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SAN DIEGO, CA, United States

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 599.51K | Year: 2010

DESCRIPTION (provided by applicant): The objective of this proposal is to assess the feasibility of using recombinant virus-like-particles (VLPs) to elicit neutralizing antibodies and prime CD4+/CD8+ T cells reactive with hepatitis B viral (HBV) antigens as candidate immunotherapeutics for chronic HBV infection. For this purpose, selected well- defined neutralizing B cell epitopes representing HBV envelope Pre-S (1) and (2) antigens are being inserted onto a species variant of the HBV core protein, namely the woodchuck hepatitis core antigen (WHcAg). Pre-S B cell epitopes were chosen because of their preferential expression on HBV virions. We have previously developed the WHcAg as a VLP vaccine carrier for a number of heterologous B and T cell epitopes and use in this particular application will permit circumvention of the T cell immune tolerance that exists in chronically infected patients. The WHO estimates that more than 400 million individuals are chronically infected with HBV and approximately 20-40% will develop serious complication such as cirrhosis, liver failure and hepatocellular carcinoma. Although a safe and efficacious preventative vaccine for HBV has been available for over 20 years, HBV infections continue (with more than 50 million HBV infections per year) to be a major health problem and no effective treatments for chronic infection exist. Antiviral drugs such as lamivudine, adefovir, entecavir and pegylated interferon-alpha have improved the therapeutic options for chronic HBV, but, their efficacy remains limited due to reactivation of HBV replication upon drug withdrawal. Because chronic HBV infection is an immune-mediated disease and adoptive transfer of immunity to HBV through bone marrow transplantation has achieved resolution of chronic HBV infection, vaccine-based immunotherapy has been suggested as a possible monotherapy or as a combination therapy with antiviral drugs. To this end a number of clinical trials have been conducted using the HBV envelope antigens (i.e., HBsAg, HBsAg- PreS(2) and HBsAg-PreS(2)-PreS(1) containing subviral particles) either singly or in combination delivered as proteins in adjuvant or as DNA constructs, all with rather disappointing results. The most important factor to explain the defective T cell responses to the HBsAgs in chronic HBV carriers is immune tolerance. To circumvent the obstacle of immune tolerance in HBV chronic carriers, we have chosen to construct hybrid VLPs consisting of HBsAg Pre-S neutralizing B cell epitopes inserted onto the WHcAg, which is approximately 66-68% homologous with the HBcAg. The WHcAg and the HBcAg are not crossreactive at the B cell level and, just as importantly for our purposes, are only partially crossreactive at the CD4+ T cell level based on unique WHcAg-specific T cell sites and shared WHcAg/HBcAg-specific T cell sites in regions of the WHcAg that are conserved between WHcAg and HBcAg. Therefore, CD4+ T cells specific for WHcAg-unique T cell sites will provide cognate T-B cell help for anti-PreS antibody production and will not be curtailed by immune tolerance to HBcAg-specific T cell sites. In fact, in preliminary studies in HBcAg-Tg mice, which are tolerant to HBcAg, immunization with hybrid WHcAg-PreS VLPs elicits equivalent high titer anti-PreS antibodies in wildtype and HBcAg-Tg mice. Another advantage of immunizing with a closely related species variant of the HBcAg is that CD4+ and possibly CD8+ T cell sites within the WHcAg that differ only marginally from the sites within the HBcAg (i.e., 1 or 2 amino acids) may elicit so-called bystander T cell help and may also even break T cell tolerance of the HBV patient's HBcAg-specific T cells by virtue of higher avidity T cell crossreactivity. Historically, breaking T cell tolerance to self antigens has been accomplished by immunization with closely related species variant proteins (induction of experimental autoimmune arthritis, diabetes, encephalitis etc.). Specifically, in Aim 1 we propose to insert 3 HBsAg-PreS(1) and 1 HBsAg-PreS(2) neutralizing B cell epitopes onto the WHcAg VLP carrier and optimize the constructs based on assembly, yield, stability and immunogenicity. In Aim 2 the therapeutic efficacy of the VLP-based vaccine candidates will be evaluated in a transgenic (Tg) mouse model of HBV replication, in which HBV replicates in hepatocytes at levels comparable to that in the infected livers of chronic HBV patients without evidence of cytopathology. The hybrid WHcAg-PreS VLP candidates have the potential to reduce HBV load in at least 3 ways: (1) anti-PreS antibodies should clear serum HBV through immune complexes; (2) WHc/HBcAg-crossreactive CD4+ T cells may reduce HBV replication in the liver through inflammatory cytokine production; and (3) WHc/HBcAg-crossreactive CD8+ T cells may reduce viral replication in the liver through cytokine production as well as through direct hepatocyte cytolysis. The ability of immunization with the WHcAg-PreS VLP candidates to reduce HBV load through all of these mechanisms will be monitored in the HBV-Tg mouse model (Aim 2). It is anticipated that the combination of these two technologies, the ability to produce hybrid-VLPs (VLP Biotech) and the murine model of chronic HBV infection (TSRI), will enable us to produce and test the therapeutic efficacy of at least 4 hybrid WHcAg-PreS VLPs in a two-year timeframe. PUBLIC HEALTH RELEVANCE: It is estimated by the WHO that worldwide more than 400 million people are chronically infected with the hepatitis B virus (HBV) and approximately 20-40% will develop serious complications such as cirrhosis, liver failure and hepatocellular carcinoma. Although a safe and effective preventative vaccine for HBV is available, the existing treatments for chronic infection are unsatisfactory for a number of reasons. This is a proposal to develop virus-like-particles (VLPs) capable of eliciting neutralizing anti-HBV antibodies and priming CD4+/CD8+ T cells reactive with HBV antigens as a candidate therapeutic vaccine for chronic HBV infection.

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 273.75K | Year: 2016

DESCRIPTION provided by applicant Overall Staphylococcus aureus is a gram positive bacteria which possesses a multitude of virulence factors It is a frequent and severe pathogen in hospitals and of increasing concern in the community where it results in severe skin infections pneumonia bacterial endocarditis and sepsis A significant proportion of these infections are the result of methicillin resistant S aureus MRSA We have developed a highly immunogenic nanoparticle vaccine capable of rapidly eliciting antibody against the pore neutralizing determinant PND within alpha toxin AT a ubiquitous and critical virulence factor of MRSA Previous work has demonstrated that Ab against the PND is highly efficacious in preventing tissue injury and bacterial growth in a rigorous mouse dermonecrosis model and in protecting mice in a lethal model of S aureus pneumonia In this project we will develop a bivalent vaccine which targets both the PND as well as critical epitopes within both Staphylococcal enterotoxin B and C which have been shown to be particularly important virulence factors in MRSA infections but also have the potential to be formulated as bioweapons The vaccine emerging from these studies will be uniquely efficacious against MRSA infections and for protection against the potential for SEB and SEC intoxication PUBLIC HEALTH RELEVANCE Infections with methicillin resistant S aureus or MRSA constitute a public health imperative Emerging from these studies will be a uniquely efficacious nanoparticle vaccine against critical virulence factors which will be efficacious in preventing MRSA

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.14K | Year: 2016

DESCRIPTION provided by applicant Although respiratory syncytial virus RSV infection occurs in of infants during the first year of life and are infected one or more times by year representing the greatest risk for hospitalization for infants no vaccine or therapeutic treatment exists for this unmet medical need The first clinically tested vaccine a formalin inactivated RSV FI RSV preparation not only did not protect infants and young children but seriously enhanced respiratory disease ERD in a majority of children and resulted in deaths The complication of ERD has contributed to the failure to develop a RSV vaccine for the past years No killed or subunit vaccines have been tested in na ve infants since the s and live attenuated RSV vaccines have other attendant risks i e insufficient attenuation for the immature pulmonary and immune systems of infants and reversion to wildtype Our approach to this problem is to focus on producing an andquot epitope basedandquot vaccine that elicits the one anti RSV specificity that is known to protect against severe disease and is known not to enhance disease A monoclonal antibody Mab palivizumab specific for a site A domain on the fusion F protein neutralizes RSV and prophylactically acts against severe disease and is licensed to be prescribed for high risk infants The palivizumab specific antibody epitope has been well defined within a residue site F Our approach is to insert the F epitope onto a well characterized virus like particle VLP i e the WHcAg In other words we propose to elicit palivizumab like neutralizing antibodies by active immunization as opposed to the expensive and laborious method of passive Mab transfer This goal has proven to be challenging because the F epitope is conformational and the inserted epitope must approximate the antigenic structure that is present on the intact virus However we have succeeded in the design and production of several RSV WHcAg VLPs that bind palivizumab elicit high titer neutralizing antibodies and efficiently protect mice against RSV challenge Our success may be partly attributable to the fact that the immunodominant portion of our VLP carrier has a helix loop helix structure similar to that of the F epitope Our approach has been to use the Combinatorial Technology developed for the WHcAg platform to generate a library of hybrid VLPs displaying the F epitope to select several candidates In this SBIR we will assess the feasibility of exploiting a panel of F displaying VLPs to produce an epitope focused RSV vaccine with increased diversity for the palivizumab epitope In a final pivotal experiment we will perform a cotton rat immunization RSV challenge study to assess the potential of this approach to overcome ERD PUBLIC HEALTH RELEVANCE Narrative Human respiratory syncytial virus RSV is the leading worldwide agent of serious pediatric respiratory tract disease No vaccine or therapeutic treatment exists for this unmet medical need This project describes the development of a RSV vaccine candidate that has been demonstrated to protect rodents against a RSV challenge

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 300.00K | Year: 2007

DESCRIPTION (provided by applicant): The overall objective is to develop hepatitis C virus (HCV)-specific immunogens that may be useful as vaccines for the prevention of chronic HCV infection. In the first approach (Specific Aim 1), an HCV vaccine using a particulate carrier platform to deliver envelope-derived hypervariable region 1 (HVR1) consensus neutralizing epitopes will be developed. Modified woodchuck hepatitis core (WHcAg) particles will be used as a vaccine platform for several reasons: hybrid-WHcAg particles elicit extremely high levels of anti-insert antibodies; use of the WHcAg will not compromise the use of the anti-HBc diagnostic assay because the WHcAg and human hepatitis core antigen (HBcAg) are not crossreactive at the antibody level; the immune tolerance to HBcAg in HBV chronic carriers can be circumvented by the use of the WHcAg platform because the HBcAg and WHcAg are only partially crossreactive at the T cell level; a "WHcAg combinatorial technology" more versatile than the HBcAg in terms of accommodating the insertion of a greater variety of foreign epitopes has been recently developed. We propose to insert into the WHcAg platform consensus neutralizing sequences derived from the variable HVR1 region of E2 in order to address the problem of genetic variability of HCV. An important advantage of the WHcAg platform is that it is comprised of 240 subunits that self-assemble into particles. Therefore, multiple HVR1 consensus peptides can theoretically be inserted into the same WHcAg-HVR1 hybrid particle. In the second approach (Specific Aim 2) an HCV vaccine using the same WHcAg carrier platform to deliver E1-E2 conserved neutralizing epitopes will be designed and developed. An important problem in developing a prophylactic vaccine against HCV is the high genetic variability of the virus. In addition to multiple HVR1 consensus epitopes, an alternative approach is to identify epitopes or antigenic regions which are genetically stable or conserved. Therefore, highly or semi-conserved (across genotypes) neutralizing epitopes identified within the E1 or E2 domains, which may be poorly immunogenic during natural infection, will be inserted onto the WHcAg platform. The efficacy of these HVR1 consensus and conserved E1/E2-WHcAg hybrid particles will be analyzed for immunogenicity and characterized by testing the ability of the anti-HVR1 and anti-E1/E2 antisera generated by immunization to neutralize HCV pseudoparticle infection. Finally (Specific Aim 3) we propose to insert into the WHcAg platform a domain in NS3 containing CD4 and CD8 epitopes to broaden the efficiency of the immune response against HCV. This "T cell rich" domain of NS3 will be fused to the C-terminal of the hybrid-WHcAg platform. To efficiently induce a CTL response, we propose to use the equivalent of a prime-boost strategy. The immune system will be first primed by a DNA vaccine encoding the HCV-WHcAg-CD4+/CD8+ platform also containing neutralizing B cell sites, then we will boost with the homologous HCV-WHcAg-CD4+/CD8+ particulate protein.

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