Infants and Elderly: is your approved for these groups?

25 March 2014

1 | in infants and elderly, 25 March 2014 Available Influenza vaccines - USA, 2013–14 influenza season TIV Standard dose (http://www.cdc.gov/flu/protect/vaccine/vaccines.htm)

Trade name Manufacturer Presentation Mercury content Age indications Route (µg Hg/0.5 mL) 0.5 mL single-dose 0 ≥9 yrs prefilled syringe Afluria bioCSL IM 5.0 mL MDV 24.5 ≥9 yrs Fluarix GSK 0.5 mL single-dose 0 ≥3 yrs IM prefilled syringe Flucelvax Novartis 0.5 mL single-dose 0 ≥18 yrs IM prefilled syringe FluLaval ID Biomedical 5.0 mL MDV ≥25 ≥3 yrs IM Corporation of Quebec Fluvirin Novartis 0.5 mL single-dose ≤1 prefilled syringe ≥4 yrs IM 5.0 mL MDV 25.0 0.25 mL single-dose 0 6-35 mo IM prefilled syringe 0.5 mL single-dose 0 ≥36 mo IM Fluzone Sanofi Pasteur prefilled syringe 0.5 mL single-dose 0 ≥36 mo IM prefilled vial 5.0 mL MDV 25.0 ≥6 mo IM Fluzone Sanofi Pasteur 0.1 mL prefilled 0 18-64 yrs ID 2intradermal| Influenza vaccines in infants and elderly, 25 March 2014microinjection system Available Influenza vaccines - USA, 2013–14 influenza season (http://www.cdc.gov/flu/protect/vaccine/vaccines.htm)

Vaccine Trade name Manufacturer Presentation Mercury Age Route content indication (µg Hg/0.5 s mL) Inactivated 0 ≥65 yrs IM Influenza Vaccine, Fluzone High- 0.5 mL single-dose Sanofi Pasteur Trivalent, High Dose prefilled syringe Dose Fluarix 0.5 mL single-dose ≥3 yrs IM GlaxoSmithKline 0.0 Quadrivalent prefilled syringe ID Biomedical ≥3 yrs IM FluLaval 5.0 mL multi-dose Corporation of <25.0 Inactivated Quadrivalent vial Quebec Influenza Vaccine, 0.25 mL single-dose ≥3 yrs IM 0.0 Quadrivalent, prefilled syringe Standard Dose Fluzone Sanofi Pasteur 0.5 mL single-dose Quadrivalent 0.0 prefilled syringe ≥4 yrs IM 0.5 mL single-dose 0.0 vial Recombinant 0.5 mL single-dose Influenza Vaccine, FluBlok Protein Sciences 0.0 18-49 yrs IM vial Trivalent Live-attenuated FluMist 0.2 mL prefilled Influenza| Vaccine, MedImmune 0.0 (per 0.2 mL) 2-49 yrs IN 3 Influenza vaccines Quadrivalentin infants and elderly, 25 March 2014 intranasal sprayer Quadrivalent Influenza Vaccines in Europe http://www.ecdc.europa.eu/en/healthtopics/seasonal_influenza/vaccines/Pages/influenza_vaccination.aspx

Manufacturer Name of product Vaccine type Administration Age recommended route Abbot healthcare Influvac Inactivated im >6 mth Imuvac AstraZeneca Fluenz Live attenuated intranasal 24 mth to 17 yrs (US trade name Flumist) Baxter Preflucel Inactivated im >18 yrs

Crucell Viroflu Inactivated/virosomal im >6 mth, increased fever reported in Inflexal Inactivated/virosomal im children 6 mth to 5 yrs

GlaxoSmithKline Fluarix Inactivated im >6 mth Novartis Agrippal Inactivated im >6 mth

Fluvirin Inactivated im >4 yrs

Optaflu Inactivated im >18 yrs

Fluad Inactivated im >65 yrs (MF59) Omninvest Fluval AB Inactivated im >6 mth Pfizer/CSL Australia Afluria Inactivated im

Enzira Inactivated im >5 yrs

Sanofi Pasteur Vaxigrip** Inactivated im >6 mth

Intanza 9µg Inactivated Intradermal >18-59 yrs

4 | Influenza vaccines in infantsIntanza and elderly, 15µg 25 March 2014 Inactivated Intradermal >60 yrs Seasonal Influenza vaccines registered in Australia [Inactivated, IM, 45ug (3 x 15ug) total dose for adults]

Currently used Currently Not supplied  Agrippal (Novartis) (>6mo)  FluAd (Novartis) (>65y)  Fluarix (GSK) (>6mo)

 Fluvax (BioCSL) (>5; 5-9 RA)  Fluarix Quadrivalent (GSK) (>3)  Influvac (Abbott) (>6mo) – Influvac Jr (Abbott)  XFLU (GSK)  Vaxigrip (Sanofi Pasteur) (>6mo) – Vaxigrip Jr (Sanofi Pasteur)

 Intanza (Sanofi Pasteur) (9ug SC) (18-59)

5 | Influenza vaccines in infants and elderly, 25 March 2014 WHO Age indication (y)

1 Flulaval GSK (IDBiomed) TIV 12-59 2 GC Flu Green Cross TIV 1-59 3 Fluvirin Novartis, UK TIV 1+

4 Vaxigrip Sanofi (France) TIV 1+ 5 Fluzone Sanofi (US) TIV 1+ Canada 1 Influvac Abbott TIV subunit 18+ 2 Fluviral GSK TIV split 1+ 3 Agriflu Novartis TIV subunit 1+ 4 Fluad Novartis TIV subunit + Adj. >65 5 Vaxigrip Sanofi TIV split 1+ 6 Fluzone Sanofi TIV split 1+ 7 Intanza Sanofi TIV-split ID 18+

8 FluMist Medimmune LAIV 2-59

6 | Influenza vaccines in infants and elderly, 25 March 2014 – TIV split or subunit

Age indication 1 Seasonal influenza Tiantan Biological Products Co., Ltd >4 2 Seasonal influenza Sinovac Biotech Co., Ltd. 1+ 3 Seasonal influenza Changchu Institute of Biological Products 1+ 4 Seasonal influenza Changchun Changsheng Life Science Co. , Ltd. 1+ 5 Seasonal influenza Shanghai Institute of Biological Products 1+ 6 Seasonal influenza Hualan Biological Engineering Inc. 1+ 7 Seasonal influenza Dalian Hissen Bio-pharm Co., Ltd. 1+ 8 Seasonal influenza Dalian Aleph Biomedical Co., Ltd. >4 9 Seasonal influenza Jiangsu Simcere Vaxtec Bio-Pharmac. Co.,Ltd. 1+ 10 Seasonal influenza Jenner Biotech Co., Ltd. Tianjin (sub unit) 1+ 11 Seasonal influenza Lanzhou Institute of Biological Products 1+ 12 Seasonal influenza Zhejiang Tianyuan Bio-Pharma Co.,Ltd 1+ 13 Seasonal influenza Shenzhen Sanofi P. Biol. Products Co., Ltd. 1+

7 | Influenza vaccines in infants and elderly, 25 March 2014 Thailand

Age indication 1 Agrippal S Novartis Germ. TIV 1+ 2 Fluzone Sanofi US TIV >3 3 Fluarix GSK, Germ. TIV 1+ 4 Vaxigrip Sanofi Fr. TIV-split 1+ TIV subunit + 1+ 5 Fluad Novartis Germ. Adj. 6 Fluarix NH GSK, Germ. TIV 1+ Sanofi F-GPO- 1+ 7 Influenza vaccine MBP TIV 8 Inflexal V Crucell Switz. Viros adj 1+ Split Influenza 1+ 9 Vaccine SIBP, China TIV 10 Begrivac Novartis Germ. TIV-split 1+ 11 Influvac Abbott NL TIV 1+ 12 Intanza 9 ug Sanofi TIV-split ID >18

8 | Influenza vaccines in infants and elderly, 25 March 2014 Mexico

Age indication 1 Fluzone Sanofi US 1+ TIV 2 Vaxigrip Sanofi F 1+ TIV 3 Fluarix GSK B 1+ TIV 4 Agrippal S1 Novartis, Siena 1+ TIV-subunit 5 Influvac Abbott, NL 1+ TIV 6 Fluad Novartis, Siena >4 TIV subunit + Adj. 7 Fluvirene Novartis, UK >4 TIV 8 IDFlu Sanofi F >4 TIV-split ID 9 Ollinflu Birmex (SF) 1+ TIV

10 Fluvaxsin-SV Lab. Imp (Anflu-Sinovac)1+ split

9 | Influenza vaccines in infants and elderly, 25 March 2014 Age indication 1 Sanofi >2 2 GSK >2 3 Butantan >2 4 Novartis ? ?? Kazakhstan 1 Agrippal S1 Novartis, I >1 TIV-subunit 2 Influvac Abbott, NL >1 TIV 3 Fluarix GSK, G >1 TIV-split 4 Vaxigrip Sanofi, F >1 TIV-split 5 Grippol Petrovax, R >1 TIV-subunit-pol Romania 1 Fluarix GSK, B >3 TIV 2 Influvac Abbott. NL >1 TIV 3 Intanza /IDFlu Sanofi, F >18 TIV-split ID 4 Optaflu Novartis >18 TIV-cell based 5 Vaxigrip Sanofi, F >1 TIV

10 | Influenza vaccines in infants and elderly, 25 March 2014 Iran 1 Agrippal Novartis >1 2 Fluad Medimmune >1 3 Fluarix GSK >1 4 Inflexal Crucell Switz. >1 5 Vaxigrip Sanofi >1 1 Vaxigrip Sanofi >1 2 Fluarix GSK >1 3 Agrippal Novartis >1 4 Flubio Bio Farma >18 Serbia 1 Fluad Novartis >65 2 Fluarix GSK >7 3 Fluimum ? >3 4 Intanza Sanofi >59 5 Vaxigrip Sanofi >1

11 | Influenza vaccines in infants and elderly, 25 March 2014 Differing age indications between countries

Vaccine EU USA Canada Australia Mexico Serbia Thailand

Fluarix > 6 months * > 3 years N/A > 6 months > 6 months > 7 years > 6 months (GSK)

Influvac > 6 months * N/A > 18 years > 6 months > 4 years N/A > 6 months (Abbott)

Fluvax > 5 Years > 5 Years ** N/A > 5 Years ** N/A N/A N/A /Afluria/ Enzira

(Bio-CSL)

* UK approval ** 5-9 years use on careful consideration of risks vs benefits

12 | Influenza vaccines in infants and elderly, 25 March 2014 Fluarix (GSK) in the UK > 6 months

13 | Influenza vaccines in infants and elderly, 25 March 2014 Fluarix (GSK) in the US > 3 years

14 | Influenza vaccines in infants and elderly, 25 March 2014 Influvac (Abbott) in UK > 6 months

15 | Influenza vaccines in infants and elderly, 25 March 2014 Influvac (Abbott) in Canada > 18 years

16 | Influenza vaccines in infants and elderly, 25 March 2014 Fluvax / Afluria (Bio CSL) > 5 years

17 | Influenza vaccines in infants and elderly, 25 March 2014 In some studies, split vaccine can be poorly immunogenic in infants

prime boost Adjuvant none Adjuvant none

% HI>40

Vesikari et al 2009

18 | Influenza vaccines in infants and elderly, 25 March 2014 And in some studies efficacy can also be low…

Age Relative efficacy (95% CI) TIV

6-72 Mo 43 (15-61)

36-72 45 (6-68)

6-36 40 (-6-66)

6-24 11 (-89-58)

Vesikari 2011 NEJM

19 | Influenza vaccines in infants and elderly, 25 March 2014 Vaccine efficacy in the elderly

 "young elderly vs old elderly "

 TIV vs adjuvanted TIV in: 65-75, 75-85, >85yr

Population VE% (univariate) TIV TIV + adjuvant All -12 35 Not in long-term care 42 73

Van Buynder et al. 2013 Vaccine 31, 6122

 Not all elderly are the same…

20 | Influenza vaccines in infants and elderly, 25 March 2014 Alternative vaccines for the elderly

 Adjuvant 10 8  Intradermal delivery 6 4 2 0 GMTR ID IM

HAI GMT  High dose antigen H1N1 H3N2 B – (60 ug vs 15) High dose 116 609 69 60 ug Normal 67 333 52 dose 15 ug

21 | Influenza vaccines in infants and elderly, 25 March 2014 Conclusions

 SAGE recommendations include infants and elderly as priority groups. – Age indications vary between countries

 Developing vaccines for use in these populations should include data generation on safety and efficacy – These populations are variable and clinical trial design and product development should take this into account

 For these populations there are opportunities to make targetted improved vaccines – E.g. SC vaccines, high dose, adjuvanted vaccines, LAIVs,

22 | Influenza vaccines in infants and elderly, 25 March 2014 Considerations for QIVs

Clinical Manufacturers . Is there interference between the Bs for Ab. response? They will need to start production before the WHO rec is made and try and 2nd guess Potential extra ADRs because of extra 33 percent of 2 strains. material A triple or quadruple Change one year there LAIV or recombinant QIVs may be best for safety and will be practical difficulties. immunogenicity. SH more affected as time lines tighter. Wheezing a possible issue. Children with allergic reactions and asthma will need exclusion. Programme managers Lab issues and pharmacopoeial Cost Extra SRIDs and calibrations on an already stressed If TIV and QIV out there will be marketing system. issues The Bs seem to interfere with each other in lab tests and perhaps conflicting advice. Adjuvants are v difficult

The upper fiducial limit will come into play for protein

Stability studies needed

23 | Influenza vaccines in infants and elderly, 25 March 2014