New Strategies for Influenza Vaccination

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New Strategies for Influenza Vaccination

• Paul Lewis, MD
• Oregon State Public Health

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Outline

• Influenza Background
• A moving target
• The disease and its burden
• Vaccine history
• Flu vaccine challenges
• Annual production
• Outcomes and efficacy
• Uptake by target groups

• New Strategies
• Production
• Targets(antigens)
• Boosting response
• Redefining goals
• Regulatory issues
• Increased use
• Kids, Women
• Everyone?
• Marketing

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Self-portrait with Spanish Influenza, Edvard
Munch 1919
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Influenza Clinical Features

• Fever, often sudden
• Systemic Sx
• Chills, rigors
• Malaise
• Headache
• Myalgia
• Resp Sx
• Rhinitis, pharyngitis, cough
• GI Sx
• Nausea, vomiting, diarrhea, pain

• Complications
• Viral Pneumonia
• Bacterial pneumonia
• Croup
• Bronchiolitis
• Sepsis in infants
• Myositis
• Encephalitis
• Reye Syndrome

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NIH web conf
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Drift and Shift of human influenza A

• Drift small changes from RNA mutations
• Most people are susceptible each year
• Vaccines require frequent modification to be
  effective

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Drift and Shift

• Drift small changes from RNA mutations
• Requires frequent small changes in vaccine
• Shift major changes
• Non-human virus infecting humans
• Reassortment btw human and animal strains
• Pandemic requirement

Earthquake fault, New Zeeland Health Emergency
Management, NZ
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Average influenza-associated illness rates by age
group
Low estimate based on Tecumseh community
studies. High estimate based on Houston family
studies. Adapted from Sullivan KM.
PharmacoEconomics 19969 Suppl.326-33.
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Vaccination targets are at higher risk of
influenza complications

• Extremes of age
• 6-23 months
• Over 65 yrs
• Underlying disease
• Cardiac, pulmonary, renal, metabolic, immune
  compromise
• Pregnancy

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Influenza-Associated Deaths By Age Group (CFRlt1
even in seniors,ltlt0.01 in others)
(Thompson, JAMA 2003)
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Influenza Virus Milestones
Gerberding, J. L. et al. N Engl J Med
20043501236-1247
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Influenza Virus Milestones
1936 Growth in fertilized eggs
1933 Influenza A isolated(ferret)
1940 Influenza B isolated
Gerberding, J. L. et al. N Engl J Med
20043501236-1247
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Influenza Virus Milestones
1970s subvirion vaccine (eggs)
1945 Commercial whole virus vaccine(eggs)
1933 Influenza A isolated
1940 Influenza B isolated
Gerberding, J. L. et al. N Engl J Med
20043501236-1247
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Influenza Virus Milestones
1970s subvirion vaccine (eggs)
1945 Commercial whole virus vaccine(eggs)
1933 Influenza A isolated
Live virus Vaccine development
2003 Live virus Vaccine Licensed in US
1940 Influenza B isolated
Gerberding, J. L. et al. N Engl J Med
20043501236-1247
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The challenge of influenza prevention

• Adequate annual production
• Efficacy in target groups
• Uptake in target groups

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Outline of the Annual Process of Development,
Manufacturing, and Distribution of Influenza
Vaccine
Treanor, J. N Engl J Med 20043512037-2040
one dose of trivalent Vaccine produced per egg
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Does flu vaccine work for high risk groups?
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• Influenza and Complications Among Nursing Home
  Residents

RR1.9
RR2.0
RR2.5
RR4.2
Inactivated influenza vaccine. Genesee County,
MI, 1982-1983
CDC Pink Book (Epi and Prevention of
Vaccine-Preventable Disease) 2004
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• Influenza and Complications Among Nursing Home
  Residents

Vaccine efficacy 37 in homes with outbreaks
28 in homes with only sporadic cases
Inactivated influenza vaccine. Genesee County,
MI, 1982-1983
CDC Pink Book (Epi and Prevention of
Vaccine-Preventable Disease) 2004
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• Influenza and Complications Among Nursing Home
  Residents

Vaccine efficacy against death 76 Vaccine
efficacy against pneumonia52
Inactivated influenza vaccine. Genesee County,
MI, 1982-1983
JAMA 19852531136-9
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Inactivated Influenza Vaccine Efficacy
Large Meta- analyses

• gt65 yrs 30-40 VE ILI
• gt65 yrs 50 VE hospitalization
• gt65 yrs 50-70 VE death
• Chronic Disease, similar to others same age
  without disease (little data on immune
  compromised)

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Inactivated Influenza Vaccine Efficacy

• gt65 yrs 30-40 VE ILI
• gt65 yrs 50 VE hospitalization
• gt65 yrs 50-70 VE death
• Chronic Disease, similar to others same age
  without disease (little data on immune
  compromised)
• Age 6-23 mo little data!
• Age 2-5 yrs VE 50 depending on outcome

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Inactivated Influenza Vaccine Efficacy

• gt65 yrs 30-40 VE ILI
• gt65 yrs 50 VE hospitalization
• gt65 yrs 50-70 VE death
• Chronic Disease, similar to others same age
  without disease (little data on immune
  compromised)
• Age 6-23 mo little data!
• Age 2-5 yrs VE 50 depending on outcome
• Healthy lt65 years 70-90 VE ILI
• Age gt5 yrs, similar to healthy adults

Vaccine Recd
Best efficacy
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Can we get vaccine to the right people?
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Influenza Vaccination Rates among high-risk and
healthcare workers
gt65 yr
Chronic Dz
HCW
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Influenza Vaccination Rates among high-risk and
healthcare workers
Goal
gt65 yr
Chronic Dz
HCW
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Influenza Vaccine Distribution, United States,
1999-2005
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Problems and Solutions
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HA surface, immunogenic, DRIFTS!
NA surface, immunogenic, DRIFTS!
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HA surface, immunogenic, DRIFTS!
NA surface, immunogenic, DRIFTS!
M2e surface, ?immunogenic, Little drift,
non-sterilizing immunity
NP(nucleoprotein)internal, CTL
responsenon-sterilizing, Done as DNA so far in
mice
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HA surface, immunogenic, DRIFTS!
NA surface, immunogenic, DRIFTS!
M2e surface, ?immunogenic, Little drift,
non-sterilizing immunity
NP(nucleoprotein)internal, CTL
responsenon-sterilizing, Done as DNA so far in
mice
Combination?
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HA surface, immunogenic,
Target conserved sequence, Transiently accessible
on Infected cell surface- worked In mice
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HA surface, immunogenic, DRIFTS!
NA surface, immunogenic, DRIFTS!
M2e surface, ?immunogenic, Little drift,
non-sterilizing immunity
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LAIV aka CAIV-TLive attenuated Influenza vaccine

• Licensed age 5-49 yrs
• Side effects (congestion common)
• Increased RAD/asthma age 12-60 months
• CP111 focuses this risk on kids lt2 yrs for 42
  days after 1st vaccine (3.2 vs 2.0in control)
• Efficacy gt inactivated vaccine
• Measurable protection in subsequent years without
  vaccine
• Efficacy against drifted variants

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More on Medimmune CP111Presented by Robert
Belshe at Pediatric Academic Society April 2006

• Compared injected flu vaccine TIV with
  refrigerator-stable CAIV-T(FluMist) 0.1 cc
• Kids 6-59 months
• Outcome culture confirmed influenza

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Will cell culture replace fertilized eggs?
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Belsey et al. Nature Reviews Drug Discovery 5,
183184 (March 2006) doi10.1038/nrd1988
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DNA vaccination using gold particles
http//www.powdermed.com/ pdf/Flu20Brochure20De
c202005.pdf
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DNA Vaccines

• Purported advantages
• Speed(world supply of pandemic vaccine in 3 mo)
• Stable
• amenable to stockpiling
• no cold chain
• needle-free administration
• The companies (partial list)
• Powdermed (UK)
• Vical (US)

• Commercial use
• Infectious Haematopoietic Necrosis Virus approved
  in Canada for fish
• Melanoma(dogs) US approval awaited
• Human Clinical trials
• Influenza, hep B, HSV-2

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Comparison of methods
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Many Measures of Efficacy Respiratory
Illness Influenza-like Illness Lab-confirmed
Influenza Hospitalization Hospitalization from
Influenza Pneumonia Pneumonia from
Influenza Death Death from PI
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Many Measures of Efficacy Respiratory
Illness Influenza-like Illness Lab-confirmed
Influenza Hospitalization Hospitalization from
Influenza Pneumonia Pneumonia from
Influenza Death Death from PI
less
Specific and Severe
more
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Many Measures of Efficacy Respiratory
Illness Influenza-like Illness Lab-confirmed
Influenza Hospitalization Hospitalization from
Influenza Pneumonia Pneumonia from
Influenza Death Death from PI
less
more
Specific and Severe
Ease of Study
more
less
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Many Measures of Efficacy Respiratory
Illness Influenza-like Illness Lab-confirmed
Influenza Hospitalization Hospitalization from
Influenza Pneumonia Pneumonia from
Influenza Death Death from PI
less
more
Specific and Severe
Ease of Study
more
less
50
Many Measures of Efficacy Respiratory
Illness Influenza-like Illness Lab-confirmed
Influenza Hospitalization Hospitalization from
Influenza Pneumonia Pneumonia from
Influenza Death Death from PI
less
more
Specific and Severe
Ease of Study
more
less
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Regulatory Obstruction to advances in flu vaccine?

• 2003-04 mismatch attributed to antiquated FDA
  rules (Peter Palese)
• Fujian strain available on time but isolated in
  cell culture not egg!
• Reverse genetics not currently used
• Initial cell culture approval hurdle large
• Serology as surrogate for immunity
• Wrong test? Neutralization or CMI alternatives
• Live attenuated vaccine works as well or better
  than TIV but not on this surrogate test

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Does one vaccine size fit all?

• Seniors, infants, toddlers respond less well to
  TIV
• Dose
• Route
• Adjuvants

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Safety of High Doses of Influenza Vaccine and
Effect on Antibody Responses in Elderly
PersonsWendy A. Keitel, MD Robert L. Atmar, MD
Thomas R. Cate, MD Nancy J. Petersen,
PhDStephen B. Greenberg, MD Fred Ruben, MD
Robert B. Couch, MDArch Intern Med.
20061661121-1127

• 202 seniors (gt65 yr) randomized
• Placebo, 15, 30, 60 ug per strain of TIV
• 2001-02 formuation
• Clinical, serologic responses
• More is better here
• Consider adult vs peds formulations of other
  vaccines

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Percentage of participants with 4x or greater
neutralizing Antibody response
40
30
20
10
0
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Intradermal dose-sparing Flu Vaccination NEJM
20043512295

• 100 subjects 50 per group aged 18-40 yrs
• 0.5 cc IM (15 ug/strain) vs 0.1 cc ID
  (3ug/strain)
• Safety more local reactions with ID
• Immunogenicity equivalent (or even a little
  better with ID)
• Similar results in 119 subjects 18-60 yrs, NEJM
  2004351222286

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Immune Response to Vaccination (or infection)
Secondary (booster) response
Response
Primary response
Time
Vaccine 1
Vaccine 2
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Immune Response to Vaccination (or infection)
Faster, stronger
Response
Primary response
Time
Vaccine 1
Vaccine 2
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Immune Response to Vaccination (or infection)
Protective level
Response
Time
Vaccine 1
Vaccine 2
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Adjuvants improve immune response
Vaccination with adjuvant
Protective level
Response
Time
Vaccine 1
Vaccine 2
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Most Vaccines have adjuvant
potassium aluminum sulfate
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Most Vaccines have adjuvant
Others dont need it or are live virus
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Most Vaccines have adjuvant
TIV, a so-so vaccine with no adjuvant
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Adjuvants in flu testing

• Alum (controls antigen release without
  immunostimulation)
• MF59 (Novartis)
• Glaxo proprietary(MPL, lipid A derivative)
• QS-21 purchased from Antigenics
• Interferon A
• Cholera toxin
• E.coli enterotoxin
• IL-2
• Cationic lipids
• Viral-like particles

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Adjuvants could help the H5N1 Example
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Should more age groups get annual vaccine?

• All kids?
• Everyone? (the universal strategy)
• Huge implications
• Cost
• Implementation
• Risk to vaccine credibility if safety issues arise

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Science 12 Nov 2004
Vaccine. 2000 18(18)1902-9 N Engl J Med
2001344889-96 Vaccine 2005231284-93 Vaccine.
2005 23(13)1540-8.
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Tecumseh, weekly Surveillance since 1959
Weekly surveillance Starting 1967 Lansing,
Flint, Adrian
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Steps to improving target group rates

• Large stable supply
• Incentive, liability, market
• Education
• Value and safety of vaccine
• Free, convenient vaccine for HCWs
• Marketing to public and providers

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Influenza Vaccine Answers at hand
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Family on car closer!