prof kim mulholland @ mrf's meningitis & septicaemia in adults & children

Pneumococcal vaccines – impact in the developing world

Kim MulhollandMurdoch Children’s Research Institute, MelbourneLondon School of Hygiene and Tropical medicine

University of Melbourne

Pneumococcal vaccines - history

• 1911 – 1st pneumococcal vaccine trial in South Africa

• 1930-34 – 7-valent pneumococcal vaccine protected miners against types 1,2,3,5,7,12,14 (Pub South African Inst Med Research 1935;37:7)

• 1945 – 4-valent vaccine (1,2,5,7) in US Air Force recruits– ↓ pneumococcal pneumonia– ↓ pneumococcal carriage of vaccine types

(J Exp Med 1945;82:445-65)

– Licensed by Squibb, abandoned in 1951

• 1960s – Robert Austrian argued that pneumococcus remained an important cause of death

• 1977 – 14-valent PS vaccine licensed by Merck

• 1983 – 23-valent PS vaccine licensed

• 1986 – Trial of PS vaccine in Papua New Guinea children published (I Riley et al)

• 1988 – work begins on pneumococcal conjugate vaccine (NIH-Praxis Biologics)

• 1990 – Hib conjugate vaccine licensed for use in infants

• 2000 – Gavi Alliance launched

• 2000 – 1st PCV licensed (PCV7 or Prevnar-7®, Wyeth Vaccines)– $57/dose

– ST1 and ST5 excluded

– PCV9 (with 1 & 5) produced and used in key trials in Gambia and South Africa

• Around 2003 – PCV11 (Sanofi Pasteur) abandoned midway through Philippines trial

• 2003 – Initiatives to make PCVs available– PneumoADIP

– Advance Market Commitment

– International Finance Facility for Immunization

• 2009 – PCV7 introduced into South Africa, Gambia and Rwanda

• 2009 – PCV7 introduced into South Africa, Gambia and Rwanda

ES Donkor et al. Vaccination against pneumococcus in West AfricaInt J Gen Med 2013;6:757-764

Invasive pneumococcal disease in West Africa

• 2009 – PCV7 introduced into South Africa, Gambia and Rwanda

• 2009 – PCV10 licensed (Synflorix®, GSK)

• 2010 – PCV13 licensed (Prevnar-13®, Pfizer)

• 2011 – PCV13 introduced Gambia, S Africa

• 2012 (April) – PCV13 introduced Ghana

• 2016 – January-February major meningitis outbreak in Ghana– Most pneumococcus ST1

Ghana meningitis outbreak 2016

• Dec 2015 – March 2016• Over 12 weeks:• 567/886 suspected cases had LP• 135 confirmed meningitis• 104 pneumococcal meningitis

Brenda Kwambana-Adams et al. BMC Infectious Diseases 2016;16:575

Ghana meningitis outbreak 2016

Brenda Kwambana-Adams et al. BMC Infectious Diseases 2016;16:575

Ghana meningitis outbreak 2016

Kwambana-Adams BA et al. BMC Infectious Diseases 2016;16:575

Ghana pneumococcal meningitis cases

Kwambana-Adams BA et al. BMC Infectious Diseases 2016;16:575

PCV introduced April 20126,10,14 weeks

Do PCVs protect against ST1 in Africa?

• Gambia and SA PCV9 trials (combined)

– Vaccinees – 5

– Controls – 5

• Is a late (booster) dose preferable to just a primary series?

– Is 2+1 superior to 3+0?

• OPA data suggests much better ST1 response after booster, so…

POET study (PCV11, GSK) OPA data

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10

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ST1 ST6B ST19F ST23F

Chart Title

post-primary pre-boost post-boost

Vaccine 25 (2007) 1962–1968

UK Serotype 1 disease

2+1 schedule

Ghana pneumococcal meningitis cases

Kwambana-Adams BA et al. BMC Infectious Diseases 2016;16:575

PCV introduced 4 years earlier

Unasnwered questions

• Do PCV10 and PCV13 protect individuals/communities against ST1 disease?

– Is 2+1 schedule better than 3+0?

• Is there a role of monovalent type 1 PCV for controlling outbreaks?

– Or combined with Mening. conjugate vaccine?

Pneumococcal conjugate vaccines

• 7-valent Pnc-CRM (Prevnar7®, Wyeth/Pfizer) licensed in US, 2000

• 9-valent Pnc-CRM trialed in South Africa and Gambia, but never licensed (includes 1&5)

• 11-valent vaccine from Sanofi Pasteur trialedin Philippines, but never licensed

• 10-valent Pnc-Protein D (Synflorix®, GSK) licensed in Europe 2009

• 13-valent Pnc-CRM (Prevnar13®, Pfizer) licensed in US 2010

Pneumococcal vaccines under development

• Conjugate vaccines– PCV10 – Serum Institute of India (in Phase 3)

– PCV10 – Panacea, India

– PCV11, PCV12 – GSK

– PCV15 – Merck

– PCV16 – Sanofi

– PCV20 – Pfizer

• Other vaccines– Whole Cell vaccine (BioFarma Indonesia)

– Various protein vaccines

Pneumococcal Conjugate Vaccine national immunization programmes, 2017

* Includes partial introduction

Data source: WHO/IVB Database, as of 14 April 2017

Map production Immunization Vaccines and Biologicals

(IVB),

World Health Organization

The boundaries and names shown and the designations used on this map do not imply

the expression of any opinion whatsoever on the part of the World Health

Organization concerning the legal status of any country, territory, city or area or of its

authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines

on maps represent approximate border lines for which there may not yet be full

agreement. ©WHO 2017. All rights reserved.

Introduced* to date (133 countries or 68.6%)

Planned introductions in

2017

(4 countries or 2.1%)

Not Available, Not Introduced/No Plans

(57 countries or 29.4%)Not applicable

PCV impact studies

• Options

– Pre and post – ecological approach

• Surveillance

• Routine data (eg. UK)

– Case control study

• OK for IPD

• Probably not OK for pneumonia

– Phased introduction

• Eg. Mongolia

Pneumonia hospitalizations - USA

PCV introduction

Ongoing PCV impact studies in Asia

• Laos – PCV13 impact study

• Mongolia – PCV13 pilot introduction in 2 districts of Ulaanbaatar (June 2016)

• Fiji – PCV10 impact study

• Nepal – PCV13 impact study

• Pakistan – PCV10 impact study

• India – PCV13 impact on pneumonia

PDR Laos

• Introduced PCV13 in 2013

• Pneumonia burden high – 20% of paediatric admissions

• Evaluation started around the time of PCV introduction– Community carriage surveys

– Monitor pnc carriage in pneumonia cases

– Monitor % of IPD cases due to PCV13 types

– Compare vaccinated and unvaccinated cases

Laos – early findings

• Hypoxic pneumonia was less common in

vaccinated than unvaccinated children

with pneumonia (12.6% vs 22.3%, p=

0.0001)

• Pneumococcal carriage rates were similar

between vaccinated and unvaccinated

children with pneumonia (p=0.757)

IPD cases in children under 5

Bacterial meningitis in Beijing Children’s Hospital, China

Data fromProf H Yang

PCV impact in Mongolia

Pre-vaccination IPD data for Mongolia

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Chart Title

VT non-VT

Dominant serotypes: 19F – 23; 6A/B/C – 17; 9V – 11; 14 – 9; 19A – 6;

Fiji

• Population of 840,000

• Hib vaccine – 1998

• PCV – 2012

• Since 2012 meningitis remains a problem

• Antibiotic abuse minimal

In Fiji since 2012…

• 13/16 meningococcal meningitis Group B

• 1/14 pneumococcal meningitis cases VT

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2013 2014 2015 2016 2017

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Meningococcal Cases at CWMH

Conclusions

• Pneumococcal vaccines have major potential benefits

• IPD surveillance– possible in selected sites in Africa

– very difficult in Asia

• Impact demonstration will be demanded by the community and politicians

• To be valid must be done very carefully and well in selected sites