INFLUENZA VACCINE PRODUCTION

CONSIDERATIONS
Ethan C. Settembre, PhD
Head of Research
Seqirus
GoF Research Workshop
National Academy of Sciences
March 11, 2016

Global Influenza system generated to address variability

Many groups need to act in concert

141NICs
6WHOcc

ERLs

Strain
Selection

Release
Assay

Vaccine
Clinical
Isolate

Virus
Generation

Manufacturing

Vaccine

Complexglobalsysteminvolvesinfluenzasurveillanceandcandidatevirusgenerationaswellasthe
potencyassayreagentgeneration
Advancementsateverystepcouldstreamlineoverallprocess

2 |GoF ResearchWorkshop|ECSettembre|March11,2016
Settembreetal.,Hum.Vac.AndImmuno.2014

Industrial reality: 4-5 months from strain to first H1N1 pdm

vaccine, despite unparalleled global efforts
Subm/Review

March 18, 1st case in Mexico

Approval

Clinicaltrials

Availability of clinical material

Influenza
seasonNH

QC
Bulkproduction

2009
May
JuneSystem | 1/22/14
July
4 April
| Settembre | Improving
the Global Influenza
3 |GoF ResearchWorkshop|ECSettembre|March11,2016

August

September

June 11, declaration of pandemic

October

November

Vaccines can be produced quickly but pandemics can be faster

numberofcasesperweek[000]

45,000

numberofdelivereddosesperweek[cumulative,000]

7,000

40,000
numberofcasesperweek[000]

6,000
35,000
5,000

30,000

4,000

Worldnowatthestartof
2009influenzapandemic

3,000

WHODirectorGeneralDr
MargaretChan

25,000
20,000
15,000

2,000
10,000
1,000

5,000
0

NovartisdeliveriestoUS,dosesperweek[cumulative,000]

50,000

8,000

23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 1 2 3 4 5
Jun

Jul

Aug

Sep

Oct

Nov

Dec

Jan

Closeto40%ofcasesoccurredinatimewhennomeaningfulvaccinequantitieswereavaiable

Vaccineonlyavailableinsubstantialquantitiesafterthe2ndpandemicwavepeak
Source:sourceis:http://www.cdc.gov/h1n1flu/estimates_2009_h1n1.htm andhttp://www.cdc.gov/flu/weekly/index.htm;AsofJan16,2010theCDCestimatedthatabout57millionpeopleareinfectedwith2009H1N1.weekly
dataoninfluenzapositivetestsreportedtoCDCbyU.S.WHO/NREVSScollaboratinglaboratoriesappliedtoCDCestimatetoarriveattheweeklyestimatefornumberofcasesintheUS.

| GoF Research Workshop | EC Settembre | March 11, 2016

With SGVI and JCVI established process for rapid generation of

synthetic influenza viruses
Syntheticbiologyimprovesthespeed ofvaccineseedgeneration
Enzymaticerrorcorrectionimprovestheaccuracyofseedgeneration
OptimizedbackbonesproducesuperiorvirusandHAyield
Processrobustness shownbymaking>50syntheticfluAandBvirusstrains

5 | GoF Research Workshop | EC Settembre | March 11, 2016

Chronology: Novartis H7N9 response the first days

Synthetic technology applied to make vaccine virus

March31 Chinareportsthefirst3humaninfectionswithH7N9influenza,2ofthem
fatal.TheChinaCDCpostssequencesonGISAID.
Viral coding
region sequences
posted online

March 31 April 1
HA and NA
gene
synthesis
started

Genes received at NVD

Virus rescue started
Genes shipped to CDC

April 2

April 3

April 4

Gene
assembly
completed

Genetic identity of
viruses confirmed

April 5

April 6

April 7

First evidence of
virus rescue!

April11 USCDCreceiveswildtypevirusfromChina,enablingthestartof
reassortment togenerateaconventionalvaccinevirus
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April 8