PI: Ian Lipkin
Award Location: Columbia University
Accurate, early diagnosis is essential to reduce the morbidity and mortality associated with emerging infectious diseases. In many cases, existing laboratory tests are insufficient to guide selection of antibiotic and antiviral drugs. To address this challenge, the Center for Research in Diagnostics and Discovery will develop tools that can be used to provide physicians, other healthcare personnel, and public health agencies with actionable information. The Center brings together leading investigators in genetics, systems biology, genomics, engineering, conservation biology, and public health from Columbia University, EcoHealth Alliance, New York City Department of Health and Mental Hygiene, Stanford University School of Medicine, University of North Carolina at Chapel Hill, University of Washington, and the Wadsworth Center.
PI: Dennis Kasper
Award Location: Harvard University (Medical School)
Since 1980, the mortality rate due to infectious disease in the United States has doubled. Emerging and re-emerging bacterial pathogens are a major cause of the increased mortality and there is an urgent need for new approaches to combat these pathogens. This CETR supports five projects organized around a single theme: targeting the bacterial cell envelope to develop innovative countermeasures against bacterial pathogens. The Center will leverage the powerful synergies and comprehensive knowledge of seven leading Harvard investigators in the area of bacterial cell envelope biology.
The goal will be to establish novel platforms for the production of antibacterial vaccines targeting cell surface carbohydrates and for the discovery of antibacterials. These platforms will be used to develop vaccines for Francisella tularensis, Burkholderia pseudomallei, Vibrio cholerae, and Salmonella typhi, among others, and to discover antibiotics that kill antibiotic-resistant ESKAPE pathogens, including Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter baumannii, by inhibiting cell envelope targets. One vaccine platform will enable rational design of highly effective glycoconjugate vaccines from pure peptide and oligosaccharide components, while the other will provide technologies to rapidly produce cost-effective, cell envelope-based vaccines as countermeasures for emerging and re-emerging infectious diseases. The antibacterial discovery projects focus on different cell envelope pathways and pathogens, but a cornerstone of all three projects is a highly effective new paradigm for high throughput screening that combines the strengths, while overcoming the weaknesses, of traditional target- and cell-based screening approaches. The CETR aims to provide as deliverables to development pipelines at least one new vaccine and three to five antibacterial compounds that have validated cell envelope targets and demonstrate efficacy in animal models—while simultaneously making significant advances in the underlying science of cell envelope biology.
PI: Megan Murray
Award Location: Harvard University (Medical School)
Despite the availability of curative therapy, tuberculosis (TB) continues to be the leading cause of death from a bacterial pathogen worldwide. Effective TB control requires the early diagnosis and treatment of infectious cases to prevent further transmission of the disease. The global TB case detection rate in 2011 was reported to be only 66 percent; thus, more than 30 percent of 8 million incident TB cases weren’t diagnosed or started on effective therapy. Much of the problem stems from the failure of TB diagnostic tools that rely on microscopy and culture confirmation of disease and drug resistance. While microscopy is inexpensive and readily available, its sensitivity is particularly low in two groups: HIV-infected patients and young children. In addition, Mycobacteria tuberculosis (Mtb) grows notoriously slowly. Since drug resistance is traditionally assessed by growth inhibition by antibiotics, resistant TB is often detected months after the initiation of empirical treatment. These delays not only lead to the acquisition of further resistance in patients but also to the further spread of drug-resistant strains.
The development of rapid molecular diagnostics has potential to revolutionize TB control. Such tests can be performed directly on clinical samples and rely on the rapid detection of pathogen-specific genetic signatures as well as resistance-associated mutations. However, existing tools suffer from two important limitations. First, current platforms are less sensitive than culture. And second, gaps in the knowledge of the genetic determinants of phenotypic resistance limit the spectrum of drugs to which resistance can be detected. The CETR will address these gaps through a multi-disciplinary collaboration emphasizing discovery of new biomarkers of resistance, identification of optimal clinical sampling strategies directed toward detection of Mtb DNA, and development of a sensitive microarray-based rapid diagnostic. This collaboration involves researchers at Harvard; Texas A&M; Baylor; National Jewish Health (Denver); the Lima-based non-governmental organization, Socios En Salud; Partners in Health/Zanmi Lasante, Haiti; Cambodian Health Committee; and Akonni Biosystems.
PI: Sean Whelan
Award Location: Harvard University (Medical School)
The goal of this CETR is to develop small molecule inhibitors of enveloped virus entry and test their efficacy in animal models of disease. The underlying hypothesis is that enveloped viral entry is replete with therapeutic targets to which small molecule inhibitors can be developed, blocking receptor engagement, membrane fusion, and cellular trafficking. Most classes of licensed antiviral drugs block intracellular steps of the replication cycle, often by interfering with virally encoded enzymes required for replication. A handful of antiviral agents block enveloped virus entry. These include
- Maraviroc, a small-molecule that blocks engagement of the CCR5 co-receptor by gp120 of human immunodeficiency virus-1
- Enfuvirtide, a synthetic peptide that binds gp41 of HIV1 and interferes with fusion
- Amantadine/rimantidine, which blocks the M2 ion channel of certain strains of influenza A virus to prevent release of the viral ribonucleoprotein segments into the cell
That paucity of synthetic entry inhibitors starkly contrasts with the natural protection mechanism of neutralizing antibodies that frequently block viral entry. This CETR will advance two general approaches to small molecule inhibition of viral entry: direct targeting of viral envelope proteins and specific targeting of cellular factors requisite for infectious virus entry. Targeting envelope proteins has the advantage that the small molecules do not need to enter cells, thus eliminating uptake and potential export concerns, and such inhibitors may be less likely to have unwanted interactions with cellular proteins. Targeting cellular proteins offers the attractive though yet unproven possibility to inhibit the entry of multiple viruses with a single small molecule. A team of six investigators working on interdependent projects will work to discover and advance small molecule inhibitors of both categories. Late stage developmental and translational research capabilities will be provided by SRI International and Wolfe Laboratories. the U.S. Army Medical Research Institute of Infectious DIseases will collaborate on Projects 2 and 3 for BSL-4 facilities and Boston University and the National Emerging Infectious Diseases Laboratory for studies under BSL-3 conditions.
PI: Christopher Basler
Award Location: Mount Sinai School of Medicine
Ebola viruses and Marburg viruses, collectively known as the filoviruses, are of public health concern because they are extremely lethal to humans and could potentially be used as bioweapons. Currently, there are no approved treatments for infections caused by these pathogens. This CETR seeks to address the unmet need for anti-filovirus drugs by proposing an innovative approach to develop therapeutics that will specifically block two critical filovirus capabilities: their suppression of immune defenses and their synthesis of viral proteins. To achieve these goals, the CETR has assembled a diverse team with scientific expertise in filovirus immune evasion, filovirus replication, antiviral drug development, and medicinal chemistry.
Several members of the team previously demonstrated that Ebola virus and Marburg virus produce multiple proteins that block the interferon response, a critical component of the infected host’s defense against virus infection. Ebola and Marburg viruses each make VP35 proteins that render cells unable to produce interferon. In addition, each virus makes a protein, the Ebola VP24 protein and the Marburg VP40 protein, that makes the virus-infected cell unable to respond to interferon. The investigators have also shown that the viruses need these anti-interferon functions in order to cause disease. Therefore, drugs that block these functions should alleviate illness. Other members of the team have identified a strategy that targets the function of the filoviral VP30 protein. This approach blocks filovirus transcription, a process that is required for the viruses to express their proteins. Inhibition of this function significantly decreases virus production and should therefore lead to reduced disease. Combining inhibitors of viral immune evasion with viral transcription inhibitors is expected to lead to synergy, where the two strategies work together to potently decrease virus growth and disease.
This CETR involves collaborations with Washington University, University of Texas Southwestern Medical Center, Microbiotix, Inc., Howard University, and University of Texas Medical Branch at Galveston.
PI: David S. Perlin
Award Location: Rutgers-New Jersey Medical School
An epidemic of multidrug-resistant (MDR) bacterial infections plagues global and U.S. healthcare. Since few new antibiotics make it to market from a diminished pipeline, there is an unmet medical need for new therapeutics to treat drug-resistant infections. Furthermore, effective therapies are urgently needed to address ongoing public health and biosecurity concerns posed by high-threat select agent bacteria that could potentially be engineered to become resistant to currently available antibiotics.
The goal of the Rutgers Center CETR is to help develop a new generation of antibiotics against known MDR bacteria. The CETR is a collaborative public-private partnership involving senior investigators at Rutgers University, Rockefeller University, and Cubist Pharmaceuticals. It will serve to jump-start the discovery of novel antibiotics by joining together highly creative senior researchers and providing critical core resources to turn highly promising early concept molecules into potential therapeutics suitable for clinical evaluation. The CETR will examine well- established and novel therapeutic targets, and it will facilitate target validation, chemical lead identification, structure-activity relationship analysis, pharmacokinetics, and therapeutic efficacy in animal models. The goal is to develop optimized chemical lead compounds that are suitable antibiotic candidates for preclinical evaluation. Critical factors for success include highly accomplished project and core leaders; a comprehensive and integrated infrastructure for lead compound optimization and validation; and access to the Rutgers Regional Biocontainment Laboratory, a national research center for high-threat agents.
PI: Erica Saphire
Award Location: The Scripps Research Institute
The Viral Hemorrhagic Fever Immuotherapeutics Consortium aims to provide lifesaving antibody cocktails for pre- or post-exposure protection. The antibodies are directed against filoviruses and arenaviruses, which cause hemorrhagic fever with up to 90 percent lethality, but against which no specific treatments are yet available for human use. This CETR will combine a variety of information to optimize results. This includes: molecular structure; in vitro and in vivo analysis to determine where antibodies bind on these viruses; which epitopes or modes of binding lead to greatest in vivo efficacy; which in vitro assays best predict in vivo efficacy; and which monoclonal antibodies can be combined into cocktails for greatest synergy.
A unique aspect of this CETR is that it is an open, field-wide collaboration. This type of singular global collaboration to develop benchmark therapeutics for all to use is unprecedented. For Ebola virus, the teams aims to gather all antibodies of known in vitro or in vivo efficacy, and compare them side-by-side in blinded studies. Data tracking will be available, so that potential users of such cocktails for occupational exposure will have the opportunity to provide input and commentary on the therapies that the team aims to make available at the completion of the study. For Marburg, Sudan, Bundibugyo, Lassa, and other viruses, we aim to identify new antibodies from human survivors to fill in existing resource gaps. Partners include U.S. Army Medical Research Institute of Infectious Diseases, Public Health Agency of Canada, Albert Einstein College of Medicine, Ben Gurion University, Uganda Virus Research Institute, Tulane University, University of Wisconsin, Mapp Biopharmaceutical, Zalgen Labs, Emergent Biosolutions, Integrated Biotherapeutics, and The Scripps Research Institute.
PI: Jeffrey Glenn
Award Location: Stanford University
There is a huge unmet need for novel antiviral strategies. The current paradigm for treating viral infections focuses on targeting viral enzymatic functions. As such, it provides a “one bug-one drug” approach and is often limited by rapid emergence of viral resistance. The overall objective of the Stanford University CETR is to develop new classes of host-targeting antiviral drugs that are capable of treating multiple important viral diseases, when used alone or in combination with other available agents.
Focusing on multiple diseases enables the most efficient use of available resources. Our activities will include identifying new leads focused on novel human host targets, validating promising lead molecules, and advancing optimized leads to the clinic, as well as repurposing already-approved drugs with known safety profiles for newly discovered antiviral applications. The CETR will pursue therapies for a wide range of new and re-emerging viral priority pathogens for which there is great clinical and public health need. The research will be conducted by a multi-disciplinary team of Stanford investigators along with collaborators from the University of California-San Francisco, the University of California-Berkeley, the Albert Einstein College of Medicine, Rockefeller University, and the U.S. Army Medical Research Institute of Infectious Diseases. The Center’s efforts will be enhanced and accelerated by a dedicated Pharmacology Core that will provide medicinal chemistry, in vitro and in vivo drug metabolism and pharmacokinetics (DMPK) support, along with industry consultants, and a Translational Incubator Core, that will provide strategic scientific, regulatory, preclinical and clinical guidance to all Center projects and identify pilot projects and technologies within the greater Stanford community.
PI: Richard Whitley
Award Location: University of Alabama at Birmingham
The Antiviral Drug Discovery and Development Center (AD3C), coordinated out of the University of Alabama at Birmingham (UAB), focuses on the development of new small molecule therapeutics for emerging and re-emerging viral infections. AD3C will focus on developing drugs for four virus families: influenza, flaviviruses, coronaviruses, and alphaviruses—infections causing diseases including West Nile virus, SARS, chikungunya, and dengue viruses. Researchers will work to target and inhibit enzymes essential for viral replication, with AD3C providing an infrastructure to accelerate the development of new potential drugs from the lab towards the clinic.
UAB will perform the research along with top virologists across the country already working with these agents, at institutions that include Oregon Health and Science University, Washington University, Vanderbilt University, the University of North Carolina at Chapel Hill, and Southern Research Institute.
The families of viruses targeted within AD3C are of the highest priority for the U.S. government. They represent both biologic threats and unmet medical needs. The global burden of these diseases is enormous, with West Nile virus and influenza routinely infecting U.S. citizens. AD3C will also strive to develop therapies for emerging infections such as coronaviruses and dengue which pose risks for traveling U.S. citizens or could be imported into the country, and chikungunya, which was locally acquired in the United States for the first time in 2014.
The research will focus on the inhibition of viral replication, especially viral polymerases. The participating researchers will focus on target validation, high throughput screening to identify novel chemical scaffolds, and basic virologic research to prove and further probe the exact mechanism of action of identified lead molecules in viral replication. Medicinal chemistry and lead development activities will advance identified compounds down the drug discovery and development pathway, ultimately leading to preclinical evaluation of promising new drug candidates to treat these diseases.
PI: Myron Levine
Award Location: University of Maryland, Baltimore
Enteric infections, which include different types of diarrheal illnesses, dysentery (bloody diarrhea), and typhoid and paratyphoid fevers, represent unsolved clinical problems affecting persons of all ages (but particularly young children and the elderly) in both developing and industrialized countries. Certain enteric pathogens are epidemiologically emerging or re-emerging, and others are of special interest due to their potential to promulgate bioterror. This Enteric CETR, focused on “Immunoprophylactic Strategies to Control Emerging Enteric Infections,” will undertake translational research towards developing products to prevent enteric disease caused by several important bacterial and protozoal pathogens. Several projects intend to progress new vaccine candidates through testing in innovative animal models. These include
- A Shigella live vector vaccine expressing protective antigens to prevent clinical illness caused by several pathotypes of diarrhea-causing Escherichia coli
- Core-O polysaccharide-flagellin conjugate parenteral vaccines, as well as engineered recombinant attenuated strains, to prevent invasive disease caused by non-typhoidal Salmonella Group C1 & C2 serovars
- A vaccine based on sporozoite proteins from the protozoan species Cryptosporidium hominis and C. parvum
- A bivalent adjuvanted cTxAB toxoid vaccine to prevent recurrent Clostridium difficile disease
The CETR will also investigate a unique passive antibody approach to prevent C. difficile disease. Finally, the CETR will explore the immune mechanisms responsible for cross protection among enteric fever Salmonella serovars. All Enteric CETR projects are interactive and multi-institutional, including investigators at the University of Maryland, Baltimore; the University of Virginia; and Tufts University. Overall, success of this program will accelerate the development of innovative, safe, and effective vaccines and other interventions to prevent some of the most devastating and difficult to treat enteric infections, thereby potentially resulting in lives saved both in the United States and worldwide.
PI: Jennifer Ting
Award Location: University of North Carolina
The purpose of this CETR is to use a novel nanoparticle technology to deliver vaccines and vaccine adjuvants with the goal of improving vaccine outcome. As vaccination remains the most effective way to combat infectious diseases, effective ways to increase immune response is one of the best means to control infections. This is particularly true for viral diseases as many viral diseases lack adequate therapeutics. The application is cross-disciplinary and requires expertise in material sciences, immunology, virology, and animal models. The platform will be tested using viruses of high-medical need. Once optimized, this platform should be adaptable for the delivery of vaccines against a variety of microbial pathogens. A major advantage of the nanoparticle technology used is that particles produced are immunologically inert and are of precise size, chemistry, porosity, flexibility, and shape.
This CETR has three projects based at the University of North Carolina at Chapel Hill (UNC) and is supported by four cores of industry-academia partnerships that include UNC, Duke University, and Liquidia Technologies, Inc. All three projects are highly inter-related and have the ultimate goal of enabling an eventual application for optimized vaccine/adjuvant biologics. The first project will optimize the nanoparticle chemistries to enhance biologic efficacy as a vaccine delivery system. The second project will focus on the co-delivery of small molecule adjuvants to stimulate antiviral immunity in mice and other appropriate animal models. The third project will use a novel humanized mouse system to assess human immune responses to products produced in Projects 1 and 2. These three projects are highly integrated to discover the most optimal platform needed for vaccine and adjuvant delivery for enhancing vaccine outcome in humans.
PI: Thomas W. Geisbert
Award Location: University of Texas Medical Branch
The goals of this CETR are to advance the treatments of deadly hemorrhagic fever viral infections caused by Ebola and Marburg viruses. In collaboration with Profectus Vaccines, Tekmira Pharmaceuticals Corporation, and Vanderbilt University Medical Center, researchers will develop and test new vaccines and broad spectrum treatments for Ebola and Marburg viruses, also known as filoviruses. Filoviruses are considered “Tier 1” pathogens by the U. S. Department of Health and Human Services, which means they are considered agents with the highest risk because they could be deliberately misused and cause mass casualties, or produce devastating effects to the economy, critical infrastructure, or public confidence. There are no vaccines or treatments approved for human use against filoviruses, and infection causes high mortality rates that range between 50 to 90 percent.
The new project combines three of the most promising post-exposure treatments that have shown the ability to completely protect animals against these deadly viruses. The Center makes use of biosafety level (BSL)-4 facilities, the highest level containment that is required to safely work with the deadly viruses.
This research will expand the arsenal of treatments and vaccines in the war against deadly viral diseases, especially Ebola virus.
PI: David Andes
Award Location: University of Wisconsin
The dwindling supply of antibiotics and the rising number of deadly infections with antibiotic-resistant strains represent one of the 21st century’s most compelling problems. A health crisis is imminent, and a robust and sustainable antimicrobial discovery pipeline is needed to combat these lethal infections. Yet, at the same time the threat of infectious disease is intensifying, the discovery of new antibiotics has slowed to a crawl.
Researchers have assembled a multidisciplinary team of microbiologists, chemists, and pharmacologists. The team proposes a novel antimicrobial drug discovery platform that exploits innovative conceptual and technical advances to overcome bottlenecks common to traditional pharmaceutical industry discovery methods. One of the seminal advances has been identification of a rich, diverse, untapped source of novel natural product antimicrobials. These unique drug sources are evolutionarily selected symbiotic environments between an animal and microbe in which colonizing bacteria produce molecules to defend the host animal from invasive infection. In addition to selecting for active antibiotics, the environments favor production of compounds not toxic to animals. Further discovery and development components of this infrastructure include the ability to: 1) identify the genetic circuits that microbes use to produce potent natural products; 2) coax the production of unique antimicrobials from these microbes, 3) rapidly and accurately identify novel chemical structures, 4) perform high throughput screens that predict potent drug activity, safety, and efficacy in humans, and 5) decipher modes of drug action. This CETR has already established a success rate in finding drug leads that is proving to be substantially more successful than traditional methods.
This work tackles the major unmet need of antimicrobial resistance, which is one of the most urgent biomedical challenges confronting our society today. Investigations will employ complementary, cutting-edge technologies to test the most innovative concepts in drug discovery and involves a collaboration with investigators at the Harvard Medical School.
PI: Herbert Virgin
Award Location: Washington University
Antimicrobial treatments routinely target specific pathogens. As microbial pathogens develop resistance to current treatments, it is important to develop new approaches to develop broad-spectrum therapeutics that can be used to treat a wide variety of infections. This CETR focuses on developing therapeutics that enhance the host autophagy pathway and autophagy-related genes (ATG genes) that have been shown to have broad protective effects against viruses, bacteria, and parasites, including West Nile virus, chikungunya virus, norovirus, Mycobacterium tuberculosis, Listeria monocytogenes, Salmonella typhimurium, and Toxoplasma gondii.
Autophagy is an evolutionarily conserved pathway by which eukaryotic cells envelop and degrade intracellular components. These intracellular components, or cargo, are captured in a double membrane-bound compartment that then fuses with lysosomes to degrade the cargo. Autophagy can capture pathogens or pathogen components as cargo, resulting in killing of the pathogens or clearance of pathogen-encoded molecules. Autophagy is a multi-step process that requires the concerted effects of a series of ATG genes. Interestingly, some antimicrobial effects appear to utilize some but not all ATG genes and do not depend on lysosomal degradation, suggesting the existence of novel mechanisms of ATG gene-dependent cell-intrinsic immunity. This Center will identify mechanisms of autophagy and ATG genes in host defense and develop small molecules that stimulate the activity of autophagy and/or ATG genes as broad-spectrum anti-infective agents.
Researchers have already identified an autophagy-inducing peptide that protects mice against infection with diverse viruses and have completed a high-density compound screen that has identified autophagy-inducing molecules that inhibit bacterial replication. The team has developed these initial candidates and will identify additional validated targets for further compound screens. Our collaborating institutions are the Broad Institute, Massachusetts General Hospital, Washington University School of Medicine, and the University of Texas Southwestern Medical School.