WO2018201025A1 - Vaccin à flavivirus qui atténue une infection croisée par d'autres flavivirus - Google Patents

Vaccin à flavivirus qui atténue une infection croisée par d'autres flavivirus Download PDF

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WO2018201025A1
WO2018201025A1 PCT/US2018/029909 US2018029909W WO2018201025A1 WO 2018201025 A1 WO2018201025 A1 WO 2018201025A1 US 2018029909 W US2018029909 W US 2018029909W WO 2018201025 A1 WO2018201025 A1 WO 2018201025A1
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vaccine
virus
accordance
zikv
flavivirus
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David Curiel
Igor Dmitriev
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University of Washington
Washington University in St Louis WUSTL
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/86—Viral vectors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/10011—Adenoviridae
    • C12N2710/10311—Mastadenovirus, e.g. human or simian adenoviruses
    • C12N2710/10341—Use of virus, viral particle or viral elements as a vector
    • C12N2710/10343—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/10011—Adenoviridae
    • C12N2710/10311—Mastadenovirus, e.g. human or simian adenoviruses
    • C12N2710/10341—Use of virus, viral particle or viral elements as a vector
    • C12N2710/10345—Special targeting system for viral vectors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/24011—Flaviviridae
    • C12N2770/24111—Flavivirus, e.g. yellow fever virus, dengue, JEV
    • C12N2770/24134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Flavivirus Vaccine which Mitigates Cross-Reactive Infection by Other Flaviviruses Reference to Prior Application
  • the present teachings disclose methods and compositions for the mitigation of cross- infectiviry of Zika virus with other viruses.
  • Zika virus is a member of the genus Flavivirus, which also includes Dengue (DENV), yellow fever (YFV), and West Nile (WNV) viruses (Lazear, H.M., et al., J. Virol, 2016, 90, 4864-4875). Although the majority of human ZIKV infections result in
  • ZIKV Besides the main mode of ZIKV transmission through mosquitoes of the Aedes genus (Fernandez-Salas, L, et al., Antiviral Res., 2015, 124, 30-42), ZIKV also can be spread by mother-to-child transmission (Martines, R.B., et al., MMWR, 2016, 65, 159-160; Mlakar, J., et al., N. Engl. J.
  • ZIKV is an enveloped positive-sense RNA virus with a 10,7 kb genome.
  • the genome encodes a polyprotein that is cleaved post-translationally into three structural proteins-the capsid (C), membrane precursor (prM), and envelope (E)--and seven non-structural (NS) proteins (Kuno, G., et al., Arch. Virol., 2007, 152, 687-696).
  • C capsid
  • prM membrane precursor
  • E envelope--and seven non-structural proteins
  • the pr region of the prM protein is subsequently cleaved by cellular furin-like proteases leaving the M-E proteins on mature virions (Zhu, Z., et al., Emerging Microbes & Infections, 2016, 5, e22).
  • the B protein mediates cellular attachment, entry, and fusion (Mukhopadhyay, S., et al., Nat. Rev.
  • the Zika virus E protein includes Domains I, II and III; Domain II mediates dimerization of E protein, and includes a "fusion loop" at amino acids 98-109 (Dai, L., et al., Cell Host & Microbe 2016, 19, 696-704) This fusion loop is highly conserved in flaviviruses (Dai, L., et al., Cell Host & Microbe 2016, 19, 696-704).
  • the prM protein also is a target of the anti-fiavivirus response, however anti-prM antibodies generally are non-neutralizing (de Alwis, R., et al., PLoS Negl. Trop. Dis., 2011, 5, el 188; Dejnirattisai, W., et al., Science, 2010, 328, 745-748).
  • Chikungunya virus is an alphavirus that has caused periodic but sporadic outbreaks in tropical Africa and Asia and has recently (2005-2007) caused the largest outbreak of this virus in recorded history. Over 260,000 cases ( ⁇ l/3 of the population) were reported in Reunion Island (France) (Pialoux, G., et al., Lancet Infect. Dis., 2007, 7, 319-327) with 1.39 million cases reported in India (Mavalankar, D., et al., Lancet Infect. Dis., 2007, 7, 306-307).
  • the disease usually involves weeks to months of debilitating arthralgia/arthritis, and can involve myalgia, fever, headache, nausea, vomiting and/or a rash (Brighton, S.W., et al., South African Medical Journal, 1983, 63, 313-315) with arthritis/arthralgia affecting 73-80% of patients (Pialoux, G., et al., Lancet Infect. Dis., 2007, 7, 319-327). Disease can persist for two years or more in some patients (de Andrade, D.C., et al., BMC Infectious Diseases, 2010, 10, 31; Larrieu, S., et al., J.
  • CHIKV Viruses within the new clade of CHIKV are efficiently transmitted by Aedes albopictus mosquito, whereas the usual vector for CHIKV is Aedes aegypti (Tsetsarkin, K.A., et al., PloS One, 2009, 4, e6835; Tsetsarkin, K.A., et al., PLoS Pathog., 2007, 3, e201).
  • the new viruses also appear to be associated with more severe disease in humans (Charrel, R.N., et al., The New England Journal of Medicine, 2007, 356, 769-771; Ng, L.F., et al., PloS One, 2009, 4, e4261).
  • viruses within this new clade have been associated for the first time with human mortality (Suryawanshi, S.D., et al., The Indian Journal of Medical Research, 2009, 129, 438-441; Economopoulou, A., et al., Epidemiology and Infection, 2009, 137, 534-541; Mavalankar, D., et al., Emerg. Infect. Dis. 2008, 14, 412-415).
  • Dendritic cells prime adaptive immune responses.
  • DCs dendritic cells
  • APC antigen presenting cells
  • Conventional myeloid DCs link innate and adaptive immunity and are responsible for the initiation and regulation of immune responses via the activation of T cells, natural killer cells and B cells.
  • antigen targeting to specific APC types may tailor immune responses for optimal protection against individual pathogens.
  • the targeting to Clec9A+ DCs has been shown to enhance presentation of both MHC class I and II -restricted antigens (Caminschi, I., et al., Blood, 2008, 112, 3264-3273).
  • Targeting of DCs via Clec9A also induced robust, long-lasting humoral responses even without adjuvants (Park, H.Y., et al., J.
  • Adenoviral vector have utility for flavivirus vaccine development.
  • Ad Adenovirus
  • Ad-based vectors are promising vaccine platforms to stimulate innate and adaptive immune responses (Hartman, Z.C., et al., Virology, 2007, 358, 357-372; Huang, X., et al., Human Gene Therapy, 2009, 20, 293-301; Lore, K., et al., J. Immunology, 2007, 179, 1721-1729).
  • Ad2 and Ad5 Ad2 and Ad5
  • Ad5 vectors are highly utilized with the greatest number of clinical trials ongoing in the cancer vaccine and infectious disease fields (Gene Therapy Clinical Trials Worldwide, www.wiley.com).
  • Ad vectors have been used for the development of DEN V vaccines (Holman, D.H., et a!., Clin. Vaccine Immunol., 2007, 14, 182-189) including a tetravalent vaccine expressing domain III of the E protein (E-DIII) from the four different DENV serotypes (Khanam, S., et al., Vaccine, 2009, 27, 6011-6021).
  • This vaccine candidate was tested using Ad5 vector as a priming immunization and DNA immunization as a boosting and induced neutralizing antibodies and T cell responses against all DENV serotypes.
  • Ad5 vector as a priming immunization and DNA immunization as a boosting and induced neutralizing antibodies and T cell responses against all DENV serotypes.
  • tetravalent vaccination using a mixture of two bivalent Ad vectors encoding both the prM and the E proteins of DENV induced neutralizing antibodies and T cells responses against the 4 vaccination serotypes and protected monkeys against a live DENV challenge occurring at 4 or 24 weeks after two immunizations (Raviprakash, K., et al., J. Virology, 2008, 82, 6927-6934).
  • mice did not develop overt clinical illness after infection with contemporary clinical strains of ZIKV
  • mice lacking the ability to produce or respond to type I interferon (IFN) e.g., Ifharl-/- mice
  • IFN type I interferon
  • WT mice treated with a blocking anti-ifnar antibody (MAR 1-5 A3)
  • MAR 1-5 A3 a less severe model of ZIKV pathogenesis that also resulted in replication of ZIKV in several organs was developed (Lazear, H.M., et al., Cell Host Microbe, 2016, 19, 720-730).
  • the Diamond laboratory has generated an adapted ZIKV strain that causes significant morbidity and mortality in adult WT mice treated with a blocking anti-ifnar antibody; this model allows for induction of vaccine- derived immune responses in WT immunocompetent mice, and then after administration of the anti-Ifhar antibody, a stringent challenge model of protection against ZIKV infection.
  • the Diamond laboratory also has generated an in utero transmission model of ZIKV infection and pathogenesis.
  • CHIKV vaccines have been developed, but none have been licensed.
  • Formalin-killed CHIKV vaccines have been shown to be immunogenic in humans (Edelman, R., et al., J. Infectious Diseases, 1979, 140, 708-715), nonhuman primates (Nakao, E., et al, Bulletin of the World Health Organization, 1973, 48, 559-562) and mice (Tiwari, M., et al., Vaccine, 2009, 27, 2513-2522).
  • growth of large quantities of CHIKV for vaccine manufacture is complicated by the requirement for appropriate BSL3 containment.
  • CHIKV vaccine strain known as TSI-GSD-218, induced neutralizing responses and protected mice and monkeys against challenge (Levitt, N.H., et al., Vaccine, 1986, 4, 157-162).
  • this vaccine caused side effects in several recipients that included arthralgia (Edelman, R., et al., Am. J. Trop. Med. Hyg., 2000, 62, 681-685).
  • DNA -based CHIK vaccines encoding El, E2 and capsid on three separate plasmids have been shown to be immunogenic in mice (Muthumani, K., et al., Vaccine, 2008, 26, 5128-5134).
  • DNA vaccines have so far not been particularly effective at generating antibody responses in humans (Kutzler, M.A., Nature Reviews Genetics, 2008, 9, 776-788), which is a concern as antibodies are believed to be required for protection against CHIKV infections (Couderc, T., et al., J. Infectious Diseases, 2009, 200, 516-523).
  • CHIKV El , E2 and capsid with the non-structural genes from Venezuelan Equine Encephalitis virus (VEEV), Eastern Equine Encephalitis virus (EEEV) or Sindbis virus (SINV) have been shown to be immunogenic and protective against nasal CHIKV challenge in mice (Wang, E., et al., Vaccine, 2008, 26, 5030-5039).
  • VEEV Venezuelan Equine Encephalitis virus
  • EEEV Eastern Equine Encephalitis virus
  • SINV Sindbis virus
  • manufacturing and safety remain significant hurdles given the known ability of alphaviruses to recombine and generate replication competent viruses (Strauss, J.H., et al., Seminars in Virology, 1997, 8, 85-94).
  • VLP first alphavirus Virus-like particle
  • Vaccination by current methods against one flavivirus or alphavirus can induce antibodies to other flaviviruses or alphaviruses but can, paradoxically, enhance infection with these infectious agents.
  • a vaccine of the present teachings can encode flavivirus or alphavirus antigens modified to mitigate the induction of
  • a vaccine of the present teachings can comprise a dendritic cell-targeted adenovirus that is deleted for an El A/B region and can also comprise at least one structural gene or a portion thereof of a heterologous virus.
  • a flavivirus antigen such as a Zika virus-like particle (VPL) antigen can be modified so that it does not induce activating antibodies against other arbovirus.
  • VPL Zika virus-like particle
  • a vaccine of the present teachings can mitigate induction of vaccine-enhanced infection by other viruses.
  • a heterologous virus of the present teachings can be a flavivirus or an alphavirus.
  • a structural gene of a flavivirus such as, without limitation, Zika
  • at least one structural gene can be prM-E.
  • the prM-E gene can be deleted for a conserved fusion-loop epitope in the E protein.
  • the prM-E gene can contain one or more point mutations that destroy a conserved three-dimensional structure of a conserved fusion-loop epitope in the E protein.
  • the prM-E gene can contain one or more mutations that destroy a conserved fusion-loop epitope in the E protein.
  • the structural gene can be E.
  • the at least one structural gene of a flavivirus can be at least two structural genes of a flavivirus. In various configurations, the at least one structural gene of a flavivirus can be at least three structural genes of a flavivirus. In some
  • the structural genes of a flavivirus can be El, E2, capsid, or a combination thereof. In some configurations, the structural genes of a flavivirus can be E 1, E2 and capsid.
  • the vaccine can mitigate induction of vaccine-enhanced infection by other flaviviruses. In various configurations, the vaccine can mitigate induction of vaccine-enhanced infection by chikungunya virus.
  • the at least one flavivirus or alphavirus can be Zika virus (ZIKV), Chikungunya virus (CH1K), Dengue virus (DENV), yellow fever virus (YFV), or West Nile (WNV) virus.
  • the at least one heterologous virus can be Zika virus or Chikungunya virus (CHIK).
  • the at least one flavivirus can be Zika virus (ZIKV).
  • the at least one alphavirus can be CHIK.
  • a vaccine of the present teachings can be a vaccine that confers immunity against a flavivirus such as Zika virus (ZIKV).
  • a vaccine of the present teachings can be a vaccine that confers immunity against an alphavirus such as Chikungunya virus (CHIK).
  • the present teachings include a vaccine comprising a dendritic cell-targeted adenovirus that is deleted for an E1A/B region, and at least one structural gene of a heterologous virus, wherein the vaccine mitigates induction of vaccine- enhanced infection by other viruses.
  • the heterologous virus can be a flavivirus or an alphavirus.
  • the heterologous virus can be, without limitation, a Zika virus or a CHIK virus.
  • the at least one structural gene can be C, prM or E, or a combination thereof.
  • the prM-E gene can be a prM-E gene deleted for a conserved fusion-loop epitope in the E protein.
  • the at least one structural gene can be E.
  • a vaccine of the present teachings can mitigate induction of vaccine-enhanced infection by other flaviviruses. In some configurations, a vaccine of the present teachings can mitigate induction of vaccine-enhanced infection by chikungunya virus.
  • a vaccine of the present teachings can confer immunity against at least one flavivirus such as Zika virus (ZIKV), Dengue virus (DENV), yellow fever virus (YFV), or West Nile (WNV) virus.
  • flavivirus such as Zika virus (ZIKV), Dengue virus (DENV), yellow fever virus (YFV), or West Nile (WNV) virus.
  • the present teachings include vaccination methods.
  • a method of vaccinating a subject against a flavivirus or an alphavirus can comprise administering to a subject a vaccine in accordance with the present teachings.
  • vaccination methods of the present teachings can be used to induce immunity against a flavivirus or an alphavirus without inducing immunization to another flavivirid or alphavirus.
  • FIG. 1 illustrates a dendritic cell targeted adenoviral vaccine for Zika which circumvents flavivirus cross-reactivity.
  • FIG. 2 illustrates ZIKV protein E expression using Ad5ZprM-E-ecto vector.
  • FIG. 3 illustrates a structural comparison between wild type Ad5 fiber and a fiber- fibritin-ligand chimera.
  • FIG. 4 illustrates Ad5FF1.8 vector targeting to DC via the fiber knob replacement with sdAb Nbl.8.
  • FIG. S illustrates a lethal challenge model of WT mice with ZIKV and protection with antibodies.
  • FIG. 6 illustrates daily weights measured for a lethal challenge model of WT mice with ZIKV and protection with antibodies.
  • FIG. 7 illustrates survival curves for a lethal challenge model of WT mice with ZIKV and protection with antibodies.
  • FIG. 8 illustrates mouse viremia after challenge with the Reunion Island isolate of
  • FIG. 9 illustrates mouse foot swelling after challenge with the Reunion Island isolate of CHIK.
  • FIG. 10 illustrates mouse viremia after challenge with the Asian isolate of CHIK.
  • FIG. 11 illustrates mouse foot swelling after challenge with the Asian isolate of
  • An adenovirus-based vaccine of the present teachings has enhanced potency, and can encode one or more fiavivirus or alphavirus antigens modified to mitigate the induction of immunization against alternative fiavivirus or alphavirus. The modifications can mitigate paradoxical infection that can occur with other vaccines.
  • the adenoviral vector can be replication incompetent.
  • the adenoviral vector can be deleted for the viral El A/B genes.
  • an adenoviral vector of the present teachings can comprise a full length prM-E ectodomain fusion region of a flavivirus such as a Zika virus, or a fiavivirus E gene deleted or mutated for a conserved fusion-loop epitope.
  • a fiavivirus prM-E can be modified with one or more mutations that destroy a conserved fusion-loop epitope in the E protein, so that an adenovirus vaccine can provide protection against Zika without paradoxical augmentation of infection by other arboviruses.
  • This example illustrates expression of ZIKV soluble E protein by recombinant Ad vector.
  • Ad5 vector To validate the expression of ZIKV proteins by Ad5 vector we incorporated the DNA sequence encoding the full prM gene and the ectodomain of E of ZIKV (strain H/PF/2013 from French Polynesia) containing a heterologous N-terminal IL-2 signal peptide and C-terminal hexahistidine tag (6-His) under transcriptional control of cytomegalovirus (CMV) immediate early promoter in place of the early El A/B genes deleted in Ad5 genome.
  • CMV cytomegalovirus
  • Ad5ZprM-E-ecto vector was used to infect AS49 cells to validate the expression of secreted E protein.
  • FIG. 3-4 the 6-His-tagged E protein band with molecular mass of approximately 48 kDa was detected 48 and 72 hours post-infection in both cell lysates and culture medium by Western blotting.
  • A549 cells were infected with Ad5ZprM-E- ecto vector at a multiplicity of infection (MOI) of 900.
  • MOI multiplicity of infection
  • the cells and culture medium samples mixed with Laemmli loading buffer, boiled, and run on 4-20% gradient SDS- PAGE as follows.
  • the ZIKV protein E purified from culture medium of HEK293 cells transiently expressing the same CMV-driven prM-E-ecto plasmid was used as a positive control. These data demonstrate soluble ZIKV E expression using recombinant Ad5ZprM-E-ecto vector.
  • Ad5 cellular entry is mediated by distinct binding and internalization events; the knob domain of Ad5 fiber initiates attachment through interactions with coxsackie virus and adenovirus receptor (CAR) expressed on epithelial cells (Bergelson, J.M., et al., Science, 1997, 275, 1320-1323), whereas internalization is mediated by distinct interactions between integrins and the RGD motif within the Ad5 penton (Tsetsarkin, K.A., et al., PloS One, 2009, 4, e6835) as illustrated in FIG.
  • CAR coxsackie virus and adenovirus receptor
  • FIG. 3 illustrates a structural comparison between wild type Ad5 fiber and a fiber- fibritin-ligand chimera, which comprises a phage T4 fibritin trimerization foldon to replace the Ad5 fiber knob.
  • the sdAb Nbl.8 targeting ligand is fused to the foldon C -terminus.
  • BM DC murine bone marrow-derived DCs
  • iBMDC immature BMDC
  • the sdAb Nbl .8-coding sequence was incorporated in-frame following fiber-fibritin fusion within Ad5 genome by homologous recombination in E. coli and the resultant viral genome was rescued in 293F28 cells (Belousova, N., et al., J.
  • Ad5FF1.8 vector mediates DCs transduction.
  • Ad5FFl .8 vector gene transfer in a relevant animal DC substrate, we used murine iBMDC to assess their transduction using GFP reporter gene expression.
  • Ad5FFl .8 showed superior gene transfer into DCs compared to the control AdS vector, as demonstrated by the markedly increased number of GFP-positive DCs (FIG.4).
  • FIG. 4 illustrates Ad5FF1.8 vector targeting to DC via the fiber knob replacement with sdAb Nbl .8.
  • the upper panel illustrates iBMDC monolayers infected with the indicated Ad vectors imaged 40 h post-infection using epifluorescence microscopy.
  • FIG. 4 illustrates a flow cytometry analysis of gene transfer levels in iBMDC transduced with Ad5FFl .8 or control Ad5 vector, measured as the percentage GFP+CD1 lc+ cells.
  • sdAb binding Clec9A was carried out using the recombinant murine Clec9A protein (MyBioSource, Inc., San Diego, CA) to immunize alpacas. Seven unique sdAb clones were selected using the constructed phage- display sdAb library and validated by EL1SA for Clec9A recognition. Most of the selected sdAbs showed high binding efficiency in the range of 1 nM or less (data not shown) thus providing several sdAb-coding sequences to be exploited for genetic capsid incorporation to achieve GAd vector targeting to CD8a+/C1ec9A+ DC subset.
  • This example illustrates mouse models of ZIKV pathogenesis.
  • the Diamond laboratory has developed several mouse models of ZIKV pathogenesis in mice deficient in type I interferon (1FN) signaling.
  • a loss of Ifnar expression or blockade of Ifhar function is necessary because ZIKV does not replicate efficiently in wild-type (WT) mice due in part to a species-specific lack of antagonism of mouse Stat2 (Grant, A., Cell Host Microbe, 2016, 19, 882-890) a key signaling intermediate downstream of type 11FN signaling.
  • the different adult mouse models have possible utility for vaccine testing, each with its own limitations.
  • FIG. 7 illustrates survival curves for a lethal challenge model of WT mice with ZIKV and protection with antibodies.
  • Anti-ZIKV mAbs provided statistically significant protection in the percentage of surviving animals compared to the control CHK-166 mAb (***, P ⁇ 0.001 , log rank test for ZV-54 and ZV-67).
  • the results are pooled from independent experiments; n - 8-9 mice for each treatment condition.
  • the present methods thus allow for immunization in WT mice with a stringent requirement for protection against challenge.
  • an African ZIKV strain is used, although concern is mitigated by immunization with an Ad encoding structural genes from a contemporary Asian (or American) isolate.
  • This model can be high- throughput (WT mice can be purchased in large cohorts from commercial vendors), uses immune-competent mice for induction of vaccine responses, and challenges with a heterologous ZIKV strain (which can account for breadth/diversity of response).
  • This model can be used for vaccination and lethal challenge.
  • This example illustrates CHIK challenge of CAdVax-CHIK immunized C57BL/6 mice.
  • adenovirus vectors have been widely tested in humans and have been shown to be safe in an extensive series of human trials. They are also stable, immunogenic and relatively easy to manufacture (Seregin, S.S., et al., Expert Opinion on Biological Therapy, 2009, 9, 1521 -1531).
  • the non-replicating Complex Adenovirus vaccine (CAdVax) vectors (Wang, D., et al., J. Virol. 2006, 80, 2738-2746) contain deletions in El, E3 and most of the E4 regions (except orf3 ⁇ 4) of the adenovirus 5 (Ad5) genome.
  • deletions coupled with multiple engineered transgene-expression sites, allow the insertions of multiple antigens at di fferent locations, or a large antigen insert at the location of choice within the Ad5 genome.
  • the technology has been used to generate recombinant dengue, influenza, Marburg, Ebola, West Nile and Rift Valley fever virus vaccines, and has been shown to be efficacious in murine, guinea pig, ferret and non-human primate models (Raviprakash, K., et al., J.
  • CAdVax a single insert encoding the structural polyprotein (comprising the envelope glycoproteins El , E2 and capsid) of CHIKV was inserted in the right hand of the genome.
  • the major advantage of this particular configuration of the CAdVax is that it prevents the generation of replication-competent adenovirus through homologous recombination in the packaging cell line, HEK293, a common problem of first generation Ad5 vectors.
  • the antigen sequences are from a CHIKV isolate from the recent epidemic on Reunion Island, and the complete structural polyprotein gene was expressed in order to retain the native processing sequences.
  • mice were vaccinated with CAdVax-CHIK, a control CAdVax vaccine or PBS. At 6.5 weeks post-immunization, mice were challenged with CHIKV.
  • FIG. 8 illustrates viremia after challenge with the Reunion Island isolate. Viremia was significantly different between CAdVax-CHIK and CAdVax -control vaccinated groups on days 1-3 (all p ⁇ 0.037, Mann Whitney U test).
  • FIG. 9 illustrates foot swelling after challenge with the Reunion Island isolate.
  • FIG. 10 illustrates viremia after challenge with the Asian isolate. Viremia was significantly different between CAdVax-CHIK and CAdVax - control vaccinated groups on days 1-4 (all p ⁇ 0.014, Mann Whitney U test).
  • FIG. 11 illustrates foot swelling after challenge with the Asian isolate. Swelling was significantly different between CAdVax-CHIK and CAdVax -control vaccinated groups on days 3-10 (all p ⁇ 0.04, Mann Whitney U test).

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Abstract

La présente invention concerne des procédés pour atténuer une infection renforcée par un vaccin, tel que des vaccinations contre un flavivirus tel que Zika qui peut conduire à une infection renforcée par d'autres virus tels que le virus Chikungunya. L'invention concerne en outre des adénovirus chimériques délétés pour la région E1A/B, des protéines de flavivirus étant incluses pour la vaccination. L'invention concerne en outre des adénovirus chimériques comprenant une séquence Zika, telle qu'une région de fusion d'ectodomaine prM-E de pleine longueur ou un gène E délété pour un épitope de boucle de fusion conservé. La délétion de cet épitope atténue l'infectivité croisée.
PCT/US2018/029909 2017-04-27 2018-04-27 Vaccin à flavivirus qui atténue une infection croisée par d'autres flavivirus Ceased WO2018201025A1 (fr)

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WO2006078279A2 (fr) * 2004-04-28 2006-07-27 The Trustees Of The University Of Pennsylvania Liberation sequentielle de molecules immunogenes par administrations mediees par un adenovirus ou un virus adenoassocie
WO2015161314A1 (fr) * 2014-04-18 2015-10-22 Washington University Ciblage adénoviral, compositions et procédés associés

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WO2006078279A2 (fr) * 2004-04-28 2006-07-27 The Trustees Of The University Of Pennsylvania Liberation sequentielle de molecules immunogenes par administrations mediees par un adenovirus ou un virus adenoassocie
WO2015161314A1 (fr) * 2014-04-18 2015-10-22 Washington University Ciblage adénoviral, compositions et procédés associés

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