the more effective flu vaccine problem - who · source: markus a rose, stefan zielen & ulrich...
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Resilient People. Healthy Communities. A Nation Prepared.
THE MORE EFFECTIVE FLU VACCINE PROBLEM
WHO Meeting August 23, 2016
Source: Abbas, Abul K, Andrew H. Lichtman, and Shiv Pillai. Cellular and Molecular Immunology. Philadelphia: Saunders/Elsevier, 2010. Print.
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Perpetual challenge of responding to influenza
Seasonal Influenza Epidemic in US 5%-20% of population infected year
3,000-49,000 deaths every year
>200,000 hospitalizations
$87.1B economic burden every year
$10.4B medical costs every year
2009-H1N1 Pandemic 74 countries affected
60.8M infected in U.S.
123,000-203,000 deaths worldwide
12,469 deaths in US
274,304 hospitalizations in US
1918 ‘Spanish’ Pandemic All countries affected
20%-40% infected worldwide
50M deaths worldwide
675,000 deaths in US
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BARDA is achieving national pandemic vaccine goals
More, faster to More, faster & better!
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Limitations of current influenza
vaccines • Vulnerable to antigenic drift and shift
• Antibodies target highly variable regions of HA and NA
• Single site mutations can impact immunogenicity • Provide minimal cross-protection within subtypes or
against other subtypes of influenza • Short duration of immunity, particularly in at-risk
populations (e.g., pediatric, geriatric) • Requires viral isolate for production • Predominantly produced in chicken eggs • Avian influenza strains will likely require adjuvant • Vaccine efficacy is modest
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Innate and adaptive immunity
Most vaccines in use today work by inducing humoral immunity
Source: Abbas, Abul K, Andrew H. Lichtman, and Shiv Pillai. Cellular and Molecular Immunology. Philadelphia: Saunders/Elsevier, 2010. Print.
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Optimizing Humoral Immunity Adjuvants
Antigenically advanced vaccines
Rationally designed heterologous prime boost
By permission D. Smith, R. Fouchier, Y. Kawaoka
Cross-reactive stalk-based epitopes
By permission K. Erlandson
Structure-based modification of HA
specificity
Role of CMI No correlation between pre-existing influenza- specific total-cytokine- secreting T-cells to live virus and rate of infection
The frequency of pre-existing cross-reactive T cells is inversely associated with illness severity
Higher frequency of baseline T cells in virus non-shedder
Not everyone is primed to respond with a CMI response
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Severe H7N9 disease immune protection model
Conservation of T-cell epitopes
Certain influenza virus T-cell epitopes are shared more than others
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Population Impacts of Improved Vaccine
Could we consistently reduce these P&I mortality spikes?
Could we reduce Peds deaths?
The efficacy of influenza vaccine can be assessed at both the individual and population level
Mucosal Immunity
11 Source: Markus A Rose, Stefan Zielen & Ulrich Baumann (2012) Mucosal immunity and nasal influenza vaccination, Expert Review of Vaccines, 11:5, 595-607, DOI: 10.1586/ erv.12.31
The potential of mucosal immunization to impact CMI is not yet clear. Are adjuvants needed?
Source: Abbas, Abul K, Andrew H. Lichtman, and Shiv Pillai. Cellular and Molecular Immunology. Philadelphia: Saunders/Elsevier, 2010. Print.
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Innate immunity?
Can/should innate immunity be primed for influenza prophylaxis?
Source: Abbas, Abul K, Andrew H. Lichtman, and Shiv Pillai. Cellular and Molecular Immunology. Philadelphia: Saunders/Elsevier, 2010. Print.
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More Effective Influenza Vaccines: Bringing it all together
IIV, attenuated vectors, recombinant – VLPs and nanoparticles,
nucleic acid Epitope content,
structure Humoral, CMI, mucosal, innate
MF59, AS03, poly IC, Resiquimod, other TRL agonists Innate
immunostimulators?
Oral, intranasal, injection
HtPB Boost regimen
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More effective influenza vaccine: Target Product Profile
Property/Vaccine Desired Primary Characteristics
Breadth of Protection
Protects against antigenically divergent influenza A viruses and viruses from both influenza B virus lineages
Efficacy
Shows 20% or greater efficacy above a licensed influenza vaccine comparator as measured by clinical endpoints or surrogate endpoints (e.g. seroprotection or seroconversion rates) predicative of clinical benefit
Duration of Immunity
Protects for two years or more against influenza A subtypes and influenza B lineages
Priming Immunity
Primes for baseline immunity such that a single dose of pandemic influenza vaccine will boost immune response to protective levels against the pandemic influenza virus
Safety Comparable to licensed vaccines
Landscape of more effective influenza vaccine candidates
There is a need for specific and convincing immunological data
? Data is lacking
Presence of desirable immune response
More effective influenza vaccine development pipeline at BARDA
Resilient People. Healthy Communities. A Nation Prepared.
THE MORE EFFECTIVE FLU VACCINE PROBLEM…. ….NEXT STEPS
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