Seasonal and Pandemic Influenza Vaccines:

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Seasonal and Pandemic Influenza Vaccines
Vaccine Development and Production
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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

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Outline

• Overview of vaccine production
• Seasonal influenza vaccination
• Progress in developing vaccines for influenza
  viruses with pandemic potential

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Overview of Vaccine Production
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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,
  Live-attenuated 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

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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

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Types of Influenza Vaccines

• Non-Replicating Vaccines

• Replicating Vaccines

• Antigens are manufactured outside the host
• InactivatedWhole or split virus
• Recombinant proteinSingle protein, virus-like
  particles
• Peptide

• Antigens are replicated in host
• Live attenuated vaccinesReplication restricted
  to the cooler upper airways
• Microbial vector vaccines Bacterial vectors
  deliver DNA or RNA to host
• DNA vaccines

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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 bio-containment
• Cannot use wild type highly pathogenic viruses

CDC/ Dr. Stan Foster
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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

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Production of Seasonal Influenza Vaccines (U.S.
example)
Jan-Mar
Jul-Sep
Oct-Jan
Apr-Jun
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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

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Review Question 1

• What type of manufacturing is most commonly used
  for influenza vaccines?
• Egg-based
• Cell-culture based
• Reverse genetics
• None of the above
• Answer A. Currently available vaccines are
  manufactured using embryonated chicken eggs or
  egg-based manufacturing

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Seasonal Influenza Vaccination Safety and
Effectiveness
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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

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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

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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

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Effect of Co-circulation of Non-influenza
Pathogens/Outcome Specificity on VE Estimate
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.
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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
gt65 years, community Influenza 50-70
Elderly, nursing home Influenza 30-40
Elderly, nursing home Hospitalization or death 40-80
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. Laboratory-confirmed
influenza virus infection
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Global Distribution of Influenza Vaccines,
1994-2003
WHO Global Influenza Vaccine Distribution
http//www.who.int/csr/disease/influenza/vaccinedi
stribution/en/index.html
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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

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Developing Vaccines for Influenza Viruses with
Pandemic Potential
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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

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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

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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 developmentIncluding
  vaccines that provide broad cross protection

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Potentially Pandemic Viral Strains under Study

• H5N1
• Multiple clades
• H9N2
• H7N7
• H5N2
• Swine-origin novel influenza A(H1N1)

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Immunogenicity of a Candidate Influenza A (H5N1)
Vaccine (Sanofi) (A/Vietnam/1203/H5N1 Clade 1)
Vaccine dose (ug) GMT at baseline 28 days after 1st dose of vaccine No. with tested HI gt140 28 days after 1st dose of vaccine No. with tested HI gt140 28 days after 2nd dose of vaccine No. with tested HI gt140 28 days after 2nd dose of vaccine No. with tested HI gt140 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 20063541343-51
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Influenza A (H5N1) Clade 1 Vaccine with Adjuvant
(GlaxoSmithKline)

• Inactivated influenza A (H5N1) clade 1 antigen
  and proprietary adjuvant
• Design
• Placebo-controlled, 400 healthy adults
• 2 doses vaccine /- adjuvant in doses from 3.8 to
  30 micrograms

• Results
• Adjuvanted formulations more immunogenic
• Good antibody response (even at 3.8 micrograms)
• Induced cross-reactive antibody responses against
  clade 2 strain
• Met FDA requirements for licensure

Leroux-Roels et al. Lancet. 2007370(9587)580-9.
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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

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Target paradigm of an ideal H5N1 pandemic
vaccine From S Sambhara, CB Bridges, GA
Poland. Lancet 2007.
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Review Question 3

• Which technology that might be used to reduce the
  dose of antigen that is needed in a vaccine?
• Cell-based technology
• Adjuvants
• Universal vaccine
• None of the above
• Answer
• b. Adjuvants

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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

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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.

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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

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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.

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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.

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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.

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Seasonal and Pandemic Influenza Vaccines
Programmatic Issues and Pandemic Preparedness
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Learning Objectives

• Recognize the differences and challenges of
  seasonal vs. pandemic influenza vaccine
  development, manufacturing, and distribution

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Outline

• Vaccine capacity
• Vaccine access
• Planning
• WHO strategies

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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?

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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

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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
  countrys needs are met

CDC/ Judy Schmidt
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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

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WHO Strategy to Increase Pandemic Influenza
Vaccine Capacity

• Development of immunization policy to reduce
  seasonal influenza burden
• Will increase demand for seasonal influenza
  vaccines
• Increase influenza vaccine production capacity
• Research and development for more effective
  influenza vaccines

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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

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2. Increase Influenza Vaccine Production Capacity

• Objectives
• Produce enough vaccine to immunize two billion
  people within 6 months after transfer of vaccine
  prototype strain to industry.
• 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

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3. Research and Development for More Effective
Influenza Vaccines

• Objectives
• Development of influenza vaccines using new
  technologies
• Recommend a research agenda
• 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

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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

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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

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Review Question 4

• What are the three WHO strategies for increasing
  pandemic vaccine capacity?
• Answer
• Development of immunization policy to reduce
  seasonal influenza burden
• Increase in influenza vaccine production
  capacity
• Research and development for more effective
  influenza vaccines

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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

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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.

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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).