Pandemic Influenza Vaccine Supply Issues April 20, 2005

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Pandemic Influenza Vaccine Supply IssuesApril
20, 2005

• Raymond A. Strikas, M.D.
• National Immunization Program, Centers for
  Disease Control and Prevention

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Presentation Outline

• Pandemic Vaccine Supply and Timelines (some
  reminders from yesterdays and todays
  discussions)
• Current status of vaccine supply
• Potential expansion of vaccine supply
• Capacity increase
• Antigen-sparing approaches

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Pandemic Influenza Vaccine Production Timelines

• Development of reference strain
• Use of reverse genetics allows HA and NA from
  pandemic strain to be combined with other genes
  from a strain well adapted to growth in eggs
• Vaccine production (monovalent)
• Master seed developed from reference strain
• Growth in eggs and purification
• Formulation and filling
• Regulatory process
• Optimal timing 3-4 months (if reference strain
  and potency testing reagents already developed)

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Pandemic Spread and Seasonality

• Spread of a pandemic/shifted virus
• Months before U.S. community outbreaks for prior
  pandemic strains
• 1918 0 1957 4-5 1968 2-3 1977 3-4
• Spread of the next pandemic
• More rapid because of increased international
  travel
• More warning because of better surveillance
• Seasonality
• Fall Spring seasonality generally preserved
• Multiple pandemic waves occur potentially in
  the same season

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Timeline of First and Second Pandemic Waves,
1957-58
Ref Trotter, Am J Hyg, 1959
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Asian Influenza, 1957-58

• No national or state plans in place
• 6 US based manufacturers
• States formed advisory committees on influenza
  control in August-September
• Voluntary vaccine allocation recommended by PHS
  and ASTHO no large public purchase of vaccine.
  60 million doses produced, but only 35 million
  available by October 26 (outbreak 1st wave
  ending)
• PHS considered priority for HCWs, essential
  personnel, and high-risk (those with heart
  disease, TB, and other chronic ailments
  including pregnancy)
• Recommendations were not made from PHS, but left
  to state health departments some added children
  lt1 year, and all persons gt50 years.

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Avenues for Exploration in the Inter-pandemic
Period
Work should be done with attenuated live
vaccines Mineral oil adjuvant vaccines offer
another promising line of attack. More work can
be done in the inter-pandemic years on
potency, dosage, route of introduction, number of
doses, interval between doses, rapid diagnostic
techniques. Some suggest working toward two
separate vaccines in the future, one for children
and one for adults. The challenge is unlimited.
U.S. Public Health Service, Influenza 1957,
1958, unpublished
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Hong Kong Influenza, 1968

• Ad hoc response (again)
• No national or state plans
• ACIP recommendations same as for that years
  polyvalent vaccine
• Chronically ill persons
• Older age groups (beginning at gt45 years)
• 21 million persons vaccinated (40 million doses
  produced)

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Swine Influenza Program, 1976
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Pandemic Influenza Vaccine Supply Estimates
Current Status

• Pandemic vaccine supply assumptions
• Only US produced vaccine will be available (1
  mfr)
• 15 ug antigen/dose and 2 doses/person will be
  needed for protection
• Monovalent vaccine production capacity will be
  3-fold that of annual vaccine (e.g., similar Ag
  yield/egg)
• Current Sanofi production is sufficient to
  deliver 250 M monovalent doses/year (5
  million/week)
• Implication about 1 of the population can be
  protected per week

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Pandemic Influenza Vaccine Supply Possible
Additional Options

• If 7.5ug/dose is immunogenic, vaccine supply is
  doubled
• If whole virus vaccine were used, production may
  be increased 50
• One to two additional manufacturers may have U.S.
  licensed vaccine soon, may offer additional
  pandemic supply

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New Technologies and Antigen-sparing Concepts
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Potential Antigen-SparingApproaches to Influenza
Vaccination

• Vaccine delivery strategies
• Partial doses (1/2 dose or other)
• Alternate route of injection (e.g., intradermal)
• Immune enhancement strategies
• Adjuvanted vaccine (e.g., alum, MF59)
• Alternative delivery technologies
• Immunostimulant patch, dose-sparing needles,
  syringes, jet injectors

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Influenza Vaccine Partial Doses

• Treanor et al, Vaccine 2002, documented small
  differences in healthy adults 18-49 yrs, between
  7.5ug and 15ug doses
• lt20 in achieving hemagglutinin inhibition titer
  of 140
• lt1.5 in ratios for GMTs between doses for all 3
  antigens
• Authors concluded that vaccinating N healthy
  adults with half dose will protect more persons
  than vaccinating ½ N with full dose
• DoD conducting study with 2004 vaccine data to
  be available spring, 2005

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Alternate route of injection for Influenza Vaccine

• Options include intradermal, subcutaneous,
  intranasal, oral
• Antigens delivered to nasal, other mucosal
  surfaces, dermis may increase immunogenicity
  (more immune receptors)
• Belshe et al, Kenney et al, NEJM, 2004
  intradermal studies suggest ID delivery may allow
  dose sparing, but small studies. Not as
  immunogenic in adults gt59 years
• Need larger studies, proper controls

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Immune enhancement strategiesAdjuvanted vaccine

• No licensed U.S. influenza vaccine contains an
  adjuvant
• MF59, ISCOMS (immunostimulating reconstituted
  influenza virosomes) licensed in Europe
• Adding an adjuvant may provide greater
  immunogenicity with less antigen
• Alum, MF59 may be most likely choices do
  increase local reactions
• Studies with U.S. licensed vaccines necessary

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Alternative Delivery Technologies

• Immunostimulant patches (e.g., with E. coli heat
  stable enterotoxin)
• Jet injectors for intradermal vaccination
• Dose-sparing needle/syringe combinations (may add
  ½ to 1 dose to a 10 dose vial)

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Potential Timeline of Interventions to Expand
Pandemic Vaccine Supply
Partial dose
Alternate route of administration
Expanded U.S. egg-based production
Adjuvanted vaccine
U.S. cell-culture production
0 1 2 3 4 5 6 7 8
Number of years until licensure or possible
recommendation
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Inter-Pandemic and Pandemic Vaccine Target Groups

• Inter-pandemic vaccine recommendations
• Persons at high risk of severe influenza
  complications
• Persons who can transmit disease to those at high
  risk (HCWs and family members of high risk)
• Pandemic considerations
• Pandemic impacts may extend beyond health of
  infected persons
• Need to maintain quality health care system
• Need to maintain essential community services
• Vaccine supply will be more limited relative to
  need

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Potential Vaccine Target Groups and Population
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Questions?