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Sunnyvale, CA, United States

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

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.

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.

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.

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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