progress, challenges and opportunities for vaccines to reduce under-5 childhood mortality - prof....

National Institute for Communicable Diseases & University of Witwatersrand, South Africa

Respiratory and Meningeal Pathogens Research Unit,& DST/NRF: Vaccine Preventable Diseases

Shabir A. Madhi

Progress, Challenges and Opportunities for Vaccines to

Reduce Under-5 Childhood Mortality

● Institution received research grants from GSK, Pfizer and Novartis

● Honoraria for speaking from GSK, Pfizer, Abbott and Sanofi Pasteur

● Investigator in clinical vaccine trials for GSK, Wyeth, Novartis, Medimmune and Sanofi Pasteur

● Consultant/member of advisory boards for GSK, Pfizer, Merck and Novartis

Disclosure

Overview

● Trends in Global and sub-Saharan Africa under-5 childhood mortality.

● Recent contribution and challenges of childhood vaccines in reducing under-5 mortality.

● Potential of new childhood vaccines in reducing under-5 mortality.

● New horizons in reducing under-5/neonatal morbidity and mortality by vaccination.

Global Trends in Under-5 Childhood Deaths, 2000 to 2010

• Reduction in all-cause under-5 mortality from 9.629 to 7.622 million between 2000 to 2010.

• 3.55 million deaths occurred in Africa in 2010

Liu L et al. Lancet 2012; 379: 2151-61

Global Causes of Under-5 Childhood Deaths in 2013

Liu L et al. Lancet 2015; 385: 430-440

• Under-5 mortality declined to 6.3 million in 2013.• 51.8% (3.275 million) died due to infectious causes.• 44% (2.76 million) died during neonatal period.

Liu L et al. Lancet 2015; 385: 430-440

Causes of Under-5 Childhood Deaths in Sub-Saharan Africa in 2013

2013: Sub-Saharan Africa: 25% of global under-5 births50% of under-5 childhood deaths

Estimated Annual Rate of Reduction by Cause at the Global Level between 2000 to 2013

Target of 4.4% year on year decline was required to achieve MDG4 Goal of Reducing Under-5 Mortality by Two-thirds Between 1990 and 2015.

Liu L et al. Lancet 2015; 385: 430-440

Global Cause-Specific Mortality on 2030 Within the Achievement Scenario by Comparison with Cause-

Specific Mortality in 2013.

Liu L et al. Lancet 2015; 385: 430-440

• 4.4 million childhood deaths still expected in 2030.

Sub-saharan Africa (2030):● 33% of births globally in 2030 vs. 25% in 2015● 60% of under-5 deaths in 2030 vs. 50% in 2015

Overview





Percentage of deaths (2.5 million) from vaccine-preventable diseases (VPDs) among children <5 years worldwide, 2002

Oth

er V

PD

s1

% (

25

000)

MMWR; 2006: 55:511-5 &WHO. 2004: Global Immunization Data

Over 50% of VPDs in under-5 children in 2002 due to diseases for which vaccine available since the 1930s-early 90s.

Progress and Challenges Toward Measles Elimination

Source: http://www.immunize.org/photos/polio-measles.asp

Measles Containing Vaccine Coverage By WHO Region,1980-2011; Global Coverage At 84% In 2011

Source: WHO/UNICEF coverage estimates 1980-2011193 WHO Member States. Date of slide: 2 Nov 2012

Estimated measles deaths in 2000 and 2010

10 100

48 600

139 300 measles deaths in 2010

Simons E et al. Lancet 2012; 379: 2173-78

74% decrease in global measles deaths between 2000 to 2010.

Target: 90% reduction in measles mortality by 2010 compared to 2000.

85%26%

76%1

78%

78%

1 Per cent reduction in 2010 compared to 2000

13.8 Million Measles Deaths Averted Globally between 2000 to 2012.

Simons E et al. Lancet 2012; 379: 2173-78

During 2000-2012:77% decrease in incidence78% decline in deaths

ARE WE ON TRACK TO REACH OUR GVAP COVERAGE GOALS ?

Global Immunization 1980-2015 and projections to reach 90% global coverage goals in 2020 - MCV1 coverage

0

20

40

60

80

10019

8019

8119

8219

8319

8419

8519

8619

8719

8819

8919

9019

9119

9219

9319

9419

9519

9619

9719

9819

9920

0020

0120

0220

0320

0420

0520

0620

0720

0820

0920

1020

1120

1220

1320

1420

1520

1620

1720

1820

1920

20

%

cove

rag

e

Global African American Eastern Mediterranean

European South East Asian Western Pacific

Source: WHO/UNICEF coverage estimates 2015 revision. July 2016Immunization Vaccines and Biologicals, (IVB), World Health Organization.194 WHO Member States. Date of slide: 26 July 2016

0 2,100 4,2001,050 Kilometers

Immunization coverage with 1st dose of measles containing vaccines in infants, 2015

Source: WHO/UNICEF coverage estimates 2015 revision. July 2016. Map production: Immunization Vaccines and Biologicals, (IVB). World Health Organization. 194 WHO Member States.Date of slide: 25 July 2016

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 2016. All rights reserved

<50% (4 countries or 2%)

50-79% (38 countries or 20%)

80-89% (33 countries or 17%)

>=90% (119 countries or 61%)

Not available

Not applicable

Percentage of children under one year age who received measles vaccine, by household wealth quintile and region

Pe

rce

nt

Source: UNICEF. Pneumonia and Diarrhoea. June 2012. Available: www.childinfo.org/publications

• Need to focus immunization efforts on reaching out to the poorest quintile, who are also disadvantaged to access to curative health services

Global Immunization 1980-2015, DTP3 coverage

global coverage at 86% in 2015

212426

3945

495256

6468

7672707073737271727272737375767879808284858585858586

0

20

40

60

80

1001980

1981

1982

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

% c

ove

rag

e

Global African American Eastern Mediterranean

European South East Asian Western Pacific

Source: WHO/UNICEF coverage estimates 2015 revision. July 2016Immunization Vaccines and Biologicals, (IVB), World Health Organization.194 WHO Member States. Date of slide: 16 July 2016.

19.4 million infants not immunized (DTP3), 2015

African

American

Eastern Mediterranean

European

South East Asian

Western Pacific

Source: WHO/UNICEF coverage estimates 2015 revision. July 2016 / United Nations, Population Division. The World Population Prospects - the 2015 revision". New York, 2015.Immunization Vaccines and Biologicals, (IVB), World Health Organization.194 WHO Member States. Date of slide: 28 July 2016.

0 2,100 4,2001,050 Kilometers

“Developing”* countries with % of districts achieving at least 80% DTP3 coverage, 2015


<50% of districts (27 countries or 17%)

50-79% of districts (34 countries or 22%)

80-99% of districts (36 countries or 23%)

100% of districts (39 countries or 25%)

Developed economies (39 countries )

Not Available (19 countries or 12%)

Not applicable

*155 developing countries and economies in transition per UN World Economic & Social Survey, 2015 classification

Source: WHO Database as at 28 July 2016. Map production: Immunization Vaccines and Biologicals, (IVB). World Health Organization. 194 Member States. Date of slide: 29 July 2016

Progress in Polio Eradication, Estimated and Reported Polio Cases, 1985-2015

Source: WHO/Polio database, Aug 2016

194 WHO Member States.

0

100

200

300

400

Nu

mb

er (

tho

usa

nd

s)

19

85

19

86

19

87

19

88

19

89

19

90

19

91

19

92

19

93

19

94

19

95

19

96

19

97

19

98

19

99

20

00

20

01

20

02

20

03

20

04

20

05

20

06

20

07

20

08

20

09

20

10

20

11

20

12

20

13

20

14

20

15

Reported Estimated

1988: WHA Resolution to Eradicate Polio

2000: Original Target Date for Interruption of Transmission

Reported cases: 2 971Estimated cases: 3 500

1999: WHA Resolution to accelerate polio eradication

activities

2015: Reported wild poliovirus

cases: 74

Polio Eradication Progress, 1988 – 2015

Source: WHO/POLIO database, as of Aug 2016

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 2016. All rights reserved

Certified polio-free regions (126 countries)

Endemic with wild poliovirus ( 2 countries)

Not certified but non-endemic (65 countries)

Global estimates of burden of deaths due to H. influenzae type b in children younger than 5 years; 2000

Watts JP, et al. Lancet 2009; 374:903=11

• Hib caused 8.13 (7.33-13.2) million serious illnesses worldwide in 2000

• Hib caused 371 000 (247 000-527 000) deaths in 2000

Africa: 181 000(126 000-251 000)

Americas: 8 400(5200-11700)

SE Asia: 75 300(53 000-109 900)

Western Pacific: 17 600(12 400-25 600)

Europe: 6 500(4 600-9 500)

Eastern Mediterranean41 600

(29 300-60 700)

Proportion of countries, by income-group, that have introduced Hib conjugate vaccine into immunization

programs

Source: UNICEF. Pneumonia and Diarrhoea. June 2012. Available: www.childinfo.org/publications

Per

ce

nt

cou

ntr

ies

in w

hic

h H

ibC

V

intr

od

uce

d

Overview





Substantial Experience in last 15 years with New Vaccine Introduction to EPI

Malaria (≈ 2015)

Maternal Tetanus (1983)

1920-1939: 1 vaccine1940-1959: 3 vaccines1960-1979: 4 vaccines1980-1999: 3 vaccines2000-2019: > 12 vaccines

Rabies(1880’s)

1974: EPI(BCG, OPV, DTP, Measles)

DTP+HepB+Hib(Pentavalent)(1998)

Courtesy Kate O’Brien. IVAC, JHU

Global Causes of Under-5 Childhood Deaths in 2013 (n=6.3 million)

Liu L et al. Lancet 2015; 385: 430-440

Overview





Death rate of pneumococcal disease in children <5 years (per 100,000)

0

50

100

150

200

250

300

350

400

450

500

Africa America EasternMediterranean

Europe Southeast Asia Western Pacific

Inci

denc

e ra

tes

per 1

00 0

00

100,100 15,100 187,000 43,000Number of deaths: 447,000 33,100

O’Brien K et al. Lancet 2009;374;893–902

90% of the 830 000 pneumococcal deathsassociated with pneumonia

Invasive Pneumococcal Disease in South African Children < 2 years age: 2005-2012

>80% reduction in PCV7 serotype IPD in HIV-infected and HIV-uninfected children within 3 years of vaccine introduction.

Von Gottberg A et al New Eng J Med; 2014. 371 (20): 1889-99.

Time Series Analysis of PCV7/13 Against All-Cause Pneumonia Hospitalization (Soweto) in HIV-uninfected

Children, 2006 to 2014

Izu A et al. ISPPD June 2016

Reduction: 54% (95%CI: 37, 65) Reduction: 32% (95%CI: 10, 48)

Reduction: 13% (95%CI: -23, 37) Reduction: 50% (95%CI: 30, 64)

Reduction compares 2012-2014 vs. 2006-2008

PCV and HibCV Vaccine Introduction by Income Group

http://www.jhsph.edu/research/centers-and-institutes/ivac/resources/PCVImpactGapAnalysis_MAR2016_FINAL_public.pdf

PCV Introduction by GAVI and Country Income Status

http://www.jhsph.edu/research/centers-and-institutes/ivac/resources/PCVImpactGapAnalysis_MAR2016_FINAL_public.pdf

Immunization coverage with PCV3 containing vaccines in infants, 2015



50-79% (22 countries or 11%)

80-89% (26 countries or 13%)

>=90% (57 countries or 29%)

Not available / not in national immunization schedule (65 countries or 34%)

Not applicable

PCV in schedule but no coverage data available (9 countries or 5%)Source: WHO/UNICEF coverage estimates 2015 revision, July 2016. Map production: Immunization Vaccines and Biologicals, (IVB). World Health Organization. 194 WHO Member StatesDate of slide: 02 August 2016

0 2,100 4,2001,050 Kilometers

Point estimates of Rotarix* and RotaTeq† vaccine Efficacy in Relation to Country GDP

Nelson EAS & Glass RI, Lancet 2010; 367: 568-9

Possible reasons for lower efficacy in developing countries• High maternal antibody titres• Breastfeeding at vaccination

• Micronutrient deficiencies • Interfering microorganisms

• HIV and malaria

Severe Rotavirus GE Episodes Prevented per 100 children

0

1

2

3

4

5

6

7

8

9

Africa South Africa MalawiSev

ere

rota

viru

s G

E e

pis

od

es p

er 1

00

Placebo

Vaccine

3 episodes prevented

2.5 episodes prevented

3.9 episodes prevented

VE:61.2% 76.9% 49.5%

(44.0 – 73.2) (56.0 – 88.5) (19.2 – 68.3)

Madhi SA, Cunliffe NA et al. NEJM. 2010; 362: 289-298

Number of diarrhea-related deaths among children aged <59 months in Mexico by age group; July 2002 to May

2009

Richardson V et al. N Eng J Med 2010; 362; 299-305

41%; 95%CI 36 to 47

29%; 95%CI 17 to 39

Rotavirus Vaccine Introduction by GAVI and Country Income

Immunization coverage with Rotavirus vaccine in infants, 2015



50-79% (17 countries or 9%)

80-89% (29 countries or 15%)

>=90% (22 countries or 11%)

Not applicable

Rotavirus vaccine in schedule but no coverage data available (6 countries or 3%)

Not available / not in national immunization schedule (110 countries or 57%)Source: WHO/UNICEF coverage estimates 2015 revision, July 2016. Map production: Immunization Vaccines and Biologicals, (IVB). World Health Organization. 194 WHO Member StatesDate of slide: 02 August 2016

0 2,100 4,2001,050 Kilometers

Overview

● Trends in Global and South American under-5 childhood mortality.

● Recent contribution of childhood vaccines in reducing under-5 mortality.

● Potential of new childhood vaccines in reducing under-5 mortality:

Malaria vaccine


Cause-specific mortality rates in African Children aged 1-59 months, 2000 to 2010

Liu L et al. Lancet 2012; 379: 2151-61

Kaplan-Meyer Survival Plots for RTS,S Malaria Vaccine; Pooled Data of Phase 2 Data

Severe Malaria Deaths

Bejon P et al. Lancet Infect Dis; 2013; 13: 319-27.

Vaccine Efficacy Varied from 36% (95%CI: 24 to 45) at time of vaccination to 0% (-38 to 38) after 3 years

Changes In Malaria Indicators, Relative to Introduction or Upscaling of Control Measures in Bioko Island,

Equitorial GuineaIn

cid

en

ce

of

Pe

dia

tric

inp

ati

en

t m

ala

ria

(p

er

10

00

ch

ild

ren

)

Bioko Island, Equitorial GuineaBioko Island, Equitorial Guinea

• IRS: Indoor residual spraying• ACTs: Artemisinin combination therapies• LLITNs: Long Lasting Insecticide treated bed nets

O’Meara WP; Lancet Infect Dis; 2010; 10: 545-55

The Meningitis Belt in Africa and meningococcal A Conjugate Vaccine (PsA-TT) rollout 2010-2016.

Novak RT; Lancet Infect Dis; 2012; 12: 757-64

Cumulative Curve Rates per 100 000 of Suspected Meningitis Cases and Deaths; Burkina Faso (1997:2011)

Suspected meningitis cases

Suspected meningitis deaths

Novak RT et al. Lancet Infect Dis; 2012; 12: 757-64

Proportion of Confirmed Meningitis Cases by Year Attributable to Different Bacteria; Burkina Faso

Novak RT et al. Lancet Infect Dis; 2012; 12: 757-64

Effectiveness of MenAfriVac on Incidence of meningitis in Chad (2009-2013)

Daugla DM; Lancet 2014; 383: 40-47 94% difference in crude incidence of

meningitis

Number of Suspected Meningitis Cases by Week In Niger: 1 Jan- 30 June 2003 to 2015.

Sidikou F et al. Lancet Infect Dis; 2016

Laboratory-confirmed Cases of Meningitis by Epidemiological Week and Pathogen;

1 Jan 2015- 30 June 2015

Sidikou F et al. Lancet Infect Dis; 2016

Overview

● Trends in Global and South American under-5 childhood mortality.

● Recent contribution of childhood vaccines in reducing under-5 mortality.


● New horizons in reducing under-5 (neonatal) morbidity and mortality by vaccination.

Global Causes of Under-5 Childhood Deaths in 2013

Liu L et al. Lancet 2015; 385: 430-440

• 44% (2.76 million) of under-5 deaths occur during neonatal period.

Vaccination of Pregnant Women: An Evolving Paradigm Shift Aimed at Protection of The Fetus and Young

Infants.

Estimated Preterm Birth Rates by Country for Year 2010

Blencome H, et al. Lancet; 2012; 379: 2162-72

• In 2010 14.9 million (Range 12.3-18.1) born preterm.• 11.1% of all births born preterm; 5% in Europe to 18% in Africa.• Only 3 of 65 countries reduced preterm birth rate between 1990-2010.

Blencowe et al. Lancet Global Health; 2016; 4: e98-108.

Estimated Country-level Stillbirth Rates, 2015.

Potential Benefits of Maternal Immunization (MI)

MI may protect infants <5-mo against infection-related deaths

MI can have an impact on maternal morbidity and mortality

MI may also prevent a portion of infection-related stillbirths (10 – 50%1

of the overall stillbirths)

1. McClure EM, "Stillbirth in Developing Countries: A review of causes, risk factors and prevention strategies" , J. of Matern Fetal Neonatal Med. (2014); 2. WHO-CHERG 2013 ● 4

Global neonatal mortality2

Infectionrelated606K(22%)

Pre-term births965K(35%)

Other1,190K(43%)

Success of Maternal Tetanus Vaccination in Preventing Neonatal Tetanus Deaths

1.270.000

787.000

490.000

248.000 200.000 180.000

128.000 59.000

… 49.000 9

37

5659 57

62 61 61

7468

75

65

0

10

20

30

40

50

60

70

80

90

100

-

200.000

400.000

600.000

800.000

1.000.000

1.200.000

1.400.00019

8019

8119

8219

8319

8419

8519

8619

8719

8819

8919

9019

9119

9219

9319

9419

9519

9619

9719

9819

9920

0020

0120

0220

0320

0420

0520

0620

0720

0820

0920

1020

1120

1220

13

Reported TT2+ coverage & estimated NT deaths1980-2013

Est NT Deaths TT2+ (%)WHO-UNICEF Data & CHERG Reports

TT2+ Coverage (percentage)

Num

ber N

T D

eath

s

Neonatal Tetanus Global Annual Reported Cases and TT2plus coverage, 1980-2013

Zaman K; NEJM;2008

Madhi S; NEJM;2015

Vaccination of HIV- pregnant women in preventing Influenza-confirmed illness in their infants <6 months age.

Meta-analysis on Effect of Maternal Seasonal Influenza Vaccination on Preterm Births

Nunes M et al. Am J Perinatology; 2016

Overall (I-squared = 47.4%, p = 0.107)

Adedinsewo et al.

Dodds et al.

Legge et al.

Omer et al.

Nordin et al.

Study

2013

2012

Year

2010-2012

2011

2014

Published

0.87 (0.77, 0.99)

0.83 (0.59, 1.16)

0.84 (0.69, 1.02)

Adjusted Odds

0.75 (0.60, 0.94)

0.83 (0.55, 1.26)

0.97 (0.93, 1.02)

Ratio (95% CI)

0.87 (0.77, 0.99)

0.83 (0.59, 1.16)

0.84 (0.69, 1.02)

Adjusted Odds

0.75 (0.60, 0.94)

0.83 (0.55, 1.26)

0.97 (0.93, 1.02)

Ratio (95% CI)

1.5 .75 1 1.25 1.5 1.75 2

TIV containing or not H1N1 papers not restricted to flu season Preterm

2014

Hazard ratio of Stillbirth by Seasonal Influenza Activity (Australia 2012-2013)

Regan AK et al. Clin Infect Dis; 2016;62(10):1221–7

Other Vaccines Currently Recommended or In Clinical Development For Immunization of Pregnant Women to

Protect Young Infants

● Pertussis vaccine:

80% pertussis deaths occur in infants <2 months age

Recommended in many High-Income countries and studies underway on LMIC

Group B Streptococcus serotype-specific protein-polysaccharide conjugate vaccine

Leading cause of neonatal sepsis in high-income and LMIC countries

Phase II studies on trivalent vaccine completed.

Respiratory Syncytial Virus

Leading cause of pneumonia hospitalization globally, with estimated 66,000-240,000 deaths annually.

Multiple vaccine candidates aimed at pregnant women under clinical development.

Conclusions

● Significant advances made since 1990 in reduction of mortality from polio, measles and neonatal tetanus over relative short periods because of vaccination.

● Newly licensed vaccine against major pathogens causing diarrhoea (rotavirus), pneumonia (pneumococcus) and meningitis (pneumococcus and meningococcus A/B/C/Y/W) have potential of preventing approximately 650-750 thousand childhood deaths annually.

● Next frontier is targeting vaccination of pregnant women for reducing death from neonatal and early-infancy vaccine-preventable diseases.

● Full benefit of advances in vaccine development will only be realised when equity of access addressed between and within countries.

Reported Cases of Meningitis in Chad; 1930-2012

Daugla DM; Lancet 2014; 383: 40-47

progress, challenges and opportunities for vaccines to reduce under-5 childhood mortality - prof....

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