Download National Institute of Allergy and Infectious Diseases

Vaccine Manufacturing and Clinical
Trial Services for Diarrheal Disease
Product Development
Rodolfo M. Alarcón, PhD
Enteric and Hepatic Diseases Branch
Division of Microbiology and Infectious Diseases (DMID)
Enteric and Hepatic Diseases Branch
EHDB, NIAID, NIH, DHHS
Vaccines & Vaccination July 27-29, 2015
Brisbane, Queensland, Australia
1
Overview
• Introduction to NIH/NIAID/DMID/EHDB
– Organization and Mission
– EHDB pathogen list and area of focus
– EHDB PO contacts
• DMID grant, preclinical, and clinical
support services
• DMID clinical services
– EHDB Phase IV Rotavirus Vaccine Trial
NIH Organization
27 IC’s (Institutes and Centers)
Each with its own Goals, Programs, Approaches
http://www.nih.gov/icd/
http://www.nih.gov/about/
National Institute of Allergy and Infectious Diseases
(NIAID) — Est. 1948
NIAID research strives to understand, treat, and
ultimately prevent the myriad infectious, immunologic,
and allergic diseases that threaten millions of human
lives.
How is NIH Organized?
• Director’s Office – sets policies, represents NIH to
Congress, public, has modest discretionary $, etc.
• Institutes and Centers (I/C’s) – Each has focus, e.g.,
NCI, NIAID, NHBLI, NIDDK, etc.
– Develop Specific Programs and Priorities
– Intramural and Extramural
• Intramural conducts research
• Extramural - Administer funding awards
• Center for Scientific Review (CSR) – special function to
review grants via study sections (sometimes called
Scientific Review Groups or SRG’s) directed by
Scientific Review Officers (SRO’s).
National Institutes of Health
Office of the Director
National Institute
on Aging
National Institute
on Alcohol Abuse
and Alcoholism
National Institute
of Allergy and
Infectious Diseases
National Institute
of Arthritis and
Musculoskeletal
and Skin Diseases
National Cancer
Institute
National Institute
of Child Health
and Human
Development
National Institute on
Deafness and Other
Communication
Disorders
National Institute
of Dental and
Craniofacial
Research
National Institute
of Diabetes and
Digestive and
Kidney Diseases
National Institute
on Drug Abuse
National Institute
of Environmental
Health Sciences
National Eye
Institute
National Institute
of General
Medical Sciences
National Heart,
Lung, and Blood
Institute
National Human
Genome Research
Institute
National Institute
of Mental Health
National Institute
of Neurological
Disorders and
Stroke
National Institute
of Nursing Research
National Institute of
Biomedical Imaging
and Bioengineering
National Center
for Complementary
and Alternative
Medicine
Fogarty
International
Center
National Center
for Research
Resources
National Library
of Medicine
National Center on
Minority Health and
Health Disparities
Clinical Center
Center for
Information
Technology
Center for
Scientific Review
Peer
Review
Extramural Research Staff
Program Staff
•
Responsible for the programmatic, scientific, and/or technical
aspects of a grant
Review Staff
•
Responsible to NIH for scientific and technical review of
applications
• Center for Scientific Review (CSR)
• Regular and Ad Hoc Study Sections
Grants Management Staff
•
Responsible for ensuring that all required business
management actions are performed by the grantee and the
federal government in a timely and appropriate manner both
prior to and after award.
Overall NIH Budget
Intramural
Intramural
Grants
Grants and Contracts
Admin.
Other
NIAID: Find us on the web
http://www.niaid.nih.gov
NIAID Research: A Dual Mandate
Credit: AS Fauci
Division of Microbiology and Infectious Diseases
Office of the Director
Clinical Research
Coordination
Office of
Regulatory
Affairs
Bacteriology and
Mycology Branch
Office of
Clinical Research
Affairs
Enteric and
Hepatic Diseases
Branch
International Research
in Infectious Diseases
Office of Clinical
Research
Resources
Sexually
Transmitted
Infections Branch
Office of
Biodefense
Research Affairs
Respiratory
Diseases Branch
Office of
Genomics
and Advanced
Technologies
Office of
Scientific
Coordination
and Program
Operations
Parasitology and
International
Programs
Branch
Virology Branch
NIH/NIAID
ENTERIC AND HEPATIC
DISEASES BRANCH
Fred Cassels
Branch Chief
Christian Gonzalez
Product Manager
Susan Payne
Health Specialist
TBD
Admin
ENTERIC
HEPATIC
Shahida Baqar:
E. coli, Stx,
ricin, Bacterioides
Robert Hall:
Vibrio, Aeromonas
Bill Alexander:
Salmonella, Yersinia
Melody Mills:
Helicobacter, Listeria,
Shigella, normal flora
Ryan Ranallo:
Clostridia spp.,
Campylobacter, SEB
DIAGNOSTIC
Rajen Koshy:
HCV, HBV, HAV,
HEV, HDV
Rodolfo Alarcon:
Enteric Viruses – NoV, RV
Product Development
CLINICAL
TBD
Clinical Project Mgr
Robert Hall:
Enterics,
Hepatic, toxins
Gabi Feolo
Clinical Project Mgr
Rahsan Erdem
Medical Officer
Find your PO
http://www.niaid.nih.gov/about/findingpeople/dmid/Pages/ehdb.aspx
Diarrheal Disease
• Diarrheal disease is the second leading cause of death in
children under five years old.
• It is both preventable and treatable.
• Each year diarrhea kills around 760,000 children under
five.
• Diarrhea is a leading cause of malnutrition in children
under five years old.
• A significant proportion of diarrheal disease can be
prevented through safe drinking-water and adequate
sanitation and hygiene.
• Globally, there are nearly 1.7 billion cases of diarrheal
disease every year.
Credit: WHO
Hepatitis
• Hepatitis viruses B and C cause acute and/or chronic
infection and inflammation of the liver.
• Major causes of severe illness and death.
• The global burden of disease due to acute hepatitis B and
C and to cancer and cirrhosis of the liver is high (about
2.7% of all deaths)
• Forecast to become a higher ranked cause of death
over the next two decades.
• 57% of cases of liver cirrhosis and 78% of cases of
primary liver cancer result from hepatitis B or C virus
infection.
Credit: WHO
Hepatitis
• An estimated two billion people worldwide have been infected with
hepatitis B virus
• 360 million have chronic (long-term) liver infections.
• 620 000 people die every year as a result of hepatitis B virus
infection.
• A vaccine against hepatitis B has been available since 1982.
• Some 150 million people are chronically infected with hepatitis C virus
• 350,000 people are estimated to die from hepatitis C-related liver
diseases each year.
• Vaccination is one of the strategies used to prevent hepatitis infection.
• Vaccines exist against hepatitis A and B.
• Effective candidate vaccines for hepatitis E prevention exist.
• Progress has been shown in developing candidate vaccines against hepatitis C
Credit: WHO
Research Steps in Vaccine Development
Credit: AS Fauci
How does the NIH support Vaccine
Development?
Credit: AS Fauci
NIAID Support Mechanisms Across the
Product Development Pipeline
Contract
Resources
Resource Centers
Discovery
Target ID
& Validation
Preclinical
Development
Clinical Trial Support:
VTEU, other
Mechanisms
Clinical
Development
STTR/SBIR,
STTR/SBIR-AT-NIAID
R34/U01
R01, R21, R03
Partnerships
Vaccine
Academia and Industry
• Peer-reviewed grants and contracts to public or
private institutions and for-profit and non-profit
organizations
– Investigator-initiated grants
• Basic and Partnerships - R01, R21, R03
• Clinical – R34/U01
– Targeted initiatives supporting both grants
and contracts - PA, RFA, RFP, IAA, BAA
• Allows support for diverse research projects
http://www.niaid.nih.gov/researchfunding/Pages/default.aspx
DMID Resources for Researchers
http://www.niaid.nih.gov/LabsAndResources/resources/dmid/
Animal Models of Infectious Diseases
• Provision of a broad range of in vivo models
(small animal, non-human primate, and nontraditional models)
• Development of novel models
• Refinement of existing models
• Screening of products and efficacy testing to
support FDA submissions
Vaccine Manufacturing Services
• Training and Workshops
• Feasibility, Gap Analysis, and Product Development
Plan Support
• Process Development Including Assay Development for
• Product Release
• Pilot/GLP and cGMP Manufacture
• Audits
Includes vaccines, other biologics, challenge material,
antigen enhancing substances, and delivery systems.
Assay Development: Examples
• ELISA
– Serum responses
– IgG subclass
– Avidity/ELISA
• Cytokine
–
–
–
–
mRNA levels (qRT-PCR)
ELISAs
Intracellular staining
Quantitation Luminex
• Functional
– Toxin neutralizing
– Microneutralization
– Opsonophagocytic /
bactericidal
• Flow Cytometry
– T-Cell proliferation
– Cell viability
• Additional
–
–
–
–
–
Memory B cell ELISpot
Affymetrix Gene Chip
Immunohistochemistry
Viral plaque assay
TCID50
Evaluation and Testing Services
• Assay Development
– Measure humoral and cell mediated responses
– Broad range of assays
• Immunogenicity and efficacy testing
– GLP and non-GLP studies
– Pivotal efficacy studies under the animal rule
• Clinical and Non-clinical sample testing
– Support phase I-III
• Safety and toxicology studies
– Tissue cross-reactivity
– Biodistribution
Reagent Repository: BEI Research
Resources
• Provide reagents and
resources for biodefense
and emerging infections
agents to the scientific
community for use in
basic and applied
research
– Academic, industry
scientists
– Global access
– “Free” (shipping costs)
www.beiresources.org
NIAID Resources for Researchers
http://www.niaid.nih.gov
NIAID Resources for Researchers
http://www.niaid.nih.gov/labsandresources/resources/
NIH’s Network of Vaccine and
Treatment Evaluation Units (VTEUs)
 Established in 1962
 Clinical trials to
evaluate vaccines,
diagnostics and
therapeutics
 Epidemiologic studies
 Access to healthy and
sick populations
 Pediatric
 Adult
 Elderly
 Domestic and
international
capabilities
Summary
• NIAID/DMID/EHDB is assisting many investigators through
grants and preclinical services
• EHDB has conducted preclinical services and multiple
clinical trials for multiple investigators
• Program Officers are subject matter experts and entry point
for services
• Get to know your program officer (funded or not)
• Website: www.niaid.nih.gov
• Contact: [email protected]
Direct NIAID Contributions to Selected
FDA-Licensed Vaccines, 1994 - 2015
Credit: AS Fauci
Selected Infectious Diseases of Global
Public Health Importance
Credit: AS Fauci
DMID Partnerships: Two Mechanisms
R21/R33
R01
NIAID Small Business Innovation
Research/Small Business Technology
Transfer Programs
• Standard SBIR and STTR solicitations
(PA-11-096; PA-11-097), US companies
• NIAID Advanced Technology Programs
(PA-10-123; PA-10-124)
• Phase II Competing Continuation
NIAID Small Business Innovation
Research/Small Business Technology
Transfer Programs
• Vaccine development for tuberculosis, STIs,
hepatitis B and C, and malaria and other highimpact global parasitic diseases.
• Therapeutics for tuberculosis, hepatitis B and
C, and malaria and other high-impact global
parasitic diseases.
• Therapeutic enhancement and formulation
technologies with the goal of improving drug
development timeframes, productivity, efficacy,
specificity, safety, stability, and delivery.
http://www.niaid.nih.gov/researchfunding/sb/Pages/default.aspx
Phase IV Rotavirus
Vaccine Trial (VTEU)
Vaccination Schedule by Study Group
Subject Age at
Group 1
Group 2
Group 3
Group 4
Group 5
243 infants
243 infants
243 infants
328 infants
328 infants
RotaTeq®
RotaTeq®
RotaTeq®
Rotarix®
Rotarix®
4 months
RotaTeq®
Rotarix®
RotaTeq®
Rotarix®
RotaTeq®
6 months
RotaTeq®
Rotarix®
Rotarix®
N/A
RotaTeq®
Vaccination
2 months
Note: The minimum age at first vaccination is 6 weeks, and the maximum age at first vaccination is 14 weeks, 6 days. The
minimum interval between doses is 4 weeks. The maximum age for the last vaccination is 8 months.
ClinicalTrials.gov
A service of the U.S. National Institutes of Health
NCT 01266850
Phase IV RV Vaccine Trial Enrollment
Twelve VTEU sites and subsites involved and reporting
100% enrolled (04/08/13), 2 year completion