Vaccine Manufacturing and Clinical Trial Services for Diarrheal Disease

Product Development

Rodolfo M. Alarcón, PhDEnteric 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).

Office of the DirectorOffice of the Director

National Instituteon Alcohol Abuseand Alcoholism

National Instituteon Alcohol Abuseand Alcoholism

National Instituteof Arthritis andMusculoskeletal

and Skin Diseases

National Instituteof Arthritis andMusculoskeletal

and Skin Diseases

National CancerInstitute

National CancerInstitute

National Instituteof Diabetes andDigestive and

Kidney Diseases

National Instituteof Diabetes andDigestive and

Kidney Diseases

National Instituteof Dental andCraniofacial

Research

National Instituteof Dental andCraniofacial

Research

National Instituteon Drug Abuse

National Instituteon Drug Abuse

National Instituteof Environmental Health Sciences

National Instituteof Environmental Health Sciences

National Instituteon Aging

National Instituteon Aging

National Instituteof Child Health

and HumanDevelopment

National Instituteof Child Health

and HumanDevelopment

National Institute onDeafness and Other

CommunicationDisorders

National Institute onDeafness and Other

CommunicationDisorders

National EyeInstitute

National EyeInstitute

National HumanGenome Research

Institute

National HumanGenome Research

Institute

National Heart,Lung, and Blood

Institute

National Heart,Lung, and Blood

Institute

National Instituteof Mental Health

National Instituteof Mental Health

National Instituteof NeurologicalDisorders and

Stroke

National Instituteof NeurologicalDisorders and

Stroke

National Instituteof General

Medical Sciences

National Instituteof General

Medical Sciences

National Instituteof Nursing Research

National Instituteof Nursing Research

National Libraryof Medicine

National Libraryof Medicine

Center for InformationTechnology

Center for InformationTechnology

Center for Scientific Review

Center for Scientific Review

National Centerfor Complementary

and AlternativeMedicine

National Centerfor Complementary

and AlternativeMedicine

National Instituteof Allergy and

Infectious Diseases

National Instituteof Allergy and

Infectious Diseases

National Centerfor ResearchResources

National Centerfor ResearchResources

Clinical Center

Clinical Center

National Center on Minority Health andHealth Disparities

National Center on Minority Health andHealth Disparities

National Institute of Biomedical Imagingand Bioengineering

National Institute of Biomedical Imagingand Bioengineering

FogartyInternational

Center

FogartyInternational

Center

National Institutes of HealthNational Institutes of Health

PeerReview

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

Grants and Contracts

Intramural

NIAID: Find us on the web

http://www.niaid.nih.gov

Credit: AS Fauci

NIAID Research: A Dual Mandate

Division of Microbiology and Infectious Diseases

Respiratory Diseases Branch

Office of Biodefense

Research Affairs

Office of Regulatory

Affairs

Office of Scientific

Coordination and Program

Operations

International Research in Infectious Diseases

Sexually Transmitted

Infections BranchVirology Branch

Enteric and Hepatic Diseases

Branch

Parasitology andInternational

Programs Branch

Bacteriology andMycology Branch

Office of the Director

Office of Genomics

and Advanced Technologies

Office of Clinical Research

Affairs

Office of Clinical Research Resources

Clinical Research Coordination

NIH/NIAID

ENTERIC AND HEPATIC DISEASES BRANCH

Fred CasselsBranch Chief

Christian GonzalezProduct Manager

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

HEPATIC

Rajen Koshy: HCV, HBV, HAV,

HEV, HDV

CLINICAL

TBDClinical Project Mgr

Gabi Feolo Clinical Project Mgr

Robert Hall: Enterics,

Hepatic, toxins

ENTERIC DIAGNOSTIC

Rodolfo Alarcon: Enteric Viruses – NoV, RV

Product Development

Susan PayneHealth Specialist

TBDAdmin

Rahsan ErdemMedical Officer

Find your POhttp://www.niaid.nih.gov/about/findingpeople/dmid/Pages/ehdb.aspx

Credit: WHO

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

Research Steps in Vaccine Development15

– 2

0 y

ears

or m

ore

Credit: AS Fauci

Discovery and Product

Development Research

How does the NIH support Vaccine Development?

Credit: AS Fauci

DiscoveryTarget ID & Validation

Preclinical Development

Clinical Development

Vaccine

Resource CentersClinical Trial

Support: VTEU, other Mechanisms

STTR/SBIR, STTR/SBIR-AT-NIAID

R01, R21, R03 R34/U01

Contract Resources

Partnerships

NIAID Support Mechanisms Across the Product Development Pipeline

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 projectshttp://www.niaid.nih.gov/researchfunding/Pages/default.aspx

http://www.niaid.nih.gov/LabsAndResources/resources/dmid/

DMID Resources for Researchers

Animal Models of Infectious Diseases

• Provision of a broad range of in vivo models (small animal, non-human primate, and non-traditional 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.orgwww.beiresources.org

http://www.niaid.nih.gov

NIAID Resources for Researchers

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: rodolfo.alarcon@nih.gov

Rodolfo.alarcon@nih.gov

Direct NIAID Contributions to Selected FDA-Licensed Vaccines, 1994 - 2015

Credit: AS Fauci

Credit: AS Fauci

Selected Infectious Diseases of Global Public Health Importance

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 high-impact 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

Vaccination

Group 1

243 infants

Group 2

243 infants

Group 3

243 infants

Group 4

328 infants

Group 5

328 infants

2 monthsRotaTeq® RotaTeq® RotaTeq® Rotarix® Rotarix®

4 months RotaTeq® Rotarix® RotaTeq® Rotarix® RotaTeq®

6 months RotaTeq® Rotarix® Rotarix® N/A RotaTeq®

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 EnrollmentTwelve VTEU sites and subsites involved and reporting100% enrolled (04/08/13), 2 year completion