Pneumococcal conjugate vaccines Jerusha Naidoo, MBChB (UCT) Pfizer - - PowerPoint PPT Presentation
Pneumococcal conjugate vaccines Jerusha Naidoo, MBChB (UCT) Pfizer Vaccines jerusha.naidoo@pfizer.com Annual African Vaccinology Course: Developing Vaccinology Expertise for Africa OUTLINE S. pneumoniae, pneumococcal disease and
Annual African Vaccinology Course: Developing Vaccinology Expertise for Africa
Braz J Infect Dis. 2006;10:293─303. 3. Regev-Yochay G, et al. Clin Infect Dis. 2004;38:632─639. 4. Chi DH, et al. Am J Rhinol. 2003;17:209─214.
AOM Pneumonia Bacteremia Meningitis Sinusitis Spread to other individuals Nasopharyngeal colonization is generally a prerequisite for invasive and non-invasive pneumococcal disease2,4
Image adapted from: http://www.1911encyclopedia.org/images/f/f4/Olfactorysystem-2.jpg.
Invasion of bloodstream
Crossing of mucosal barrier Otitis media, sinusitis, nonbacteremic pneumonia Local invasion Meningitis Sepsis Bacteremic pneumonia
Pneumococcal disease: Pathogenesis
Prevenar 13 Summary of Product Characteristics 2009 (Section 4.1) and adapted from Bogaert D, et al. Lancet Infectious
Disease classification: Invasive disease4
Bacteraemic pneumonia
cases also have bacteraemia
bacteraemia in childhood
Bacteraemia/ sepsis
manifestation of IPD
long-term neurological sequelae)
important pathogen causing bacterial meningitis in HIV
Meningitis
Sinusitis Pneumonia
Disease classification: Non-invasive disease4
pneumococcal disease
bacterial pneumonia in children
pneumonia worldwide
Otitis Media
infection in children
childhood visits to a doctor’s office
28-55% of all cases of
Pneumococcal disease burden in children4
Disease severity Noninvasive Invasive
For each case
meningitis: > X 2000 X 166 X 16
Prevalen ce Adapted from: CDC4
Africa: Population-based studies of IPD (children <5 years of age)
Country Year(s) Type Setting Cultures Age (mo) Incidence (per 100,000)
The Gambia1 1989-1991 Clinics Rural Blood, CSF, lung aspirate <12 554 <24 458 <60 242 Kenya2 1998-2002 Inpatients Rural Blood <12 241 <24 213 <60 111 Mali3 2002-2003 Inpatients Urban Blood, CSF <12 84 12-59 19 Kenya4 2003 Outpatients Rural Blood <60 597 The Gambia5 2000-2004 Clinics: controls in a vaccine trial Rural Blood, CSF, lung aspirate 3-29 3,700
IPD is a substantial cause of morbidity and mortality in Africa
Post-discharge outcomes: Bacterial meningitis in children in Africa
Ramakrishnan M, et al. BMC Medicine. 2009;7:47.
Mortality in pneumococcal meningitis in Africa
*Zaria
Global pneumococcal disease mortality rates per 100,000 in children <5 years of age (HIV-negative only)
O’Brien KL, et al. Lancet. 2009;374:893-902.
Source: Black R, Cousens S, Johnson H, Lawn J, Rudan I, Bassani D, Jha P, Campbell H, Walker C, Cibulskis R, Eisele T, Liu L, and Mathers C, for the Child Health Epidemiology Reference Group of WHO and UNICEF, 2010, “Global, Regional, and National Causes of Child Mortality in 2008: A Systematic Analysis,” Lancet 375(9730): 1969–87.
More than one- third of child deaths attributable to undernutrition
Major causes of child mortality - 2008
Pneumococcus Polysaccharide capsule
Serotype isolates causing IPD in children <5 years of age, 1980–2007
Global distribution of serotypes causing IPD in children <5 years of age
Pneumococcal Global Serotype Project. http://www.preventpneumo.org/pdf/GS P%20Summary%20for%20SAGE%20Nov6-8%202007_Oct%2019-07.pdf. Accessed September 8, 2009.
Figure 3. Proportion of IPD in young children globally due to the most common serotypes by age.
Johnson HL, Deloria-Knoll M, Levine OS, Stoszek SK, et al. (2010) Systematic Evaluation of Serotypes Causing Invasive Pneumococcal Disease among Children Under Five: The Pneumococcal Global Serotype Project. PLoS Med 7(10): e1000348. doi: 10.1371/journal.pmed.1000348 http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1000348
Mark Fletcher, Scientific Affairs, Paris
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Montgomery, J. M., D. Lehmann, et al. (1990). Rev.Infect.Dis. 12 Suppl 8: S1006-16 & Brueggemann AB, et al. J.Infect.Dis. 2004;190(7):1203-11
Mark Fletcher, Scientific Affairs, Paris
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invasive infections and also mucosal infections (e.g., pneumonia or AOM)
serotypes (6B, 9V, 14, 19F, 23F) and some of the important non-vaccine serotypes (6A, 19A) THE “PEDIA THE “PEDIATRIC” SERO TRIC” SEROTYPES TYPES Examples, 6B, 9V, 14, 19F, 23F and 6A, 19A
Mark Fletcher, Scientific Affairs, Paris Montgomery, J. M., D. Lehmann, et al. (1990). Rev.Infect.Dis. 12 Suppl 8: S1006-16 & Brueggemann AB, et
Mark Fletcher, Scientific Affairs, Paris
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children
– Brief duration of colonization? – Survive better in the environment?
infections (e.g. meningitis or bacteremic pneumonia)
– More likely to bypass the mucosal barrier? – Less pro-inflammatory / inhibit inflammatory response?
serotypes (e.g., 4 and 18C) and some of the important non-vaccine serotypes (e.g., 1, 3, 5, and 7F) THE “OUTBREAK” SERO THE “OUTBREAK” SEROTYPES TYPES Examples, 1, 3, 4, 5, 7F, and 18C
Mark Fletcher, Scientific Affairs, Paris Montgomery, J. M., D. Lehmann, et al. (1990). Rev.Infect.Dis. 12 Suppl 8: S1006-16 & Brueggemann AB, et
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Serotype 19F (Rob Smith, Wyeth); Macrophage http:// www.people.virginia.edu/~rjh9u/macro.html)
Ca Capsular poly psular polysacc saccharide haride Str Streptococcus ptococcus pneumoniae pneumoniae
PCV7 (7-valent Oligo/ polysaccharide - CRM197) Polysaccharide serotypes 4, 6B, 9V, 14, 19F, 23F /
CRM197 CRM197 Ca Capsular poly psular polysacc saccharide haride Str Streptococcus ptococcus pneumoniae pneumoniae Ca Capsular poly psular polysacc saccharide haride Str Streptococcus ptococcus pneumoniae pneumoniae Ca Capsular poly psular polysacc saccharide haride
Conjug Conjugation c tion chemistry to f hemistry to form a
co covalent bonds betw alent bonds between the een the poly polysacc saccharide and the car haride and the carrier rier pr protein
Str Streptococcus ptococcus pneumoniae pneumoniae Ca Capsular poly psular polysacc saccharide haride Str Streptococcus ptococcus pneumoniae pneumoniae Ca Capsular poly psular polysacc saccharide haride Str Streptococcus ptococcus pneumoniae pneumoniae Coryne Corynebacterium bacterium diphtheriae diphtheriae Ca Capsular poly psular polysacc saccharide haride Str Streptococcus ptococcus pneumoniae pneumoniae
4 6A 9V 14 18C 19F 23F 4 6A 9V 14 18C 19F 23F
Pneumococcal conjugate vaccine (PCV)
Ada, G. (2001). "Vaccines and Vaccination." N Engl J Med 345(14): 1042-1053
In Panel A, a polysaccharide antigen binds to an IgM receptor on the surface of a B cell in lymphoid
and then secrete IgM antibody molecules. The individual Fab segments of the IgM molecule have
such segments, an IgM molecule has a high avidity. In contrast, in Panel B, some polysaccharide –protein conjugates will be taken up by dendritic cells, which present peptides from the protein portion of the conjugate to type 2 helper T (Th2)
that have IgM receptors specific for the carbohydrate moiety and will undergo endocytosis and be processed by the B cell; the resulting peptides will be expressed with class II MHC molecules on the surface of the B cell. This complex is recognized by the activated Th2 cell, which then secretes interleukin-4, interleukin-5, and interleukin-6. These cause the B cell to differentiate and express IgG molecules with polysaccharide specificity. These cells mature in the lymphoid follicles; only cells that express very
and secrete high-affinity IgG that binds strongly to the encapsulated bacteria and mediates opsonic activity and complement-mediated bactericidal activities.
Property Polysaccharide Conjugate Effective in infants No Yes Immune memory No Yes Prolonged duration of protection No Yes Reduction of carriage No Yes Contributes to herd effect No Yes Hyporesponsiveness with repeated dosing Yes No
Harrison LH. Clin Microbiol Rev. 2006;19(1):142─164. Richmond P, et al. J. Infect. Dis. 2000;181 (2):761─764.
Pneumoccocal serotypes, in descending order, causing laboratory- confirmed, invasive pneumococcal disease reported to GERMS-SA in children <5 years, South Africa, 2009-2012.
http://www.nicd.ac.za/assets/files/NICD%20CommDisBull-%20August%202013.pdf
The global burden of pneumonia
each year
annual 8.1 million childhood deaths in the world
90% of pneumonia-related deaths occur in the developing countries
WHO, 2010
Global incidence rates and death rates due to pneumococcal disease*
Disease Incidence (per 100,000) Death Rate (per 100,000) Case-fatality Rate Pneumonia 2,228 119 5% Meningitis 17 10 59% NPNM 87 4 45% Total 2,331 133 n/a
*Children <5 years of age. NPNM=nonpneumonia, nonmeningitis. O’Brien KL, et al. Lancet. 2009;374:893-902.
children <5 years of age
meningitis has a case-fatality rate more than 10-times that of pneumonia
In the analysis of pneumococcal disease worldwide, O’Brien et al estimated that 14.5 million cases of pneumococcal disease
deaths due to pneumococcal disease occurred in children <5 years of age.
Clinical episodes of community-acquired pneumonia (CAP) Bacterial etiology, 50% Bacterial pneumonia Pneumococcal etiology, ~50% to 75% Pneumococcal pneumonia Vaccine serotypes (7v), ~60% to 80% Active against all bacteria: Anticipate a 50% reduction in incidence of CAP Active against all pneumococcus: Anticipate a 25% to 40% reduction in incidence of CAP Active against all vaccine-serotype pneumococcus: Anticipate a 15% to 30% reduction in incidence of CAP
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[Lobar (“radiologically confirmed”) pneumonia is associated with pneumococcal pneumonia]
(min. 25 days apart)
(Tetramune)
protocol 8,189: 8,151
hospital admission, and mortality was investigated
– 48% were PCV7 serotypes
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Cutts, FT, Zaman SMA , et al. Lancet. 2005;365(9465):1139-1146.
*Trademark
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Condition Vaccine cases (incidence) n=8189 Control cases (incidence) n=8185 Vaccine efficacy (%) (95% CI) All-cause hospital admissions 1,065 (89) 1,216 (105) 15 (7 – 21) Age 3 – 11 months 12 – 23 24 – 29 388 (112) 576 (89) 101 (51) 469 (138) 612 (97) 135 (71) 19 (7 – 29) 8 (0 – 18) 28 (7 – 44) All-cause mortality 330 (25) 389 (30) 16 (3 – 28) Age 3 – 11 months 12 – 23 24 – 29 92 (25) 189 (26) 49 (22) 100 (28) 224 (32) 65 (29) 9 (-20 – 31) 17 (0 – 31) 25 (-10 – 48)
Cutts, FT, Zaman SMA , et al. Lancet. 2005;365(9465):1139-1146.
(incidence), cases / 1,000 child-years
35 Cutts, FT, Zaman SMA , et al. Lancet. 2005;365(9465):1139-1146.
(incidence), cases / 1,000 child-years
Condition Vaccine cases (incidence) n=8189 Control cases (incidence) n=8185 Vaccine efficacy (%) (95% CI) Overall 333 (26) 513 (41) 37 (27 – 45) Outpatient visits 180 (14) 253 (20) 30 (15 – 43) Hospital admissions 153 (12) 260 (21) 42 (30 – 53) Age 3 – 11 months 12 – 23 24 – 29 124 (34) 181 (26) 28 (13) 188 (53) 285 (42) 40 (19) 35 (19 – 45) 38 (25 – 49) 32 (-10 – 58)
All pneumonia/LRTI: cough 14 days and tachypnoea or lower chest wall indrawing
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Cutts, FT, Zaman SMA , et al. Lancet. 2005;365(9465):1139-1146.
Vaccine-attributable Reduction in Pneumococcal Related Pneumonia and Vaccine Efficacy Value
17 cases, 7% VE (1% to 12%)
15 cases, 37% VE (27% to 47%)
2 cases, 70% VE (31% to 88%)
Cases / 1,000 child-years
Grijalva CG et al. Lancet 2007 369:1179
Trends in Monthly All Cause Pneumonia Hospitalization Rates in Children < 2 yrs of Age
Annual Hospitalization Rates for Pneumonia in Children < 2 and 2-4 Yrs of Age Pre and Post Introduction of PCV7 in a 3+1 Schedule
Grijalva CG et al. Clin Infect Dis 2010; 50:805–813
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Version Date: DD-MM-YYYY
Hospitalizations for Pneumonia among U.S. Children. 3+1
Griffin et al, NEJM, 369:155-63, 2013
The annual rate of hospitalization for pneumonia among children <5 years declined by 251 per 100,000 children, (which translates to 54,000 fewer hospitalizations annually than expected on the basis of the rates before PCV7 was introduced
~ x20
Pneumonia hospitalizations IPD
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Version Date: DD-MM-YYYY
Incidence rates per 1000 child-years
Decrease in Pneumonia Hospitalisations After Introduction of PCV13 in Nicaragua in Children <2 Years of Age All-cause infant mortality (0–11 months) also decreased 33% within the first 2 years following the introduction of the PCV13 immunisation program
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26% reduction 33% reduction
Becker-Dreps S, et al. Pediatr Infect Dis J. 2014 Jan 17.
Incidence of Hospitalisations for Pneumonia in Infants <2 Years of Age in Nicaragua*
*Nicaragua introduced routine immunisation with PCV13 on December 12, 2010, using a 3+0 dosing schedule at 2, 4,
and 6 months of age. Children 12–24 months of age were also offered PCV13 during the first year of the program. Vaccine effectiveness* Age 0 to 11 months 12 to 23 months
mortality 33% (20, 43)
visits for pneumonia 13% (-1, 25) 16% (5, 26)
hospitalisation 33% (25, 41) 26% (19, 33) Age
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Acute Otitis Media (AOM) Pneumonia Bacteraemia Antibiotic resistance Spread to other individuals Meningitis
BoD
These slides are Pfizer owned and have been provided for the purpose of medical education only – Not for distribution or reproduction, in whole or in part without Pfizer authorisation.
Mark Fletcher, Scientific Affairs, Paris
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Age, birth to 3 - 6 months Age, 4 - 7 to 23 months Age, 23 to 60 months Age, > 5 years
SHORT-TERM DIRECT PROTECTION LONG-TERM DIRECT PROTECTION INDIRECT (HERD) PROTECTION
Steens A, et al. Prompt effect of replacing the 7-valent pneumococcal conjugate vaccine with the 13-valent vaccine on the epidemiology of invasive pneumococcal disease in Norway. Vaccine (2013), http://dx.doi.org/10.1016/ j.vaccine.2013.10.032
100 200 300 400 500 600 700 800 900 1000 2004 2005 2006 2007 2008 2009 2010 2011 2012
PCV7 (<5) Plus PCV6 (<5) Non-PCV13 (<5) PCV7 (>5) Plus PCV6 (>5) Non-PCV13 (>5)
PCV7 PCV1 3 Number of isolates
EU-PREV-2012/04/0002 April 2012
Montgomery, J. M., D. Lehmann, et al. (1990). Rev.Infect.Dis. 12 Suppl 8: S1006-16 & Brueggemann AB, et
Carriage
Illness (IMCI)
– Community-based – Facility-based
– Pneumococcal conjugate – Hib – Pertussis
– Breastfeeding – Complementary feeding after 6 months – Micronutrient intake
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Accessed June 5, 2011.
Pneumonia morbidity and mortality could be reduced 50% if the following interventions are implemented
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2009: N=4,765; age unknown for n=163; 2010: N=4,199; age unknown for n=142; 2011: N=3,804; age unknown for n=219; 2012: N=3,222, age unknown for n=253; 2013: N=2,866, age unknown for n=142 *Incidence rates were calculated based on population denominators provided by Statistics South Africa, and are expressed as cases per 100,000 population
PCV7 introduced April 2009 PCV13 introduced June 2011 GERMS SA Annual Report 2013
2009: N=1,337, n=1,009 with viable isolates; 2010: N=909; n=649 with viable isolates; 2011: N=696, n=464 with viable isolates; 2012: N=509, n=353 with viable isolates; 2013: N=498, n=322 with viable isolates
PCV7 introduced April 2009 PCV13 introduced June 2011 = PCV7 Serotypes = Additional 6 Serotypes in PCV13 GERMS SA Annual Report 2013
Incidence of IPD Among Those <15 Years of Age by Year and Age Group South Africa, 2005‒2012
Von Gottberg, A. et al. NEJM, Nov 2014
*Percentage change in IPD incidence: post-vaccine (2012) vs. pre-vaccine (2005‒2008) years. <2 years old: -69% (-65% to -72%)* 2‒4 years old: -59% (-50% to -67%)* 5‒9 years old: -44% (-33% to -54%)* 10‒14 years old: -6% (+23% to -28%)*
Age group, years:
VST: -85% (-89% to -79%)* *% change in IPD incidence: post-vaccine (2012) vs. pre-vaccine (2005-2008) years
PCV7 PCV13
VT: -86% (-91% to -78%)* *% change in IPD incidence: post-vaccine (2012) vs. pre-vaccine (2005-2008) years
PCV7 PCV13
15‒24 years of age: -29% (-16% to -42%)* 25‒44 years of age: -34% (-29% to -39%)* 45‒64 years of age: -14% (-3% to -23%)* >64 years of age : +1% (+22% to -26%)* *Percentage change in IPD incidence: post-vaccine (2012) vs. pre-vaccine (2005‒2008) years.
Age group, years:
PCV7 introduced in April 2009 and replaced with PCV13 in June/July 2011.
PCV7 PCV13
Bliss SJ, O'Brien KL, Janoff EN, Cotton MF, Musoke P, Coovadia H, et al. The evidence for using conjugate vaccines to protect HIV-infected children against pneumococcal disease. Lancet Infect Dis. 2008 Jan;8(1):67-80.
Absolute rate reduction Absolute rate reduction Vaccine efficacy Vaccine efficacy
Vaccine Efficacy in HIV-infected children and HIV-uninfected children
Absolute rate reduction = events prevented per 100,000 child-years
Mali Mauritania Chad Ethiopia Somalia Eritrea Niger 2014 Nigeria Sudan Central African Republic Tanzania DR Congo Angola Lesotho Zimbabwe Zambia Madagascar Malawi Kenya Uganda Congo Cameroon Senegal Guinea Sierra Leone Liberia Ghana Cote d’ Ivoire Benin Burkina Faso Togo Rwanda Burundi Djibouti Guinea- Bissau Gambia Comoros São Tomé and Príncipe
PCV 10, GAVI program (3+0)
Namibia 2+1 Libya 2+1 Algeria Western Sahara
Gabon
Egypt
Botswana 3+0 (catch up)
Swaziland 2+1(catch up)
South Africa 2+1 (catch up)
Morocco 2+1
PCV 13, NIP South Africa, Libya, Swaziland, Namibia (2+1 ) Botswana (3+0) PCV 10, NIP (2+1) GAVI program, Pending launch PCV 13 GAVI Program (3+0)
1. Data on file, Pfizer as at 10 April 2014 2. Gavi Alliance Progress Report 2012. http://www.gavialliance.org/results/gavi-progress-reports/
– Background
– The burden of disease
– Vaccines
– Recommendations Pneumococcal disease is the most common preventable cause of death BoD high in the young, >50y and those with chronic diseases Conjugate