Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 299.28K | Year: 2005
DESCRIPTION (provided by applicant): The HIV-1 epidemic has resulted in approximately 5 million new infections in 2004 for a total of 40 million people living with HIV/AIDS. A preventative vaccine for HIV-1 is urgently needed. It is generally agreed that an antibody-inducing vaccine will be essential for an efficacious public health strategy. In previous work, we have identified several novel immunogens based on the HIV-1 envelope protein that demonstrate an improved ability to induce neutralizing antibodies to primary isolates of the virus. Each of these novel immunogens is heavily glycosylated, which is typical of the HIV-1 envelope. Previous studies of envelope glycosylation suggest the hypothesis that modifications of glycosylation can lead to further improvements in the immunogenicity of envelope proteins. Beginning with three lead immunogens, we will systematically evaluate the effect of glycosylation on the ability of these proteins to induce broadly cross-reactive antibodies to clinically relevant isolates of HIV-1. In the present Phase I SBIR Proposal, a large number of combinatorial glycosylation variants will be created using a novel in vitro gene recombination technology. The biosynthesis of the envelope variants as well as their ability to bind CD4 and various neutralizing monoclonal antibodies will be evaluated. The output of the current Phase I workplan will be a collection of glycosylation variants that are suitable for testing by immunization in animals. Only in vivo studies can truly measure the ability to induce virus-neutralizing antibodies. This latter work will be the subject of a Phase II SBIR application. The ultimate goal is to identify one or a small number of immunogens that can be tested for immunogenicity in clinical trials in humans. The Specific Aims of the current Phase I SBIR submission are: (1) create libraries of glycosylation variants using in vitro recombination; (2) isolate thousands of individual clones from the libraries; and (3) select variants that are well secreted, properly folded, and carry the known conserved neutralizing epitopes. This Proposal is targeted to one of the Areas of Interest of the Division of AIDS, NIAID relative to the preclinical development and evaluation of HIV vaccines, adjuvants, delivery systems, and new formulations for agents to prevent HIV infection.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 599.98K | Year: 2008
DESCRIPTION (provided by applicant): Influenza pandemics occur when an abrupt change in the composition of the circulating viruses results in a strain to which individuals have little or no immunity. The three pandemic outbreaks that occurred in the 20th c entury in 1918, 1957, and 1968 represent three different antigenic subtypes of influenza A virus: H1N1, H2N2, and H3N2, respectively. The concern of a future pandemic has focused attention on the avian H5N1 virus, which has demonstrated not only the possib ility of infecting humans but to do so with a high case-fatality rate. Vaccinating populations to protect them from a future pandemic virus poses an obvious problem. David Nabarro, UN senior coordinator for avian and human influenza, stated: We cannot hav e a vaccine against a pandemic virus until the pandemic virus appears and then there will be an interval of perhaps six months until we have a reasonable quantity of vaccine. Efforts are underway to create pre-pandemic vaccines to H5N1 viruses that can co nfer broad protection against different strains. However, the divergence of highly pathogenic H5N1 viruses into distinct clades has increased the complexity of developing a prophylactic vaccine against multiple H5N1 subtypes. We propose here a novel way to approach this problem, using the power of directed molecular evolution. This technology encompasses a method for creating novel protein sequences coupled with a means of screening the protein variants. In vitro homologous DNA recombination can create libr aries of high-quality functional diversity from pathogen genes encoding the proteins needed to create a vaccine. Libraries of the variant proteins can then be screened for improved immunogenicity. The only major correlate of protection against influenza is antibody to its surface glycoproteins, primarily the hemagglutinin (HA). We hypothesize that variants of the H5 HA protein can be created that are more immunogenic than the wild-type proteins, and will induce immune sera with potentially broad neutralizat ion potency. Genes encoding the variants to test this hypothesis will be created by in vitro DNA recombination of wildtype H5 HA-encoding genes. The specific product that is being targeted by this work is an HA-based vaccine with broad neutralization activ ity against many H5N1 viruses. The creation of a stockpile of variants and the sera induced by them will nonetheless provide a means to rapidly choose the immunogen needed to prepare a vaccine once a pandemic strain has appeared. The current proposal will assess the feasibility of this idea. A study by the Congressional Budget Office estimates that the consequences of a severe pandemic could include 200 million people infected, 90 million clinically ill, and 2 million dead in the United States alone. If a p andemic is caused by H5N1, the numbers of deaths could be considerably higher given the observed gt50% case-fatality rate for infection by this virus. A strategy such as that proposed here could - if successful - provide a measure of protection against a p andemic H5 influenza strain and potentially save millions of lives. PUBLIC HEALTH RELEVANCE: Influenza pandemics occur when individuals are poorly protected from the virus. We propose to create a collection of vaccine candidates that can rapidly be tested against an emerging pandemic. A strategy such as that proposed here could provide protection against a pandemic flu virus and save millions of lives.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 995.36K | Year: 2006
DESCRIPTION (provided by applicant): Venezuelan, eastern, and western equine encephalitis viruses (VEEV, EEEV, WEEV respectively) are arthropod-borne alphaviruses that cause periodic epizootics in the Americas. No licensed vaccines exist for these pathogens, and the experimental vaccines used under Investigational New Drug status suffer from high reactogenicity or poor immunogenicity. Vaccines against specific viruses causing encephalitis, including EEEV and WEEV, are regarded as High Priority Biodefense Products by the NIAID. VEEV has been "weaponized" for use in biowarfare, due largely to its considerable stability and high infectivity in aerosols. EEEV and WEEV are less well studied than VEEV, but both have potential uses as agents of biowarfare or bioterrorism. EEEV is in fact the most lethal of arboviruses. Clinical data of naturally acquired infection by WEEV suggest that the disease is less severe. However, by analogy to VEEV, aerosol exposure to EEEV and WEEV could be even more lethal. The present Proposal to develop improved immunogens for vaccines against EEEV and WEEV involves a collaboration between Maxygen and the USAMRIID laboratory of Dr. Connie Schmaljohn. Substantial improvements in the immunogenicity of the envelope glycoproteins of VEEV have already been obtained using in vitro multigene DNA recombination and directed molecular evolution. This demonstrates the potential of this approach for improving EEEV and WEEV immunogens. In this Phase I SBIR submission, we will focus on improving the immunogenicity of envelope glycoproteins from each of EEEV and WEEV separately. A separate Phase II SBIR application will target the creation of a single multivalent vaccine for VEEV, EEEV, and WEEV. The Specific Aims of the current Phase I SBIR submission are: (1) create expression libraries of recombined genes producing variants of the envelope glycoproteins from EEEV and WEEV; (2) perform prescreening of individual clones from the expression libraries; and (3) evaluate the immunogenicity of chimeric clones in mice using DNA vaccines.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 240.44K | Year: 2006
DESCRIPTION (provided by applicant): The HIV-1 epidemic has resulted in ~5 million new infections in 2004 for a total of 40 million people living with HIV/AIDS. Clinical trials have shown that HIV-1 infection cannot be prevented by immunization with subunits of naturally occurring viral envelope (Env) proteins. However, it is clear from experimental studies that neutralizing antibodies to the Env protein can protect primates from infection. Modified Env proteins that better expose the neutralizing epitopes are now required to accelerate vaccine development. Detailed structural studies of the HIV-1 and SIV Env glycoproteins have revealed that this molecule undergoes substantial changes when it is bound by CD4, which is the initial step of virus-cell interaction. A major objective of HIV vaccine research is to create stable structures that are based on the unliganded form of the trimeric Env molecule. Molecules that resemble a stabilized version of the mature envelope trimer on the virion surface and that better expose existing neutralizing epitopes are currently being investigated. However, the Env structure carried by circulating HIV-1 clearly does not induce broadly neutralizing antibodies in infected individuals. Therefore, whatever the benefits of using a trimeric Env complex as an immunogen for vaccination, the Env protein must still be modified to improve the immunogenicity of conserved neutralizing epitopes. We propose to use directed molecular evolution to accomplish two main objectives. In this Phase I SBIR proposal, we will first use in vitro multigene DMA recombination to create libraries of novel chimeric HIV env genes that will be screened to identify a number of stable, cleaved, trimeric forms of the HIV-1 Env ectodomain. Second, upon reaching the goals of the present work, we will evaluate the immunogenicity of these proteins in a subsequent Phase II SBIR proposal. This work will provide a rigorous assessment of the value of trimeric Env molecules as immunogens and will provide lead molecules for further development as vaccine candidates. We are ultimately targeting a commercial vaccine product that will be of value in the prevention of HIV/AIDS. The Specific Aims of this Phase I SBIR proposal are summarized below. They are designed to evaluate the feasibility of creating stable and soluble forms of the HIV-1 Env trimer. - Specific Aim #1: Create libraries of recombined env genes encoding the gp140 ectodomain - Specific Aim #2: Identify and characterize at least 10 stable forms of fully cleaved Env trimers - Specific Aim #3: Prepare monomeric gp120 from each of the stable, cleaved Env trimers
News Article | October 3, 2011
Antti Ylimutka has just returned to his home in Helsinki after a trip to the far-flung reaches of Siberia. In particular, he was visiting the city of Novosibirsk. Nestled on the unforgiving plains of central Russia, and closer to Mongolia than Moscow, he admits it’s not exactly a stop on the tourist trail, even if it is Russia’s third largest city and about the same size as Philadelphia or Vienna. “Let’s just say at 2 a.m., when it’s cold and dark, you really feel like you are in Siberia,” he says. “Novosibirsk was voted the world’s ugliest city five times in a row.” The visit wasn’t meant to be part of a commentary on the city’s architecture, however. It was about trying to find startups. Ylimutka acts as the “wingman” for Startup Sauna, a Northern European accelerator program that is starting to extend its reach deep into Russian territory as a way of unearthing talent. And even though Novosibirsk isn’t officially in Europe at all, Startup Sauna sees cities like it as a crucial breeding ground for future generations of world-changing startups. That’s why the organization recently toured around the country, including not just the top-tier cities but also places like Novosibirsk, and the more central cities of Yekaterinburg and Kazan. Searching for great companies was interesting, although not exactly easy. “Finns have so many prejudices about Russia,” laments Ylimutka, “But St. Petersburg is like the Venice of Northern Europe. And Moscow’s such a big city. It is a really distant culture, but on a people level, they are really similar… they want to create awesome startups with awesome products too.” Startup Sauna’s blog has detailed a few of the companies that were invited to join the program, including Osklad (warehouse inventory software for business) and AppScale, which allows apps to tap into social network APIs more easily. But a lot of the action came from companies from traditions outside software and the web. That included high-tech healthcare companies such as Maxygen, a vaunted Moscow startup focused on low-cost, rapid DNA testing; and Celoform, a sort of next generation bandage hailing from Yekaterinburg. Then there was St. Petersburg’s RosTechnoExport, which makes small autonomous helicopters that can be used by the oil industry. “The more you move away from Moscow and St. Petersburg, the more technical it gets,” says Ylimutka. “The high-tech stuff is what really makes Russia interesting. Part of it is probably because there is more of a military influence in these parts of Russia.” Still, it wasn’t a parade of business ideas that span out of military technologies. Most of the companies Startup Sauna met were clones or versions of other services. “It’s really difficult getting out of the Russian-centric mindset, and it’s still mostly me-too products. The West has Facebook; Russia has Vkontakte, for example.” In reality, it’s easy to think that this market is big enough or important enough, even if that’s a mistake. After all, the region that Startup Sauna covers — Finland, Estonia, Latvia, Lithuania, Poland and Russia — have almost 200 million people between them, though admittedly Russia and Poland count for the vast majority of that. Culturally, they are distinct and often suspicious of each other (not surprising given the history of the Soviet Union) but they also have a lot in common. In the end, Ylimutka says, having broader ambitions is about fostering an entrepreneurial culture that looks beyond borders. “In our region,” he says, “Since we’re lagging behind in business skills, it is really important to help build them.” Photograph used under Creative Commons license courtesy of Flickr user mksystem