"Role of vaccines in making the world a better place for children" - Slideset by professor Madhi (WAidid Board Member) presented at the 2015 World Congress of Nephrology, held in Cape Town from March 13-17 2015. Find more on www.waidid.org

1. 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

2. 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.

3. 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

4. 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.

5. 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

6. Distribution of Livebriths and under-5 deaths in
2013 and 2030
Liu L et al. Lancet 2015; 385: 430-440

7. 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.

8. 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

9. 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.
OtherVPDs
1%(25000)
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.

10. Progress and Challenges Toward Measles
Elimination
Source: http://www.immunize.org/photos/polio-measles.asp

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

12. 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

13. 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.
Percent
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

14. 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)

15. 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.

16. 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 Eastern
Mediterranean
Europe Southeast Asia Western Pacific
Incidenceratesper100000
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 deaths
associated with pneumonia

17. 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/100,000population
0
10
20
30
40
50
60
70
80
90
1998 1999 20012000 2002 2003 2004 2005 2006 2007
Year
PCV7introduced
Serotype group
PCV7 type
Non-PCV7 type
19A
Pilishvili T, et al. J Infect Dis. 2010;201:32-41.
*

18. 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

19. 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/100,000population
0
5
10
15
20
25
30
35
40
1998 1999 20012000 2002 2003 2004 2005 2006 2007
Year
PCV7introduced
Serotype group
PCV7 type
Non-PCV7 type
19A
*

20. 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).
DeathspreventedCasesprevented
Moore M et al. Lancet Infect Dis; 2015; 15: 301-309

21. 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

22. 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

23. 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.

24. 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.

25. 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.

26. 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.

27. 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

28. 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

29. 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 Malawi
SevererotavirusGEepisodesper100
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

30. 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

31. 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

32. 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

33. 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.

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

35. Success of Maternal Tetanus Vaccination in
Preventing Neonatal Tetanus Deaths

36. 1 270 000
787 000
580 000
490 000
248 000
200 000180 000
128 000
59 000
58 000 49 0009
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
1980
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
Reported TT2+ coverage & estimated NT deaths
1980-2013
Est NT Deaths TT2+ (%)
WHO-UNICEF Data & CHERG Reports
TT2+Coverage(percentage)
NumberNTDeaths
Neonatal Tetanus Global Annual Reported
Cases and TT2plus coverage, 1980-2013

37. 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

39. 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

40. 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

41. 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
Cumulativeinfluenzacases
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

42. 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

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

44. 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.

45. 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)

46. 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.

47. 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.