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BRM Virology, Viral Immunology and Pathology
BRM Virology, Viral Immunology and Pathology
BRM Virology, Viral Immunology and Pathology
BRM Virology, Viral Immunology and Pathology
BRM Virology, Viral Immunology and Pathology
BRM Virology, Viral Immunology and Pathology
BRM Virology, Viral Immunology and Pathology
BRM Virology, Viral Immunology and Pathology
BRM Virology, Viral Immunology and Pathology
BRM Virology, Viral Immunology and Pathology
BRM Virology, Viral Immunology and Pathology
BRM Virology, Viral Immunology and Pathology
BRM Virology, Viral Immunology and Pathology
BRM Virology, Viral Immunology and Pathology
BRM Virology, Viral Immunology and Pathology
BRM Virology, Viral Immunology and Pathology
BRM Virology, Viral Immunology and Pathology
BRM Virology, Viral Immunology and Pathology
BRM Virology, Viral Immunology and Pathology
BRM Virology, Viral Immunology and Pathology
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BRM Virology, Viral Immunology and Pathology

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BRM's Capabilities in Virology, Viral Immunology and Pathology: HSV-1, HSV-2, Influenza, RSV, LCMV, and CMV. For more information, please visit our website at www.BRMCRO.com.

BRM's Capabilities in Virology, Viral Immunology and Pathology: HSV-1, HSV-2, Influenza, RSV, LCMV, and CMV. For more information, please visit our website at www.BRMCRO.com.

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  • 1. Biomedical Research Models, Inc. Contract Discovery Research Virology, Viral Immunology and Pathology
  • 2. BRM Capabilities in Infectious Diseases • NIH/NIAID, CDC funded mucosal HSV-2 and RSV vaccine research grants ($6.8M) • NIAID has awarded a seven year contract to develop animal models of infectious diseases to a research consortium including: ◦ BRM ◦ University of Massachusetts Medical School ◦ US Army Medical Research Institute of Infectious Diseases ◦ Jackson Laboratories
  • 3. In Vivo • Virus Infection Models • Vaccines • Antiviral In Vitro • Immunology (B, T cell and mucosal responses), Virology (Plaque assay, RT-PCR) and Pathology
  • 4. Viral Infection Models • HSV-2 ◦ Female mice and guinea pigs (female and male) • HSV-1 ◦ Mouse ocular infection model and lung infection • Influenza virus ◦ Mouse adapted human infection model and others • Respiratory syncytial virus (RSV, mice and cotton rats) • Lymphocytic choriomeningitis virus (LCMV) and Cytomegalovirus (CMV) ◦ Chronic and Acute infection in Mice • Humanized mouse models for infectious diseases ◦ NIH has awarded a seven year contract to a research consortium
  • 5. Influenza Virus Infection Model • Intranasal instillation of virus to monitor mortality, morbidity (body weight loss, decreased activity, less food and water intake, show tendencies to huddle, increased respiration, ruffled fur is evident) • Test protective and therapeutic efficacy of vaccines, immunomodulation agents and antivirals • Evaluate immune responses, protection and pathology
  • 6. Survival Post Influenza Infection (mice, n=5/group) Percentage of Survival 100% 80% 60% 40% 10 µg Flu Vaccine 1 µg Flu Vaccine 20% 0.1 µg Flu Vaccine naïve 0% D0 D1 D2 D3 D4 D5 D6 D7 D8 Days Post Infection D9 D10 D11 D12 D13 D14
  • 7. Body Weight Post Influenza Infection (mice, n=5/group) Relative weight change post influenza challenge 115 (10 mg vaccine) Relative weight change post influenza challenge 120 (0.1 mg vaccine) Relative weight Relative weight 110 110 105 100 100 90 80 70 95 60 0 2 4 6 8 0 Days post infection 2 4 6 8 Days post infection 110 Relative weight Relative weight change post influenza challenge 120 (Naive ) 110 Relative weight Relative weight change post influenza challenge 120 (1 mg vaccine) 100 90 100 90 80 80 70 70 60 0 2 4 Days post infection 6 8 0 2 4 Days post infection 6 8
  • 8. HSV Infection Models • Intravaginal inoculation of HSV-2 virus to monitor mortality, morbidity (clinical score, body weight loss) and viral load during primary and recurrent phases for both female mice and guinea pigs. • HSV-2 infection model in male guinea pig • Intranasal infection with attenuated and virulent HSV-1 strains • Test systemic and mucosal immune responses and protection • Investigate latency and recurrence using clinical scores and RTqPCR methods
  • 9. HSV-2 Clinical Score Grading System • • • • • 0 – No apparent clinical signs 1 – Redness or mild swelling 2 – Raw patch, blister, moderate swelling 3 – Multiple blisters or raw patches 4 – Large blisters with severe and/or deep sores; and/or urinary retention; and/or hind limb paralysis; animal euthanized • 5 – Animal found dead
  • 10. Survival Post HSV-2 Infection (mice, n=5/group) 100 Percent of Survival 80 60 40 Naïve Vaccine 1 20 Vaccine 2 Vaccine 3 0 0 5 10 Days Post Infection 15 20
  • 11. Body Weights Post HSV-2 Infection (mice, n-5/group) 103 Percent of Body Weight 101 99 97 95 93 91 naïve 89 Vaccine 1 87 Vaccine 2 Vaccine 3 85 0 1 2 3 4 5 6 7 8 9 10 11 12 Days Post Infection 13 14 15 16 17 18 19 20
  • 12. HSV-1 Ocular Infection Model Acclimation of mice (4-7 days) Day 1: Corneal delivery of compound(s) Day 1: Corneal Infection of HSV-1 viruses Daily Clinical Assessment: Observe Facial lesions and swelling (3 weeks) Humane Endpoints Collection of fluid from both eyes for testing viral shedding (Days 0 to 7, 14, 21) Organ and Tissue Collection
  • 13. HSV-1 Clinical Readouts • HSV-1 KOS strain • Daily Clinical Scoring ◦ Facial swelling based on a grading scale of 0-6 ◦ Bilateral facial lesions on a grading scale of 0-8 (usually initiating after day 6) • Virus titration of lacrimal drainage • Histopathology of eyes and brain and other organs of interest ◦ Stained with Luxol fast blue-periodic acidSchiff reagent and hematoxylin
  • 14. Respiratory Syncytial Virus (RSV) • RSV virus A2 strain (High titer, quality stock) • Infection of Balb/c mice results in low and moderate level of replication that peaks on day4. • Clinical symptoms: weight loss, changes in lung function, ruffled fur • Pulmonary eosinophilia
  • 15. Acute and Chronic LCMV Infection Models • Mouse LCMV infection has been widely used to evaluate therapeutic treatments against human viral infections ◦ Viral clearance or persistent infection • Acute infection (Armstrong strain) ◦ Robust anti-viral T cell response ◦ Mediated by CD8+ virus-specific T cells ◦ Cleared within 2 weeks post infection • Chronic infection (clone 13) ◦ Associated with functional impairment, exhaustion, and deletion of virus-specific CD8+ T cells ◦ Lasting several months
  • 16. CD8+ T Cell Responses 29 Days Post LCMV Infection TNF-a GP 276 IFN-g TNF-a GP 276 IFN-g LCMV Clone 13 NP 396 NP 396 LCMV Armstrong CD44 CD44 CD44
  • 17. The Establishment of Chronic Infection in LCMV clone 13 Infected Mice Viral titers in the serum post LCMV infection Viral titers in Kidney and Lung (Day 29 post infection) 5.00 5.00 4.50 4.00 Day 2 Day 8 3.50 Day 15 Day 22 3.00 Day 29 Viral titer (PFU/mL) Viral titer (PFU/mL) 4.50 4.00 3.50 3.00 Kidney Lung 2.50 2.00 2.50 1.50 2.00 1.00 LCMV Armstrong LCMV Clone 13 LCMV Armstrong LCMV Clone 13
  • 18. Humanized Mouse Models • Under the aegis of the NIAID contract, the following humanized mouse strains are being evaluated: ◦ ◦ ◦ ◦ ◦ NODscidIL2rgnull mice HLA-A2 transgenic NOD-scid IL2rnull mice Human Blys transgenic NOD-scid IL2rnull mice TLR4KO NOD-scid IL2rnull mice, Myd88 KO NOD-scid IL2rnull mice
  • 19. Cytomegalovirus (CMV) • Infection is species-specific for HCMV, MCMV, RCMV and guinea pig CMV • Serious diseases in immunosuppressed patients ( 50-60% organ and bone marrow transplantation patients) • Primary infection is followed by persistent and recurrent infections • Severe combined immunodeficient (SCID) mice, CB-17 SCID mice which lack of T and B cells are sensitive to MCMV infection i.p. (blood, liver, spleen, lung, adrenal, pancreas, kidney, brain, sali vary) • Infection of Balb/c mice (3-week-old) i.p. , dose-dependent mortality • SCID-hu mice for ocular HCMV infection
  • 20. Summary • Scientific team with decades of combined experience • Tailored study design for your project needs • Competitive pricing • Flexible and rapid study start to your timelines

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