Vaccine 101

July 22, 2009

DynPort Vaccine Company LLC, A CSC Company

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Overview
• Vaccines and how they work
• Making a vaccine
• Vaccine manufacturing
• Putting things together
• Biodefense and vaccines

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Vaccines and How They Work

Vaccine 101

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What is a Vaccine?
• A vaccine is a biological material intended to induce a specific
immune response in humans or animals.
• Vaccines work because the body’s immune system
“remembers” how to protect itself from microbes it has
previously encountered.
• Vaccines are one of the greatest success stories in public
health.
– Vaccines have ended smallpox, and lowered the incidence rates
of serious illnesses including diphtheria, tetanus, measles and
polio by more than 95% since the beginning of the 20th century.

DVC has experience with

many kinds of vaccines.

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Some Types of Vaccines
• “Live” vaccines include a live variant of the target pathogen.
– Live attenuated vaccines: recombinant DNA technology removes
critical pieces of the virus or bacteria genome to make it less
virulent.
– Subunit vaccines: made using only part of the virus or bacteria.
• Recombinant vaccines – proteins expressed in various
mediums including E. coli and yeast, likely to be a
heterogenous mixture of strains
• DNA vaccines – employ the genes that code for specific
antigens (antigen = a substance that stimulates immune
response, particularly production of antibodies)
– No DNA vaccines have been licensed, though several are in
clinical testing
• Combination vaccines – combine protection against several
diseases (e.g., MMRmeasles, mumps and rubella)

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Making a Vaccine

Vaccine 101

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From Test Tube to FDA Review

Source: CDER
Handbook, FDA
3/16/98,
http://www.fda.gov/cd

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Advanced Development
• All DVC products are transitioned from research labs after
early research and development, including proof-of-concept.
• DVC specializes in “advanced development” of vaccines.
– Encompasses nonclinical and clinical research, and all activities
up to and including licensure by the U.S. Food and Drug
Administration (FDA).
• Biopharmaceutical development is lengthy and expensive.
– On average, 10 to 15 years and nearly $600 million.*

*Source:
Advanced Development http://csdd.tufts.edu/InfoServices/Outloo

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Animal Studies in Vaccine Development -
Terminology
• Nonclinical research
– Proof-of-concept animal models (does it work?)
– Toxicology, including acute/repeat-dose, and reproductive (is it
safe?)
– Efficacy/immunogenicity (will it protect against disease?)
– Product testing using animals (is it potent and stable?)
• Preclinical research
– Any nonclinical study conducted prior to use of the product in
humans

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Why Can’t Computers and Cell Cultures Replace
Animal Research?
• Animal and non-animal models both used to answer
biological questions.
• Animal studies may pave way for computer models.
Computer models and cell culture may extend what is
learned in animals.
• Computer models and cell culture still don’t reflect the
complexity and dynamics of a living organism.
• A complete answer currently requires animal studies.

DVC ensures that no animal will suffer

needlessly, and that the fewest animals are
used to obtain scientifically defensible data.

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Types of Animal Studies
• Dose and schedule requirements
– Animal data supports effective dose in humans
• Toxicology – is it safe?
– Includes reproductive toxicology
• Efficacy – does it work?
– Demonstrate that the vaccine actually works under its intended
conditions of use (dose and regimen)
– Demonstrates that the vaccine
• Protects against what it was designed to protect against
• Protects against a certain level of challenge
• Protects for a certain period of time

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Human Clinical Trials
• Human clinical trials are required by the FDA to test drugs
and biologics (including vaccines) in humans.
• The Food, Drug and Cosmetic Act requires drug
manufacturers to prove that products are safe for human
consumption and effective for a specific indication before
licensure and marketing in the U.S.
• After (years of) successful nonclinical research, the Sponsor
submits an Investigational New Drug (IND) application to the
FDA, which within 30 days either:
– Notifies the Sponsor of deficiencies and places a clinical hold, or
– Does not notify the Sponsor, which means it is OK to start the
clinical trial.

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Phases of Clinical Trials
• Phase 1
– Evaluate safety and tolerability of the investigational product in
humans
– Involves 20 to 80 normal, healthy volunteers
– Typically closely monitored
– Designed to determine the metabolism and pharmacologic
actions or drugs, side effects associated with increasing doses,
and (if possible) gain early evidence on efficacy
• DVC has successfully advanced 8 products into clinical trials
in the last 10 years. Phase 1 trials completed include:
– Anthrax vaccine
– Botulinum neurotoxin vaccine
– Butyrylcholinesterase (chemical defense therapeutic)
– Influenza vaccines (seasonal and pandemic)
– Tularemia vaccine
– Smallpox vaccine 13
Phases of Clinical Trials (continued)
• Phase 2
– Evaluate safety and effectiveness for a particular indication
– Typically involves several hundred subjects at multiple sites
– Controlled study
– DVC products in Phase 2: botulinum, plague and tularemia
vaccines
• Phase 3
– Expanded controlled trial
– Involves several hundred to thousands of subjects, multiple sites
– Long-term safety and efficacy
– DVC product in Phase 3: seasonal influenza vaccine (Baxter)
• Phase 4 – clinical evaluation is ongoing, even after FDA
licensure
– Post-marketing studies
– Ongoing safety evaluation
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Proving Safety and Efficacy in Humans
• Safety
– Safety assessments in study volunteers include:
• Physical exam, vital signs, blood pressure
• Clinical laboratory assessments: hematology, serum chemistry,
urinalysis, pregnancy test for females
• EKG
• Monitoring adverse events
– Supporting pharmacology/toxicology data in animal models
• Efficacy
– Immunogenicity testing in volunteers includes:
• Measurement of humoral immune responses (specific antibody
measurement)
• Cell-mediated immune responses (T cell proliferation, cytotoxicity
assay)
– Challenge data from animal models to support efficacy

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Regulations
• Good Clinical Practices (GCP)
– GCP is an international ethical and scientific quality standard for
designing, conducting, recording and reporting trials that involve
the participation of human subjects.
– Clinical trials must be conducted following GCPs.
• Good Laboratory Practices (GLP)
– Govern protocol and conduct of nonclinical (animal) studies.
• Current Good Manufacturing Practices (CGMP)
– Requires manufacturers to document production, inspect and
release quality drug products.
– Covers all vaccine manufacturing and post-production (shipping,
storage, etc.).

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Additional DoD Regulations
• In addition to all applicable ICH/FDA regulations for human
clinical trials, the DoD requires a second level of review and
approval for DoD-sponsored research.
– Human Subjects Research Review Board (HSRRB)
– Approval must be obtained prior to initiation of research protocol
– HSRRB policies:
• Format of clinical protocol
• Volunteer database
• Informed consent
• Reporting of adverse events
– 13 more required clauses for additional protection of study
volunteers

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Clinical Trials at DVC
• DVC outsources conduct of clinical trials to contract research
organizations (CROs)
– DVC remains responsible for trial design, oversight and
documentation/deliverables
• Clinical trial deliverables
– Investigator’s brochure (IB) and trial protocols
– Final clinical study reports (CSRs)
– IND safety reports at various intervals
– Serious adverse event reporting

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Adverse Events
• An adverse event (AE) is any adverse change in health or
side effect that occurs while a subject is taking part in a
clinical trial.
– May be related or unrelated to the investigational product.
– AEs happen in every clinical trial.
• A serious adverse event (SAE) is any adverse experience
that results in death, is life-threatening or requires
hospitalization.

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Biologics License Application (BLA)
• If products are successful in proving safety and efficacy
through nonclinical and clinical testing, the Sponsor may
apply for FDA licensure through the BLA process.
• DVC received FDA licensure of the first biodefense product in
2005
– Vaccinia Immune Globulin, a smallpox vaccine antiserum
– Many biopharmaceutical companies never reach this milestone

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Launch and Post-Marketing
• Post-licensure activities may be required by licensing
authority (FDA)
– Further safety database
– Special populations (pediatric, elderly, high-risk)
– Pregnancy registry

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 DVC Milestones Throughout the
Product Development Life
Cycle

2008: 2005-
2003-2009:
DoD plague ongoing:
DVC completes 2005:
RAD allocates DVC initiates
six Phase 1 DVC receives
all future DoD and manages
clinical trials for first-ever FDA
plague vaccine Phase 2
biological and licensure for a
funding to clinical trials
chemical biodefense
existing DVC for botulinum
defense product
contract neurotoxin and
countermeasure (VIGIV)
plague
s vaccines

2008: DVC 2006: DVC and

and Quintiles Baxter win $242
win $32M M HHS award to
NIAID Phase 1 develop
clinical trial seasonal and
unit contract pandemic
influenza
vaccines
DVC biodefense
milestone
Emerging diseases
/ services
milestone 22
Vaccine Manufacturing

Vaccine 101

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Manufacturing: Getting There
• Research and development
– Provides material for early studies
• Process development
– Takes R&D process and develops a process for manufacturing
– This is a complex endeavor, with many variables (i.e.,
opportunities for things to go wrong)
• Manufacturing
– Executes the process in an environment compliant with Current
Good Manufacturing Practices (CGMPs), as required by FDA

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Product and Manufacturing Stages
• Product stages
– Cell banks
– Bulk drug substance Testing at all stages to
demonstrate control
– Final drug product
• Stages of manufacturing
– Banking
– Production
– Recovery
– Purification
– Formulation and filling
– Finish

NuncTM cell factory

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A Few More Notes on Manufacturing
• Manufacturing biopharmaceuticals is time-intensive.
– Facility: 2 to 3 years
– Equipment: 6 to 12 months
• Manufacturing is expensive.
• Changes in the process have huge cost/schedule
implications.
– Careful subcontractor management and long-term relationships
required for success.
• A manufacturing facility is part of the license requirement.

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Putting Things Together

Vaccine 101

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Regulatory Affairs
• Guides all DVC programs in areas of regulatory strategy and
compliance.
– Recommends testing requirements at various stages of
manufacturing (in-process, lot release, characterization, etc.).
– Reviews plans for correlates of protective immunity.
– Provides regulatory review and support strategies during product
development.
• Regulatory strategies utilized by DVC include:
– Accelerated Approval
– Fast Track Designation
• DVC maintains a 100% success rate for receiving Fast Track
designation (four products) as compared to a 63% industry standard.*

– Orphan Drug Program

– Priority Review
– Rolling Submission *Source: http://www.fda.gov/cber/inside/fastrk.htm
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Regulatory Affairs (continued)
• Acts as the DVC representative in interactions with the U.S.
FDA and foreign regulatory agencies.
– Prepares and assembles all required regulatory submissions,
including Investigational New Drug and Biologics License
Applications.
• Reviews all publicity materials (press releases, brochures,
Web pages, etc.) to ensure that no unproven marketing
claims are made regarding FDA-regulated products.

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FDA Animal Rule
• Regulatory Affairs oversees DVC’s use of the FDA Animal
Rule.
– Allows for FDA licensure of vaccines and other products in which
efficacy testing in humans is unethical
– At least two species (nonhuman primates and rodents)
– Must understand pathophysiology of the disease
– Well-controlled animal studies will provide data that are likely to
predict a benefit in humans
• The Animal Rule is NOT a shortcut to licensure.
– So far, no vaccines have been licensed using the Animal Rule.

DVC is an industry leader in

Animal Rule development.

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Quality Assurance
• To ensure impartiality, the Quality Management Office (QMO)
is independent of the product teams and functional
departments.
• The QMO performs audits, conducts quality reviews and
initiates investigations to demonstrate that both DVC and its
subcontractors are operating in a state-of-control to ensure
compliance with Section 501(a)(2)(B) of the Food, Drug and
Cosmetic Act.
– Compliance failures could affect the quality of the product, which
could lead to death of the volunteer/patient.
– Compliance failures could lead to lost credibility with the FDA and
enforcement actions including product seizure, injunctions,
criminal fines and imprisonment.
• Administers (federally required) Standard Operating
Procedures (SOPs) and SOP training, and Document
Control.

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Quality Assurance (continued)
• QA is comprised of two arms:
– Product Quality Assurance (PQA)
• Ensures compliance of manufacturing, testing and storage
subcontractors
– Clinical Quality Assurance (CQA)
• Primary responsibilities are to manage safety risk to clinical study
volunteers and to assess data integrity
• QA also monitors data integrity and oversees validation of
computer systems.

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Program Management
• Program managers of biopharmaceutical development
programs must balance:
– Cost
– Schedule
– Risk
– Technical requirements
– Product life cycle
– External influences (changes in regulatory guidance, client
funding profiles, etc.)
• Good program management is often at odds with “good
science.”
– Must curtail the “what-ifs” and stop at “good enough”

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Biosafety
• Biological surety
– New and evolving DoD requirements for personnel,
subcontractors working with select agents
– Narrows field of prospective subcontractors even further
• Shipping
– Shipping biological agents is complicated and highly regulated
(much more so internationally)
– Temperature control is crucial for vaccines (for now)
– Test shipments must be conducted with vendors before actual
product is put at risk

DVC is a pioneer in this

new requirement.

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Biodefense and Vaccines

Vaccine 101

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Priority Pathogens
• Centers for Disease Control and Prevention (CDC) identifies
three threat agent categories.
• Category A* – The most severe threats, Category A agents
pose a risk to national security and can be transmitted
person-to-person or easily disseminated. These agents
result in high mortality rates and would be most likely to
cause public panic and social disruption:
– Anthrax
– Botulinum neurotoxin
– Plague
– Smallpox DVC has experience
– Tularemia with nearly all of these.
– Viral hemorrhagic fevers
• Filoviruses (e.g., Ebola, Marburg)
• Arenaviruses (e.g., Lassa)
*Source:
http://www.bt.cdc.gov/agent/agentlist-category.asp
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Questions?

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