Biodefense and Emerging Infectious Diseases
Key NIAID Biodefense-related Accomplishments since 2001
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Category A Pathogens
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Bacillus anthracis (Anthrax)
- NIAID supported production, testing and evaluation of the next-generation anthrax vaccine, known as recombinant protective antigen, or rPA. Specifically, NIAID contracts supported the development of animal models, manufacture of clinical-grade vaccine, and Phase I and Phase II clinical trials. The investigational rPA vaccines were found to be safe and immunogenic in people, and protected rabbits and nonhuman primates against aerosol challenge with anthrax spores. NIAID has transitioned the rPA vaccine program to HHS’ Biomedical Advanced Research and Development Authority (BARDA) for further advanced development related to commercial scale manufacturing.
- NIAID, in collaboration with BARDA, is supporting the preclinical and clinical development of several antibody-based therapeutics as anthrax antitoxins:
- Elusys Therapeutics Inc. is being supported to perform advanced product development studies of Anthim, a human monoclonal antibody intended as an intravenous treatment for patients with inhalational anthrax disease. Two phase I clinical trials in humans and multiple studies in animals have been completed. BARDA has awarded Elusys an advanced development contract to support final development stages.
- Emergent Biosolutions is developing human monoclonal antibody AVP-21D9 as a therapeutic for the treatment of inhalational anthrax. In 2010, Emergent’s investigational new drug application for AVP-21D9 was accepted by the FDA for fast-track designation and granted orphan drug status. Subsequently, Emergent initiated a Phase I study that completed enrollment and dosing in 2011.
- Emergent Biosolutions also is assessing the efficacy of a polyclonal human anthrax immunoglobulin (AIGIV) as an intravenous therapeutic for the treatment of patients with anthrax disease. Emergent has completed a Phase I clinical trial of the product.
- PharmAthene is performing advanced product development studies of Valortim, a human monoclonal antibody intended as an intravenous treatment for inhalational anthrax. Progress has been made in advanced manufacturing, formulation, non-clinical and clinical assay development and clinical development. A Phase I clinical study was completed in 2011.
- Using whole genome sequencing and comparative genomics analysis, NIAID assisted the Federal Bureau of Investigation (FBI) to sequence and analyze more than 10 anthrax isolates related to the investigation of the 2001 anthrax letter attack in the United States. Through the genomic sequencing of two critical anthrax reference strains and a subsequent genomic analysis of all of the sequenced data, genetic markers were identified and provided to the FBI. The FBI then used this data to develop critical molecular assays used in the anthrax investigation. The genomic and bioinformatic strategies applied to anthrax have revolutionized how scientists now study genetic variation in microbes and pathogens and have evolved into a critical research, clinical and forensic tool for analyzing pathogens and microbes.
- NIH intramural researchers studying the pathogenesis and treatment of shock related to lethal anthrax infection have discovered that lethal toxin and edema toxin both play an important role. Their work also investigates the potential contribution of other bacterial components to the pathogenesis of anthrax. Their research points the direction for future studies in anthrax shock, including investigation of the basis for myocardial changes, the usefulness of novel toxin inhibitors delivered orally, investigation of the cell wall’s role in the pathogenesis of anthrax shock, the role of edema toxin and lethal toxin to the coagulopathy seen in this condition, and further definition of the optimal management of shock related to lethal toxin and edema toxin, individually and combined.
- NIAID intramural researchers discovered that a single gene controls mice and rat sensitivity to anthrax lethal toxin, an important first step in determining the mechanism through which toxin causes vascular collapse in all animal models and humans.
Clostridium botulinum (Botulism)
Botulinum toxin serotypes A, B and E
- NIAID has supported the development of XOMA 3AB, a monoclonal antibody designed to treat ingested and aerosolized botulinum toxin A, from basic research through discovery and preclinical testing. In 2011, this therapeutic is entering a Phase I clinical study at a NIAID-supported clinical unit at Johns Hopkins University. NIAID also has supported the development of monoclonal antibodies against botulinum toxin types B and E with significant progress made toward identifying suitable candidates.
Dengue virus
- With NIAID support, InViragen Inc. has developed a tetravalent dengue vaccine candidate designed to protect against any of the four related viruses that cause dengue fever. Two Phase I studies of the vaccine began in 2010: one in the United States, through NIAID’s Vaccine Treatment and Evaluation Units (VTEUs), and the other in Colombia with support from InViragen. Preliminary data suggest that the vaccine is well-tolerated and immunogenic in healthy adults. A needle-free delivery system developed by PharmaJet is being tested concurrently with the goal of delivering the vaccine through the skin at rapid speed.
- NIAID support to another small company, Hawaii Biotech, Inc., enabled early- to late-stage development of their tetravalent recombinant subunit vaccine, called HBV003. Merck & Co. acquired all dengue vaccine products from the company in 2010; the HBV003 vaccine candidate is undergoing further clinical development.
- NIAID intramural investigators developed an investigational tetravalent dengue vaccine that began Phase I testing in 2010 at Johns Hopkins University.
Ebola and Marburg viruses
- NIAID’s Vaccine Research Center (VRC) developed an investigational DNA-based prime/boost vaccine regimen targeting Ebola virus that was found to be effective in monkey studies. The individual components of the regimen also were found to be safe when tested in successive phase I studies. A Phase Ib clinical trial evaluating concomitant administration of the investigational DNA Ebola vaccine and a VRC-developed DNA Marburg virus vaccine candidate is currently underway in Uganda. The study is attempting to demonstrate proof of concept for a combination (Ebola and Marburg) filovirus vaccine. The goal is to develop a safe and effective vaccine that can prevent infection with both viruses.
Marburg virus
- Investigators with NIAID’s Division of Intramural Research demonstrated in non-human primates that a recombinant vesicular stomatitis virus vaccine provided near complete protection (5 out of 6) from death from Marburg virus infection when provided in a single dose 24 hours after exposure to the virus. The vaccine afforded only 33 percent protection when provided 48 hours after exposure. The finding has implications for treating potential laboratory exposures to Marburg virus and for further vaccine development for humans.
Monkeypox
- NIAID Intramural investigators identified in 2010 a new mouse model to study monkeypox virus. The model offered several advantages for studying the pathogenesis of monkeypox virus and evaluating potential vaccines and therapeutics compared to the previous mouse model, including sensitivity to the virus through multiple routes, genetic homogeneity, available immunological reagents and commercial production.
Yersinia pestis (Plague)
- In collaboration with the U.S. Army Medical Research Institute of Infectious Diseases and the FDA, NIAID supported testing of licensed antibiotics (gentamycin, doxycycline, ciprofloxacin, levofloxacin, and ceftriaxone) for efficacy against pneumonic plague as tested among non-human primates exposed to aerosolized Yersinia pestis. The data are currently being prepared for FDA evaluation.
- Initial cooperative agreement awards and additional NIAID pre-clinical service support have paved the way for Phase I clinical testing of two investigational vaccine candidates, a recombinant subunit vaccine (rV10-2) and Flagellin/F1/V. The two vaccine candidates will be tested in NIAID’s VTEUs.
Variola major (Smallpox)
- NIAID is supporting SIGA Technologies Inc.’s new drug application-enabling studies for ST-246, an oral treatment against smallpox virus infection. ST-246 has been shown to be highly efficacious in animal models challenged with a lethal dose of orthopoxvirus infection. Using animal studies, SIGA continues to work to determine the human equivalent efficacious dose and dosing schedule to design a human safety trial for the drug. BARDA recently announced a contract for late-stage development and procurement of ST-246.
- An NIH-supported clinical study carried out by NIAID’s VTEUs found that the existing U.S. supply of Dryvax smallpox vaccine (15.4 million doses) could be successfully diluted at least five times and retain its potency, effectively expanding the number of individuals that could be protected.
- Through a NIAID contract awarded in FY 2004, Bavarian Nordic completed validation of its large-scale manufacturing process and delivered to the NIH 500,000 doses of Imvamune®, modified vaccinia ankara (MVA) vaccine for smallpox. Studies have been initiated to identify formulation improvements to increase the product’s shelf life, and several phase I and phase II clinical trials have been conducted to evaluate multiple aspects of the vaccine’s safety and immunogenicity in healthy adults, individuals infected with HIV, and people with atopic dermatitis. These additional studies are important because 25 percent of the U.S. population, particularly immunocompromised people, cannot receive Dryvax, the currently approved smallpox vaccine, because they are at increased risk for post-vaccine complications. Imvamune has been added to the Strategic National Stockpile.
Category B Pathogens
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West Nile virus
- The NIAID VRC developed a DNA-based West Nile Virus vaccine that completed Phase I testing in 2007 and was found to be safe, well-tolerated and immunogenic. Importantly, the vaccine produced similar cellular and neutralizing antibody responses among younger and older study participants. Older people often have diminished responses to traditional vaccines in comparison to younger people.
Category C Pathogens
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Chikungunya virus
- The NIAID VRC developed a non-infectious virus-like particle vaccine against Chikungunya virus that is projected to enter Phase I clinical trials in 2011. NIAID has established a cooperative research and development agreement with Merck for advanced development of the vaccine.
Influenza virus
- The VRC is focused on developing a “universal” flu vaccine that is designed to provide protective immunity across many flu strains, including those causing seasonal outbreaks and those strains with the potential to cause pandemics. The VRC has conducted several clinical studies with candidate vaccine to test this concept beginning in 2006.
- Beginning in 2004, NIAID supported numerous Phase I and Phase II multi-site clinical trials performed by NIAID’s VTEUs to evaluate the safety and immunogenicity of H5N1 influenza vaccine formulations in healthy adults, the elderly and children. These included studies to evaluate vaccine types and dosages, vaccine strategies, adjuvant use, and delivery methods. Results from NIAID-supported research helped support the 2007 FDA approval of the first U.S. licensed H5N1 influenza vaccine.
- NIAID Intramural Research scientists are conducting a program to generate and evaluate candidate live-attenuated vaccines against a range of influenza A subtypes that have pandemic potential. The candidate vaccines, formulated for nasal administration, are characterized in preclinical studies and then evaluated for safety, infectivity, and immunogenicity in Phase I clinical trials in healthy adults.
- Little is known about how chronic illness and immunosuppression affect immune response to influenza virus. Intramural investigators are evaluating patients with influenza by recording their symptoms, collecting blood and nasal fluid specimens, performing genomic analysis of the viral isolates, and gathering other clinical information about immune response to infection. Correlation of these results with clinical symptoms and outcomes is under way. With the emergence of the H1N1 influenza pandemic in 2009, the original clinical protocol was expanded to allow recruitment of immunocompetent patients with influenza for study of the natural history of infection with the 2009 pandemic virus. Investigators developed a rapid and sensitive RT-PCR assay that allows influenza virus samples to be subtyped as 2009 pandemic H1N1 influenza or seasonal H1N1 influenza.
Prions
- NIAID intramural researchers developed a blood test called enhanced quaking-induced protein conversion (eQuIC) capable of detecting prion diseases in people and animals. eQuIC is 10,000 times more sensitive than existing diagnostics for detecting variant Creutzfeldt-Jacob disease, and accurately differentiated between healthy hamsters and those infected with scrapie. NIAID and Prionics AG have applied for a patent for the test.
Severe Acute Respiratory Syndrome-associated Coronavirus (SARS)
- The NIAID VRC developed a DNA-based vaccine for SARS that was well-tolerated and produced cellular immune responses and neutralizing antibodies when tested among healthy adults in a Phase I clinical trial.
Tuberculosis
- NIAID supported the pre-clinical development of a molecular test that has been shown to detect tuberculosis (TB), including the multidrug-resistant form, in a more specific, sensitive and rapid way than currently available TB diagnostics. The assay, known as the Xpert MTB/RIF TB test, is planned for further clinical evaluation. Additionally, the multi-assay platform on which the test is based has been used to develop assays for other infectious disease indications, such as sepsis.
Broad-spectrum Therapies (various Categories)
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Broad-spectrum Antimicrobial Therapies
- NIAID intramural investigators with support from a NIAID-funded Regional Center of Excellence developed a novel compound composed of DNA and cellular material from a weakened version of Francisella tularensis (tularemia) that controlled infections caused by different, unrelated yet highly pathogenic bacteria in lab-based mice and human cells. Specifically, the compound limited replication of virulent forms of F. tularensis, Burkholderia pseudomallei, Yersinia pestis (plague) and Brucella abortus also was effective in controlling lethal pulmonary infections with F. tularensis.
Broad-spectrum Antivirals: (Implications for pox viruses, cytomegalovirus, herpes simplex viruses, Epstein Barr Virus, adenovirus, BK virus, JC virus, papilloma virus)
- NIAID has supported the discovery, preclinical screening and clinical evaluation of CMX001, a broad-spectrum antiviral agent that has shown considerable potential as a candidate antiviral for smallpox as well as other DNA virus infections that are life-threatening to immunocompromised individuals. Specifically, NIAID support has included the development of animal models (rabbit pox model), preclinical efficacy testing in rabbits and mice, and three Phase I studies of the drug’s safety, tolerability and pharmacokinetics. NIAID’s in vitro and animal testing has shown the drug’s broad spectrum activity against virtually all classes of DNA viruses that are pathogenic to humans. CMX001 has been used, under an emergency investigational new drug application, in more than 100 immunocompromised individuals with life-threatening adenovirus infections.
Broad-spectrum Antivirals against All Enveloped Viruses (Implications for HIV-1, Influenza, Ebola, Rift Valley Fever, and Nipah virus)
- NIAID-supported researchers identified a small-molecule broad-spectrum antiviral, named LJ001, with significant activity against multiple deadly viruses, including HIV-1, Ebola, Rift Valley Fever, influenza, and Nipah virus. Researchers identified LJ001 after screening about 30,000 molecules to find one capable of blocking the entry of the deadly Nipah virus into a host cell. Subsequent testing found that the compound also blocked other lipid-enveloped viruses, suggesting that it likely targets a component common to all of the viruses.
Diagnostics
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Diagnostic for Respiratory Pathogens (Influenza A, Influenza A subtype H1, Influenza A subtype H3, Influenza B, Respiratory Syncytial Virus, human Metapneumovirus, Coronavirus NL63, Coronavirus OC43, Coronavirus 229E, Coronavirus HKU1, Adenovirus, Parainfluenza 1, Parainfluenza 2, Parainfluenza 3, Parainfluenza 4, Bocavirus, Rhinovirus, Bordatella pertussis, Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Streptococcus pneumonia)
- NIAID supported Idaho Technology, Inc. in the development of its FilmArray Respiratory System, which detects viral nucleic acids in nasopharyngeal swabs obtained from individuals suspected of respiratory tract infections. The FilmArray system, approved by the FDA in 2011, is capable of simultaneously detecting 15 respiratory viruses in one hour. NIAID support was key to the creation of the platform for the diagnostic system. Additionally, influenza sequences generated by the NIAID-funded Genomics Sequencing Centers facilitated the design of the influenza detection assays included in the platform. Avian influenza strains obtained from NIAID’s Biodefense and Emerging Infections Research Resources Repository were used to validate these assays.
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