primates; both viruses also conferred of SeV vaccine development have emerged; recombinant SeV protection from challenge in vivo similar to that noted in ani- vaccines targeted against respiratory viruses and HIV. These Expert Review of Vaccines Downloaded from informahealthcare.com by 174.97.229.189 on 11/08/14 mals after previous infection with hPIV-3 [212–214]. The rB/ areas will be the focus in the following sections. HPIV3 virus was tested in adults, hPIV-3 seropositive children Recombinant SeV vectors expressing the RSV G or F gene and hPIV-3 seronegative children and was shown to be safe have been tested in mice, cotton rats and nonhuman and immunogenic [207]. primates [228–233]. The recombinant SeV RSV vaccines were The rB/HPIV3 vector was engineered to express the G and/ shown to induce both humoral and cellular immune responses or F genes of RSV subgroup A and B as possible vaccines and provided protection from RSV challenge. Importantly, no against both RSV-A and RSV-B and hPIV-3 [215,216]. The six evidence of exacerbation of disease in vaccinated animals was [228–233] new vectors (rB/HPIV3-GA, rB/HPIV3-FA, rB/HPIV3-GAFA, detected after RSV challenge . An important consider- rB/HPIV3-GB, rB/HPIV3-FB and rB/HPIV3-GBFB) were char- ation in RSV vaccine development as vaccine-mediated acterized in vitro and evaluated in hamsters and nonhuman pri- enhancement of disease was noted early in RSV vaccine clinical mates to examine immunogenicity; robust immune responses testing [234,235]. to all three viruses (RSV-A, RSV-B and hPIV-3) were detected. All recombinant SeV are bivalent in nature due to the In parallel, RSV G and F and hMPV F genes were introduced pPIV-1 immunity they provide coupled with expression of a into the b/hPIV-3 vector described above to determine if the heterologous gene. Development of recombinant SeV vaccines location of gene placement in the first or second 3´ genomic that can provide immunity to PIV other than hPIV-1 was a

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logical extension of this vector. Recombinant SeV expressing Recombinant MeV vectors have been used to express a large the F or HN genes of either hPIV-2 or hPIV-3 have been con- range of proteins (see TABLE 1). Of particular note is their use in structed and tested [228,236,237]. Experiments conducted in cotton both cancer and HIV vaccine development as these vaccines rats demonstrated that the SeV hPIV-2 and hPIV-3 F or HN have advanced into human clinical evaluation. The oncolytic vaccines could induce protective immune responses to their nature of MeV has been linked to changes in receptor tropisms respective hPIV and when combined with recombinant SeV that occur as a result of passage in cell culture to generate RSV-F provided protection from hPIV-1, hPIV-2, hPIV-3 and attenuated vaccine viruses; specifically, attenuated MeV are RSV [228,237]. In addition, recombinant SeV expressing the capable of using CD46 as a cell entry receptor [255,256]. There is influenza HA gene have also been tested and shown to induce an upregulation of CD46 on many tumor cells relative to nor- protection from influenza virus challenge in mice [238]. mal cells so MeV have a natural tropism for cancer cells over Recombinant SeV expressing HIV genes have been tested normal cells [257–264]. Given the long safety history of attenu- extensively and have been shown to induce both cellular and ated MeV vaccines and the fortuitous shift of cell entry recep- humoral immune responses in a range of animal models tor to one predominantly found on many cancer cells, including nonhuman primates [239–246]. A recombinant SeV development of recombinant MeV cancer vaccines was an obvi- expressing the HIV gag gene has been used alone or in combi- ous direction for the system to go. nation with DNA and adenovirus vectors, expressing the same Although attenuated MeV without recombinant genome gene, in a prime-boost vaccination regimen [242,244,245]. Initial manipulation have been clinically tested in cancer patients [265], studies used a replication-competent SeV-gag recombinant vac- the inability to follow the pharmacokinetics of treatment make cine [240,242] and similar studies followed using the SeV DF vec- informed clinical development with oncolytic viruses difficult. tor [244,245]. The replication-competent SeV vaccine, termed In response to this, researchers engineered nonimmunogenic SeV-G (NP), is currently in clinical evaluation in combination soluble marker peptides with no biological function into MeV with an adenovirus 35 vector expressing four HIV genes (gag, vectors. The soluble extracellular domain of human CEA and reverse transcriptase, integrase and nef), termed Ad35-GRIN, the b-subunit of human chorionic gonadotropin (bhCG) were in a prime-boost regimen in Kenya, Rwanda and the chosen as marker peptides and were engineered into recombi- UK [247,248]. Although not discussed in this review, in addition nant MeV [266]. These recombinant MeV can be tracked by fol- to vaccines, recombinant SeV are being used as gene-delivery lowing the kinetics of marker gene expression and this has been vehicles; one example is a nontransmissible SeV expressing the correlated with therapeutic outcomes [266,267]. The MeV-CEA human fibroblast growth factor-2 gene [249]. This recombinant vector retained oncolytic potency in preclinical testing against SeV has been tested clinically in patients with peripheral arte- ovarian and brain cancer and has moved into clinical evaluation For personal use only. rial disease and shown to be well tolerated [249]. Because preex- for each indication ([268–271], ClinicalTrails.gov Identifier: [272]). isting immunity to hPIV-1 can neutralize SeV, the influence of A further refinement of the noninvasive monitoring approach preexisting immunity in human populations to successful SeV was to engineer the human thyroidal sodium iodide symporter vaccine vector development in a clinical setting will ultimately (NIS) membrane ion channel gene into recombinant be determined as more vaccine studies are conducted [250]. MeV [273]. NIS is found on thyroid follicular cells where it functions to transport iodine into cells. Furthermore, NIS Genus: Morbilivirus expression has successfully been exploited in clinical settings for Measles virus vectors thyroid imaging and ablation when combined with radioactive A safe and immunogenic measles virus (MeV) vaccine has iodine [274,275]. By using single photon emission computed been available since 1963 (reviewed in [251]); the original vac- tomography or positron emission tomography imaging and cine strain, Edmonston B, was reactogenic and was eventually radioactive iodine, MeV-NIS infected tissues can be monitored Expert Review of Vaccines Downloaded from informahealthcare.com by 174.97.229.189 on 11/08/14 replaced with the Schwarz/Moraten strain, which was derived in a noninvasive manner as infected tissues will concentrate through chicken embryo fibroblast passage of the Edmonston radioactive iodine used as a tracer [276,277]. MeV-NIS has been A and B viruses [252]. In addition to the Schwarz/Moraten used in preclinical noninvasive monitoring against a host of dif- strain, attenuated Edmonston AIK-C and EZ strains are also ferent cancer indications [269,273,276,278,279]. These MeV-NIS pre- used as human vaccines [251]. The MeV vaccine is estimated clinical successes have resulted in a large number of clinical to have been given to more than a billion people and has an trials that are either active, recruiting or about to recruit outstanding history of safety and efficacy [253]. For this reason, patients for the following indications: ovarian cancer, multiple recombinant MeV vaccine vectors enjoy a regulatory advan- myeloma, head and neck cancer and mesothelioma [280–285]. tage over some other paramyxovirus-based vaccine vectors. In addition to using recombinant MeV in cancer virotherapy, The first rescue of MeV completely from cDNA occurred in significant effort has been made in the HIV vaccine field. 1995 and the system was based on the Edmonston B MeV Expression of individual SIV or HIV genes as well as multiple strain [140]. Subsequently, the Schwarz/Moraten and genes individually or as fusion proteins, in a single MeV recom- Edmonston-Zagreb strains of MeV have been rescued from binant, have undergone extensive preclinical testing [286–296]. cDNA and developed as vaccine vectors due to their more One candidate vaccine expresses a fusion protein of p17, p24, attenuated phenotypes [253,254]. reverse transcriptase and Nef (termed MV1-F4) from Clade B

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HIV-1 [291,292]. The MV1-F4 vaccine has been shown to be of hMPV infections can be dated back to 1958 suggesting that immunogenic, inducing both cellular and humoral responses to many of the cases of bronchiolitis and pneumonia without the F4 antigen, and safe as no toxic effects or virus shedding known etiology may be related to hMPV infection [312,313]. was detected in vaccinated cynomologous macaques [291,292]. Human and avian MPV have been rescued from cDNA and The MV1-F4 vaccine has been tested in a human clinical trial their genomes have also been engineered to express a GFP in young healthy adults aged 18–27 years; the trial is complete reporter gene or for hMPV, extra copies of the hMPV G and but the results have not been made public [297]. F genes [314,315]. Subsequently, recombinant hMPV were gener- ated with either the G or SH or G and SH genes deleted. Genus: Rubulavirus These viruses replicated in cell culture but the DG and DG/D Mumps & parainfluenza virus 5 vectors SH hMPV demonstrated restricted replication in the respira- Two viruses in the Rubulavirus genus have been developed into tory tract of hamsters yet provided protection from wild-type recombinant vaccine vectors, Mumps (MuV) and parainfluenza hMPV replication in their lungs [316]. Additional hMPV dele- virus 5 (PIV5) [298,299]. PIV5 was previously named simian virus tion mutants in the context of DGorDSH backgrounds have 5 (SV5) but in 2009 the International Committee on Taxonomy been generated in the M2 gene, which contains two overlap- of Viruses changed the designation to PIV5 because the virus ping reading frames (M2-1 and M2-2) [317]. Examination of had been isolated from many different species other than mon- replication in the respiratory tract of hamsters and nonhuman keys and the new designation was adopted to remove the primates has demonstrated that hMPV DG and DM2-2 viruses assumption that monkeys were the natural host of the virus. may be promising hMPV vaccines [317,318]. Chimeric hMPV Although the first rescue of MuV occurred in 2000 [298], there viruses incorporating avian MPV N or P orthologs have also [319] has not been significant use of it as a vaccine vector to date. been generated . Both hMPV-NA and hMPV-PA replicated A recombinant MuV vaccine expressing the HIV-1 gag gene was efficiently in cell culture and demonstrated restricted replica- used in a prime-boost vaccination regimen with a recombinant tion in the respiratory tract of nonhuman primates yet pro- [300] [319] VSV expressing the same HIV-1 antigen . The highest Gag- vided protection from hMPV challenge . The hMPV-PA specific T-cell responses were detected when the rMuVgag was chimeric virus is about to undergo clinical testing in adults used as the priming dose followed by the rVSVgag vaccine [300]. aged 18–49 years, hMPV-seropositive children aged 12–59 More preclinical vaccine development has occurred with months, and hMPV-seronegative infants and children aged PIV5 vectors than MuV vectors although no recombinant 6–59 months [320]. PIV5 vectors have progressed past preclinical testing. The first rescue of PIV5 (SV5 at that time) from cDNA occurred in Genus: Avulairus For personal use only. 1997; this group also demonstrated stable expression of a Newcastle disease virus vectors reporter gene (GFP) in recombinant virus passaged up to Newcastle disease virus (NDV) is a worldwide disease of avian 20-times [299] – an important characteristic in replication- species that is capable of causing serious economic losses in the competent vaccine vectors. Mice vaccinated with a recombinant poultry industry [321]. Two groups rescued NDV from cDNA PIV5 vector expressing a model antigen (chicken ovalbumin) separately for the first time in 1999 [322,323]. Prior to reverse were shown to generate high avidity cytotoxic T cells to the genetics approaches to modify NDV, it was known to have antigen equivalent to those induced by a recombinant vaccinia oncolytic potential and has been tested extensively in human virus expressing the same antigen [301]. Arimilli et al. (2008) clinical trials; although oncolytic NDV vectors are being engi- engineered a PIV5 vector to express the TLR5 ligand flagel- neered to express biomolecules to increase their antitumor activ- lin [302]. The recombinant PIV5-flagellin was superior to wild- ity, this review will focus on the infectious disease aspects of type PIV5 at activating IFN-g from both CD8+ and CD4+ NDV vector development. A review of oncolytic NDV vaccine Expert Review of Vaccines Downloaded from informahealthcare.com by 174.97.229.189 on 11/08/14 T cells [302]. Subsequently, recombinant PIV5 vectors have been development was recently published and readers are directed to engineered with antigens from vaccinia virus, influenza virus, it for more information on NDV-based cancer treatment [324]. RABV and RSV; all of the recombinant PIV5 vectors demon- NDV strains can have varying virulence and the different strated significant protection from the respective pathogen even virulence categories have been described as velogenic (highly in the face of preexisting PIV5 immunity [303–311]. Interestingly, virulent), mesogenic (intermediate virulence) or lentogenic a recombinant PIV5 vector expressing the H5N1 HA gene (nonvirulent) [321]. Recombinant NDV vaccine vectors have incorporated H5 HA into the recombinant PIV5 virion; inacti- been made from either mesogenic (Beaudette) or lentogenic vated rPIV5-H5 were still capable of protecting mice from (LaSota, Hitchner B1 and Clone-30) NDV strains. In general, challenge, albeit a protective response required a boost of the recombinant NDV vectored vaccines are delivered by the intra- inactivated rPIV5-H5 vaccine [309]. nasal/intratracheal routes of administration; this route induces robust mucosal immune responses that in turn make respira- Genus: Metapneumovirus tory disease targets attractive for NDV vectors. From a veteri- Metapneumovirus vectors nary perspective, all NDV vector vaccines are bivalent in nature Human metapneumovirus is a newly discovered paramyxovi- as immunity to wild-type NDV is provided as a matter of rus [312]. Although only recently described, serological evidence course by the base system in addition to the incorporated

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heterologous gene [325,326]. Recombinant NDV vaccines against parent virus [338,340–342]. At least two recombinant hRSV vec- influenza virus have been developed with more focus being tors have been developed that express a heterologous placed on viruses with pandemic potential [325–331]. NDV vac- gene [343,344]. The first is a hRSV vector constructed to express cines expressing the HA gene from H5N1 influenza virus have the cystic fibrosis transmembrane conductance regulator and is been tested in mice, chickens and nonhuman primates and being tested as a gene delivery vehicle for treatment of cystic shown to induce robust protective immune responses both in fibrosis [343]. The second is a hRSV replicon that is noncyto- circulation and on mucosal surfaces [326,329,332,333]. Other respi- toxic and capable of long-term gene of interest expression [344]. ratory pathogens have also been targeted for NDV vectored The hRSV replicon is propagation defective, that is, it cannot vaccines [327,334,335]. Recombinant NDV vaccines, based on both make progeny once it enters a cell. The hRSV replicon was Beaudette and LaSota strain backbones, against SARS-CoV and engineered to express both a GFP reporter gene and a blastici- hPIV-3 have been tested in nonhuman primates and shown to din S deaminase (bsd) selectable marker gene [344]. Although be immunogenic and protective [327,334]. A recombinant NDV not tested as a vaccine vector yet, the hRSV replicon has vector expressing the RSV F gene was shown to be more potential for that and potentially as a self-limiting gene deliv- immunogenic than even wild-type RSV infection in a mouse ery vector [344]. model [335]. Nonhuman primates vaccinated by the intranasal/ intratracheal route with a recombinant NDV vector expressing Expert commentary & five-year view the glycoprotein from EBOV demonstrated robust humoral In the nearly 30 years since the development of reverse genetics and cellular immune responses to EBOV glycoprotein, and IgA tools to manipulate RNA virus genomes, this diverse and com- antibody titers were detected in respiratory tract secretions plex group of viruses has become a source of powerful vaccine showing a mucosal immune response [332]. vector systems. This is evidenced by the fact that all five virus HIV has also been a focus of recombinant NDV vaccine devel- families discussed in this review have members that have pro- opment. Early studies incorporated the SIV gag into a recombi- gressed to human clinical evaluation and even to FDA and nant NDV vector [123]. A number or different routes of USDA vaccine licensure. Alphavirus replicon vectors have administration were examined and intranasal NDV-SIVgag shown promise clinically against both infectious disease and administration was found to be superior in a mouse model [123]. cancer targets and fully licensed VEEV VRP vaccines are cur- The optimal site to introduce a HIV-1 gag gene into an NDV rently available for veterinary diseases of swine. Live attenuated vector was determined both in terms of vaccine yield and induc- influenza viruses generated completely from cDNA represent a tion of an immune response [336]. In other NDV-gag vaccine safe and immunogenic alternative to traditionally inactivated studies, the HIV-1 gag gene was modified by fusing it with a vaccines and the same technology, supported by rapid DNA For personal use only. single-chain Fv antibody specific for the dendritic cell receptor, synthesis, has proven ability to produce synthetic seed viruses DEC205. Mice vaccinated with the NDV vaccine expressing the used to produce traditionally inactivated vaccines for pandemic gag-DEC205 Fv fusion induced enhanced CD4+ and CD8+ T- influenza viruses. Vaccine vectors based on recombinant para- cell immune responses [337]. An NDV-gag vaccine was also shown myxoviruses represent real promise for development of poten- to be compatible in a prime-boost vaccine schedule when com- tial RSV vaccines as well as vectors with powerful oncogenic bined with other virus vectors also expressing the gag gene [187]. capacity. Chimeric flaviviruses based on the YFV-17D back- A search of ClinicalTrails.gov indicated that, to date, none of the bone have been approved for use in humans (JEV) and horses infectious disease-specific recombinant NDV vectored vaccines (WNV). The nature of WNV epidemiology presents challenges have entered human clinical evaluation. for clinical efficacy study design and ultimate regulatory approval. Three different tetravalent vaccines for DENV are Genus: Pneumovirus advancing through the clinic, with the CYD-TDV candidate Expert Review of Vaccines Downloaded from informahealthcare.com by 174.97.229.189 on 11/08/14 Respiratory syncytial virus vectors now completing Phase III trials. Dengue vaccine candidates Recombinant RSV vectors have been generated from both the based on chimeric DEN/DEN viruses are in Phase I and II tri- human (hRSV) and bovine (bRSV) RSV counter- als. Trials conducted over the next several years will dramati- parts [137,144,338]. Human RSV is a very important pediatric cally advance the practical understanding of DENV respiratory pathogen with impact noted worldwide, yet no vaccinology. Novel replication-defective flaviviruses may pro- licensed vaccine for it is available [339]. This is in large part due vide a tool to improve the safety profile of existing efficacious to clinical testing of an inactivated RSV vaccine in young chil- vaccines. Chimeric pestivirus vaccines show great promise as a dren revealing more severe clinical illness in vaccinated individ- tool for the control of diseases in domestic livestock and wild- uals than unvaccinated individuals who subsequently became life. Vaccines based on recombinant rhabdoviruses have only infected with RSV [234,235]. just begun to enter human clinical trials, initially for HIV. Sev- Development of hRSV or bRSV as a vaccine vector for eral VSV-based preclinical candidates for diseases that represent other pathogens is limited to date. Most recombinant RSV biodefense hazards or public health risks are also being com- viruses tested have been gene deletion or temperature-sensitive mercialized. Oncolytic VSV promises to be an active area of mutant versions of the wild-type virus generated to produce clinical research in the future, with one clinical trial already attenuated live vaccines against either the human or bovine underway.

doi: 10.1586/14760584.2015.979798 Expert Rev. Vaccines RNA-based viral vectors Review

Financial & competing interests disclosure includes employment, consultancies, honoraria, stock ownership or options, The authors have no relevant affiliations or financial involvement with expert testimony, grants or patents received or pending, or royalties. any organization or entity with a financial interest in or financial conflict No writing assistance was utilized in the production of this with the subject matter or materials discussed in the manuscript. This manuscript.

Key issues

• Chimeric flaviviruses and live attenuated influenza vaccines (orthomyxoviruses) have achieved regulatory approval for use in humans, while chimeric flaviviruses and alphavirus replicons have reached approval in veterinary animals. • Recombinant alphavirus replicon, chimeric flavivirus, paramyxovirus and vaccines are advancing through human clinical trials supported by preclinical efficacy against a wide variety of infectious disease and cancer targets. • Rational design of flavivirus-, alphavirus- and rhabdovirus-based vaccines has increased vector safety that will support continued testing of these vector platforms. • Most flavivirus and paramyxovirus vector development has focused on the expression of sequences derived from other flaviviruses or paramyxoviruses, respectively; these chimeric vectors offer increased attenuation and great promise for development of vaccines against some of the most important insect-borne and pediatric respiratory illnesses known to man. • The oncolytic nature of many RNA viruses (ex paramyxoviruses and rhabdoviruses) that can be manipulated through reverse genetics represents a significant advancement in cancer treatment. New and continued clinical evaluation of these oncolytic viruses will likely shape the future of cancer therapy.

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gp160DeltaV1V2 is strongly immunogenic. 298. Clarke DK, Sidhu MS, Johnson JE, encoding the influenza virus hemagglutinin Virology 2009;388(1):191-203 Udem SA. Rescue of mumps virus from protects against H5N1 highly pathogenic 287. Liniger M, Zuniga A, Morin TN, et al. cDNA. J Virol 2000;74(10):4831-8 avian influenza virus infection following Recombinant measles viruses expressing 299. He B, Paterson RG, Ward CD, Lamb RA. intranasal or intramuscular vaccination of single or multiple antigens of human Recovery of infectious SV5 from cloned BALB/c mice. J Virol 2013;87(1):363-71 immunodeficiency virus (HIV-1) induce DNA and expression of a foreign gene. 310. Phan SI, Chen Z, Xu P, et al. A respiratory cellular and humoral immune responses. Virology 1997;237(2):249-60 syncytial virus (RSV) vaccine based on Vaccine 2009;27(25-26):3299-305 300. Xu R, Nasar F, Megati S, et al. Prime-boost parainfluenza virus 5 (PIV5). Vaccine 2014; 288. 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