Shabir A. Madhi Progress and Challenges of Immunization Contributing Toward Attaining the MDG Goal to Reduce under-5 Childhood Mortality. National Institute for Communicable Diseases & University of Witwatersrand, South Africa Respiratory and Meningeal Pathogens Research Unit, & DST/NRF: Vaccine Preventable Diseases
Disclosure of interest Received grants from : GSK, Pfizer, Novartis Received honoraria from: GSK, Pfizer, Novartis, Merck Investigator in clinical vaccine trials for: GSK, Wyeth/Pfizer, Novartis, Medimmune Consultant/ member of advisory boards/ lecturer for: GSK, Pfizer, Merck, Abbott
Overview Trends in Global under-5 childhood mortality. Recent contribution 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.
Overview Trends in Global under-5 childhood mortality. Recent contribution 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. Liu L et al. Lancet 2012; 379: 2151-61
Progress in reduction of potentially vaccinepreventable disease between 2000 to 2010 Cause 2000 estimates (x1000) 2010 estimates (x1000) Under-5 children 615 555 633 555 Total deaths 9 629 7 622 Annual Percentage reduction Pneumonia 1 847 (1 604-2124) 1 396 (1 189-1 642) 3.1% (2.4-3.9%) Diarrhoea 1.160 (911-1.570) 801 ( 555-1 182) 4.0% (2.4-5.6%) Malaria (2004) 700 (540-875) 564 ( 432-709) 4.0% ( 3.1-4.7%) Measles 477 (400-586) 114 ( 92-176) 14.6% (12.2-15.6%) Neonatal sepsis 412 (323-541) 393 ( 252-552) 0.7% (-5.1-4.5%) Neonatal tetanus 146 ( 68-590) 58 ( 20-276) 9.5% (0.9-17.8%) Liu L et al. Lancet 2012; 379: 2151-61
Regional Causes of Death In Children under-5 Years Age: Western Pacific Liu L et al. Lancet 2012; 379: 2151-61
Overview Trends in Global and South African under-5 childhood mortality. Recent contribution 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.
Percentage of deaths (2.5 million) from vaccine-preventable diseases (VPDs) among children <5 years worldwide, 2002 Pneumococcus 28% (716 000) Other VPDs 1% (25 000) Pertussis 11% (294 000) Measles 21% (540 000) Over 50% of VPDs in under-5 children in 2002 due to diseases for which vaccine available since the 1930s-early 90s. MMWR; 2006: 55:511-5 &WHO. 2004: Global Immunization Data
Measles Containing Vaccine Coverage By WHO Region,1980-2006 Global Coverage At 80% In 2006 100 MCV coverage (%) 80 60 40 20 16 19 20 37 41 47 47 73 67 69 69 70 71 73 73 71 71 71 72 73 73 75 76 78 80 62 54 0 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 Global AFR AMR EMR EUR SEAR WPR Source: WHO/UNICEF coverage estimates 1980-2006, August 2007 193 WHO Member States. Date of slide: 16 August 2007
Estimated measles deaths in 2000 and 2010 48 600 Africa Eastern Mediterranean SE-Asia India Western Pacific 535300 measles deaths in 2000 13100 88000 16% 2% 337000 9% 9% 64% 26% 2% 47% Africa Eastern Mediterranean SE-Asia India Western Pacific 139 300 measles deaths in 2010 65 500 3 100 76% 1 36% 50 000 85% 48 600 8% 10 100 78% 7% 10500 78% 1 Per cent reduction in 2010 compared to 2000 74% decrease in global measles deaths between 2000 to 2010. Target: 90% reduction in measles mortality by 2010 compared to 2000. Simons E et al. Lancet 2012; 379: 2173-78
Global Estimated Measles Mortality and Measles Deaths Averted. 9.6 million measles deaths averted between 2000 compared to 2010 assuming complete absence of measles vaccine. Simons E et al. Lancet 2012; 379: 2173-78
Percentage of children under one year age who received measles vaccine, by household wealth quintile and region, 2000-2008 Percent Need to focus immunization efforts on reaching out to the poorest quintile, who are also disadvantaged to access to curative health services Source: UNICEF. Pneumonia and Diarrhoea. June 2012. Available: www.childinfo.org/publications
Global estimates of burden of deaths due to H. influenzae type b in children younger than 5 years; 2000 Europe: 6 500 (4 600-9 500) Eastern Mediterranean 41 600 (29 300-60 700) Americas: 8 400 (5200-11700) SE Asia: 75 300 (53 000-109 900) Western Pacific: 17 600 (12 400-25 600) Africa: 181 000 (126 000-251 000) 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 Watts JP, et al. Lancet 2009; 374:903=11
Countries having Introduced Hib Vaccine in 1997 and 2010 2013 Source: WHO/IVB database, September 2011 and IVAC VIMS Report Dec 2013
Proportion of countries, by income-group, that have introduced Hib conjugate vaccine into immunization programs Per cent countries in which HibCV introduced Source: UNICEF. Pneumonia and Diarrhoea. June 2012. Available: www.childinfo.org/publications Estimate: Improved HibCV coverage by 2011 in low-income countries, particularly in Africa, possibly prevents approximately 125 000 additional deaths annually.
Overview Trends in Global and South African under-5 childhood mortality. Recent contribution 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.
Acceleration in Development of Vaccines
Global Causes of under-5 Mortality, 2010 Liu L et al. Lancet 2012; 379: 2151-61
Treatment and preventative strategies for the prevention of childhood pneumonia and diarrhoea Source: UNICEF. Pneumonia and Diarrhoea. June 2012. Available: www.childinfo.org/publications
Challenges in treatment-access for diarrhea and pneumonia contribute to high childhood mortality, in developing countries Proportion of children under age 5 with diarrhea receiving ORS Proportion of children with suspected pneumonia receive antibiotics (2006-11). Source: UNICEF. Pneumonia and Diarrhoea. June 2012. Available: www.childinfo.org/publications
Proportion of children under-5 with suspected pneumonia taken to appropriate healthcare provider, by wealth quintile and region, 2006-2011 Source: UNICEF. Pneumonia and Diarrhoea. June 2012. Available: www.childinfo.org/publications
Overview Trends in Global and South African under-5 childhood mortality. Recent contribution of childhood vaccines in reducing under-5 mortality. Potential of new childhood vaccines in reducing under-5 mortality:: Pneumococcal Conjugate Vaccine New horizons in reducing under-5/neonatal morbidity and mortality by vaccination.
Death rate of pneumococcal disease in children <5 years (per 100,000) Incidence rates per 100 000 500 450 400 350 300 250 200 150 100 50 0 Number of deaths: 447,000 Africa America Eastern Mediterranean 33,100 90% of the 830 000 pneumococcal deaths associated with pneumonia Europe Southeast Asia Western Pacific 100,100 15,100 187,000 43,000 O Brien K et al. Lancet 2009;374;893 902
Impact of 7-valent PCV on Incidence of Vaccineserotype Invasive Pneumococcal Disease Adapted from: Fitzwater SP et al. PIDJ; 2012: 31: 501-508
Impact of 7-valent PCV on Reduction in Incidence of all-cause pneumonia hospitalization. Adapted from: Fitzwater SP et al. PIDJ; 2012: 31: 501-508
PCV significantly improves child survival in The Gambia All-cause mortality was decreased by 16% (95% CI: 2 38) in children vaccinated with PCV9 over a median follow-up period of 2 years Seven deaths were prevented for every 1000 children vaccinated with PCV9 in The Gambia Cutts F et al. Lancet 2005;365:1139 46
Proportion of Paediatric Pneumococcal Disease Preventable by Vaccination 7-valent Assumes cross protection within serogroup 6 86% 60% 71% 62% 38% 73% 10-valent 13-valent 88% 84% 92% 89% 81% 66% 87% 73% 81% 81% 87% 86% Hausdorff et al. Clin Infect Dis 2000;30:122 40
Introduction of pneumococcal conjugate vaccines into national immunization programs. Percent of countries in which PCV been introduced Source: UNICEF. Pneumonia and Diarrhoea. June 2012. Available: www.childinfo.org/publications Uptake of PCV to current DTP3 coverage levels in low income countries could potentially prevent approximately 430 000 under-5 childhood deaths annually.
PCV Introduction into Countries by 2013 2013: Sixty-five percent worlds infants unlikely to be vaccinated with PCV. Sixty percent world s infants live in countries where PCV not introduced. Source: IVAC VIMS Report. Dec 2013
Overview Trends in Global and South African under-5 childhood mortality. Recent contribution of childhood vaccines in reducing under-5 mortality. Potential of new childhood vaccines in reducing under-5 mortality: Rotavirus vaccine New horizons in reducing under-5/neonatal morbidity and mortality by vaccination.
Proportional Decline in all-cause diarrhea related death greater than decline in rotavirus attributed to mortality.? Parashar UD et al. J Infect Dis; 2009: 200 (S1):S9-S15; Tate JE, et al. Lancet Infect Dis; 2012; 12: 136-41; Black RE et al. Lancet 2010; 375:1969-87; Bryce J et al. Lancet 2005; 365: 1147-52; Liu L et al. Lancet; 20122151-61
Improved access to drinking water may be contributing to reduction in diarrhoea morbidity and mortality. The MDG drinking water target has been met. Per cent reduction in diarrhoea morbidity, by intervention Source: UNICEF. Pneumonia and Diarrhoea. June 2012. Available: www.childinfo.org/publications
Rotavirus detection rates and deaths due to diarrhoea and rotavirus by WHO child mortality group and region. Country category Very low child mortality Mean rotavirus detection rate (95%CI) Number of diarrhoea related deaths Number of deaths attributed to rotavirus 49% (34-64) <1 000 <1 000 Low child mortality 40% (36-44) 67 000 27 000 Asia 1 42% (35-48) 452 000 188 000 Americas 1 42% (37-47) 13 000 5 000 Africa 1 33% (28-38) 704 000 232 000 Total 1 236 000 453 000 1 High and medium mortality countries. 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 Tate JE, et al. Lancet Infect Dis; 2012; 12: 136-41 (adapted)
Point estimates of Rotarix* and RotaTeq vaccine Efficacy in Relation to Country GDP Possible reasons for lower efficacy in developing countries High maternal antibody titres Breastfeeding at vaccination Micronutrient deficiencies Interfering microorganisms HIV and malaria Nelson EAS & Glass RI, Lancet 2010; 367: 568-9
Effectiveness of rotavirus vaccination in children younger than 5 years Patel MM et al. Lancet Infect Dis 2012; 12: 561-70 (Adapted)
Number of diarrhea-related deaths among children aged <59 months in Mexico by age group; July 2002 to May 2009 41%; 95%CI 36 to 47 29%; 95%CI 17 to 39 Richardson V et al. N Eng J Med 2010; 362; 299-305
Proportion of countries, by income-group, that have introduced rotavirus vaccine into immunization programs Source: UNICEF. Pneumonia and Diarrhoea. June 2012. Available: www.childinfo.org/publications Increasing vaccination against rotavirus to levels of DTP3 coverage in low-income countries estimated to potentially prevent 250 000 under-5 deaths annually. Tate JE, et al. Lancet Infect Dis; 2012; 12: 136-41 (adapted)
Countries in Which Rotavirus Vaccine Has Been Introduced. Source: IVAC VIMS Report. Dec 2013
Rotavirus Vaccine Introduction Into GAVI Eligible Countries (2013) 2013: Eighty percent of worlds infants (103 million) unlikely to receive rotavirus vaccine Seventy-percent of world s infants live in countries where RV has not been introduced Source: IVAC VIMS Report. Dec 2013
Overview Trends in Global under-5 childhood mortality. Recent contribution of childhood vaccines in reducing under-5 mortality. Potential of new childhood vaccines in reducing under-5 mortality. New horizons in reducing childhood morbidity and mortality by vaccination.
Regional Causes of Death In Children under-5 Years Age: Western Pacific Liu L et al. Lancet 2012; 379: 2151-61
Cause-specific mortality rates in Western Pacific Children aged 0-27 days, 2000 to 2010 Liu L et al. Lancet 2012; 379: 2151-61
Neonatal Tetanus Global Annual Reported Cases and TT2plus coverage, 1980-2011
Maternal vaccination for reducing neonatal morbidity and mortality: Influenza vaccination. Acellular pertussis vaccine. GBS vaccination. RSV vaccine.
Reduced Influenza-confirmed Illness in Young Infants Whose Mothers received TIV vs. PPV. Enrollment Historic Influenza Season 63% (95%CI: 5 to 85) reduction in influenza confirmed illness in infants of TIV vaccinated mothers. 29% (95%CI: 7 to 46) reduction in febrile respiratory illness. 36% (95%CI: 4 to 57) reduction in maternal respiratory illness with fever. Zaman K et al. NEJM 2008; 359: 1555-64
Vaccine Efficacy of Influenza Vaccination of Pregnant HIV- Women against PCR-confirmed Influenza Illness up Until 24 weeks Post-partum. AR: 3.6% AR: 1.8% VE (ITT): 50.4% (95%CI: 14.5; 71.2) VE (PP): 54.4% (95%CI: 19.5; 74.2) HIV- unpublished data (Madhi SA et al. ISID, Apr 2012, Cape Town, South Africa)
Vaccination of HIV- Pregnant Women in Preventing Influenza-Confirmed illness in their Infants up until 24 Weeks of age. AR: 3.6% AR:1.9% VE (ITT): 48.8% (95%CI: 11.5; 70.3) VE (PP): 45.6% (95%CI: 2.4; 69.7) HIV- unpublished data (Madhi SA et al. ISID, Apr 2012, Cape Town, South Africa)
Da Vinci 1510-1513
Fetal Outcomes of the 1918 Influenza Pandemic Bloom-Fesbach K et al. J Infect Dis 2011; 204:1157-64
Prevented Fraction of Prematurity in Georgia, USA by Influenza Activity Period Omer S PlosMed 2011:8 e100041
Newborn and Fetal Effects of Maternal Influenza Vaccination or Illness Steinhoff M et al; Am J Obs Gynec. 2012
Guidelines for Vaccinating Pregnant Women, USA
Conclusions Vaccines have potential toward reducing under-5 childhood mortality. 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) and pneumonia (pneumococcus) have potential of preventing approximately 600-700 thousand childhood deaths annually. Also, promise of other soon-to-be licensed vaccines against other major infectious causes of under-5 mortality. Next frontier is targeting vaccination of pregnant women for reducing death from neonatal vaccine-preventable diseases.
Challenge: Sustaining, secured supply of live-saving vaccines at affordable prices to low and low-middle income countries, particularly to most economically marginalized sectors of communities.