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, 2010. Print. Resilient People. Healthy Communities. A Nation Prepared.

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. 123,000-203,000 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

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

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 2004-2005 season to the 2014-2015 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 2014-2015 mismatch season.

Innate and adaptive immunity Source: Abbas, Abul K, Andrew H. Lichtman, and Shiv Pillai. Cellular and Molecular Immunology. Philadelphia: Saunders/Elsevier, 2010. Print. Most vaccines in use today work by inducing humoral immunity

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

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

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.

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

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 Source: Abbas, Abul K, Andrew H. Lichtman, and Shiv Pillai. Cellular and Molecular Immunology. Philadelphia: Saunders/Elsevier, 2010. 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, 595-607, DOI: 10.1586/ erv.12.31

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, 2010. Print. Innate immunity? Can/should innate immunity be primed for influenza prophylaxis?

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

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.

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

More effective influenza vaccine development pipeline at BARDA

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.