FLU VACCINEEGG- BASED, CELL-BASED & RECOMBINANT JANUARY 18, 2018

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Influenza Overview:

4 main influenza virus types/strains:

• A/H3N2, A/H1N1, B/Yamagata, and B/Victoria

A/H3N2:

• Is the most virulent of the 4 strains

• Accounts for the majority of influenza-associated hospitalizations and influenza-associated deaths in the United States

• Accounts for the greatest disease burden among the older adult population

• Most common strain for 2017-18 season

• Vaccine effectiveness (VE) against H3N2 viruses has been around 30%

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Vaccine Effectiveness (VE) and Antigenic Drift

• VE• Lower VE against H3N2 viruses may be caused by egg-adapted

changes introduced when H3N2 viruses are optimized for growth in eggs.

• Antigenic Drift• Two types of genetic changes can impact the similarity between a

vaccine virus and circulating seasonal viruses (“antigenic drift”).• Genetic changes can occur when influenza viruses are grown in

eggs• Influenza viruses constantly undergo small genetic changes that

may result in antigenic changes. • Egg-adapted changes in H3N2 viruses are more complex and likely

to have antigenic implications that can make these H3N2 viruses less similar to circulating H3N2 viruses.

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Antigenic Drift and the 2017-2018 Season

No significant antigenic drift has occurred among circulating wild-type influenza viruses at this time.

• Most (98%) of circulating H3N2 influenza viruses remain similar to the cell-grown reference viruses used in production

• However, a smaller percentage (70%) of circulating H3N2 viruses are similar to the egg-grown reference virus used in production

These differences are likely a result of egg-adapted changes introduced when the H3N2 virus was grown in eggs.

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Flu Vaccine Production Technologies

There are 3 production technologies used to develop flu vaccine:

• Egg-Based

• Cell-Based

• Recombinant

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Egg-Based Production

• Most common way that flu vaccines are made

• All 2017-18 presentations are egg-based

Step 1: Candidate vaccine viruses (CVVs) grown in eggs

Step 2: CVVs are then injected into fertilized hen’s eggs and incubated for several days to allow the viruses to replicate

Step 3: The virus-containing fluid is harvested from the eggs

Step 4: Influenza viruses for the vaccine are then inactivated (killed), and virus antigen is purified

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Egg-Based Influenza Vaccine Challenges

• Egg-adapted changes may result in antigenic shift with A/H3N2

• This production method requires large numbers of chicken eggs to produce vaccine and usually takes longer than other methods used to produce vaccine.

• Acquisition of eggs requires significant lead time

• Reliability and quality of embryonated egg supply can be compromised by avian influenza outbreaks

• Not all strains can grow well in eggs creating vaccine production challenges

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Recombinant Production

Step 1: HA protein is isolated from a naturally occurring (“wild type”) recommended vaccine viruses

Step 2: Proteins are combined with portions of another virus that grows well in insect cells

Step 3: This “recombinant” vaccine virus is then mixed with insect cells and allowed to replicate

Step 4: The flu HA protein is then harvested from these cells and purified

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Recombinant Benefits

• H3N2 components are genetically more similar to circulating H3N2 viruses than the egg-adapted viruses used for egg-based manufacturing

• Requires the shortest amount of production time

• Only 100% egg-free flu vaccine on the market

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Cell-Based Production

Step 1: Candidate vaccine viruses (CVVs) are identified

Step 2: CVVs are then inoculated into cultured Mamalian cells and allowed to replicate for a few days

Step 3: The virus-containing fluid is collected from the cells

Step 4: The virus antigen is purified

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Cell-Based Benefits

• Cell-based flu vaccine has the potential to offer better protection than traditional, egg-based flu vaccines as a result of being more similar to flu viruses in circulation

• Faster production than egg-based method

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Non Egg-Based Vaccine Options

Recombinant influenza vaccine (Flublok)

Cell-grown influenza vaccine (Flucelvax).

Trivalent/Quadrivalent Quadrivalent

Flublok is indicated for persons 18+ Flucelvax is indicted for persons 4+

Influenza Vaccines: https://www.cdc.gov/flu/protect/vaccine/vaccines.htm

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Pediatric Influenza Vaccine Price List

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Ending Statements

At this time there is insufficient data to conclude that cell-based or recombinant vaccine are more effective than egg-based vaccine.

Additional data is needed (including vaccine effectiveness data) before policy decisions on this topic could be considered.

Per CDC:

While the use of cell-grown reference viruses and cell-based technology may offer the potential for better protection over traditional, egg-based flu vaccines because they result in vaccine viruses that are more similar to flu viruses in circulation, there are no data yet to support this. There is no preferential recommendation for one injectable flu vaccine over another.

https://www.cdc.gov/flu/about/season/flu-season-2017-2018.htm

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Discussion Questions

Does the science available at this time, compel VAC to recommend adding Flucelvax as a presentation for the 2018-2019 flu season?

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Questions

Production of US Inactivated Influenza Vaccines Has Relied on Embryonated Chicken Eggs

~6 monthsWHO and US FDA decide vaccine formulation

Vaccine delivery

Split with ether and a detergent or solubilized using a detergent

Vaccine is purified by ultracentrifugation

Inactivated by formalin or β-propiolactone

Seed strains harvested in allantoic cavity ofembryonated eggs

Seed strains adapted for large-scale production

Seed strains sent to manufacturers

Candidate strains reassorted with master strain growing well in egg

WHO selects candidate strains from clinical isolates;FDA approvesor modifies selection

Monovalent bulk antigens are blended1

Concentration and purity of antigens are verified

Processing of vaccine

Propagation of vaccine strain

Seed strainevaluation

Strain selection and reassortantdevelopment Formulation

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FDA=Food and Drug Administration; WHO=World Health Organization.Gerdil C. Vaccine. 2003;21(16):1776-1779.

Subunit quadrivalent seasonal influenza vaccine contains 15 µg of HA per strain1

Vaccine production can begin at any time of the year, independent of egg availability, and can be scaled up rapidly relative to egg-based production

Surface antigen subunits extracted and purified

Harvested viruses Inactivated usingβ-propiolactone

Seed strainsreplicated in in MDCK cells

MDCK cellsuspensionsexpanded million-fold

Seed strains adapted for large-scale production

Seed strains sent to manufacturers

Candidate strains reassorted with master strain growing well in egg

WHO selects candidate strains from clinical isolates;FDA approvesor modifies selection

Monovalent bulk antigens are blended2

Concentration and purity of antigens are verified

Antigen purification

Virus propagation

Seed strainevaluation

Strain selection and reassortantdevelopment Formulation

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FDA=Food and Drug Administration; HA=hemagglutinin; MDCK cells=Madin-Darby canine kidney cells; WHO=World Health Organization.1. Food and Drug Administration (FDA). Clinical Review Flucelvax Quadrivalent. 2016;1-82. http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM504789.pdf. Accessed April 8, 2017. 2. Gregersen JP. Vaccine. 2008;26:3332-3340. 3. Mabrouk T et al. Dev Biol (Basel). 2002;110:125-134.

Cell- Based Production Process