Transcript Seasonal and Pandemic Influenza Vaccines: Vaccine Development and Production Learning Objectives • Develop a basic understanding of how influenza vaccines are developed • Be familiar.

Seasonal and Pandemic
Influenza Vaccines:
Vaccine Development and Production
1
Learning Objectives
• Develop a basic understanding of how influenza
vaccines are developed
• Be familiar with the major types of vaccines and
methods of vaccine production
• Understand the importance of vaccine effectiveness
and testing
2
Outline
• Overview of vaccine production
• Seasonal influenza vaccination
• Progress in developing vaccines for influenza
viruses with pandemic potential
3
Overview of Vaccine Production
4
5
6
Approaches to Influenza Vaccine
Development
• Subtype/strain-specific vaccines:
 Induce immune response to hemagglutinin (HA) and
neuraminidase (NA) viral proteins
 Examples: Inactivated influenza virus vaccines, Liveattenuated vaccines, virus-like particles
• Universal vaccines
 Current area of investigation
 Immunize with conserved proteins (for example: M2)
 Broad-based immunity
 Immune response against multiple subtypes
7
Composition of Vaccines against
Seasonal Influenza
• Three strains selected to make a trivalent vaccine
 Based on global viral surveillance
• Selection decision precedes typical peak influenza season
by 10-12 months
 Northern Hemisphere strains selected in February
 Southern hemisphere strains selected in September
• “New vaccine” (one or more new strains) every year
8
Types of Influenza Vaccines
Non-Replicating Vaccines
Replicating Vaccines
Antigens are manufactured outside
the host
Antigens are replicated in host
•
Inactivated
Whole or split virus
• Recombinant protein
Single protein, virus-like
particles
• Peptide
•
•
•
Live attenuated vaccines
Replication restricted to the
cooler upper airways
Microbial vector vaccines
Bacterial vectors deliver DNA
or RNA to host
DNA vaccines
9
Egg-based Manufacturing of Inactivated
Influenza Vaccines
• Must maintain flocks and viable
eggs
• Bacteria inherent on surface of eggs
• Seed viruses must be adapted to
eggs
• Not set-up for high-level biocontainment
Cannot use wild type highly pathogenic
viruses
CDC/ Dr. Stan Foster
10
Cell-based Manufacturing of Inactivated
Influenza Vaccines
• Storage in a working cell bank
• Fermenter for growth of tissue cultures
• Requirement for special supplements:
 Carrier beads (to maximize cell growth surface area)
 Protease or growth additives
• Variable replication efficiency: wild type and “high
•
growth” reassortants
Manufacturing with high biocontainment (BSL3) must
be used for highly pathogenic strains
11
Production of Seasonal Influenza Vaccines
(U.S. example)
Jan-Mar
Apr-Jun
Jul-Sep
Oct-Jan
12
Constraints with Current Seasonal Vaccines
•
•
•
•
Selection of strains difficult and time consuming
Annual, seasonal production
Technical process, specialized facilities
Lack of cross protection against antigenic variants
Long term protection uncertain
•
•
Relatively high cost
Annual vaccine administration is required
13
Review Question 1
What type of manufacturing is most commonly used
for influenza vaccines?
a.
b.
c.
d.
Egg-based
Cell-culture based
Reverse genetics
None of the above
Answer: A. Currently available vaccines are
manufactured using embryonated chicken eggs or eggbased manufacturing
14
Seasonal Influenza Vaccination:
Safety and Effectiveness
15
Antibody Response to Influenza
Vaccination
• Post-vaccination antibody correlates with protection
• Peak antibody response 2 weeks after vaccination in
people needing only one dose
• Immunity wanes during the year
Lasts through the influenza season
Requires annual vaccination
16
Determinants of Antibody Response to
Influenza Vaccines
• Age
 Elderly and young children can have lower antibody response
• Prior exposure to virus strains similar to those in vaccine
(infection or vaccination)
• Immune competence of person being vaccinated
• Amount of antigen in vaccine
• Type of vaccine
• Presence of adjuvants
17
Measuring Effectiveness of Seasonal
Influenza Vaccine
•
•
Effectiveness varies by age group, risk group, and antigenic
match
Different study methods make comparisons difficult
 Observational studies: Easier to do but differences between
vaccinated and unvaccinated persons can bias results
 Randomized controlled trials: Reduce bias, but costly
•
Variety of outcomes can be measured that make
comparisons between studies difficult
 Less specific: Influenza-like illness (ILI)
 More specific: Laboratory-confirmed influenza
18
Percentage with influenza-like
illness
Effect of Co-circulation of Non-influenza
Pathogens/Outcome Specificity on VE Estimate
25
20
Non-influenza
illnesses
Influenza illnesses
15
10
5
0
Situation A
Situation B
Situation A
Situation B
Assuming 100 vaccinated and 100 unvaccinated in each set:
VE against influenza infection = 75% for both sets A and B,
VE against respiratory illness = 30% in set A and 15% in set B.
19
Inactivated Seasonal Influenza Vaccine Effectiveness,
by Age and Risk Group, when Vaccine Strains Match
Circulating Strains
Age/Risk group
Outcome
Effectiveness*
6 months-18 years
Influenza**
50-90%
18-64 years
Influenza**
50-90%
>65 years, community
Influenza**
50-70%
Elderly, nursing home
Influenza**
30-40%
Elderly, nursing home
Hospitalization or 40-80%
death
*Effectiveness lower when vaccine and circulating strains antigenically different. No vaccine effectiveness
is sometimes observed when the prevalence of antigenically different strains in the community is high.
20
**Laboratory-confirmed influenza virus infection
Global Distribution of Influenza Vaccines, 1994-2003
292
300
257
231
Millions of doses
250
191
200
150
151
158
28
31
120
57
135
139
26
23
21
74
75
77
81
74
77
35
38
44
49
50
1994
1995
1996
1997
1998
89
92
96
80
53
65
68
73
77
1999
2000
2001
2002
2003
50
Western Europe
100
105
86
138
100
0
271
Canada, US
WHO Global Influenza Vaccine Distribution
http://www.who.int/csr/disease/influenza/vaccinedistribution/en/index.html
Rest of the world
21
Review Question 2
What are some of the individual or demographic
attributes that affect vaccine effectiveness?
Answers:
•Age
•Immunocompetence
•Amount of antigen present in vaccine
•Vaccine type
•Prior exposure to similar viral strains
22
Developing Vaccines for Influenza
Viruses with Pandemic Potential
23
From Seasonal to Pandemic
Influenza Vaccine Production
•
•
Manufacturing facilities could shift
production from seasonal vaccine to
pandemic vaccines
Pandemic vaccines will not available at
beginning of pandemic
 Likely available within 4-6 months
•
•
Once available, there will be limited
quantities initially
By this time there might be wide spread
circulation of the pandemic strain
24
Challenges to Development of Vaccines
against Influenza A (H5N1)
• Reduced immunogenicity compared to seasonal
•
influenza vaccines, unless formulated with an adjuvant
Expense
Reduced yield in egg-based manufacturing processes
High antigen content
Proprietary adjuvants
• Unknown cross protection against other clades
• Predictive value of pre-clinical studies not established
25
Priorities in Development of Pandemic
Influenza Vaccines
•
•
•
Evaluation of dose-sparing strategies including use of
adjuvants
Accelerated development of cell-culture based
vaccines
Novel approaches to vaccine development
Including vaccines that provide broad cross protection
26
Potentially Pandemic Viral Strains under
Study
•
H5N1
Multiple clades
• H9N2
• H7N7
• H5N2
• Swine-origin novel influenza A(H1N1)
27
Immunogenicity of a Candidate Influenza A (H5N1)
Vaccine (Sanofi)
(A/Vietnam/1203/H5N1; Clade 1)
Vaccine
dose (ug)
28 days after 1st
dose of vaccine
No.
% with
GMT at
baseline tested HI >1:40
28 days after 2nd
dose of vaccine
No.
% with
tested HI >1:40
GMT after
2nd dose
90
10.4
99
28%
99
57%
46.3
45
10.8
95
23%
93
41%
34.7
15
10.3
100
10%
100
24%
20.3
7.5
11.4
99
5%
95
13%
14.9
Placebo
10.6
48
0%
48
0
10.9
Treanor et al. N Eng J Med 2006;354:1343-51
28
Influenza A (H5N1) Clade 1 Vaccine with
Adjuvant (GlaxoSmithKline)
Inactivated influenza A
(H5N1) clade 1 antigen and
proprietary adjuvant
•
• Adjuvanted formulations
more immunogenic
• Good antibody response
Design:
• Placebo-controlled,
Results:
(even at 3.8 micrograms)
~400
healthy adults
2 doses vaccine +/- adjuvant
in doses from 3.8 to 30
micrograms
• Induced cross-reactive
antibody responses against
clade 2 strain
• Met FDA requirements for
licensure
29
Leroux-Roels et al. Lancet. 2007;370(9587):580-9.
Candidate Influenza A (H5N1) Vaccines:
Experience to Date
• Inactivated subvirion vaccines: Immunogenicity suboptimal
 High antigen content required (90 micrograms)
 Require 2 doses
 Few adverse events
•
Adjuvanted inactivated subvirion vaccines
 Similar or better response compared to subvirion vaccines
 Without adjuvant at doses as low as 3.8 micgrgrams
 Need for 2 doses less certain
 Antigen sparing (reduced antigen content needed)
 Proprietary adjuvants have shown best antigen-sparing effects
 Increased reactogenicity with adjuvants
30
Target
paradigm of
an ideal
H5N1
pandemic
vaccine
From: S Sambhara,
CB Bridges,
GA Poland. Lancet
2007.
31
Review Question 3
Which technology that might be used to reduce the
dose of antigen that is needed in a vaccine?
a.
b.
c.
d.
Cell-based technology
Adjuvants
Universal vaccine
None of the above
Answer:
b. Adjuvants
32
Summary
• Production using traditional methods will not meet global
demand for a pandemic vaccine
• H5N1 Vaccines produced using traditional seasonal
influenza vaccine methods have relatively poor
immunogenicity
Improved with use of adjuvants
• Considerable progress with alternative vaccines
33
Glossary
Antigen: Are proteins or polysaccharides that are parts of viral or bacterial
structure and which prompt the immune system response
Adjuvant: A pharmacological or immunological agent added to a vaccine to
modify (improve) the immune response to the vaccine, while having few if
any direct affect when given by itself.
Biocontainment or Biosafety level (BSL): The isolation and containment of
extremely infectious or hazardous materials in specialized and secure
scientific facilities
Genetic engineering: the manipulation of genetic material, generally to
produce a therapeutic or agricultural product either more quickly, or in
greater quantities, than is seen in nature.
34
Glossary
Embryonated: Egg containing an embryo, used to incubate viruses for
vaccine study or production
Reassortant: Viruses that contain 2 or more pieces of genetic material
from different viruses. Reassortant happens when two viruses mix
within a cell (or lab environment).
Inactivated vaccine: a vaccine made from an infectious agent that has
been inactivated or killed in some way.
Live, attenuated vaccine: Vaccine includes live pathogens that have
lost their virulence but are still capable of inducing a protective
immune response to the virulent forms of the pathogen.
Immunogenicity: Measure or ability of a substance (virus, drug, etc)
to produce an immune system response
35
Glossary
Clades: A biological group (for example, a viral species) that is classified
according to genetic similarity
Subivirion: An incomplete virus or virus particle
Chemoprophylaxis: The use pharmaceutical or medical treatment to
prevent disease or spread of infection
Virulence: The virulence of a microorganism (such as a bacterium or
virus) is a measure of the severity of the disease it is capable of causing.
Pathogenicity: is the ability of an organism, a pathogen, to produce an
infectious disease in another organism.
36
Glossary
Trivalent influenza vaccine: synthetic vaccine consisting of three
inactivated influenza viruses, two different influenza type A strains and
one influenza type B strain. Trivalent influenza vaccine is formulated
annually, based on influenza strains projected to be prevalent in the
upcoming flu season. This agent may be formulated for injection or
intranasal administration.
Candidate strains: strains of influenza that are used in vaccines that are
still early in developmental stages
Antibody response: The immune system responds to antigens by
producing antibodies. Antibodies are protein molecules that attach
themselves to invading microorganisms and mark them for destruction or
prevent them from infecting cells. Antibodies are antigen specific. That is
antibodies produced in response to antigen exposure are specific to that
antigen.
37
Glossary
(S13) Egg-based (vaccine) manufacturing: Method of
making influenza vaccines by inoculating live flu virus
into fertilized chicken eggs, then purifying and inactivating
the resulting egg-adapted virus. Vaccines created using this
technique represent the majority of the currently licensed
and marketed influenza vaccines worldwide
(S14) Cell-based (vaccine) manufacturing: Method of
manufacturing influenza vaccine that is more rapid than
egg-based manufacturing. The live flu virus is used to
infect cells in culture. Once the viral infection has
propagated through the cells, the live virus is harvested and
inactivated for use in vaccines.
38
Seasonal and Pandemic Influenza
Vaccines:
Programmatic Issues and Pandemic
Preparedness
39
Learning Objectives
• Recognize the differences and challenges of seasonal
vs. pandemic influenza vaccine development,
manufacturing, and distribution
40
Outline
• Vaccine capacity
• Vaccine access
• Planning
• WHO strategies
41
Pre-pandemic: Vaccine Planning
• Definition: Vaccines developed against influenza viruses
that are currently circulating in animals and that have the
potential to cause a pandemic in humans
• Rationale: might provide priming or “limited protection”
against pandemic strain
Goal: Reduce morbidity or mortality
Might not reduce number of viral infections
• Problem: Which vaccine strains, and when should it be
given?
42
Pandemic Preparedness:
Access to Vaccine
• Global influenza vaccine production capacity is limited:
 300 million doses trivalent vaccine (900 million doses)
 Monovalent vaccine (2 dose course) = 450 million courses
• 65% of capacity is located in Europe
• 85% of influenza production is by 3 companies
• Countries with manufacturing capacity represent 12% of
global population
43
Pandemic Preparedness: Global Response
• Increasing pressure from
developing countries for access
to influenza vaccine
• When pandemic declared,
potential for:
“Rationing” of vaccine
No exportation of vaccine until
manufacturing country’s needs are
met
CDC/ Judy Schmidt
44
Pandemic Preparedness: Vaccine
Development Strategy
• Strategies “guided” by the public health community
• WHO is expected to coordinate these efforts
• Manufacturers are being encouraged to develop vaccines that
•
will meet global demand
Countries/regions are being encouraged to articulate their
needs/plans for
 Demonstrating burden of seasonal influenza
 Seasonal influenza vaccine
 Pandemic influenza vaccine
45
WHO Strategy to Increase Pandemic
Influenza Vaccine Capacity
1. Development of immunization policy to reduce
seasonal influenza burden
Will increase demand for seasonal influenza vaccines
2. Increase influenza vaccine production capacity
3. Research and development for more effective
influenza vaccines
46
1. Develop Seasonal Immunization
Policies
Objectives
1. Reduce disease burden from seasonal influenza infections
2. Increase manufacturing capacity for influenza vaccines
Strategy 1: WHO Regional Offices develop plans with input from
member states for seasonal influenza vaccination programs. These
plans should form the basis for the Global Pandemic Influenza vaccine
action plan
Strategy 2: Mobilize resources to assist in the implementation of a
global action plan to increase demand of seasonal influenza vaccine
47
2. Increase Influenza Vaccine Production
Capacity
Objectives
1. Produce enough vaccine to immunize two billion people within 6
months after transfer of vaccine prototype strain to industry.
2. Produce enough vaccine to immunize the world's population (6.7
billion people)
Strategy 1: Increase production capacity for inactivated vaccines
Strategy 2: Explore development of other types of influenza vaccines
Strategy 3: Assess alternative ways to deliver vaccine
48
3. Research and Development for More
Effective Influenza Vaccines
Objectives
1. Development of influenza vaccines using new technologies
2. Recommend a research agenda
3. Improve collaboration between academia, industry, regulatory authorities,
donors and international organizations
Strategy 1: Enhance protective efficacy and immunogenicity of
existing vaccines
Strategy 2: Develop novel vaccines that induce broad
spectrum and long lasting immune responses
Strategy 3: Improve evaluation of vaccine performance
49
Other Pandemic Preparedness Activities
• Explore use of currently available H5N1 vaccines to
prime immunity (prepandemic vaccines)
• Stockpile of H5N1 antigen in bulk
• Stockpile of vaccine supplies
• Increase egg supply
• Develop capacity for large scale influenza immunization
programs
50
Preparedness Management and
Coordination
• Technology transfer of cell culture technique to
developing countries
• Mechanism for funding investments to increase
vaccine production capacity
• Develop a management/coordination strategy
(responsibilities, leadership, WHO role)
• Define a mechanism for the flow of donor funds
51
Review Question 4
What are the three WHO strategies for increasing
pandemic vaccine capacity?
Answer:
1. Development of immunization policy to reduce seasonal influenza
burden
2. Increase in influenza vaccine production capacity
3. Research and development for more effective influenza vaccines
52
Summary
• Increasing (but still limited) use of seasonal flu vaccines in
•
•
developed countries
Linking increased use of seasonal flu vaccine to a strategy
for pandemic preparedness
Need consensus:
Strategies for use of prepandemic vaccine
Development and management of stockpile
Evolving role of WHO to manage pandemic vaccine stockpile
53
Glossary
Immunogenicity: Capability of inducing an immune response
Antigen: A substance that stimulates the production of an antibody
when introduced into the body. Antigens include toxins, bacteria,
viruses, and other foreign substances.
Antibody: A Y-shaped protein on the surface of B cells that is
secreted into the blood or lymph in response to an antigenic stimulus,
such as a bacterium, virus, parasite, or transplanted organ. Antibodies
bind antigens and mark them for destruction or prevent cells from
being infected. Antibodies are antigen specific.
Antibody Response: The immune system responds to antigens by
producing antibodies. Antibodies produced in response to an antigen
work best on that antigen, but might have some activity against
similar antigens.
54
Glossary
Clade: A group of organisms, such as influenza viruses, whose members
share homologous features derived from a common ancestor.
Reactogenic: the capacity of a vaccine to produce adverse reactions
Subvirion: An incomplete viral particle (e.g. like the HA antigen).
55