VLP Biotech Inc.

San Diego, CA, United States

VLP Biotech Inc.

San Diego, CA, United States

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Whitacre D.C.,Vaccine Research Institute of San Diego | Whitacre D.C.,VLP Biotech Inc. | Espinosa D.A.,Johns Hopkins University | Peters C.J.,Vaccine Research Institute of San Diego | And 8 more authors.
PLoS ONE | Year: 2015

In order to design P. falciparum preerythrocytic vaccine candidates, a library of circumsporozoite (CS) T and B cell epitopes displayed on the woodchuck hepatitis virus core antigen (WHcAg) VLP platform was produced. To test the protective efficacy of the WHcAg-CS VLPs, hybrid CS P. berghei/P. falciparum (Pb/Pf) sporozoites were used to challenge immunized mice. VLPs carrying 1 or 2 different CS repeat B cell epitopes and 3 VLPs carrying different CS non-repeat B cell epitopes elicited high levels of anti-insert antibodies (Abs). Whereas, VLPs carrying CS repeat B cell epitopes conferred 98% protection of the liver against a 10,000 Pb/Pf sporozoite challenge, VLPs carrying the CS non-repeat B cell eptiopes were minimally-to-non-protective. One-to-three CS-specific CD4/CD8 T cell sites were also fused to VLPs, which primed CS-specific as well as WHcAg-specific T cells. However, a VLP carrying only the 3 T cell domains failed to protect against a sporozoite challenge, indicating a requirement for anti-CS repeat Abs. A VLP carrying 2 CS repeat B cell epitopes and 3 CS T cell sites in alum adjuvant elicited high titer anti-CS Abs (endpoint dilution titer>1x106) and provided 80-100% protection against blood stage malaria. Using a similar strategy, VLPs were constructed carrying P. vivax CS repeat B cell epitopes (WHc-Pv-78), which elicited high levels of anti-CS Abs and conferred 99% protection of the liver against a 10,000 Pb/Pv sporozoite challenge and elicited sterile immunity to blood stage infection. These results indicate that immunization with epitope-focused VLPs carrying selected B and T cell epitopes from the P. falciparum and P. vivax CS proteins can elicit sterile immunity against blood stage malaria. Hybrid WHcAg-CS VLPs could provide the basis for a bivalent P. falciparum/P. vivax malaria vaccine. © 2015 Whitacre et al.


Schickli J.H.,MedImmune | Whitacre D.C.,VLP Biotech Inc. | Tang R.S.,MedImmune | Kaur J.,MedImmune | And 7 more authors.
Journal of Clinical Investigation | Year: 2015

Respiratory syncytial virus (RSV) is the most common cause of serious viral bronchiolitis in infants, young children, and the elderly. Currently, there is not an FDA-approved vaccine available for RSV, though the mAb palivizumab is licensed to reduce the incidence of RSV disease in premature or at-risk infants. The palivizumab epitope is a well-characterized, approximately 24-aa helix-loop-helix structure on the RSV fusion (F) protein (F254-277). Here, we genetically inserted this epitope and multiple site variants of this epitope within a versatile woodchuck hepadnavirus core-based virus-like particle (WHcAg-VLP) to generate hybrid VLPs that each bears 240 copies of the RSV epitope in a highly immunogenic arrayed format. A challenge of such an epitope-focused approach is that to be effective, the conformational F254-277 epitope must elicit antibodies that recognize the intact virus. A number of hybrid VLPs containing RSV F254-277 were recognized by palivizumab in vitro and elicited high-titer and protective neutralizing antibody in rodents. Together, the results from this proof-of-principle study suggest that the WHcAg-VLP technology may be an applicable approach to eliciting a response to other structural epitopes.


Patent
Medimmune Llc and Vlp Biotech Inc. | Date: 2014-03-14

The present disclosure generally relates to immunogens for eliciting an antibody response against respiratory syncytial virus (RSV). More specifically, the present disclosure relates to virus-like particles (VLPs) including a RSV F protein epitope, as well as methods of use thereof. Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract disease in infants and young children (Hall et al., NEJM, 360:5888-598, 2009; and Nair et al., Lancet, 375:1545-1555, 2010) and a vaccine to protect this young population is of high priority.


Grant
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.


The present disclosure generally relates to hepadnavirus core antigens in which one or more endogenous b cell epitopes have been effectively removed. More specifically, the present disclosure relates to rodent hepadnavirus cores modified to diminish the antibody response to the core so as to enhance the antibody response to heterologous polypeptides included therein.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 2.89M | Year: 2012

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+ T cells reactive with hepatitis B viral (HBV) antigens as candidate immunotherapeutics for chronic HBV infection. For this purpose, we have defined 8 neutralizing B cell epitopes from the HBV envelope Pre-S1 region, which will be consolidated and inserted onto a species variant of the HBV core protein, namely thewoodchuck hepatitis core antigen(WHcAg). Pre-S1 B cell epitopes were chosen because of their preferential expression on HBV virions. The WHO estimates that more than 360 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 20years, 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 have improved the therapeutic options for chronic HBV, but, their efficacy remains limited due to reactivation of HBV replication upon drug withdrawal. Vaccine-based immunotherapy has been suggested as a possible monotherapy or as a combination therapy with antiviral drugs. However, immune tolerance has prevented therapeutic vaccine efficacy. To circumvent the obstacle of immune tolerance in HBV chronic carriers, we have chosen the WHcAg, which is approximately 66-68% homologous with the HBcAg, as a vaccine carrier. 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 cel level. Therefore, CD4+ T cells specific for WHcAg-unique T cell sites will provide cognate T-B cell help for anti- PreS1 antibody production and will not be curtailed by immune tolerance. In fact, in preliminary studies in HBcAg-Tg mice, which are tolerant to HBcAg, immunization with hybrid WHcAg- PreS1 VLPs elicits equivalent high titer anti- PreS1 antibodies in wildtype and HBcAg-Tg mice. Specifically, in Aim 1 we propose to consolidate 8 HBsAg-PreS1 neutralizing B cell epitopesonto the WHcAg VLP carrier and optimize the constructs based on assembly, yield, stability and immunogenicity and the therapeutic efficacy of the VLP-based vaccine candidates will be evaluated in a transgenic (Tg) mouse model of HBV replication. In Aim 2 preclinical development of the WHcAg-PreS1 vaccine will be pursued including cGMP manufacturing and pharm/tox studies. PUBLIC HEALTH RELEVANCE: It is estimated by the WHO that worldwide more than 400 million people are chronically infected with thehepatitis 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 chronicinfection 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.


Grant
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


Grant
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

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