Sunnyvale, CA, United States
Sunnyvale, CA, United States

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Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 532.84K | Year: 2015

DESCRIPTION provided by applicant There are approximately million cases of dengue fever each year with billion people at risk mostly in low income countries There are four serotypes of dengue fever virus DENV and in its uncomplicated form the disease is worthy of its indigenous name andquot break bone feverandquot An individual may suffer sequential infections with multiple DENV serotypes and a second infection is associated with increased risk of dengue hemorrhagic fever dengue shock syndrome DHF DSS a much more serious and potentially fatal disease Altravax Inc AVI has developed a particulate single molecule tetravalent immunogen capable of inducing neutralizing antibodies directed against all four serotypes of DENV Global Vaccines Inc GVI a not for profit vaccine company has developed a novel adjuvant which is not only capable of promoting neutralizing antibody responses induced by other DENV immunogens but also catalyzing the induction of cell mediated immunity As recent evidence suggests that both arms of the immune response contribute to protection against DENV these two companies will collaborate to determine the effect of combining their respective technologies in an improved DENV vaccine The AVI immunogen will be tested in two forms First the protein immunogen will be produced in F cells and purified It then will be administered to Sv mice either alone with the GVI adjuvant or with alum as a positive adjuvant control In a second approach the gene for the AVI immunogen will be cloned into a Venezuelan equine encephalitis virus replicon particle VRP and the VRP will be administered to Sv mice for in vivo expression of the immunogen These formulations will be evaluated for induction of neutralizing antibodies and T cells to each of the four DENV serotypes The polyclonal sera also will be evaluated to determine whether the antibodies induced by the AVI tetravalent immunogen are directed to serotype specific neutralizing epitopes or to a neutralizing epitope s that is are conserved in each of the four serotypes The best of the formulations will be used to immunize Sv mice Serum T cells or a mixture of the two from the fully immunocompetent Sv mice will be transferred to na ve AG mice a congenic DENV sensitive mouse model to assess the ability of the induced immune responses to protect against challenge with each of the four DENV serotypes These experiments are the first to combine these two promising vaccine technologies and represent an important step in the preclinical development of a safe DENV vaccine candidate which induces both protective humoral and cellular responses and is appropriately inexpensive for the majority of persons at risk PUBLIC HEALTH RELEVANCE One third of the worldandapos s population is at risk for dengue fever virus infection Altravax Inc and Global Vaccines Inc a not for profit company will merge ther respective technologies in a new dengue vaccine candidate utilizing a single immunogen and a novel adjuvant to induce protective humoral and cellular immunity to all four dengue virus serotypes The overall goal is to advance this safe effective and inexpensive dengue vaccine approach through pre clinical studies and ultimately to clinical trials


Patent
AltraVax | Date: 2015-11-16

The invention provides polynucleotides and polypeptides encoded therefrom having advantageous properties, including an ability to induce an immune response to flaviviruses. The polypeptides and polynucleotides of the invention are useful in methods of inducing immune response against flaviviruses, including dengue viruses. Compositions and methods for utilizing polynucleotides and polypeptides of the invention are also provided.


Patent
AltraVax | Date: 2014-03-12

This document provides methods and materials for producing immune responses against hepatitis B viruses. For example, polypeptides, nucleic acid molecules encoding such polypeptides, virus-like particles containing such polypeptides, vaccine preparations containing one or more polypeptides provided herein, vaccine preparations containing one or more nucleic acid molecules provided herein, vaccine preparations containing one or more virus-like particles provided herein, and methods for inducing immune responses against hepatitis B viruses within mammals (e.g., humans) are provided.


Patent
AltraVax | Date: 2016-04-26

This document provides methods and materials for producing immune responses against hepatitis B viruses. For example, polypeptides, nucleic acid molecules encoding such polypeptides, virus-like particles containing such polypeptides, vaccine preparations containing one or more polypeptides provided herein, vaccine preparations containing one or more nucleic acid molecules provided herein, vaccine preparations containing one or more virus-like particles provided herein, and methods for inducing immune responses against hepatitis B viruses within mammals (e.g., humans) are provided.


The invention provides polynucleotides and polypeptides encoded therefrom having advantageous properties, including an ability to induce an immune response to flaviviruses. The polypeptides and polynucleotides of the invention are useful in methods of inducing immune response against flaviviruses, including dengue viruses. Compositions and methods for utilizing polynucleotides and polypeptides of the invention are also provided.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 599.69K | Year: 2010

DESCRIPTION (provided by applicant): The HIV-1 epidemic has resulted in ~2.7 million new infections in 2007 for a total of ~33 million people living with HIV/AIDS. Clinical trials have shown that HIV-1 infection cannot be prevented by immunization with monomeric recombinant forms of viral envelope (Env) proteins. However, it is clear that the HIV-1 Env contains epitopes that can induce neutralizing antibodies and that such antibodies can protect primates from infection. The HIV-1 Env is a transmembrane glycoprotein. Both the external subunit (gp120) and the membrane- proximal external region of Env (located within the gp41 subunit) contain epitopes that are the target of broadly neutralizing monoclonal antibodies (mAbs) isolated from infected patients. Considerable effort has been devoted to creating soluble forms of the Env trimer. The improvements in immunogenicity of these molecules relative to monomeric gp120 are limited at best. Another approach to creating improved Env-based immunogens is to produce virus-like particles (VLP). VLPs are multivalent and often very immunogenic. The full-length HIV-1 Env protein can be presented on the surface of VLPs composed of Gag protein and cellular membrane components. These VLP structures have the potential to represent true mimics of the Env trimer spike. Several challenges must be overcome to create HIV-1 vaccines based on VLPs. They must be produced at high levels. The number of Env molecules on each VLP must be maximized. Processing of the gp160 Env polypeptide must take place, without dissociation of the gp120 subunit, to create a functional form of the Env trimer. It might also be necessary to minimize the immunogenicity of the variable sequences. In preliminary studies on the creation of VLPs carrying HIV-1 Env proteins, we have begun to address the challenges outlined above. The preliminary results are encouraging and provide a basis for more detailed work on preparing VLP-based immunogens as candidates for HIV-1 vaccines. The objective is to create VLPs that carry the Env protein in a form that most resembles the current vision of the functional Env trimer of the virus. The Specific Aims of this Phase I SBIR proposal are as follows: (1) prepare optimized Env constructs for VLP production; (2) prepare VLP constructs with different Env sequences; and (3) evaluate the ability of various VLPs to induce neutralizing antibodies in rabbits If the VLP-based Env immunogens prove to be superior to soluble gp120 or gp140 constructs in their ability to induce neutralizing antibodies, then additional studies will form the basis of a Phase II SBIR proposal. PUBLIC HEALTH RELEVANCE: The HIV/AIDS epidemic has resulted in 2 million deaths and 2.7 million new infections in 2007, for a total of nearly 33 million people living with HIV/AIDS. Development of a vaccine is considered to be an essential component of the public health measures needed to slow the epidemic. This research proposal is designed to create a vaccine that can induce antibodies capable of preventing infection by the HIV virus.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 600.00K | Year: 2015

DESCRIPTION provided by applicant Influenza is associated with deaths in the US each year and vaccination is the best strategy for the prevention of influenza A major obstacle to the development of widely effective influenza vaccines is the considerable antigenic variation across strains and types of influenza viruses Influenza A H N and H N and influenza B viruses have co circulated each season since and an updated trivalent vaccine has been required every year to protect against the most recent circulating strains For Influenza B it is particularly challenging to select a single strain for the licensed trivalent vaccine Every season two antigenically distinct lineages of B strains Yamagata and Victoria lineages co circulate worldwide thus there is often inadequate protection from the vaccine against influenza B To address this issue a quadrivalent vaccine comprised of one H N one H N and two B antigens will be offered for the influenza season The additional component should reduce the morbidity and mortality associated with influenza B infections However a quadrivalent vaccine will not solve many of the problems that persist with influenza vaccines such as i lack of vaccine efficacy due to mismatched vaccine strains particularly for more deadly H N and H N ii no protection against pandemic viruses and iii a continued requirement for annual update of the vaccine Developing more andquot universalandquot vaccines or even for the individual components of the vaccine is essential for improving vaccine efficacy as well as pandemic preparedness We have used a directed molecular evolution approach to identify novel variants of the influenza B hemagglutinin or HA B that elicit cross lineage activity to both Yamagata and Victoria viruses Here we propose to evaluate the feasibility of developing these lead HA B immunogens as a universal influenza B vaccine by analysis of the breadth of the protective response and serum neutralizing activity elicited by the lead variants We will produce the HA B variants as virus like particle vaccines and use them to immunize ferrets which are a widely used highly relevant animal model for the study of influenza Ferrets will be challenged with both lineages of influenza B to deter mine if the HA B variant vaccines provide improved cross lineage protection In addition we will extensively characterize the sera from immunized ferrets against a large panel of B viruses to assess the degree of inter and intra lineage neutralization breadth Finally we will carry out assays to learn if conserved epitopes in HA such as epitopes near the receptor binding site or in the stem domain are targeted by these vaccines A single widely protective B component would be a significant and innovative advance for influenza vaccines It would relieve constraints placed on manufacturing capacity and timelines as it could be produced year round Such a vaccine could eliminate the need for yearly vaccination against influenza B Importantly a universal B component would free up space in a quadrivalent vaccine for other more deadly components particularly where pre existing immunity is lacking H N H N H N etc Inclusion of these viruses in the seasonal vaccine could save lives in the face of a pandemic PUBLIC HEALTH RELEVANCE The annual influenza season is responsible for considerable sickness and death especially among the more vulnerable members of the population such as children and the elderly Since flu strains change from year to year a vaccine that protects against many strains and avoids the need for annual immunization would be of great value This research Proposal will investigate a novel way to protect against different strains of influenza virus and could serve as the basis for improved vaccines


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 598.47K | Year: 2012

DESCRIPTION (provided by applicant): Dengue virus infection is an emerging disease and an expanding global health problem. More than one-third of the world's population is at risk for transmission in tropical and subtropical areas and vaccines are an urgent public health priority. Although dengue rarely occurs in the continental United States, it is endemic in Puerto Rico, and in many popular tourist destinations in Latin America and Southeast Asia. Vaccines are therefore also required for individuals traveling to areas where dengue is endemic. A major problem in developing vaccines for dengue is the existence of four co-circulating serotypes. Sequential infections by different serotypes can cause an enhanced disease known as dengue hemorrhagic fever. Ideally, dengue vaccines should protect against all serotypes simultaneously or within a short time period. The most advanced dengue vaccine in clinical testing is a complex mixture of four live-attenuated viruses that requires an immunization schedule covering12 months to achieve full seroconversion. The envelope (E) protein of dengue virus is the main determinant of virulence and is the major target of neutra- lizing and enhancing antibodies. The E protein, along with the smaller membrane (M) protein can formvirus- like particles (VLPs). Altravax possesses several novel dengue envelope variants that, as DNA vaccines, can individually induce neutralizing antibodies to all four dengue serotypes in monkeys. Beginning with these novel tetravalent dengue E proteinsequences, we propose to produce recombinant VLPs as vaccine candidates. VLPs are multiprotein structures that mimic the organization and conformation of authentic native viruses but lack the viral genome. Past experience with approved vaccines (HBV, HPV)has shown that recombinant VLPs are potent immunogens and offer a level of safety that is difficult to achieve with live-attenuated viruses. We will evaluate mammalian, insect, and yeast systems for optimal expression of dengue VLPs. Care will be taken atthis early stage to ensure that the cell lines, systems, and methods developed can ultimately be transferred to GMP manufacture. We will prepare monoclonal antibodies both to study the mechanism of tetravalent immunogenicity and to provide reagents for manufacturing controls for later work. We will evaluate VLP preparations in mice with several different adjuvant systems. Such additives can influence the isotypes of antibodies produced as well as stimulate more potent neutralizing antibody responses. Sincea critical part of dengue vaccine development concerns possible disease enhancement, which is thought to be antibody- dependent in humans, we will undertake a collaboration destined to investigate these phenomena in a mouse line (AG129) that is an in vivomodel of antibody-dependent severe dengue disease. The ultimate objective is to develop a safe preventative vaccine for dengue based on a single recombinant tetravalent VLP-based immunogen in a highly immunogenic format. To assist us in this work, we haveassembled a team of consul- tants and collaborators with expertise in many different fields of dengue virology, immunology, and pathology. PUBLIC HEALTH RELEVANCE: Dengue virus infection is an expanding global health problem and as many as 100 million people are infected yearly. Current vaccine candidates are complex mixtures that include all four dengue types. We propose to develop a much simpler single-component vaccine using novel tetravalent immunogens.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 600.00K | Year: 2012

DESCRIPTION (provided by applicant): Vaccines are urgently needed to slow the spread of the HIV/AIDS epidemic, and immunogens that can induce neutralizing antibodies remain an important goal of vaccine research. An increasing number of human monoclonal antibodies (mAbs) have been isolated in recent years from individuals who show remarkably broad and potent neutralizing responses. Coupled with past work, these results support the idea that the human immune system can generate rare but potent protective antibodies to the virus. Much work, including our own, has focused on identifying forms of the HIV-1 envelope glycoprotein (Env) that bind to broadly neutralizing antibodies. In contrast to approaches that optimize Env for binding to these highly affinity-matured antibodies, we and others now propose to identify immunogens that can bind to the germline form of the broadly neutralizing antibodies as a more productive approach to immunization. While three-dimensional structures of antibody-antigen interactions have informed antigen design, the corresponding germline antibody sequences rarely show any binding to the HIV-1 Env. As a result, structural information is not readily available for rational design of germline immunogens. We propose therefore to employ a directed molecular evolution approach to the problem of identifying germline-specific immunogens. Such immunogens could stimulate immature B cells that carry the germline precursor of a mature broadly neutralizing antibody. Because any individual germline sequence represents only a few percent of all rearranged immunoglobulin genes, activating specific B cells with germline-specific immunogens could increase the likelihood of inducing an appropriate antibody. One can also envision using a series ofimmunogens that stimulate partially affinity-matured antibodies along a particular path to form a mature neutralizing antibody. The recently characterized VRC01 mAb is well suited to this approach, notably because the CDRH3 domain is less important for the neutralization activity compared to most of the other broadly neutralizing mAbs. This minimizes one of the constraints in predicting the structure of the germline VRC01 precursor. We will create a number of VRC01-like mAbs that are increasing reverted to the germline sequence and use these as reagents to screen libraries of Env variants created by in vitro homologous DNA recombination. The revertants can be used in a stepwise recursive fashion, whereby Env variants that bind minimally reverted mAbs can be used as parents to create libraries of additional variants for screening with more highly reverted forms. We will evaluate the ability of these germline-specific Env immunogens to bind to myeloma cells that express VRC01-like germline antibodies on the cell surface, an interaction that resembles one of the first steps of B-cell activation. This Proposal represents an innovative approach to the identification of candidate immunogens for HIV-1 vaccines. It has general applicability to other pathogens for which protective (or broadly protective) mAbs have been identified (e.g., RSV or influenza) but induction of those antibody specificities has proven problematic. PUBLIC HEALTH RELEVANCE: The HIV/AIDS epidemic continues to cause death and newinfections with some 33 million people living with the disease. A vaccine that can reduce infection is an essential component of preventative measures. This research proposal is designed to create vaccine candidates that can prevent the HIV virus from infecting cells.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 600.00K | Year: 2012

DESCRIPTION (provided by applicant): Hepatitis B virus (HBV) is a noncytopathic, hepatotropic DNA virus that results in a self-limited acute infection in a majority of otherwise healthy individuals but can also cause chronic infection, particularly in newborns infected by vertical transmission. Chronic hepatitis B infection is a significant global health issue directly affecting 350 million people worldwide and resulting in 0.5-1.2 million deaths per year. Adults with chronic HBV infection acquired in the perinatal period develop hepatocellular carcinoma at a rate of about 5% per decade, approximately 100-fold higher than the rate among uninfected individuals. Antiviral drugs can inhibit viral replication and contribute to reducing morbidity and mortality,but they do not represent a cure. Proof-of-concept studies with chimpanzees chronically infected with HBV have shown that a DNA vaccine encoding the HBV surface antigen (HBsAg) followed by a recombinant canarypox boost can produce a large decline in HBV DNA levels for several years. Despite this encouraging result in the only non-human model, clinical trials of therapeutic vaccines have not provided a strong enough response to suppress viral replication. We hypothesize that mixtures of variant HBsAg proteins containing xenogeneic hepadnavirus T epitopes will prime helper T cells and CTLs to recognize the viral protein in chronically infected individuals, which otherwise respond poorly to the viral protein. The use of mixtures of chimeric sequences is innovative; by combining several unique variants it is possible to cover most or all wild-type epitopes while maximizing the content of immunostimulatory sequences. This hypothesis is novel and indirectly supported by data obtained in our Preliminary Studies. However, it clearly requires more extensive experimental support, notably direct data on T-cell responses, and this will be provided by the feasibility stud of this Phase I SBIR. We propose to develop a therapeutic DNA vaccine product delivered by electroporation and expressing a mixture of HBsAg variants. A number of immunogenic HBsAg variants containing xenogeneic sequences with novel T epitopes have been identified using a directed molecular evolution approach. Mixing several variants will increase the immunotherapeutic potential of the combined vaccine by including many different xenogeneic epitopes. Beginning with seven individual variants, all possible 3-variant combinations will be screened using a tiered strategy to identify the most immunogenic mixtures in normal and HBsAg-transgenic mice. The main objective of this Proposal is to identify mixtures that can induce strong T-cell responses and that are safe and well tolerated. An important feature of this work is the existence of potential backup candidates at all stages of development. Advancing multiple candidates at the early stages of lead optimization increases the likelihood of a successful outcome. Success in developing this innovative DNA-based therapeutic vaccine for chronic HBV infection would fill a considerable unmet need in the treatment of this disease, which represents a major public health burden. PUBLIC HEALTH RELEVANCE: Hepatitis B virus infection can cause chronic disease in certain people, particularly newborns. This is a majorhealth issue affecting over 350 million individuals worldwide resulting in 0.5-1.2 million deaths per year, often from liver cancer. We wil develop a vaccine to treat this chronic infection and potentially cure the disease.

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