Impact of Pneumococcal Conjugate Vaccines on

Overall Pneumococcal Disease – a Review of the Data

2016 New Zealand National Immunisation Workshop

Dr Bernard Hoet, MD, FFPM

Global Medical Affairs Lead,

Pneumococcus vaccines,

GlaxoSmithKline Vaccines

Warve, Belgium

Synflorix® knowledge test

• Go in the draw to win an iPad containing NZ immunisation resources

• At the end of this presentation, you should be able to answer questions about:

– The design of Synflorix

– The relative importance of preventing different diseases

– The impact of PCVs in New Zealand

• Pick up a Synflorix Fact Sheet and quiz at the GSK stand

• Complete the quiz entry form

• Winner announced in the conference

closing session

2

Pneumococcal disease

~100 different pneumococcus serotypes identified

– Each serotype has a different polysaccharide capsule

– Classified in serogroups of cross reactive serotypes

Most of them carried in nasopharynx and only very seldom lead to disease

– +/- 10 serogroups are responsible for the vast majority of disease in children

1. Kandasamy, Rama et al. PLoS ONE 10.2 (2015): e0114286..

Synflorix overview

10 pneumococcal serotypes1

–1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, 23F

–New indication for cross-reactive 19A

–Serotype 3 excluded during vaccine development

Conjugated to a protein1

–Protein D from non-typeable H. influenzae (NTHi)*

–To avoid interference with concomitant vaccination

Licensed in >130 countries2

–Used in > 45 countries or regions in immunisation programmes

– > 350 million doses distributed

Efficacious and effective1,3,4,5

–Randomised controlled trials

–Post-marketing studies

–Safety & reactogenicity well documented

*8 serotypes protein D-conjugated, 18C and 19F are conjugated to TT and DT respectively 1. Synflorix Medsafe Datasheet 2016 2. GSK Data on File 3. Prymula, et al. Lancet 2006; 367: 740–8 4. Tegnaghi, et al. PLoS Med, 2014. 11(6): p e1001657 5 Palmu et al, Lancet 2013.

Today >45 countries include Synflorix in UMV/NIP or high-risk programs

* Regional tenders ** Reimbursed # risk groups only – only a fraction of birth cohort is eligible for vaccination

>100M children (> 340M Doses) covered by Synflorix since launch

Europe

Albania

Austria

Belgium

Bosnia&Herzeg.#

Bulgaria

Croatia#

Cyprus

Czech Republic**

Finland

Iceland

Latvia

Lithuania

Macedonia#

Netherlands

Poland#

Serbia#

Slovenia

Slovak Republic**

Sweden*

Africa and West

Asia Azerbaijan

Armenia

Ethiopia

Georgia

Kenya

Madagascar

Morocco

Mozambique

Palestine

Uganda

Bangladesh

Nigeria

Zambia

Asia and Pacific Korea**

Fiji

Pakistan

Nepal

New Zealand

The Americas Aruba

Barbados

Bermuda

Brazil

Chile

Colombia

Ecuador

Gran Cayman

Jamaica#

Paraguay

Trinidad&Tobago

09/05/2016 GSK Data on File: Updated on Dec 2015

FinIP, Finland 47 369 subjects, primary objective: IPD

1: Palmu et al, Lancet 2013; 2: Tregnaghi PLOS Med 2014; 3: Kilpi, ICAAC 2014 (*consolidated pneumonia – WHO definition); ITT-intention-to-treat analysis; ATP-according to protocol analysis

Invasive pneumococcal diseases (IPD)

Acute otitis media Pneumonia*

Finland

93% (75-99)1

Vaccine serotypes:

100% (83-100)

Latin America/ITT/

67% (22-86)2

Vaccine serotypes:

100% (74-100)

Latin America/ITT/

19% (4-31)2

Synflorix efficacy and effectiveness: Evidence from randomised controlled trials

Finland

44% (24- 59)3

Latin America/ATP/

26% (8-40)2

Compas, Argentina, Colombia, Panama 24 000 subjects primary objective: pneumonia

-20 0 20 40 60 80 100 120

IPD efficacy point-estimates for randomised controlled trials of PCVs (IPD due to vaccine serotypes, ITT cohort)

*Not licensed Note: data put aside for clarity, trials cannot be directly compared 1. Palmu, et al. Lancet 2013; 381: 214–22; 2. Tregnani et al PLOS Medecines 2014; col 11 issue 6; 3. Black, et al. Pediatr Infect Dis J 2000; 19: 187–95; 4. O’Brien, et al. Pediatr Infect Dis J 2008; 27: 71–4; 5. Klugman, et al. New Engl J Med 2003; 349: 1341–8; 6. Cutts, et al. Lancet 2005; 365: 1139–46

9vCRM: Wyeth/Pfizer*

(The Gambia)6

9vCRM: Wyeth/Pfizer* (Soweto HIV negative, SA)5

7vCRM: Wyeth/Pfizer (N. California NCKP, USA)3

Synflorix: GSK (FinIP, Finland)1

Synflorix: GSK (COMPAS LatinA)2

7vCRM: Wyeth/Pfizer (Navajo & Apache, USA)4

100% (91–100)

100% (74–100)

97% (83–97)

77% (-9–95)

85% (32–98)

77% (51–90)

Vaccine efficacy (%) (95% CI)

-40 -20 0 20 40 60 80 100 120

IPD efficacy point-estimates for randomised controlled trials of PCVs (IPD due to any serotype, ITT cohort)

*Not licensed; †ATP cohort results Note: data put aside for clarity, trials cannot be directly compared 1. Palmu, et al. ESPID, Thessaloniki, Greece, 8–12 May 2012 (poster); 2. Tregnaghi, et al. ISAAR, Kuala Lumpur, Malaysia, March 13-15, 2013 (abstract); 3. Black, et al. Pediatr Infect Dis J 2000; 19: 187–95; 4. O’Brien, et al. Pediatr Infect Dis J 2008; 27: 71–4; 5. Klugman, et al. New Engl J Med 2003; 349: 1341–8; 6. Cutts, et al. Lancet 2005; 365: 1139–46

9vCRM: Wyeth/Pfizer*†

(The Gambia)6

9vCRM: Wyeth/Pfizer* (Soweto HIV negative, SA)5

7vCRM: Wyeth/Pfizer (N. California NCKP, USA)3

Synflorix: GSK (FinIP, Finland)1

Synflorix: GSK (COMPAS LatinA)2

7vCRM: Wyeth/Pfizer (Navajo & Apache, USA)4

93% (75–99)

67% (22–86)

89% (74–96)

52% (-7–79)

42% (-28–75)

50% (21–69)

Vaccine efficacy (%) (95% CI)

9 Kilpi, ICAAC 2014

Finland

PCV efficacy against consolidated pneumonia in double blind randomized controlled trials

(WHO definition, ITT)

Synflorix Synflorix

PCV impact on all-cause (A)OM episodes in double-blind randomised controlled trials

(cohorts of children, 3+1 schedules)

Efficacy against all (A)OM episodes except in COMPAS (first AOM episodes). Studies presented side by side, cannot be directly compared. 1. Sáez-Llorens, et al. WSPID 2013, Cape Town, South Africa; 2. Prymula, et al. Lancet 2006; 367: 740–8; 3. Kilpi, et al. Clin Infect Dis 2003; 37: 1155–64; 4. Eskola, et al. N Engl J Med 2001; 344: 403–9; 5. O’Brien, et al. Pediatr Infect Dis J 2008; 27: 71–3; 6. Black, et al. Pediatr Infect Dis J 2000; 19: 187–95; 7. Fireman, et al. Pediatr Infect Dis J 2003; 22: 10–6

COMPAS (Synflorix)1

ITT; <2y; N=7,214

POET (PCV11-PD)2

ATP; <27m; N=4,907

FinOM (PCV7-OMPC)3

ATP; <2y; N=1,599

NCKP (PCV7-CRM)6,7

ATP; <2y; N=33,766

FinOM (PCV7-CRM)4

ATP; <2y; N=1,580

Navajo (PCV7-CRM)5

ATP; <2y; N=803

Efficacy and clinical impact data generated with Synflorix

Quebec

(Canada)

IPD3

COMPAS

Panama

Colombia

Argentina

IPD, CAP, NP

carriage, AOM 2

Clinical trial

Impact / effectiveness

FinIP (Finland)

IPD, Antibiotics,

CAP, Antibiotic

use, NP

carriage1,5,8

Finland

IPD1

The

Netherlands

IPD6

New Zealand

IPD11

Iceland

IPD,

meningitis,

CAP, AOM,

antibiotic use7

Brazil

IPD, meningitis,

CAP, AOM,

carriage 4,9

Kilifi (Kenya) IPD, carriage10

1. Palmu et al, Lancet 2013; 2. Tregnaghi PLOS Med 2014; 3. Deceuninck, et al. Vaccines33 (2015) 2684–2689 ; 4. Domingues, et al. Lancet Resp Med 2014; 2: 464–71;5. Jokkinen, et al.PLOSOne 2015; 6. Knol et al, Emerging Infectious Disease Vol. 21, No. 11, November 2015; 7. Siggurdson, et al. The Pediatric Infectious Disease Journal • Volume 34, Number 12, December 2015; 8. Palmu, Lancet Infect Dis 2014; 14: 205–12; 9. Sartori, ISPPD, Hydebrad, India, 2014, poster 0244; 10. Hammit, ISPPD, Hydebrad, India, 2014, poster 0513, 11. New Zealand IPD report, https://surv.esr.cri.nz/surveillance/IPD.php, assessed on 25.01.2016

Quebec1

(Unmatched case−control) Finland3

(Impact Study)

Brazil2

(Matched case−control)

Vaccine-type (+6A)

VE=97% (95% CI: 84, 99)

Vaccine type

VE=84% (95% CI: 66, 92)

1. Deceuninck, et al. Vaccines 2015 2. Domingues, et al. Lancet Resp Med 2014 2: 464–71 3Jokinen et al PLOSone 2015 Table1

http://journals.plos.org/plosone/article/figure/image?size=medium&id=info:doi/10.1371/journal.pone.0120290.t001 4 Knol et al EID 2015 (21) 11 wwwnc.cdc.gov/eid/article/21/11/14-0780_article

Vaccine type

RR=92% (95% CI: 86, 95)

Synflorix Vaccine effectiveness:

Netherlands4

(Impact Study vs PCV7 era)

Vaccine type (1,5,7F)

RR=96% (95% CI: 73, 99)

Brazil5

(Indirect cohort)

Vaccine type

VE=73% (44,87)

5 Verani Vaccine. 2015 Nov 17 33(46):6145-8. doi:10.1016/j.vaccine.2015.10.007. Epub 2015 Oct 24.

Overall

VE= 72% (95% CI: 40, 85)

Overall

RR= 80% (95% CI: 72, 85)

Overall

RR= 65% (95% CI: 67, 39)

IPD control by vaccination in New Zealand

Institute of Environmental Science and Research Ltd (ESR): IPD in New Zealand, 2014. Porirua: ESR; 2016

Invasive pneumococcal disease is well controlled in NZ

14

IPD due to Synflorix vaccine serotypes plus 19A has

decreased by 96% in <2 year olds

Calculated from Invasive pneumococcal disease in New Zealand ESR reports 2008-2015 . Available at:

www.surv.esr.nz/surveillance/IPD

In June 2008 Prevenar® was added to the NIP. In July 2011 this was changed to Synflorix® and in July 2014 this was changed to

Prevenar 13®. Note: due to these changes there are periods where children were given a mixed schedule of vaccines.

Quebec1

(Unmatched case−control)

Finland3

(Impact Study)

Brazil2

(Matched case−control)

Vaccine-type (+6A)

VE=97% (95% CI: 84, 99)

Vaccine type

VE=84% (95% CI: 66, 92)

1. Deceuninck, et al. Vaccines 2015 2. Domingues, et al. Lancet Resp Med 2014 2: 464–71 3Jokinen et al PLOSone 2015 Table1 http://journals.plos.org/plosone/article/figure/image?size=medium&id=info:doi/10.1371/journal.pone.0120290.t001 4. Knol et al EID 2015 (21) 11 wwwnc.cdc.gov/eid/article/21/11/14-0780_article 5 Verani Vaccine. 2015 Nov 17 33(46):6145-8. doi:10.1016/j.vaccine.2015.10.007. Epub 2015 Oct 24.

19A

VE=82% (95% CI: 11, 96)

19A

VE=71% (95% CI: 24, 89)

Vaccine type

RR=92% (95% CI: 86, 95)

19A

RR=62% (95% CI: 20, 85)

Synflorix Vaccine effectiveness: Vaccine types and Serotype 19A

Netherlands4

(Impact Study vs PCV7 era)

Vaccine type (1,5,7F)

RR=96% (95% CI: 73, 99)

19A

RR=62% (95% CI: 23, 81)

Brazil5

(Indirect cohort)

Vaccine type

VE=73% (44,87)

19A

VE=71%(17,90)

Vaccine type

VE= 85% (95% CI: 64, 94]

Vaccine type

VE= 86% (95% CI: 76,92)

Vaccine type

VE= 86% (95% CI: 62,95)

Vaccine type

VE= 75% (95% CI: 58,84)

Quebec 4(Canada) (Unmatched Case control)

USA1 (ABC)

(Matched Case control)

UK5

(Indirect Cohort)

Germany3 (Indirect Cohort)

1. Moore MR Lancet Respir Med. 2016 Mar 14. pii: S2213-2600(16)00052-7; 2. Su WJ Pediatr Infect Dis J. 2016 Apr;35(4):e124-33; 3. Weinberger R Vaccine. 2016 Apr 19;34(18):2062-5; 4. Deceuninck G Vaccine. 2015 May 28;33(23):2684-9; 5. Andrews NJ et al Lancet Infect Dis. 2014 Sep;14(9):839-46;

19A

VE= 74% (95% CI: 11,92)

19A

VE= 67% (95% CI: 38,84)

19A

VE= 83% (95% CI: 41, 95)

19A

VE= 86% (95% CI: 71,94)

Vaccine effectiveness studies PCV13

PCV7 Synflorix™ PCV13

All serotypes (95%CI)

50% (29-64)

72% (46-85)

66% (29-83)

PCV-13 serotypes (95%CI)

63% (45-74)

84% (65-93)

86% (62-95)

Serotype 19 A (95%CI)

42% (-9-69)

71% (24-89)

74% (11-92)

Deceuninck et al. Vaccines, 33, 2684–2689 2015; VE computed by logistic regression model weighted for sampling fraction of controls and adjusted for age,

year, season and underlying medical conditions including asthma and severe prematurity.

Effectiveness of PCVs to prevent IPD (Case control study study; VE > 1 dose; schedule = 2+1)

• PCV7 introduced in UMV in Dec 2004, replaced by Synflorix™ in June 2009, and PCV13 in Jan 2012

• 889 eligible IPD cases in children 2 -59 months of age (2005-2013)

– 58% returned written authorization to check immunization records (n=516)

• 1767 controls identified

19A cases in children immunised with Synflorix or PCV13 in Quebec

• Synflorix: 13 cases (2009-2012)

• in children without any risk factor

• after 1st dose : 2 cases, age 3 and 4 months

• after 2nd dose : 7 cases, age 5 to 13 months old

• after 3rd dose : 4 cases, age 16 to 32 months

• PCV13: 9 cases (2011-2013)

• in children without any risk factor

• after 2nd dose : 9 cases, at age 9 to 12 month-old

• before the booster dose could be administered

18 Deceuninck et al. Vaccines 2015

Otitis media constitutes a large proportion of the

remaining pneumococcal disease in NZ children

• 83,000 GP consultations and 5,000 hospital admissions / year (children under 5 years of age)1

• Maori and Pacific twice as likely to be hospitalised 2,3

• Maori and Pacific Island children are also twice as likely to fail hearing checks as NZ European

children when they start school4

• 10% of Maori, 11% of Pacific Island and 4% of NZ European children fail tests4

19 1. Gribben, B.JPCH 2012; 4(3):205-212 2. Milne, R.J. et al, Appl Health Econ Health Policy, 2010. 8(5): 281-300. 3. McCallum, J., et al., N Z Med J,

2015. 128(1416): p. 10-20. 4. Greville Consulting, New Zealand Hearing and Vision Screening report. 2006

NZ children with OM and effusion experience long-lasting

developmental consequences

• Dunedin longitudinal, multidisciplinary study of >1,000 NZ children enrolled at 3 years and

followed up to 11 years of age.

• OME was shown to have long-lasting consequences for language development, speech

articulation, reading ability and classroom behaviour

Chalmers D et al. Clinics in Developmental Medicine No. 108. Otitis Media with Effusion in Children – The Dunedin Study. 1989.

Mac Keith Press. Oxford, Blackwell Scientific Publications Ltd

Significant differences compared with normal children for:

• Intelligence at age 5

• Verbal comprehension at ages 3 and 5

• Verbal expression at ages 3, 5 and 7

• Behaviour problems reported by teachers at age 5

Ear infections are debilitating, impact hearing and can cause

significant delays in development

20

Ethnic differences in all otitis media hospitalisations in

NZ <6 year olds decreased between 2006 to 2013

(p-value<0.0001)

↓40%

(trend test p-value<0.0001) (trend test p-value=0.31)

Petousis-Harris H et al. Australasian Society for Infectious Diseases (ASID). 2015: Auckland, New Zealand. 21

Impact of PCVs on hospitalisation for OM in New Zealand

PCV use over time in New Zealand

27,326 children

born between

01 July 2011 and

31 December

2011

22

Radke, S., N. Turner, and H. Petousis-Harris, Exploring the effect of PCV-10 on otitis media hospitalisation in New Zealand, in Public Health Association of Australia (PHAA).

2014: Melbourne, Australia..

Synflorix has a significant impact on NZ OM hospitalisations

Radke, S., N. Turner, and H. Petousis-Harris, Exploring the effect of PCV-10 on otitis media hospitalisation in New Zealand, in Public Health Association of Australia (PHAA). 2014: Melbourne, Australia..

23

Sartori, et al. ISPPD, Hyderabad, India, 10-14 March 2013 (poster)

Reduction in all cause otitis media related visits after Synflorix introduction

Children 2-23 moa in Brazil, Goiana

Significant reduction in rates of all-cause otitis in the post-vaccination period

Mean Annual Incidence/10 000

children-years

2008-10 (UnVacc)

2011 Vacc

Reduction (95%CI)

P-value

OM 1198 915 24% (13, 33)

P<0.0001

Pneumonia 422 329 23% (5, 36)

P<0.01

AOM and pneumonia in Iceland: early reduction after Synflorix introduction

Comparison of cohorts of children 3 months to 2 years of age - Reference cohort, not vaccinated: Children born in 2008 – 2010 - Vaccinated cohort (2+1 schedule): Children born in 2011

ARR: OM = 283 per 10,000 children-years. And Pneumonia: 93 per 10000 children-years

Siggurdson, et al. The Pediatric Infectious Disease Journal • Volume 34, Number 12, December 2015

More and More National Immunisation Technical Advisory Groups recommend both vaccines for use

in their UMV

Belgium2 The Netherlands3 Finland1

New Zealand4

… both vaccines to be suitable

for use in public programmes

The suggestion is

to use vaccine price only (to compare vaccines),

because the two products on the market

are very similar (…).

(…), both vaccines have a profile suitable for the

current epidemiology of S. pneumoniae infections in

children in Belgium

… both (…) are suitable for

inclusion on the National

Immunization Schedule

1.THL. Tendering process for pneumococcal conjugate vaccine. 2014; Available from: http://en.opasnet.org/w/ Tendering_process_for_ pneumococcal_conjugate_vaccine. 2. SANTE, C.S.D.L., Vaccination de l’enfant et de l’adolescent contre le pneumocoque, in AVIS DU CONSEIL SUPERIEUR DE LA SANTE N° 8813. 2015. 3. Netherlands, H.C.o.t., Vaccination of infants against pneumococcal infections (3). 2013, The Hague: Health Council of theNetherlands. 4. PTAC, Immunisation Subcommittee of PTAC, meeting minutes. 28 October 2015. 2016.

In conclusion

Synflorix is a vaccine that is widely used

–>350 million doses distributed

–>125 countries

–>45 Universal Mass Vaccination programs

PCVs were initially evaluated based on immunogenicity to the serotypes they contain

Effectiveness results show that serotype content is not an appropriate way of extrapolating effectiveness

–Variable effectiveness against serotypes included in the vaccines

–Protection against cross reactive serotype

–Replacement disease

Totality of the data does not allow to show superiority of one vaccine over the other on IPD in children

Synflorix has the potential to also help prevent otitis media which is of particular importance in the NZ context

Synflorix Prescribing Information

28

• Synflorix® (10-valent adsorbed pneumococcal polysaccharide conjugate vaccine) is an injection for intramuscular use

only. Synflorix is a prescription medicine for active immunisation of infants and children from the age of 6 weeks up to 5

years against disease caused by Streptococcus pneumoniae vaccine serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, 23F

and cross-reactive serotype 19A (including invasive disease, pneumonia, and acute otitis media). The recommended

immunisation schedule consists of three doses of 0.5 mL beginning at 6 weeks of age, with an interval of at least 1 month

between doses, plus a booster dose at least 6 months after this primary series. Children aged between 2 and 5 years

should have two doses with an interval of at least 2 months between doses. Each 0·5 mL dose contains 1mcg of

pneumococcal polysaccharide serotypes 1, 5, 6B, 7F, 9V, 14, and 23F and 3mcg of pneumococcal polysaccharide

serotypes 4, 18C, and 19F adsorbed onto 0·5mg aluminium phosphate. Synflorix also contains approximately 13mcg of

protein D carrier protein, approximately 8mcg of tetanus toxoid carrier protein, and approximately 5mcg of diphtheria

toxoid carrier protein. Contraindications: known hypersensitivity to any component of the vaccine. Precautions: As

with all injectable vaccines, provide appropriate supervision against rare anaphylactic events or fainting. Postpone in

those with acute severe febrile illness (i.e. not in minor infections). Use caution with coagulation disorders. As with all

vaccines a protective immune response may not be elicited in all vaccinees. Safety and immunogenicity data not

available in those with underlying medical conditions predisposing to pneumococcal infection (e.g. splenic dysfunction,

HIV). Data suggest that the use of prophylactic paracetamol might reduce the immune response to pneumococcal

vaccines; the clinical relevance of this observation remains unknown. Consider respiratory monitoring for 48–72h for very

premature infants. Common side effects: pain, redness, swelling, and induration at injection site; fever; drowsiness; loss

of appetite; and irritability. Uncommon side effects have also been reported, such as injection-site haematoma, apnoea,

and fits due to fever. As with some other vaccines, an increase in reactogenicity was reported after booster vaccination

compared to the primary course. Interactions: immune responses and the safety profiles of the coadministered vaccines

were unaffected, with the exception of the inactivated poliovirus type 2 vaccine, for which inconsistent results were

observed across studies. Before prescribing Synflorix, please review the full Data Sheet at www.medsafe.govt.nz.

Synflorix is a trade mark of the GlaxoSmithKline group of companies. Marketed by GlaxoSmithKline NZ Limited,

Auckland.