Frederick, MD, United States
Frederick, MD, United States
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Patent
Medigen, Inc. | Date: 2011-01-03

Described herein are i-DNA vectors and vaccines and methods for using the same. The i-DNA generates live attenuated vaccines in eukaryotic cells in vitro or in vivo for pathogenic RNA viruses, particularly chikungunya virus (CHIKV). When iDNA is injected into the vaccine recipient, RNA of live attenuated virus is generated by in vivo transcription in the recipients tissues. This initiates production of progeny attenuated viruses in the tissues of the vaccine recipient, as well as elicitation of an effective immune response protecting against wild-type, non-attenuated virus.


Patent
Medigen, Inc. | Date: 2016-01-27

Described herein are iDNA vectors and vaccines and methods for using the same. The iDNA generates live attenuated vaccines in eukaryotic cells in vitro or in vivo for pathogenic RNA viruses, particularly yellow fever virus and Venezuelan equine encephalitis virus. When iDNA is injected into the vaccine recipient, RNA of live attenuated virus is generated by in vivo transcription in the recipients tissues. This initiates production of progeny attenuated viruses in the tissues of the vaccine recipient, as well as elicitation of an effective immune response protecting against wild-type, non-attenuated virus.


Patent
Medigen, Inc. | Date: 2015-07-02

Described herein are i-DNA vectors and vaccines and methods for using the same. The i-DNA generates live attenuated vaccines in eukaryotic cells in vitro or in vivo for pathogenic RNA viruses, particularly chikungunya virus (CHIKV). When iDNA is injected into the vaccine recipient, RNA of live attenuated virus is generated by in vivo transcription in the recipients tissues. This initiates production of progeny attenuated viruses in the tissues of the vaccine recipient, as well as elicitation of an effective immune response protecting against wild-type, non-attenuated virus.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 117.99K | Year: 2011

DESCRIPTION (provided by applicant): Live attenuated vaccine 17D has been used since the 1950s for vaccination against yellow fever (YF) with a remarkable record of safety and efficacy. More than 500 million people have been vaccinated, and the World Health Organization (WHO) strongly recommends to continue vaccinations in at-risk countries. The weaknesses of the vaccine include outdated manufacturing and the need of a cold chain , which accounts for up to 80% of cost in endemic areas. In rare cases, 17D vaccine causes adverse effects including allergies, neurologic disorders, and viscerotropic disease. The vaccine represents a population of genetically distinct viruses, some of which may be responsible for adverse reactions. The main goal of this revised Phase I SBIR is the production and evaluation of a conceptually novel YF vaccine. We propose a novel technology of infectious DNA (i-DNA) as YF vaccine. A unique feature of this technology is that the full-length copy of 17D genome is placed in the i-DNAplasmid in the context of optimized eukaryotic promoter and regulatory sequences. Thus, live attenuated 17D virus can be launched in vivo directly from the i-DNA plasmid. Since the 17D i-DNA represents a molecular clone, it will generate a uniform population of 17D virus thus potentially improving safety. We will also prepare two i-DNA variants by de-optimization of translational codons within C-prM-E genes with the view to improve vaccine safety and genetic stability. Experimental YF i-DNA vaccines will be evaluated in vitro and in vivo along with the current 17D vaccine. Immunogenicity and safety profiles including neurotropic and viscerotropic adverse effects will be evaluated in the recently developed models of immunosupressed hamster and A129 knockout mouse. Thus, characteristics of candidate i-DNA vaccines will be evaluated in the two preclinical models with immunocompromised background, which mimicks frequent situation in the endemic areas and will provide accurate determination of safety and immunogenicity profiles of the vaccines. In summary, i-DNA vaccination combines the simplicity of DNA vaccines with the exceptional efficacy of live attenuated vaccines. The i-DNA can potentially improve safety, does not require cold chain and is easy to manufacture and scale-up in emergency scenarios. Further, bacterially generated i-DNA will contain CpG motifs, which are expected to activate innate immune responses and improve immunogenicity. If successful, this technology may represent a revolutionary improvement of YF vaccine and vaccination practice against yellow fever. PUBLIC HEALTH RELEVANCE: Yellow fever (YF) is a re-emerging pathogen and a public health problem worldwide. The focus of this Phase I SBIR study is the production and evaluation of a conceptually novel vaccine for YF. We hypothesize that safety and immunogenicity of live attenuated 17D vaccine can be improved by using the infectious DNA (i-DNA) technology. This will result in a unique YF vaccine, which will combine the simplicity of DNAvaccines with the exceptional efficacy of live attenuated vaccine.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 222.15K | Year: 2011

DESCRIPTION (provided by applicant): Arenaviruses represent a rapidly growing group of emerging rodent-borne viruses. Highly pathogenic arenaviruses, Lassa (LASV), Junun (JUNV), and Machupo (MACV), are the most prevalent arenaviruses in the world that represent the emerging severe threat to the U.S. public health. The development of safe and efficacious vaccines against emerging pathogens with particular emphasis on multivalent strategy and advanced platform technology is one of the top priorities of NIH/NIAID. The main goal of this project is the development and feasibility testing of the first trivalent arenaviral vaccine against LASV, JUNV, and MACV. The trivalent vaccine is based on Medigen's VLPV (virus-like-particle-vector) technology. VLPVs comprise propagation-defective particles that encapsulate recombinant vector for delivery and expression in vivo of the full-length glycoprotein (GPC) genes derived from three arenaviruses. The proposed trivalent vaccine would protect populations from the world's major arenavirus threats, including containment of the outbreaks in non-endemic areas, as well as vaccination of medical workers, military personnel, travelers, and population in endemic areas. If successful, VLPV polyvalent vaccine platform can also be usedas a generic approach for other infectious diseases. SPECIFIC AIM I: Design and Preparation of Trivalent VLPV Vaccine Expressing Arenaviral GPCs. The goal of this aim is (i) to prepare a tri-cistronic vector for expression of the full-length GPC genes derived from LASV, JUNV, and MACV; (ii) to prepare individual monocistronic VLPV vaccines for LASV, JUNV, and MACV; (iii) encapsulate tri- or monocistronic vectors into VLPVs for delivery and expression of arenaviral GPCs in vitro and in vivo; and (iv) to optimize and characterize expression levels, stability, and production yields of tri- and monocistronic VLPV vaccines. SPECIFIC AIM II: Preclinical Safety and Immunogenicity Evaluation of Trivalent Arenavirus Vaccines. Recombinant trivalent arenavirus vaccineprepared in Specific Aim I (tri-cistronic, individual, or blended combination of individual vaccines) will be used to evaluate their safety and immunogenicity in mice and guinea pigs including the ability to induce robust CD8+ T cell and neutralizing antibody (nAB) responses. PUBLIC HEALTH RELEVANCE: Highly pathogenic viruses, Lassa (LASV), Junun (JUNV), and Machupo (MACV) represent the world's most common arenaviruses and an emerging severe threat for the U.S. public health. The main goal of this project is the development and feasibility testing of the individual and trivalent vaccines against these arenaviruses. The successful trivalent vaccine can be used for the containment of disease outbreaks in non-endemic areas, as well as for vaccination ofmedical workers, military personnel, travelers, and population in endemic areas. If successful, Medigen's polyvalent vaccine platform can also be used as a generic approach for other infectious diseases.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 600.00K | Year: 2011

DESCRIPTION (provided by applicant): Venezuelan Equine Encephalitis virus (VEEV) is a dangerous, NIH/NIAID category B human pathogen and a potential bioterrorism threat. Outbreaks of VEEV occur in Central America and have previously spread into the UnitedStates. The potentially devastating effects of the virus reemergence in the U.S. demand an effective vaccine to protect population. Currently, live attenuated TC-83 vaccine is used under IND protocol for vaccination of personnel at risk. The vaccine causesadverse effects, whereas some individuals do not develop neutralizing antibodies. The efforts to develop new VEEV vaccines are underway. However, because vaccine development is a lengthy process and the supply of TC-83 vaccine is limited, the U.S. may soon experience a shortage of VEEV vaccine, which can leave the U.S. population unprotected. We propose a revolutionary new technology for vaccination against VEEV and potentially, other viral diseases. Medigen has recently developed the infectious DNA (i-DNA) vaccination technology, which represents a unique combination of conventional DNA immunization with high efficacy of live attenuated vaccines. The key feature of this technology is that live attenuated virus is launched in vivo from i-DNA plasmid carrying a molecular clone of VEEV vaccine with enhanced safety and immunogenic features. In preliminary studies we have shown that injection in vivo of the prototype i-DNA derived from the TC-83 vaccine has successfully launched live attenuated vaccine in mice. Here we propose the development and feasibility evaluation of novel i-DNA VEEV vaccine for safe and efficient vaccination against VEEV based on the rational design of i-DNA clones and i-DNA immunization technology. In Specific Aim I, we will apply innovative silent mutagenesis method to introduce additional genetic changes into the prototype TC-83 i-DNA in order to secure attenuated phenotype and to generate i-DNA clones with high levels of safety and immunogenicity. The i-DNA clones will be transfected in CHO cells and live attenuated viruses will be harvested from culture media. Safety of i-DNA-derived viruses will be evaluated in mice in collaboration with the Institute of Human Virology, University of Maryland. In Specific Aim II we will vaccinateBALB/c mice with i-DNA constructs in order to induce immune response and to evaluate immunogenicity in vivo. Further, the efficacy of the most promising i-DNA VEEV vaccine will be evaluated in a virulent VEEV challenge experiment at Southwest Foundation for Biomedical Research (SFBR), San Antonio, TX. Finally, reversion studies in vivo will be also conducted at SFBR to demonstrate genetic stability of i-DNA - derived VEEV vaccine. The goal of this 2-year research is the identification of i- DNA VEEV vaccineclone with the optimal safety and immunogenicity profiles for future evaluation and challenge experiments in non-human primates. Our preliminary results suggest that the rational vaccine design and i-DNA technology can provide a revolutionary solution for VEEV vaccine by improving safety, genetic stability, and immunogenicity, and by eliminating many costly steps of the conventional manufacturing process. Essentially, live attenuated vaccine will be manufactured within the immunized individuals. This technology also utilizes many advantages of DNA vaccines (genetic homogeneity and stability, low cost of manufacturing, storage, and transportation, no cold chain) and, more importantly, enhances immunogenicity. Recombinant i-DNA clones produced in bacteriacontains CpG motifs that activate TLR9 and MyD88-dependent signaling pathways resulting in robust production of cyto- and chemokines, which induce strong priming effects and stimulate acquired virus- specific immune responses. The final i-DNA VEEV vaccinewill represent a novel class of vaccines combining the advantages of DNA and live attenuated vaccines and preserving the backbone of a classic vaccine with a history of human use. The i-DNA technology can be easily adapted for the development of other vaccines including live attenuated vaccines for WEEV, EEEV, other alphaviruses, and flaviviruses. If successful, this technology can potentially transform the field of live attenuated vaccines for many viral diseases. PUBLIC HEALTH RELEVANCE: In this application, we propose the development of a revolutionary new technology for vaccination against VEEV by using the infectious DNA (i-DNA), a unique hybrid of DNA and live attenuated vaccines. The key feature of this technology is that live attenuatedvaccine virus is launched in vivo from i-DNA plasmid. In this study, we will generate several i-DNA vaccines and evaluate their safety, immunogenicity, and efficacy against virulent VEEV challenge in experimental mouse models. If successful, this technology can potentially transform the field of live attenuated vaccines for many viral diseases.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.48M | Year: 2011

This Phase II, SBIR contract is for the advanced vaccine efficacy studies, which involve TRAMP tumor challenge of vaccinated PSA+ transgenic mice. Engineered for increased immunogenicity PSA variants will be delivered and expressed in PSA+ mice using novelvector VLP (vVLP_ vaccine platform. The latter represent non-replicating virus-like particles configured to encapsidate expression vector for in vivo delivery and expression of engineered PSA genes.


Grant
Agency: Department of Agriculture | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 395.61K | Year: 2013

Medigen successfully designed and tested a conceptually novel VLP design as a vaccine for avian influenza (AI). This vaccine isnot dependent on egg production and allows protection against multiple AI viruses by using a single preparation of VLP vaccine. For example, we demonstrated that co-expression of H5, H7, and H9 HA proteins along with other influenza proteins resulted in a triple-HA H5/H7/H9 VLP that contained HA proteins derived from three distinct AI viruses. We showed that such triple-HA VLPs without adjuvant elicited protection of laboratory animals (ferrets) against multiple AI strains, when administered through the respiratory route. Here we propose immunogenicity and efficacy testing of triple-HA VLPs in poultry species as a broadly protectiveAI vaccine. Protection against multiple AI challenges will be tested in HPAI and LPAI models including multiple strains of H5N1 virus. If successful, this technology may allow rapid preparation of cost-effective and highly effective polyvalent poultry vaccines against AI.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 811.57K | Year: 2016

DESCRIPTION provided by applicant Venezuelan Equine Encephalitis virus VEEV is a life threatening NIH NIAID category B human pathogen and a potential bioterrorism threat Outbreaks of VEEV occur in Central America and have previously spread into the United States The potentially devastating effects of the virus reemergence in the U S demand an effective vaccine to protect population Currently live attenuated TC vaccine is used under IND protocol for vaccination of medical personnel at risk The vaccine causes adverse effects and efforts to develop an improved VEEV vaccine are underway However because vaccine development is a lengthy process and the supply of TC vaccine is limited the U S may soon experience a shortage of the VEEV vaccine This can leave both the U S population and at risk personnel unprotected Furthermore in the absence of vaccine VEEV may require re classification as a BSL Select Agent In Phase I SBIR we developed a new technology for vaccination against VEEV and potentially other viral diseases The proposed iDNA vaccination technology represents a unique combination of conventional DNA immunization with the high efficacy of live attenuated vaccines The key feature of this technology is that live attenuated virus is launched in vivo from iDNA plasmid carrying a molecular clone of VEEV vaccine with enhanced safety and immunogenic features In Phase I SBIR studies we have shown that injection in vivo of the prototype iDNA derived from the TC vaccine has successfully launched live attenuated vaccine in mice In this Phase II SBIR we propose advanced preclinical evaluation of iDNA VEEV vaccine based on the rational engineering of TC clones and iDNA immunization technology In Sp Aim we propose i optimization of iDNA vaccination in vivo including iDNA formulation and the route of administration with and without electroporation and ii dose escalation study to determine the minimal amount of iDNA sufficient to launch the vaccine virus and to induce protection in BALB c mice The iDNA will be formulated to minimize the need for electroporation and cold chain In summary the goal of Sp Aim is the development of patient and doctor friendly procedure for iDNA vaccination In Sp Aim in collaboration with the University of Louisville KY UofL we propose evaluation of safety immunogenicity and efficacy of experimental VEEV iDNA vaccines in mice rabbits as well as in rhesus non human primates NHP which represent the best model for human VEEV infection As a control the standard TC vaccine will be used Following these studies the lead VEEV iDNA vaccine will be selected for the cGMP production during Sp Aim In addition we propose a pre IND meeting with the FDA to seek input on the design of i GLP toxicology study and ii Phase I clinical trial Our preliminary data suggest that the rational vaccine design and iDNA technology can provide a revolutionary solution for VEEV vaccine by improving safety genetic stability and immunogenicity and by eliminating many costly steps of the conventional manufacturing process Essentially live attenuated vaccine will be andquot manufacturedandquot within the immunized individuals This technology also utilizes many advantages of DNA vaccines genetic homogeneity and stability low cost of manufacturing storage and transportation no cold chain and more importantly enhances immunogenicity As any recombinant DNA the iDNA activates cGAS cGAMP STING dependent signaling pathways resulting in robust production of cyto and chemokines which induce strong priming effects and stimulate acquired virus specific immune responses The final iDNA VEEV vaccine will represent a novel class of vaccines combining the advantages of DNA and live attenuated vaccines The iDNA technology can be easily adapted for the development of other vaccines including live attenuated vaccines for WEEV EEEV other alphaviruses and flaviviruses If successful this technology can potentially transform the field of live attenuated vaccines for many viral diseases PUBLIC HEALTH RELEVANCE In this application we propose the development of a potentially transforming technology for vaccination against VEEV by using novel iDNA technology a unique hybrid of DNA and live attenuated vaccines The key feature of this technology is that live attenuated vaccine virus is launched in vivo from iDNA plasmid In this study we will evaluate iDNA vaccines for their safety immunogenicity and efficacy in experimental mice rabbits and rhesus macaque non human primates If successful this technology can potentially transform the field of live attenuated vaccines for many viral diseases


Grant
Agency: Department of Agriculture | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 99.89K | Year: 2011

In this Phase I SBIR application, we propose the trivalent influenza virus-like particle (VLP) vaccine that is not dependent on egg production and allows protection of poultry against multiple AI viruses. Our hypothesis is that expression of H5, H7, and H9 HA proteins will result in a trivalent vaccine that will contain HA proteins derived from three distinct AI viruses. We hypothesize that trivalent VLPs will elicit broad protection against multiple AI strains, especially if vaccine is administered through the respiratory route. We propose preparation and feasibility testing in mice of the prototype trivalent VLPs as a broadly protective AI vaccine. VLPs will be prepared in Sf9 insect cells using baculovirus expression system. Characteristics of VLPs will be determined including expression levels in Sf9 cell culture and genetic stability. Immunogenicity and efficacy of trivalent vaccine will be evaluated in BALB/c mice in collaboration with the Centers for Disease Control and Prevention (CDC, Atlanta, GA). If successful, this technology may allow rapid preparation of inexpensive and highly effective poultry vaccines against multiple AI strains.

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