Infections Invasives à Pneumocoque

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1 Infections Invasives à Pneumocoque Actualités J. GAUDELUS Service de Pédiatrie Hôpital Jean Verdier Bondy Université Paris XIII

2 Les vaccins anti pneumococciques conjugués PCV7 Carrier Protein: CRM B 9V 14 18C 19F 23F PCV10 Carrier Proteins: Proteína D Diphtheria toxoid^ Tetanus toxoid* 4 6B 9V 14 18C^ 19F* 23F 1 5 7F PCV13 Carrier Protein: CRM B 9V 14 18C 19F 23F 1 5 7F 3 6A 19A

3 Pneumococcal carriage 1995 and 2009 Pneumococcal IPD 1995 and

4 Distribution des sérotypes chez les enfants de 6-59 mois, Atlanta, USA % Pneumococcal carriage, 1995 and Sharma D, Baughman W, Holst A, Thomas S, Jackson D, da Gloria Carvalho M, Beall B, Satola S, Jerris R, Jain S, Farley MM, Nuorti JP. Pediatr Infect Dis J Feb;32(2):196 2

5 Distribution des sérotypes chez les enfants de 6-59 mois, Atlanta, USA % Pneumococcal IPD, 1995 and Sharma D, Baughman W, Holst A, Thomas S, Jackson D, da Gloria Carvalho M, Beall B, Satola S, Jerris R, Jain S, Farley MM, Nuorti JP. Pediatr Infect Dis J Feb;32(2):196 2

6 Distribution des sérotypes chez les enfants de 6-59 mois, Atlanta, USA % Pneumococcal carriage, 1995 and Sharma D, Baughman W, Holst A, Thomas S, Jackson D, da Gloria Carvalho M, Beall B, Satola S, Jerris R, Jain S, Farley MM, Nuorti JP. Pediatr Infect Dis J Feb;32(2):196 2

7 Distribution des sérotypes chez les enfants de 6-59 mois, Atlanta, USA % Pneumococcal IPD, 1995 and Sharma D, Baughman W, Holst A, Thomas S, Jackson D, da Gloria Carvalho M, Beall B, Satola S, Jerris R, Jain S, Farley MM, Nuorti JP. Pediatr Infect Dis J Feb;32(2):196 2

8 Distribution des sérotypes chez les enfants de 6-59 mois, Atlanta, USA % Pneumococcal carriage, 1995 and Sharma D, Baughman W, Holst A, Thomas S, Jackson D, da Gloria Carvalho M, Beall B, Satola S, Jerris R, Jain S, Farley MM, Nuorti JP. Pediatr Infect Dis J Feb;32(2):196 2

9 Distribution des sérotypes chez les enfants de 6-59 mois, Atlanta, USA % Pneumococcal IPD, 1995 and Sharma D, Baughman W, Holst A, Thomas S, Jackson D, da Gloria Carvalho M, Beall B, Satola S, Jerris R, Jain S, Farley MM, Nuorti JP. Pediatr Infect Dis J Feb;32(2):196 2

10 End of PCV7 era Atlanta, CDC, US NP swabs Colonized PCV7 serotypes PCV13 serotypes IPD PCV7 serotypes 19A PCV13 serotypes remarks N=231 40% 60% N=202 83% 5% N=451 31% 0.1% 22% N=47 0% 49% 60% 6-59 months old Out patients Children < 5 years Hospitalized 2008 to A serotype ST320 in 2009 o 66% of carriage & 52% of IPD isolates o All ST320 isolates = MDR o MDR ST320 strains responsible for 2/3 of 19A carriage isolates & 1 / 2 of IPD isolates o No ST320 (NP or IPD isolates) identified before PCV7 Sharma D, Baughman W, Holst A, Thomas S, Jackson D, da Gloria Carvalho M, Beall B, Satola S, Jerris R, Jain S, Farley MM, Nuorti JP. Pediatr Infect Dis J Feb;32(2):196 MDR: multidrug-resistant

12 Singleton R., Pediatr Infect Dis J % decrease in overall IPD 65% decrease in PCV13- type IPD No cases of IPD due to PCV13 serotypes among children PCV13 immunized 12

13 Alaska (YKD); Native children aged <5 years; IPD rates Incidence /year Remarks /100, fold higher than non-alaska Native children (56/100,000) 2000 PCV7 introduced in NIP /100,000 98% VT decrease /100,000 NVT increase (19A, 7F predominant) /100, PCV13 «switch» Jan 2009-Aug /100,000 NO PCV13 cases in vaccinees Singleton R, Wenger J, Klejka JA, Bulkow LR, Thompson A, Sarkozy D, et al. PIDJMarch. 2013;32(3): YKD: Yukon Kuskokwim Delta NVT: non-vaccine serotype IPD: invasive pneumococcal disease

14 IMPACT PCV 13 US (S.I PELTON et al.) De , 756 enfants <2 ans avec méningite à pneumocoque Depuis 2010, une diminution des ST du PCV13 est observée suggérant un impact L incidence des IIP des enfants < 5 ans a diminué de 58 % entre 2001 et 2010, surtout dûe à la diminution des ST 7 F et 19A En 2011, parmi les cas dûs aux ST 19A, 5 sont survenus chez des enfants vaccinés par PCV13 (3 après seulement 1 dose de PCV13 et 2 après 2 doses) 14

16 Routine PCV13 immunization in 2010 Ongoing prospective surveillance study, Infants & children 8 children hospitals in the US; 2011 compared with Large data base denominator: > emergencies Culture-proven invasive infections caused by S. pneumoniae IPD (average number of cases) decrease 42% overall 53% for children <24 months of age N cases of IPD; 8 children hospitals PCV13 serotypes isolates decrease Overall 57% 19A, 7F & 3 decreased by 58%, 54% & 68%, respectively Number of infections caused by serotypes 1 & 6C also decreased Bacteremia, pneumonia & mastoiditis cases decreased more than meningitis cases Most common non-pcv13 serotypes encountered in 2010 & 2011 combined 33F, 22F, 12, 15B, 15C, 23A & 11. Kaplan SL, Barson WJ, Lin PL, Romero JR, Bradley JS, Tan TQ, et al. Pediatr Infect Dis J. 2013;32(3):203-7.

17 Reduction of IPD in Children All Ages After PCV13 Introduction Serotyped IPD isolates (1 July 2007 to 30 June 2011) All isolates No. of isolates s PCV13 introduced 36% No of isolates s (invasive pneumococcal infections) Isolates by serotype Serotype 19A 45% In Total isolates 0 19A 7F 3 6C 33F Serotype 17 Early trends indicate 36% reduction in IPD cases (12 months period starting 4 months after PCV13 Introduction) Kaplan SL, Barson WJ, Lin PL, Romero JR, Bradley JS, Tan TQ, et al. Pediatr Infect Dis J. 2013;32(3):203-7.

Early Trends for Invasive Pneumococcal Infections in Children After the

18 Distribution of IPI Isolates by Serotype (PCV7, PCV13, PPV23, or non-vaccine) 2007 to solates Number of is Kaplan SL, Barson WJ, Lin PL, et al. Early Trends for Invasive Pneumococcal Infections in Children After the Introduction ofthe 13-valent Pneumococcal Vaccine. Ped Inf Dis J 32(3): , March 2013.

19 Incidence des IIP chez les enfants <5 ans USA (1997 à 2011) H T T P : / / W W W. C D C. G O V / AB C S / R E P O R T S - F I N D I N G S / S U R V- R E P O R T S. H T M L

20 Incidence des IIP chez les enfants <5 ans USA (1997 à 2011) 250,0 200,0 Protection directe 150,0 100,0 0-1y 1-2y 2-4y 50,0 0,0

21 Incidence des IIP chez les enfants de 1à 2 ans, USA (1997 to 2011) 250,0 200,0 Pre-PCV7 introduction 150,0 100,0 50,0 0,0

22 Incidence des IIP chez les enfants de 1à 2 ans, USA (1997 to 2011) 250,0 200,0 Pre-PCV7 introduction 150,0 100,0 PCV7 introduction 50,0 0,0

23 Incidence des IIP chez les enfants de 1à 2 ans, USA (1997 to 2011) 250,0 200,0 Pre-PCV7 introduction 150,0 100,0 PCV7 introduction 50,0 Post-PCV7 introduction 0,0

24 Incidence des IIP chez les enfants de 1à 2 ans, USA (1997 to 2011) 250,0 225,0 200,0 Pre-PCV7 introduction 175,0 150,0 125,0 100,0 PCV7 introduction 75,0 50,0 Post-PCV7 introduction PCV13 introduction 25,0 0,0

25 Protection Indirecte (herd effect)

26 Incidence des IIP, adultes >50 ans, USA (1997 à 2011) 250,0 200,0 Protection Indirecte (herd) 150,0 100, y >65y 50,0 0,0

27 IPD incidence, adults >50 years, USA (1997 to 2011) 250,0 200,0 150,0 100,0 Pre-PCV7 introduction 50,0 PCV7 introduction Post-PCV7 introduction PCV13 introduction 0,0

29 Réduction significative des IIP dues aux sérotypes additionnels de PCV13 chez les enfants <2 ans Dès la première année d introduction du PCV13 Les cas d IIP chez les enfants <2 ans dus aux sérotypes additionnels du PCV 13 ont diminué de moitié Réduction significative des sérotypes 7F et19a reportés dans les cas d IIP. 29 Miller E, et al. Vaccine.2011 Oct 5. [Epub ahead of print] Study population: Children who were eligible for PCV13 (one or more doses) who reported to the Health Protection Agency with IPD (n=235) and had a complete vaccine history taken. IPD defined as isolation of S. pneumoniae from a normally sterile site. PCV13 was introduced nationally in week 13, 2010.

30 Impact de PCV13 sur les IIP Surveillance continue au Royaume Uni Cumulative weekly number of reports of Invasive Pneumococcal Disease due to any of the seven serotypes in Prevenar7 : Children aged < 2 Years in England and Wales by Epidemiological Year: July-June (2005- To Date) more than 1 year after PCV13 introduction in children <2 years Maintained reduction of PCV7- type IPD

Impact de PCV13 sur les IIP Surveillance continue au Royaume Uni Cumulative weekly number of reports of IPD due to any of the 6 serotypes in Prevenar13* but not in PCV7: Children aged <2 Years in

31 Impact de PCV13 sur les IIP Surveillance continue au Royaume Uni Cumulative weekly number of reports of IPD due to any of the 6 serotypes in Prevenar13* but not in PCV7: Children aged <2 Years in England and Wales by epidemiologic year: July June (2007 To Date) more than 1 year after PCV13 introduction in children <2 years Maintained reduction of PCV7-type IPD Decreased number of reported cases of IPD related to 6 additional types included in PCV13 (particularly 19A and 7F types) 31 *Trademark

33 Résultats Distribution des sérotypes et sensibilité à la penicilline Portage du Sp % Patients vaccinés par PCV7 uniquement N= 285 Patients vaccinés avec au moins 1 dose de PCV13 N= 651 Portage global serotypes du PCV sérotypes additionnels du PCV < Sérotypes non inclus dans le PCV Sp intermédiaires à la pénicilline Sp résistants à la pénicilline P 33

34 Résultats Distribution des sérotypes (6 sérotypes additionnels) Sérotypes % Patients vaccinés par PCV7 uniquement N= 285 Patients vaccinés avec au moins 1 dose de PCV13 N= A < F A / / P 34

35 Résultats Distribution des sérotypes (sérotypes non inclus dans le PCV13) % Patients vaccinés par PCV7 uniquement N= 285 Patients vaccinés avec au moins 1 dose de PCV13 N= 651 6C Sérotypes non inclus dans le PCV13 (sauf le 6C) 35B A B/C A P 35

36 Reduction of NP carriage of overall 6 additional serotypes in children with AOM Nasopharyngeal carriage, serotype distribution according to vaccination status in children aged 6 24 months NIP PCV13 in 2010 FRA p<0.001 P=0.001 Significant reduction in carriage of overall additional PCV13 serotypes p=0.003 p=0.005 Significant reduction in carriage of 19A, 7F Figure adapted from Cohen R, et al. Pediatr Infect Dis J *children were considered adequately vaccinated with PCV13 if they had received 2 doses before 12 months or at least 1 dose after this age. Data from a national surveillance program of pneumococcal carriage in children with AOM. NP swabs were taken from children with AOM aged 6 to 24 months during the period October 2010 to March Cohen R et al. Pediatr Infect Dis J 2012; 31:

37 Evolution de l incidence des infections invasives à pneumocoque vs 2009 et de la couverture vaccinale , France 000 hab. Taux pour < 2 ans 65 ans 2-5 ans PCV7 +12% -22% +32% 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% % 1 do ose à 6 mois % Sources : Epibac, CNRP, Estimation de la couverture vaccinale à partir des données de l échantillon généraliste des bénéficiaires (L. Fonteneau, InVS)

38 Evolution de l incidence des infections invasives à pneumocoque selon le sérotype chez les enfants de moins de 2 ans et les adultes de 65 ans et plus, France P C V 7 T a u x p o u r < 2 ans vs 09 : STV : - 92% STNV : + 151% 5 T a u x p o u r P C V 7 65 ans vs 09 : STV : - 70% STNV : + 109% Sources : Epibac, CNRP

Incidence des infections invasives à pneumocoque selon le sérotype chez les enfants de moins de 2 ans, 2001-2002 versus 2008-2009, France 8,0 19A, 7F : 53% des cas en 2009 7,0 6,0 Cas / 10 00

39 Incidence des infections invasives à pneumocoque selon le sérotype chez les enfants de moins de 2 ans, versus , France 8,0 19A, 7F : 53% des cas en ,0 6,0 Cas / ,0 4,0 3,0 2,0 1,0 0,0 4 6B 9V 14 18C 19F 23F A 6C 7F 19A 22F 7 Sérotypes vaccinaux 6 Sérotypes addititionnels (PCV13) F autrenonpcv13 Sources : Epibac, CNRP

40 Evolution de l incidence des infections invasives à pneumocoque selon le sérotype chez les enfants de moins de 2 ans, France P7 PCV7 impact vs : All ST : -25% PCV7: - 90% STNV : + 138% P vs 2009 : All ST : -27% PCV7 : - 56% 6V : -71% Non-13 : + 94% Sources : Epibac-CNRP

41 IMPACT du PCV 13 en ALLEMAGNE (VAN DER LINDEN et al.) 3 ans après l introduction de PCV 10&13 en Allemagne, une réduction de 80% des IIP dûes aux 6 ST additionnels du PCV13, a été observée Les cas d IIP dûes aux ST 1, 3, 5, 6A, 7F et 19A ont diminué depuis

42 IMPACT du PCV 13 en Allemagne (VAN DER LINDEN et al.) Sérotype 19A Sérotype 3 Sérotype 1

43 Effectiveness of PCV13 Harboe ZB, Valentiner-Branth P, Ingels H, Rasmussen JN, Andersen PHS, Bjerre CC, et al. Pediatric Invasive Pneumococcal Disease Caused by Vaccine Serotypes following the Introduction of Conjugate Vaccination in Denmark. PLoS ONE. 2013;8(1):e51460.

Search for PCV7 & PCV13 failures Serotype distribution of cases of Invasive pneumococcal disease in children <5 years, Denmark 2007 2010 (n = 191).

44 Search for PCV7 & PCV13 failures Serotype distribution of cases of Invasive pneumococcal disease in children <5 years, Denmark (n = 191). Laboratory surveillance data on IPD Oct 1, Dec 31, 2010 linked to the Danish Childhood Vaccination Registry o # 90% isolates obtained from hospitalized patients o Mandotory notification of IPD in children < 5 yrs PCV immunization program since Oct 1, 2007 Reduced 2+1 schedule (3, 5, 12 ms) Birth cohort: doses uptake for birth cohorts : 81 91% Catch up program uptake: 71% Harboe ZB, Valentiner-Branth P, Ingels H, Rasmussen JN, Andersen PHS, Bjerre CC, & al, plosone 2013 Jan;8:1: e51460

45 Harboe ZB, Valentiner-Branth P, Ingels H, Rasmussen JN, Andersen PHS, Bjerre CC, & al, Plosone 2013 Jan;8:1: e51460

46 Characteristics of children suspected to present with a PCV failure in Denmark Episodes of IPD reported N= 45 caused by a PCV7 serotype (23% of total N) N=105 (55%) caused by one of 6 additional PCV13 serotypes. Birth cohort: children had received >1 PCV7 dose before IPD onset & caused by a PCV7 serotype 7/10 incompletely vaccinated before IPD 3/10 fulfilled vaccine failure criteria caused by serotypes 14, 19F & 23F severely immunosuppressed child (N=1) post 3 PCV7 doses immunocompetent children (N=2) post 2 infant doses before booster eligibility IPD cases caused by 6 additional PCV13 serotypes Mostly 7F, 19A, 1 : none vaccinated by PCV13 = no PCV13-vaccine failures in the first 8-months post PCV13 introduction April 19 -Dec 31, 2010 = PCV7/PCV13 transitional period ; both vaccines offered) Harboe ZB, Valentiner-Branth P, Ingels H, Rasmussen JN, Andersen PHS, Bjerre CC, & al, plosone 2013 Jan;8:1: e51460

48 Age-specific IPD incidence (cases per 100,000 per year), USA ( ) Incidence, cases / 10 00,000 person-years <1y 1y 2-4y 5-17y 18-34y 35-49y 50-64y >65y Age range, years Source:

49 Protection croisée

50 19F 19A

51 PCV7: Immunogénicité du Sérotype 19A Immunogenicity Parameter Overall Antibody Levels (ELISA) % Achieving >0.35µg/mL Geometric Mean Concentrations Serotype 19F (Present in Vaccine) 96 (93 98) 2.86 ( ) Serotype 19A (Potentially cross-reactive) 79.2 ( ) 0.64 ( ) Functional Antibody Levels (OPA) % Achieving >1:8 Geometric Mean Titers 93.6 ( ) 166 ( ) 17.0 ( ) 7 (5 9) PCV7 elicits total antibodies by ELISA to serotype 19A, but the amount of functional antibodies are very low. Keinenger DM et al. Vaccine 2010;28:

52 PCV10: Immunogénicité du Serotype 19A Immunogenicity Parameter Overall Antibody Levels (ELISA) % Achieving >0.20µg/mL % Achieving >0.35µg/mLµ Geometric Mean Concentrations Serotype 19F (Present in Vaccine) PCV ( ) Serotype 19A (Potentially cross-reactive) PCV ( ) ( ) ( ) 184 ( ) 0.08 ( ) Functional Antibody Levels (OPA) % Achieving >1:8 Geometric Mean Titers 87.7 ( ) 148 ( ) 19.6 ( ) 8.6 ( ) Vesikari T et al. Pediatr Infect Dis J 2009;28:S66-76.

53 PCV10: Immunogénicité du Serotype 19A Immunogenicity Parameter Overall Antibody Levels (ELISA) % Achieving >0.20µg/mL % Achieving >0.35µg/mLµ Geometric Mean Concentrations Serotype 19A (Potentially cross-reactive) PCV ( ) PCV ( ) ( ) ( ) 0.08 ( ) 0.11 ( ) Functional Antibody Levels (OPA) % Achieving >1:8 Geometric Mean Titers 19.6 ( ) 8.6 ( ) 3.4 ( ) 4.5 ( ) Vesikari T et al. Pediatr Infect Dis J 2009;28:S66-76.

54 PCV10: Immunogénicité du Serotype 19A Immunogenicity Parameter Overall Antibody Levels (ELISA) % Achieving >0.20µg/mL % Achieving >0.35µg/mLµ Geometric Mean Concentrations Serotype 19A (Potentially cross-reactive) PCV ( ) PCV ( ) ( ) ( ) 0.08 ( ) 0.11 ( ) Functional Antibody Levels (OPA) % Achieving >1:8 Geometric Mean Titers 19.6 ( ) 8.6 ( ) 3.4 ( ) 4.5 ( ) Vesikari T et al. Pediatr Infect Dis J 2009;28:S66-76.

55 Cross Protection for Serotype 19A in Perspective Immunogenicity Functional Antibody Levels (OPA)* Serotype 19A (Potentially cross-reactive) Serotype 19A (Contained in the Vaccine) % Achieving >1:8 Geometric Mean Titers PCV7 1 PCV10 2 PCV ( ) 7 (5 9) 19.6 ( ) 8.6 ( ) 100 ( ) 442 ( ) *Comparison of studies with different vaccines, with immunologic assays performed at different laboratories The functional immunogenicity of PCV13, which contains serotype 19A is much greater than that of PCV7 or PCV10. PCV13 is the only PCV approved for prevention of disease due to serotype 19A. 1 Keinenger DM et al. Vaccine2010;28: Vesikari T et al. Pediatr Infect Dis J2009;28:S66-76.

56 LB-6. Indirect Effects of PCV13 on Nasopharyngeal Colonization with Streptococcus pneumonia (SP) Vaccine Serotypes Achieved with 65% to 75% Vaccine Uptake Pelton et al,2012

Current Status of PCV Use and WHO Recommendations

Current Status of PCV Use and WHO Recommendations SAGE 18 October 2017 Kate O Brien, MD MPH 1 Pneumonia remains a major cause of child deaths LMIC LMIC Pneumonia HIC HIC Pneumonia ~16% ~5% 2015 Black,