National Institute for Communicable Diseases &

University of Witwatersrand, South Africa

Respiratory and Meningeal Pathogens Research Unit,

& DST/NRF: Vaccine Preventable Diseases

Shabir A. Madhi

Role of vaccines in making the

world a better place for children

Overview

● Trends in Global under-5 childhood morbidity and

mortality.

● Impact of recently developed vaccines aimed at

reducing under-5 mortality from:

i. Pneumonia

ii. Diarrhoea

● 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 Child 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.

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

Distribution of Livebriths and under-5 deaths in

2013 and 2030

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

Overview

● Trends in Global under-5 childhood morbidity and

mortality.

● Impact of recently developed vaccines aimed at

reducing under-5 mortality from:

i. Pneumonia

ii. Diarrhoea

● New horizons in reducing under-5/neonatal morbidity

and mortality by vaccination.

Substantial Experience in last 15 years with

New Vaccine Introduction to EPI

Malaria (≈ 2015)

Maternal

Tetanus

(1983)

1920-1939: 1 vaccine

1940-1959: 3 vaccines

1960-1979: 4 vaccines

1980-1999: 3 vaccines

2000-2019: > 12 vaccines

Rabies

(1880’s)

1974: EPI

(BCG, OPV, DTP, Measles)

DTP+HepB+Hib

(Pentavalent)

(1998)

Courtesy Kate O’Brien. IVAC, JHU

Percentage of deaths (2.5 million) from vaccine-preventable

diseases (VPDs) among children <5 years worldwide, 2002 Reduction in Vaccine Preventable Deaths have Lagged Behind

Development of New Vaccines.

Oth

er

VP

Ds

1%

(2

5 0

00

)

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

Global Measles Coverage At 84% In 2012 Measles Containing Vaccine Coverage By WHO Region,1980-2012

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 incidence

78% decline in deaths

Within Region Inequity in Measles Coverage by Economic

Quintile Group Percentage of children under one year age who received measles vaccine, by

household wealth quintile and region.

Perc

en

t

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

Estimated Number of Deaths in Children aged

1-59 months by Cause, 2013 Approximately 1.2 million Vaccine Preventable Deaths in 2013

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

Cause Number of Deaths (UR; 1000s)

Other Disorders 967 (781 - 1,134)

Pneumonia 800 (681 - 923)

Diarrhea 558 (429 - 731)

Malaria 456 (351 - 546)

Injury 324 (258 - 391)

Meningitis 151 (125 - 185)

AIDS 103 ( 76- 142)

Measles 102 ( 74- 166)

Pertussis 60 ( 43- 94)

Overview

● Trends in Global under-5 childhood morbidity and

mortality.

● Impact of recently discovered vaccines aimed at

reducing under-5 mortality from:

i. Pneumonia: Pneumococcal Conjugate Vaccine

ii. Diarrhoea

● New horizons in reducing under-5/neonatal morbidity

and mortality by vaccination.

Death rate of Pneumococcal Disease in Children <5 years

(per 100,000) in 2000

0

50

100

150

200

250

300

350

400

450

500

Africa America EasternMediterranean

Europe Southeast Asia Western Pacific

Inci

den

ce r

ates

per

100

000

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

33,100

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

90% of the 830 000 pneumococcal deaths

associated with pneumonia

Direct Effect of Vaccination: Invasive Pneumococcal

Disease Among Children < 5 Years, 1998/99–2007 *100% Reduction in vaccine-serotype IPD in USA within 7 years of PCV7

introduction

Cases/1

00,0

00 p

op

ula

tio

n

0

10

20

30

40

50

60

70

80

90

1998 1999 2001 2000 2002 2003 2004 2005 2006 2007

Year

PC

V7 in

trod

uced

Serotype group

PCV7 type

Non-PCV7 type

19A

Pilishvili T, et al. J Infect Dis. 2010;201:32-41.

*

Impact of 7-valent PCV on Incidence of Vaccine-

serotype Invasive Pneumococcal Disease. 80%-100% decline in vaccine-serotype IPD following PCV immunization of

children experienced consistently in all introducing countries.

Adapted from: Fitzwater SP et al. PIDJ; 2012: 31: 501-508

Invasive Pneumococcal Disease Among Adults ≥ 65

Years, 1998/99–2007 *92% reduction in PCV7 serotype IPD in the Elderly Due to Indirect Effect Resulting from

Reduced Transmission from Children

Pilishvili T, et al. J Infect Dis. 2010;201:32-41.

Cases/1

00,0

00 p

op

ula

tio

n

0

5

10

15

20

25

30

35

40

1998 1999 2001 2000 2002 2003 2004 2005 2006 2007

Year

PC

V7 i

ntr

od

uced

Serotype group

PCV7 type

Non-PCV7 type

19A

*

Number of IPD Cases and Deaths Prevented in USA

following PCV7/13 Childhood Immunization Greater 50% of cases and 90% of deaths averted occurred in unvaccinated

agegroups (i.e. indirect effect).

Death

s p

reven

ted

C

ases p

reven

ted

Moore M et al. Lancet Infect Dis; 2015; 15: 301-309

Effectiveness of PCV7 Against All-cause Pneumonia

Hospitalization in USA Children; 1997 to 2009 40% reduction in all-cause pneumonia hospitalization in USA in children <2 years

age.

Griffin MR et al. N Eng J Med 2013; 369:155-63

Indirect Effect of Childhood PCV7 Immunization on all-cause Pneumonia Hospitalization in USA Adults; 1997 to 2009

PCV vaccination of children results in protection against pneumonia in adults

Griffin MR et al. N Eng J Med 2013; 369:155-63

Invasive Pneumococcal Disease in South African Children < 2

years age: 2005-2012 >80% reduction in PCV13 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.

PCV7/13 Introduction and Invasive Pneumococcal Disease by

age-group in South Africa: 2005-2012 Reduction in IPD Observed in Unvaccinated Agegroups, including HIV-infected

Adults 25-44 years of age.

PCV7 PCV13

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

Vaccine Introduction by Country Income Group for HibCV

and PCV Time lag for similar coverage of PCV into LMIC will be half that of HibCV.

Uptake of PCV to current DTP3 coverage levels in low income countries could

potentially prevent approximately 430 000 under-5 childhood deaths annually.

Overview

● Trends in Global under-5 childhood morbidity and

mortality.

● Impact of recently dieveloped vaccines aimed at

reducing under-5 mortality from:

i. Pneumonia

ii. Diarrhoea: Rotavirus vaccine

● New horizons in reducing under-5/neonatal morbidity

and mortality by vaccination.

Rotavirus detection rates and deaths due to diarrhoea

and rotavirus by WHO child mortality group and region.

Country category Mean rotavirus

detection rate

(95%CI)

Number of

diarrhoea related

deaths

Number of deaths

attributed to

rotavirus

Very low child

mortality

49% (34-64) <1 000 <1 000

Low child mortality 40% (36-44) 67 000 27 000

Asia1 42% (35-48) 452 000 188 000

Americas1 42% (37-47) 13 000 5 000

Africa1 33% (28-38) 704 000 232 000

Total 1 236 000 453 000

1 High and medium mortality countries.

Tate JE, et al. Lancet Infect Dis; 2012; 12: 136-41 (adapted)

• Rotavirus accounts for 37% of all diarrhoea related death; and 5% of

all-cause deaths in children under-5.

• 95% of rotavirus deaths occur in 72 GAVI eligible countries

Point estimates of Rotarix* and RotaTeq† vaccine Efficacy in

Relation to Country GDP Rotavirus Vaccine Efficacy Lower in Low-Income Settings

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

In South Africa (Middle Income) and Malawi (low income). Despite lower vaccine efficacy in low income settings, higher rate reduction of

severe cases

0

1

2

3

4

5

6

7

8

9

Africa South Africa MalawiSe

ve

re r

ota

vir

us

GE

ep

iso

de

s p

er

10

0

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

Percentage Reduction in Number of Rotavirus

Hospitalizations in Children <5 years Following Rotavirus

Vaccine Introduction.

Tate JE & Parashar UD. Clin Infect Dis; 2014, 59: 1291-1301

Number of Diarrhea-related Deaths among Children aged

<59 months in Mexico by age group. 41% reduction in all-cause diarrhoea deaths within one year of vaccine

introduction in infants

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

41%; 95%CI 36 to 47

29%; 95%CI 17 to 39

Percentage Reduction in Number of Diarrhoea Deaths

in Children <5 years Following Rotavirus Vaccine

Introduction in Middle-Income Countries.

Tate JE & Parashar UD. Clin Infect Dis; 59: 1291-1301

Overview

● Trends in Global under-5 childhood morbidity and

mortality.

● Impact of recently developed vaccines aimed at

reducing under-5 mortality from:

i. Pneumonia

ii. Diarrhoea

● New horizons in reducing under-5/neonatal morbidity

and mortality by vaccination.

Vaccination of Pregnant Women: An Evolving Paradigm

Shift Aimed at Protection of The Fetus and Young

Infants.

Success of Maternal Tetanus Vaccination in

Preventing Neonatal Tetanus Deaths

1 270 000

787 000

580 000 490 000

248 000 200 000 180 000

128 000 59 000

58 000 49 000 9

37

56 59 57

62 61 61

74

68

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

1 400 000

19

80

19

81

19

82

19

83

19

84

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

Reported TT2+ coverage & estimated NT deaths 1980-2013

Est NT Deaths TT2+ (%)

WHO-UNICEF Data & CHERG Reports

TT 2+ C

ove

rage (p

ercentage

) N

um

be

r N

T D

eat

hs

Neonatal Tetanus Global Annual Reported

Cases and TT2plus coverage, 1980-2013

Overview

● Trends in Global under-5 childhood morbidity and

mortality.

● Impact of recently developed vaccines aimed at

reducing under-5 mortality from:

i. Pneumonia

ii. Diarrhoea

● New horizons in reducing under-5/neonatal morbidity

and mortality by vaccination.

Influenza vaccination of pregnant women

Incidence of laboratory-confirmed influenza associated

hospitalization in Soweto, South Africa. Highest incidence of severe influenza hospitalization is in infants <6 months

age for whom there is no licensed vaccine.

Cohen C/Madhi SA et al. Emerg Infect Dis; 2013; 19; 1766-1774

Vaccine Efficacy of Influenza Vaccination of Pregnant

HIV- Women against PCR-confirmed Influenza Illness up

Until 24 weeks Post-partum.

● Vaccine efficacy (ITT): 50.4% (95%CI: 14.5; 71.2)

AR: 3.6%

AR: 1.8%

Madhi SA et al. New Engl J Med; 2014: 371: 918-31

Vaccination of HIV- Pregnant Women in Preventing

Influenza-Confirmed illness in their Infants up until 24

Weeks of age.

0

5

10

15

20

25

30

35

40

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Cu

mu

lati

ve in

flu

en

za c

ases

Age (weeks)

Vaccine placebo

VE (ITT): 48.8% (95%CI: 11.5; 70.3)

VE (PP): 45.6% (95%CI: 2.4; 69.7)

AR: 3.6%

AR:1.9%

Madhi SA et al. New Engl J Med; 2014: 371: 918-31

Vaccination of HIV- Pregnant Women in Preventing

Influenza-Confirmed illness in their Infants <6 months

age.

63.0%; 95%CI: 7.8-85.2

48.8%; 95%CI: 11.6- 70.4

Vaccine efficacy; 95%CI

Bangladesh

S. Africa

53.0%; 95%CI: 24.9- 70.6

Summary VE

Images from: http://www.medicinenet.com/stages_of_pregnancy_pictures_slideshow/article.htm

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 (range: 5% in Europe to 18% in Africa).

• 15% of all under-5 childhood deaths due to complications of prematurity.

Effect of Influenza Immunization During Pregnancy

on Birth Outcomes (356 930 mother-newborn pairs)

Steinhoff MC et al. Lancet; 2014; 383: 1611-2

Overall effect:

Premature birth: OR 0.78 (95%CI: 0.74 to 0.82)

Small for Gestational Age: OR 0.83 (95%CI: 0.79-0.87)

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.

● Also, promise of other soon-to-be licensed vaccines against other

major infectious causes of under-5 mortality (malaria).

● 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.