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Effectiveness of PCV13 in Reducing Nasopharyngeal Carriage of Streptococcus pneumoniae

This article explores the effectiveness of PCV13 in reducing nasopharyngeal carriage of Streptococcus pneumoniae, the bacterium responsible for pneumococcal disease. It discusses the background of the disease, the different serotypes of S. pneumoniae, and the global concern of antibiotic resistance. The clinical relevance of the additional serotypes in PCV13 is also highlighted.

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Effectiveness of PCV13 in Reducing Nasopharyngeal Carriage of Streptococcus pneumoniae

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  1. Outline • Background • Licensed pneumococcal conjugate vaccines • Effectiveness of PCV 13 • Reduction in Nasopharyngeal carriage

  2. Streptococcus pneumoniae: The bacterium responsible for pneumococcal disease Streptococcus pneumoniae: The bacterium responsible for pneumococcal disease • Major clinical syndromes are pneumonia, meningitis and bacteremia1 • Organism has an outer polysaccharide layer1, 2 • Defines the serotype • Functions as virulence factor • Is a vaccine target • More than 90 serotypes of S. pneumoniae have been identified.1, 2 • Serotypes are not equally pathogenic • Last serotypes reported are 6C, 6D and 11E • Antibiotic resistance in S. pneumoniae is a global concern.1, 2 • Exclusively human pathogen commonly carried in the nasopharynx1 Serotype 19F; Photograph courtesy of Robert P. Smith MS, MS Senior Research Scientist, Wyeth Vaccines. 1. Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Diseases. In: Hamborsky J, Kroger A, Wolfe S, eds. 13th ed. Washington D.C. Public Health Foundation, 2015. 2. World Health Organization. Initiative for Vaccine Research. Acute respiratory infections. Updated September 2009. Available from: http://apps.who.int/vaccine_research/diseases/ari/en/index3.html. Accessed July 21, 2015.

  3. Pneumococcal disease can be broadly grouped into categories of invasive and non-invasive (mucosal) disease Pneumococcaldisease1 Noninvasive(mucosal) Invasive Pneumonia Meningitis Bacteraemia Acute otitis media Sinusitis • ~25% invasive2 • ~75% non-invasive Non-invasive forms may become invasive (e.g. pneumonia when accompanied by bacteremia)1 Disease severity and invasiveness differ based on serotype3 1. World Health Organization (WHO). Wkly Epidemiol Rec. 2012;87(14):129-144. 2. Said MA, et al. PLoS One. 2013;8:e60273. 3. Jansen AG, et al. Clin Infect Dis. 2009;49(2):e23-e29.

  4. Deaths from vaccine-preventable diseases in children worldwide1−3 Pneumonia is a leading killer of children worldwide3 Hib, Haemophilus influenzae Type b. 1. World Health Organization. Global immunization data. July 2014. Available from: http://www.who.int/immunization/monitoring_surveillance/Global_Immunization_Data.pdf. Accessed July 21, 2015. 2. World Health Organization. Wkly Epidemiol Rec. 2012;87(14):129-144; 3. UNICEF/World Health Organization. Pneumonia: The forgotten killer of children, 2006. Available from: http://www.childinfo.org/files/Pneumonia_The_Forgotten_Killer_of_Children.pdf. Last Accessed July 21, 2015.

  5. Licensed pneumococcal conjugate vaccines PCV71 4 6B 9V 14 18C 19F 23F CRM Development and licensure of expanded-valent vaccines were based on serology of the expanded-valent vaccine compared with PCV7.1−3 4 6B 9V 14 18C 19F 23F 1 5 7F PCV102 Protein D TT DT Protein D PCV10 is conjugated to a Haemophilus influenzae‒derived protein D, carrier for all serotypes except 18C (tetanus toxoid) and 19F (diphtheria toxoid).2 4 6B 9V 14 18C 19F 23F 1 5 7F 3 6A 19A PCV134 PCV7 and PCV13 are conjugated to CRM197.1,4 CRM DT, diphtheria toxoid; PCV, pneumococcal conjugate vaccine (7-valent [PCV7], 10-valent [PCV10] or 13-valent [PCV13]); TT, tetanus toxoid. 1. Prevenar13 vaccine NEAR Local Product Document (LPD) version 4 effective September 2017. 2. Vesikari T, et al. Pediatr Infect Dis J. 2009;28(4 suppl):S66-S76. 3. World Health Organization. Recommendations for the production and control of pneumococcal conjugate vaccines. WHO Technical Report Series, No. 927, 2005, Annex. Available from: http://www.who.int/biologicals/publications/trs/areas/vaccines/pneumo/ANNEX%202%20PneumococcalP64-98.pdf. Last Accessed July 22,2015. 4. Prevenar 13 [abbreviated summary of product characteristics]. GLM ex Iraq: Pfizer Limited.

  6. Clinical relevance of the 6 additional serotypes in PCV 13 Clinical relevance of the 6 additional serotypes in Prevenar 13 • Complicated pneumonia • Common cause of AOM • Very multidrug resistant • Is common in AOM • Common in NPC • Multidrug resistant • Global cause of IPD and complicated pneumonias 1. Hausdorff WP. Vaccine. 2007;25(13):2406-2412. 2. Weil-Olivier C, et al. BMC Infect Dis. 2012;12:207. 3. Pilishvili T, et al. J Infect Dis. 2010;201(1):32-41. 4. Kaplan SL. Pediatrics. 2010;125(3):429-436. 5. Rodgers GL, et al. Vaccine. 2009;27(29):3802-3810. 6. Alonso M, et al. PLoS ONE. 2013;8(1):e54333. 7. Cho EY, et al. J Korean Med Sci. 2012;27(7):716-722. 8. Chappuy H, et al. BMC Infect Dis. 2013;13:357. 9. Ruckinger S, et al. Pediatr Infect Dis J. 2009;28(2):118-122. 10. Pichichero ME, Casey JR. JAMA. 2007;298(15):1772-1778. 11. Ma X, et al. PLoS ONE. 2013;8(6):e67507. 12. Wroe PC et al. Pediatr Infect Dis J. 2012;31(3):249-254.

  7. Pivotal non-inferiority study (2, 3, 4 and 11–12 months), post-infant series OPA GMTs1 10- to 100-fold higher functional activity for the 6 additional serotypes in the PCV13 group: Comparable functional activity for the 7 shared serotypes: *GMT of PCV13 versus PCV7. GMT, geometric mean titer; OPA, opsonophagocytosis assay 1. Adapted from: Kieninger DM, et al. Vaccine. 2010;28(25):4192-4203.

  8. Immunogenicity of licensed PCVs against serotype 19Afunctional antibody activity (OPA) • PCV7 did not have any impact on serotype 19A IPD.3 • The % of subjects achieving a ≥1:8 functional antibody response is at least 5x greater in PCV13 recipients than that of PCV7 or PCV10.1, 2 *Post-primary dosing in a 3+1 schedule Comparison of studies with different vaccines, with immunologic assays performed at different laboratories OPA, opsonophagocytosis assay 1. Vesikari T, et al. Pediatr Infect Dis J. 2009;28(4 Suppl):S66-S76. 2. Kieninger DM et al. Vaccine 2010;28(25):4192-4203. 3. Pilishvili T, et al. J Infect Dis. 2010;201(1):32-41. 4. Prevenar13 [Summary of Product Characteristics]. GLM ex Iraq: Pfizer Limited. 5. Synflorix [Summary of Product Characteristics]. Belgium: GlaxoSmithKline Biologicals

  9. PCV13 effectiveness

  10. United Kingdom: Incidence of IPD in children <2 years1 IPD incidence* in children <2 years of age, from epidemiological year 2000–2001 to 2013–2014, United Kingdom PCV7 PCV13 60 All 50 PCV7 40 PCV13 only NVT Corrected Incidence per 100,000 30 20 10 0 2011/2012 2012/2013 2013/2014 2010/2011 2000/2001 2001/2002 2002/2003 2003/2004 2004/2005 2005/2006 2006/2007 2007/2008 2008/2009 2009/2010 Year *Corrected for proportion of samples serotyped, missing age, denominator compared with 2009–2010, and trend in total IPD up to 2009–2010 (after which no trend correction was applied).NVT, non-vaccine serotypes; PCV13 only, serotypes in the PCV13 vaccine but not in the PCV7 vaccine. 1. Adapted from: Waight PA, et al. Lancet Infect Dis. 2015;15(5):535-543.

  11. PCV13 2+1 South Africa: Vaccine effectiveness* of PCV13 against IPD in children not infected with HIV aged ≥16 weeks in a case-control study1 Effectiveness of 2 or more doses of PCV13 versus no doses against IPD during PCV13 period† Effectiveness of 2 or more doses of PCV7 or PCV13 versus no doses against PCV7-type IPD over full study period‡ % (95% CI) % (95% CI) 92% (40–99) 90% (53–98) The overall effectiveness of 2 or more doses of PCV7 or PCV13 against PCV7-type IPD in children aged ≥16 weeks not infected with HIV over the full study period was 78%[95% CI: 46%–91%]. 85%(37–96) 87% (38–97) 82% (44–94) 77% (17–94) 74% ( -183–98) 52% (-12%–79%) Vaccine effectiveness* (%) Vaccine effectiveness* (%) PCV13 serotypes (all)§ PCV13 serotypes (additional)‖ All serotypes PCV7 serotypes Exposed to HIV Not exposed to HIV Not malnourished Malnourished *Vaccine effectiveness was adjusted for malnutrition, for diphtheria, tetanus, and pertussis vaccination status at 16 weeks (3 doses received or not), and for maternal education level. †Enrolled children born during or after August 2011. ‡Children born from February 2009 through July 2011.§PCV13 serotypes included: 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. ‖Serotypes included in PCV13 but not in PCV7 were 1, 3, 5, 6A, 7F, and 19A.CI, confidence interval 1. Adapted from: Cohen C, et al. Lancet Glob Health. 2017;5(3):e359-e369.

  12. South Africa: Age-specific incidence rates* for laboratory-confirmed IPD reported to GERMS-SA, 2009–20151 PCV7 introduced April 2009 PCV13 introduced June 2011 Incidence (cases per 100,000 population) Age category (years) • Following the introduction of PCV7/PCV13 in South Africa, the incidence of IPD was significantly reduced between 2009 and 2015 in infants <1 year of age (p<0.001). *Incidence rates were determined based on population figures obtained from Statistics South Africa. 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; 2014: N=2,734, age unknown for n=162; 2015: N=2,640, age unknown for n=158. GERMS-SA, Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa.1 1. GERMS-SA Annual Report 2015. Available from: http://www.nicd.ac.za/assets/files/2015%20GERMS-SA%20AR.pdf. Accessed March 28, 2017.

  13. England and Wales: IPD cases due to Serotype 3 in children <5 years of age1 68% reduction* (vs. 2008–2010) Number of cases PCV13 *Not statistically significant. 1. Adapted from: Waight PA, et al. Lancet Infect Dis. 2015;15(5):535-543.

  14. United States: Cases of IPD due to Serotype 6A in children ≤5 years of age1 97% reduction (vs. 1999–2000) Number of cases PCV7 PCV13 1. Adapted from: Richter SS, et al. Emerg Infect Dis. 2013;19(7):1074-1083.

  15. England and Wales: IPD incidence due to serotype 19A in children <15 years of age1 PCV7 PCV13 Serotype 19A 91% reduction in children <5 years of age (vs. 2008–2010) 6.0 <2 years of age 2–4 years of age 5.0 5–14 years of age 4.0 3.0 Corrected incidence per 100,000 2.0 1.0 0.0 2000/2001 2001/2002 2002/2003 2003/2004 2004/2005 2005/2006 2006/2007 2007/2008 2008/2009 2009/2010 2010/2011 2011/2012 2012/2013 2013/2014 1. Adapted from: Waight PA, et al. Lancet Infect Dis. 2015;15(5):535-543.

  16. New Zealand: 19A IPD cases in children <5 years of age1 PCV7 PCV10 PCV13 19A IPD cases in New Zealand <5 years of age No overall change in 19A IPD was observed in vaccinated children (children <5 years) in New Zealand while PCV10 was in the NIP. Number of IPD cases 1. Adapted from: Institute of Environmental Science and Research Limited Surveillance Report. Invasive pneumococcal disease in New Zealand 2015. Available from: https://surv.esr.cri.nz/PDF_surveillance/IPD/2015/2015IPDAnnualReport.pdf. Accessed 1 March 2018.

  17. France: Pneumococcal CAP*† cases in children 1 month–15 years of age in 8 pediatric hospitals1 Pneumococcal CAP (children 1 month–15 years of age) Pneumococcal CAP 63% reduction vs. pre-PCV13 Number of cases Pre-PCV13 (June 2009–May 2010) Transition (June 2010–May 2011) Post-PCV13 (June 2011–May 2012) *X-ray confirmed; laboratory-confirmed P-CAP defined by positive blood or pleural culture, positive pleural PCR, or positive pneumococcal antigen detection in pleural sample. Microbiologically confirmed. CAP, community-acquired pneumonia; P-CAP, pneumococcal CAP; PCR, polymerase chain reaction 1. Adapted from: Angoulvant F, et al. Clin Infect Dis. 2014;58(7):918-924.

  18. Madrid, Spain: Incidence of bacteremic pneumonia before and after withdrawal of PCV13 from public vaccination program1 Incidence of bacteremic pneumonia in children <14 years of age, Madrid, Spain, January 1, 2009−June 1, 2014 PCV 13 introduction in NIP PCV 13 withdrawal from NIP Withdrawal of government subsidy of PCV13 Introduction of universal PCV13 S. pneumoniae incidence 1. Tagarro A, et al. J Pediatr. 2016;171:111-5.e1-3.

  19. New Zealand: Frequency of S. pneumoniae serotypes from middle ear fluid (MEF) in children <3 years of age undergoing tube insertion1 30 Phase 1* (PCV7†); N=25 25 Phase 2* (PCV10†); N=25 20 • Compared with Phase 1, S. pneumoniae serotype 19A became the most commonly isolated serotype from MEF during phase 2. Percent 15 10 5 0 11A 10A 23A 33F 22F 6C 16F 15B 19A 23B 15C 9N 35B 3 35F 19F 31 38 23F Serotypes *Phase 1 conducted from May to November 2011; Phase 2 conducted from May to November 2014. †PCV7 was introduced in the New Zealand national immunization schedule in 2008 and replaced with PCV10 in late 2011. 1. Adapted from: Best EJ, et al. Vaccine. 2016;34(33):3840-3847.

  20. United States: Rates of otitis media in children <2 years of age1 PCV13 51% reduction Otitis media visit rate/child-year, <2 years of age 1. Marom TM, et al. JAMA Pediatr. 2014;168(1):68-75.

  21. Introduction of PCV13 in pediatric populations has had an indirect impact on IPD in adults IPD, invasive pneumococcal disease; PCV, pneumococcal polysaccharide vaccine 1. Dagan R, et al. J Infect Dis. 2002;185(7):927-936; 2. Cohen R, et al. Pediatr Infect Dis J. 2012;31(3):297-301; 3. Davis SM, et al. Vaccine. 2014;32(1):133-145. Children are a primary reservoir for pneumococci.1 Relationship of carriage to development of natural immunity is not clearly understood. Pneumococcal conjugate vaccines (PCVs) have been shown to reduce the carriage of vaccine-type strains in vaccinated children, thus reducing opportunities for transmission.1, 2 Decreased transmission of pneumococci from children to adults has led to the observed reduction in rates of IPD in adults since the introduction of PCV.3

  22. France: Carriage of overall six additional serotypes in children 6–24 months with acute otitis media1,2 NPC of S. pneumoniae (Sp) Serotypes, PCV7 Serotype (ST), and 6 Additional Plus 6C Serotypes as well as Antibiotic Resistance From 2001 to 2014 PCV7 PCV13 PCV7 80 Sp Recommendation for high-risk infants Recommendation for all infants Implementation PCV7 ST 70 ST 6 additional* + 6C 60 Penicillin intermediate 50 Penicillin resistant Proportion of nasopharyngeal swabs (%) 40 30 20 10 0 Period 1 (Oct 2001–Jun 2006) Period 2 (Oct 2006–Jun 2010) Period 3 (Oct 2010–Jun 2011) Period 4 (Oct 2011– Jun 2014) Vaccine coverage: 96% in 2012 (≥1 dose, 6 months old).² Adapted from Cohen et al. 2015.1 • From 2001 to 2010, carriage of 6 additional* PCV13 serotypes plus 6C increased from 17.2% to 24.3% (P<0.001) and decreased from 2011 to 2014 after PCV13 implementation from 21.4% to 3.5% (P<0.001). • Penicillin-intermediate-resistant pneumococcal strains decreased from 65.8% in 2001 to 32.2% in 2014.† • Penicillin-resistant pneumococcal strains decreased from 1.3% in 2001 to 1% in 2014.† Between 2001 and 2014, 121 paediatricians obtained nasopharyngeal swabs from children with acute otitis media aged 6–24 months. The swabs were analysed by the French National Reference Centre for Pneumococci. A total of 7991 patients were enrolled. *Serotypes 1, 3, 5, 6A, 7F, 19A. † 95% CIs and p-values not available; no conclusion can be drawn regarding statistical significance. NIP, National immunisation programme; NPC, nasopharyngeal carriage, PCV7, 7-valent pneumococcal conjugate vaccine; PCV13, 13-valent pneumococcal conjugate vaccine. 1. Adapted from: Cohen R, et al. Vaccine. 2015;33(39):5118-26. 2. INVS. Available from: http://www.invs.sante.fr/Dossiers-thematiques/Maladies-infectieuses/Maladies-a-prevention-vaccinale/Couverture-vaccinale/Donnees/Pneumocoque. Accessed February 25, 2016.

  23. Switzerland: Pneumococcal carriage and serotype Distribution in AOM patients pre- and post-PCV introduction1 Variation of pneumococcal serotypes isolated from nasopharyngeal swabs of AOM patients during PCV vaccination periods PCV13 serotypes PCV7 (p<0.001) PCV13-PCV7-Serotype 3- Serotype 19A (p=0.002) Serotype 19A (p=0.001) Serotype 3 (p=0.013) PCV13 Proportions of pneumococcal serotypes/serogroups isolated (%) Time (Year) • A decrease in PCV13 serotypes was observed following PCV13 introduction, with the exception of serotype 3 increasing from 8.5% in 2004 to 11.1% in 2015 (2 test for trend: P=0.013). • The proportion of serotype 19A isolates increased post-PCV7, then decreased significantly in the PCV13 era (2test for trend: P=0.001). • The proportion of non-PCV13 serotypes increased following PCV introduction, increasing from 26.1% in 2004 to 85.2% in 2015 (2 test for trend: P<0.001). AOM, acute otitis media. 1. Allemann A, et al. Vaccine. 2017;35(15):1946-1953.

  24. Prevention 1. Vaccination • CDC recommends administering PCV13 as a four-dose series at 2, 4, 6, and 12 through 15 months of life • Research shows that this vaccine is very effective at preventing infection resulting from the serotypes contained in the vaccine • PCV13 should also be administered to all adults 65 years or older and to some adults 19 through 64 years of age with conditions that put them at increased risk for pneumococcal disease

  25. 2. OTHER PREVENTIVE MEASURES. • Nutritional support • Chemoprophylaxis – oral Pen V for those at risk e.g functional/anatomical asplenia. • Rational use of antibiotics • Reduction of the Environmental risks- Air pollution, overcrowding.

  26. New vaccine in future? A 72- valent pneumococcal vaccine is under development. Hoped to offer ‘most comprehensive coverage’. THANK YOU.

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