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.

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