1. The more Effective FLU VACCINE PROBLEM
Welcome to the new ASPR PowerPoint template. Each slide contains helpful information for making the entire presentation user-friendly and compliant with Section 508.
WHO Meeting
August 23, 2016
Source: Abbas, Abul K, Andrew H. Lichtman, and Shiv Pillai. Cellular and Molecular Immunology. Philadelphia: Saunders/Elsevier, Print.
Resilient People. Healthy Communities. A Nation Prepared.

2. Perpetual challenge of responding to influenza
1918 ‘Spanish’ Pandemic
All countries affected
20%-40% infected worldwide
50M deaths worldwide
675,000 deaths in US
2009-H1N1 Pandemic
74 countries affected
60.8M infected in U.S.
123, ,000 deaths worldwide
12,469 deaths in US
274,304 hospitalizations in US
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

3. BARDA is achieving national pandemic vaccine goals
4/20/2018
More, faster to More, faster & better! 3

4. 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
There is need for
more effective influenza vaccines
This slide lists the shortfalls of current influenza vaccine and includes a summary table of seasonal influenza vaccine effectiveness from the season to the season indicating effectiveness ranging from about 5% to 60%. Overall vaccine uptake is improving but is still less than 50%. Also effectiveness is not improving with increasing coverage. Finally a table that shows the breakdown of effectiveness during the mismatch season.

5. Innate and adaptive immunity
Source: Abbas, Abul K, Andrew H. Lichtman, and Shiv Pillai. Cellular and Molecular Immunology. Philadelphia: Saunders/Elsevier, Print.
Most vaccines in use today work by inducing
humoral immunity

6. Optimizing Humoral Immunity
Adjuvants
By permission K. Erlandson
Cross-reactive stalk-based epitopes
Antigenically advanced vaccines
Structure-based modification of HA specificity
By permission D. Smith,
R. Fouchier, Y. Kawaoka
Rationally designed heterologous prime boost

7. Role of CMI Not everyone is primed to respond with a CMI response
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
Not everyone is primed to respond with a CMI response
Higher frequency of baseline T cells in virus non-shedder

8. Severe H7N9 disease immune protection model
The absolute numbers of H7N9-specific IFN-g producing CD8þ T cells (red symbols), CD4þ T cells (blue symbols), NAbs (grey symbols) and NK cells (green symbols) are shown across different patient recovery (R1–R3) and fatality (RD) groups. (a) Least square polynomial regression was used to calculate and model the absolute numbers for H7N9-specific IFN-g-producing CD8þ Tcells, CD4þ Tcells, antibodies NAbs and NK cells. The mean data are shown for each group and ‘No virus control’ values were subtracted.
Patients with a prominent, early H7N9-specific CD8þ CTL response recovered faster than those who lacked what seemed to be pre-existing, heterosubtypic CTL memory. In the absence of such early CTL recall, those hospitalized patients who recovered later established a more
complex profile of immune effector mechanisms before disease resolution. The longer the hospitalization with severe H7N9 disease, the more diverse these immune responses became, involving also CD4þ TH cells, and NAbs then, in those who recovered late, the emergence of prominent, innate NK cell populations.

9. Conservation of T-cell epitopes
Certain influenza virus T-cell epitopes are shared more than others

10. 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

11. Mucosal Immunity
Source: Abbas, Abul K, Andrew H. Lichtman, and Shiv Pillai. Cellular and Molecular Immunology. Philadelphia: Saunders/Elsevier, Print.
The potential of mucosal immunization to impact CMI is not yet clear. Are adjuvants needed?
Source: Markus A Rose, Stefan Zielen & Ulrich Baumann (2012) Mucosal immunity and nasal influenza vaccination, Expert Review of Vaccines, 11:5, , DOI: / erv.12.31

12. Source: Abbas, Abul K, Andrew H. Lichtman, and Shiv Pillai
Source: Abbas, Abul K, Andrew H. Lichtman, and Shiv Pillai. Cellular and Molecular Immunology. Philadelphia: Saunders/Elsevier, Print.
Innate immunity?
Can/should innate immunity be primed for influenza prophylaxis?

13. More Effective Influenza Vaccines: Bringing it all together
MF59, AS03,
poly IC, Resiquimod,
other TRL agonists
Innate immunostimulators?
IIV, attenuated vectors, recombinant – VLPs and nanoparticles,
nucleic acid
Epitope content, structure
Humoral, CMI,
mucosal, innate
All the examples of vaccine vaccine design, adjuvants and administration approaches mentioned in the presentation are listed.
Oral, intranasal, injection
HtPB
Boost regimen

14. 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
The desired primary characteristics of a more effective influenza vaccine are 1) Breadth of Protection against against antigenically divergent influenza A viruses and viruses from both influenza B virus lineages, 2) Efficacy that is 20% or greater efficacy above a licensed influenza vaccine comparator as measured by clinical endpoints or surrogate endpoints (e.g. seroprotection or seroconversion rates) predictive of clinical benefit, 3) Duration of Immunity for two years or more against influenza A subtypes and influenza B lineages, 4) Priming Immunity such that a single dose of pandemic influenza vaccine will boost immune response to protective levels against the pandemic influenza virus and 5) Safety that is comparable to licensed vaccines.

15. Landscape of more effective influenza vaccine candidates?
Data is lacking
Presence of desirable immune response
There is a need for specific and convincing immunological data

16. More effective influenza vaccine development pipeline at BARDA

17. The more Effective FLU VACCINE PROBLEM…. ….Next STEPS
Welcome to the new ASPR PowerPoint template. Each slide contains helpful information for making the entire presentation user-friendly and compliant with Section 508.
Resilient People. Healthy Communities. A Nation Prepared.