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The Board Of Regents Of The University Of Texas System and Profectus Biosciences, Inc. | Date: 2015-02-27

Certain embodiments are directed to recombinant vesiculovirus encoding a heterologous polynucleotide and methods of using the same.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 300.00K | Year: 2012

DESCRIPTION (provided by applicant): This SBIR application proposes to pre-clinically evaluate a pDNA prime - rVSV boost HCV vaccine intended to improve the sustained virologic response (SVR) rate in patients being treated with current standard of care (SOC) therapy for chronic HCV infection. Of the approaches being developed as candidate vaccines, those based on priming with pDNA followed by boosting with a live recombinant viral vector such as vesicular stomatitis virus have proven to be the most immunogenic. Preliminary results demonstrate that non-human primates (NHPs) which receive HIV pDNA prime - HIV rVSV boost mount a significantly more robust response than do macaques receiving pDNA prime - pDNA boost (plt 0.05). In addition, the vaccination strategy proposed in this application has been designed specifically to overcome the immunologic anergy that characterizes chronic HCV infection. Multiple studies have now demonstrated that immunization with pDNA vaccines is effective in the induction of antigen- specific central memory (CM) T cells that exhibit both long-term persistence in vivo and a high expansion potential. These CM T cells do not show up-regulated expression of PD-1, CTLA-4, and LAG-3, making them resistant to a range of negative regulatorymechanisms. Second, IL-12 is known to up regulate CD28 and CD127 expression on T cells and to be a potent inhibitor of tolerance induction. The pDNA prime/rVSV boost HCV vaccine proposed in this application incorporates a clinically validated IL-12 expression plasmid in the pDNA priming component, and the VSV boosting vector is a potent stimulator of IL-12 production. This phase I application proposes to conduct an enabling trial in NHPs to: ( Confirm the immunogenicity of the pDNA and rVSV vectors in a higher species. ( Confirm that co-administration of IL-12 pDNA improves the magnitude, breadth, poly-functional nature, and tolerance resistance of the HCV-specific CMI response. ( Determine if PEG-IFN administration to patients undergoing SOC treatment will need to be paused at the time of rVSV booster vaccination. PUBLIC HEALTH RELEVANCE: This SBIR application proposes to pre-clinically evaluate a hepatitis C virus vaccine intended to improve the cure rate in patients being treated with drugs forchronic HCV infection. Surveillance studies conducted by the Centers for Disease Control and Prevention (CDCP) and the NIH show that HCV accounts for 40% to 60% of chronic liver disease in the US and that chronic liver disease is currently the tenth leading cause of death among adults. HCV is the most frequent indication for liver transplantation in US; the number of patients on transplant waiting lists has doubled in the past 5 years, and about 50 percent of these patients die while awaiting an organ.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 238.76K | Year: 2014

DESCRIPTION: There is a growing consensus that protection against HIV infection will require BOTH antiviral antibody responses as well as polyfunctional CD4+ and CD8+ T cells with potent lytic activity. To stimulate the breadth, potency, and rate of response required, Profectus Biosciences intends to utilize its platform technologies based on electroporation of DNA vaccines combined with genetic adjuvants. As a step in that direction, a recent phase 1 clinical trial, HVTN-080, showed that electroporation incombination with our IL-12 adjuvant can double the CD4+ and CD8+ T cell response rate in vaccinees over electroporation alone1. Even with this success, we recognize that a truly effective HIV vaccine will require a regimen that can consistently provide high magnitude, long-lived responses at rates gt95% with as few booster immunizations as possible. We believe that adjuvants are a key to developing such a vaccine. Under a previous phase I SBIR, we identified a new class of genetic adjuvants that exploi


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 1.97M | Year: 2015

DESCRIPTION The HIV pandemic is one of the greatest public health challenges in history It is estimated that million people are living with HIV and million of those are newly infected In a number of developed countries the risk of death associated with HIV infection has sharply declined due to the use of highly active antiretroviral therapy HAART Unfortunately the rate of new HIV infections remains undiminished even with the ever increasing availability of prevention programs and HAART For these reasons a vaccine that could prevent or control the spread of HIV is urgently needed A recent study showed that a skin delivered therapeutic DNA vaccine co formulated with a novel adjuvant stimulated mucosal T cell responses in SIV infected macaques and led to durable viral suppression in a subset of animals after stopping ART These results are in striking contrast to previous therapeutic vaccines employing intramuscular delivery of DNA that failed to induce an effect or at best induced a log reduction in viremia or transient control of viral rebound We propose to make therapeutic DNA vaccination even more effective by using a more potent combination of drugs cART to maximize the effects of the vaccine using a more potent adjuvant strategy that increases DNA vaccine induction of antibody and T cell responses and stimulates homing of these responses to gut associated lymphoid tissues and using a novel electroporation DNA delivery device that more efficiently delivers DNA into the skin a more immunocompetent site than muscle for induction of systemic and mucosal responses Our overarching hypothesis is that a vaccine induced functional cure will be mediated by strong mucosal responses and that increasing and focusing these responses to the gut in maximally suppressed infections via use of an optimized mucosal adjuvant and delivery into skin will maximally reduce or prevent residual viruses from emerging from the gut reservoir after stopping cART To this end we have assembled a panel of four DNA based adjuvants that we hypothesize will induce robust anti HIV mucosal and systemic immune responses when combined Under this fast track SBIR we will investigate adjuvant combinations with our HIV SIV multi antigen MAG DNA vaccine consisting of plasmids expressing env gp a gag pol fusion and a nef tat vif fusion We anticipate that an optimal combination of these adjuvants will elevate the performance of our MAG DNA vaccine to a level worthy of human trials PUBLIC HEALTH RELEVANCE The objective of this project is to define an optimal combination of adjuvants and delivery regimen for our therapeutic HIV SIV DNA vaccine Such optimization of any HIV SIV therapeutic vaccine will be necessary for that vaccine to successfully combat established HIV SIV infections


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 2.30M | Year: 2014

DESCRIPTION Based on the prevailing evidence we believe that a highly effective vaccine for HIV prophylaxis must induce long lasting broadly cross reactive antibody responses to envelope that exhibit antiviral activity as well as multi antigen polyfunctional CD and CD T cell responses that produce antiviral chemokines and cytokines and are possibly biased towards an effector memory phenotype Our strategy utilizes a novel immunogen Full Length Single Chain FLSC to present conserved epitopes that exist on the HIV envelope spike including ones that may form within the quaternary structure of the envelope The constrained structure which is achieved with single chain complexes of gp and CD fragments stabilizes and presents conserved domains including but not limited to andquot CD inducedandquot CD i epitopes We have shown that FLSC induces cross reactive antibodies and protective immune responses in macaques To reach our goal of developing and clinically evaluating a novel prophylactic HIV vaccine strategy with the ability to induce concurrent durable and protective antibody and CMI responses we will exploit the collective developments in recombinant vesicular stomatitis virus rVSV vectors and subunit vaccine designs accrued at Profectus in an extensive series of pre clinical and clinical trials along with other key technical observations made by our academic collaborators We believe one possible way to achieve this is to combine virus based vectors expressing FLSC and subunit forms of FLSC using optimal prime boost regimens Based on preliminary data using prototypic rVSV vectors our central hypothesis is that it will be possible to generate constrained SIV HIV immunogens that contain rhesus or human FLSC anchored in cell viral membranes through linkage the VSV G stem allowing for exposure of conserved epitopes In Phase we will generate rVSVs expressing Gstem linked rhesus and human FLSCs in the attenuated rVSVN CT backbone which has recently demonstrated safety and immunogenicity in human trials Aim The immunogenicity of these vectors will be initially confirmed in a mouse study Aim In Phase we will evaluate the stability of the rVSV genomes Aim which will then be used to further determine the rank order of optimal prime boost regimens of rVSV and protein subunit FLSC vaccines in macaques by assessment of immune responsiveness Aim and efficacy Aim in a heterologous SIVmac challenge model Successful achievement of our goals will produce novel antigens and an optimal prime boost regimen for further study of protective HIV vaccines PUBLIC HEALTH RELEVANCE The objective of this project is to define an optimal prime boost regimen that yields andgt efficacy exploiting FLSC subunit and rVSV


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 2.70M | Year: 2013

DESCRIPTION provided by applicant Our primary approach to develop an effective prophylactic vaccine against HIV utilizes a novel immunogen called the Full Length Single Chain FLSC that consists of gp derived from HIV BaL genetically linked via a amino acid linker to the D D domains of human CD Rhesus macaques were inoculated with rhFLSC a surrogate version of FLSC that contains CD derived from rhesus macaques The rhFLSC provided significant protection against rectal challenge with multiple low doses of R tropic and heterologous SHIV P These observations propelled FLSC into preclinical development and evaluation in a phase clinical trial supported by BMGF MHRP NIAID Consistent with the observations made in the RV clinical trial the protection we observed waned as the antibody titers dropped The presence of significant populations of single function T cells secreting IFN or IL also appeared to inversely correlate with the protection generated by rhFLSC subunit Our collaborators found that the simultaneous coadministration of pDNA and protein dramatically heightens the potency and extends the lifespan of the antibody response Vaccination with pDNA expressing antigen and IL administered by electroporation in macaques induces multifunctional T cells that are known to correlate with protection that could also improve the efficacy provided by FLSC subunit Our goal here is to build upon these observations and determine if a pDNA subunit combination vaccine can enhance the quality and durability of the immune response necessary to provide andgt efficacy after year post vaccination Our phase objective is to rank order FLSC DNA subunit immunization regimens based on the quality and durability of the immune response in mice Using the top regimens defined in Phase I we will determine if the selected vaccination regimen provides protection from SHIV challenge that is superior to that observed in RV and remains effective out to at least one year post vaccination through the following phase II specific aims Rank order FLSC DNA subunit immunization regimens based on the quality and durability of the immune response in macaques Rank order FLSC DNA subunit immunization regimens based on their efficacy against SHIV P challenge By the end of this project we should identify a regimen that extends the longevity of humoral and cellular responses to provide andgt efficacy upon heterologous SHIV P challenge after year Should this optimized delivery regimen fulfill the phase II goals it will be fast tracked into human clinical trials The objective of this project is to identify optimal an optimal delivery regimen for an HIV DNA vaccine Such an optimized delivery regimen is needed for DNA vaccines to combat the HIV epidemic


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 3.30M | Year: 2014

DESCRIPTION: The HIV pandemic is one of the greatest public health challenges in history. It is estimated that 33 million people are living with HIV and 2.7 million of those are newly infected In a number of developed countries, the risk of death associated with HIV-1 infection has sharply declined due to the use of highly active antiretroviral therapy (HAART). Unfortunately, the rate of new HIV infections remains undiminished, even with the ever increasing availability of prevention programs and HAART. Forthese reasons, a vaccine that could prevent or control the spread of HIV is urgently needed. A recent study showed that a skin-delivered therapeutic DNA vaccine co-formulated with a novel adjuvant stimulated mucosal T cell responses in SIV-infected macaques and led to durable viral suppression in a subset of animals after stopping ART. These results are in striking contrast to previous therapeutic vaccines employing intramuscular delivery of DNA that failed to induce an effect or at best, induced a 1-


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.99M | Year: 2011

DESCRIPTION (provided by applicant): The positive outcome of the RV144 Phase III vaccine trial (the Thai trial ) that tested an ALVAC-HIV/AIDSVAX B/E prime/boost protocol has prompted the field to refocus on humoral immunity as a means of achieving sterilizing immunity. This has also renewed interest in positioned other envelope-based subunit immunogens that may provide a better booster to achieve protection. One such immunogen is the Full Length Single Chain (FLSC) a gp120 human CD4 fusion that replicatesthe conserved envelope-CD4 complex, a key transition state that all HIV isolates must realize during infection. In 2 rhesus macaque studies, rhFLSC, a surrogate version of FLSC that contains CD4 derived from rhesus macaques, provided statistically significant protection (rapid clearance of post-acute plasma viremia, as well as potent and sustained suppression of tissue viremia) against rectal challenge with R5 tropic, and heterologus SHIV162P3. This observation indicates that FLSC could provide similar effects in humans and may provide the foundation for an effective vaccine against HIV. The goal of this project, therefore, is to initiate the preclinical development of FLSC in preparation for its evaluation in Phase I clinical trial as the next step in discerning whether FLSC can be an effective HIV vaccine. To reach this goal, this Fast Track Phase 1 and 2 project has the following aims. Phase 1 Segment Aim 1. Develop pedigreed HEK293 cell lines suitable for the production of FLSC. Aim 2. Identify and optimize release assays. Phase 2 Segment Aim 3. Manufacture lots of material suitable for potency studies (Aim 4) and preclinical toxicology (Aim 5). Aim 4. Confirm that FLSC/adjuvant formulation induces CD4i responses in rabbits. Aim 5. Evaluate FLSC in preclinical safety studies. Overall, the single chain complex has emerged as one of the rare envelope-based subunit immunogen that by itself affords protection against mucosal infection with a completely heterologous SHIV. These findings suggest that single chain complexes should be considered as viable candidates for a vaccine against HIV-1. PUBLIC HEALTH RELEVANCE: The positive outcome of the RV144 Phase III vaccine trial has prompted the field to refocus on defining immunogens that can generate humoralimmunity as a means of achieving sterilizing immunity. One such immunogen is the Full Length Single Chain (FLSC) a gp120 human CD4 fusion that replicates the conserved envelope-CD4 complex, a key transition state that all HIV isolates must realize during infection. The goal of this project, therefore, is to initiate the preclinical development of FLSC in preparation for its evaluation in Phase I clinical trial as the next step in discerning whether FLSC can be an effective HIV vaccine.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 299.92K | Year: 2016

ABSTRACT A universal influenza vaccine is believed to be possible if conserved regions of influenza are effectively targeted and appropriate immune responses are generated against those targets The enhanced safety stability and accelerated product development generally provided by DNA vaccination make it an appealing approach to develop such a universal influenza vaccine Unfortunately immune responses to universal influenza antigens are typically weak and in the past DNA vaccination of humans has been disappointing To overcome these and other obstacles to developing an effective practical and truly universal influenza vaccine we intend to deliver our vaccine using a DNA prime protein boost regimen and employ novel immunogens derived from the following three conserved influenza A antigens the stem region of hemagglutinin HA the matrix protein ectodomain M e and the nucleoprotein NP We believe that together these antigens will evoke the immunological breadth necessary to protect against a broad range of both seasonal and potential pandemic influenza strains We will also use a potent DNA adjuvant combination to maximize immunogenicity and to tune the responses toward a Th phenotype Finally we will utilize a recombinant protein boost to amplify the humoral immune responses and increase their durability In this Phase I SBIR we will construct and express our influenza A immunogens and verify their immunogenicity and protective efficacy in mice to determine if the vaccine provides a wide breadth of protection from divergent seasonal and pandemic influenza A strains If we are successful in this Phase I proof of concept study we will move on to test our vaccine in a macaque challenge model under a Phase II application and begin development on influenza B and possibly type C immunogens PROJECT NARRATIVE The objective of this project is to develop a DNA prime subunit boost universal influenza vaccine Such a vaccine is needed to combat seasonal and pandemic influenza outbreaks and to lessen the dependency on seasonal vaccines


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 733.63K | Year: 2016

DESCRIPTION provided by applicant Our primary approach to develop an effective prophylactic vaccine against HIV utilizes a novel immunogen called the Full Length Single Chain FLSC that consists of gp derived from HIV genetically linked via a amino acid linker to the D D domains of human CD When rhesus macaques were inoculated with versions of FLSC that contain CD derived from rhesus macaques and either HIV gp or SIV gp significant protection against rectal challenge with multiple low doses of either an R tropic heterologous SHIV P or heterologous SIVmac was observed These observations propelled FLSC into preclinical development and evaluation in a phase clinical trial supported by BMGF MHRP NIAID Further vaccination with DNA expressing FLSC and IL administered by electroporation in macaques induces multifunctional T cells that are known to correlate with protection and improved efficacy In our most recent macaque study a FLSC DNA prime protein boost regimen yielded efficacy against a cross clade challenge In collaboration with others we have also developed a DNA protein co delivery regimen that evokes higher titered longer lived anti FLSC responses However we believe that our approach can be dramatically improved by targeting these anti FLSC responses to mucosal sites where HIV enters the host and establishes infections To improve mucosal immune responses we sought to develop a mucosal homing DNA adjuvant that targets lymphocytes to mucosal immune effector sites after systemic vaccination In preliminary studies we identified two putative mucosal homing DNA adjuvants Under phase I we demonstrated that one of these putative adjuvants does indeed induce the homing of lymphocytes to mucosal immune effector sites after systemic i m immunization Under phase II we intend to expand upon these observations and demonstrate that this adjuvant targets vaccine specific immune responses to mucosal sites in primates PUBLIC HEALTH RELEVANCE The objective of this project is to determine if a mucosal homing DNA adjuvant will improve the immune responses generated by our HIV SIV vaccine regimen

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