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 serotypes • Pneumococcal vaccines • Efficacy and effectiveness • NP carriage and the indirect effect • Issues for the future • The PneumoADIP and GAVI • Surveillance Data from RSA • Conclusions

OUTLINE • S. pneumoniae, pneumococcal disease and serotypesSerotypes • Efficacy and effectiveness • NP carriage and the indirect effect • Issues for the future • The PneumoADIP and GAVI • Conclusions

Nasopharyngeal colonization • S. pneumoniae can be a normal inhabitant of the nasopharynx 1 • Global nasopharyngeal (NP) colonization/carriage ranges: • 10% to 85% in children <5 years of age 2,3 • 4% to 45% in adults 2-4 • Developing countries: earlier colonization, higher rate of colonization • Pneumococcal disease associated with recent acquisition of a serotype in nasopharynx AOM Spread to other individuals Sinusitis Pneumonia Bacteremia Meningitis Nasopharyngeal colonization is generally a prerequisite for invasive and non-invasive pneumococcal disease 2,4 Image adapted from: http://www.1911encyclopedia.org/images/f/f4/Olfactorysystem-2.jpg. 1. Hull MW, et al . Infect Dis Clin North Am . 2007;21:265 ─ 282. 2. Cardozo DM, et al . 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.

Pneumococcal disease: Pathogenesis Colonization Crossing of mucosal barrier Invasion of bloodstream Local invasion Otitis media, sinusitis, Bacteremic Meningitis nonbacteremic pneumonia Sepsis pneumonia Prevenar 13 Summary of Product Characteristics 2009 (Section 4.1) and adapted from Bogaert D, et al. Lancet Infectious Diseases. 2004;4(3):144-154.

Disease classification: Invasive disease 4 Meningitis  Most serious clinical Bacteraemic manifestation of IPD Bacteraemia/ pneumonia  Mortality rate: 10-30%  Morbidity rate: >30% (due to sepsis  20-25% of pneumonia long-term neurological cases also have sequelae) bacteraemia  Pneumococcus causes 85%  Pneumococcus is most of all cases of cases of important pathogen causing bacteraemia in childhood bacterial meningitis in HIV -infected children + 4. CDC. MMWR 2000;49(RR-9):1-35.

Disease classification: Non-invasive disease 4 Pneumonia Otitis  Most common serious Media pneumococcal disease  Most common bacterial  Pneumococcus: infection in children • causes 50-66% of  Most common cause for bacterial pneumonia in childhood visits to a children doctor’s office • is most common cause  Pneumococcus causes of community-acquired 28-55% of all cases of pneumonia worldwide otitis media Sinusitis 4. CDC. MMWR 2000;49(RR-9):1-35.

Pneumococcal disease burden in children 4 For each Disease Prevalen case of meningitis: severity ce X 16 Invasive X 166 > X Noninvasive 2000 Adapted from: CDC 4

Africa: Population-based studies of IPD (children <5 years of age) Incidence (per 100,000) Country Year(s) Type Setting Cultures Age (mo) The Blood, CSF, 1989-1991 Clinics Rural <12 554 Gambia 1 lung aspirate <24 458 <60 242 Kenya 2 1998-2002 Inpatients Rural Blood <12 241 <24 213 <60 111 Mali 3 2002-2003 Inpatients Urban Blood, CSF <12 84 12-59 19 Kenya 4 2003 Outpatients Rural Blood <60 597 Clinics: The Blood, CSF, 2000-2004 Rural 3-29 3,700 controls in a Gambia 5 lung aspirate vaccine trial IPD is a substantial cause of morbidity and mortality in Africa 4. Brent AJ, et al. Lancet . 2006;367:482-488. 1. O’Dempsey TJD, et al. Pediatr Infect Dis J . 1996;15:431-437. 2. Berkley JA, et al. N Engl J Med . 2005;352:39-47. 5. Cutts FT, et al. Lancet . 2005;365:1139-1146. 3. Campbell JD, et al. Pediatr Infect Dis J . 2004;23:642-649.

Post-discharge outcomes: Bacterial meningitis in children in Africa Outcome S. pneumoniae (%) Mortality 13 Physical defects 26 Cognitive defects 20 Hearing loss 37 Visual loss 14 Ramakrishnan M, et al. BMC Medicine. 2009;7:47.

Mortality in pneumococcal meningitis in Africa Country Mortality Reference Egypt 33% J Egypt Publ Hlth Assoc (1969) Kenya 24% E Afr Med J (1973) Malawi 43% E Afr Med J (1975) Nigeria 44% Trop Geog Med (1979) Nigeria* 48% Q Jl Med NS (1976) Nigeria 51% Lancet (1976) *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.

Major causes of child mortality - 2008 More than one- third of child deaths attributable to undernutrition 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.

S. pneumoniae capsule/serotype and vaccine relationship S. pneumoniae Pneumococcus Polysaccharide capsule 1. Park IH, et al . J Clin Microbiol. 2007;45:1225 ─ 1233. 2. CDC. Epidemiology and Prevention of Vaccine-preventable Diseases . 11th ed. 2009:217 ─ 230.

Global distribution of serotypes causing IPD in children <5 years of age Serotype isolates causing IPD in children <5 years of age, 1980–2007 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

Serotypes classified by likelihood of colonization or IPD Montgomery, J. M., D. Lehmann, et al. (1990). Rev.Infect.Dis. 12 Suppl 8: 17 S1006-16 & Brueggemann AB, et al. J.Infect.Dis. 2004;190(7):1203-11 Mark Fletcher, Scientific Affairs, Paris

The “pediatric serotypes” • Are likely to colonize the nasopharynx of young children • Tendency to show diminished sensitivity to commonly -used antibiotics • Characterized by their likelihood to cause to cause invasive infections and also mucosal infections (e.g., pneumonia or AOM) • The “Pediatric serotypes” include many of the Prevenar 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 18 Mark Fletcher, Scientific Affairs, Paris

Serotypes classified by likelihood of colonization or IPD 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

The “outbreak serotypes” • Are infrequently isolated from the nasopharynx of young children – Brief duration of colonization? – Survive better in the environment? • Less likely to be resistant to commonly-used antibiotics • Characterized by their likelihood to cause invasive infections (e.g. meningitis or bacteremic pneumonia) – More likely to bypass the mucosal barrier? – Less pro-inflammatory / inhibit inflammatory response? • The “outbreak serotypes” include some of the Prevenar 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 20 Mark Fletcher, Scientific Affairs, Paris

Serotypes classified by likelihood of colonization or IPD 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

OUTLINE • S. pneumoniae and pneumococcal vaccines • Pneumococcal vaccines • Efficacy and effectiveness • NP carriage and the indirect effect • Issues for the future • The PneumoADIP and GAVI • Conclusions

The capsular polysaccharide of Streptococcus pneumoniae • The capsular polysaccharide (CPS) inhibits opsonization by phagocytes • Serotype-specific antibodies to the capsular polysaccharide are protective Serotype 19F (Rob Smith, Wyeth); Macrophage http:// www.people.virginia.edu/~rjh9u/macro.html) 23