Pneumococcal Disease Trends after Pneumococcal Conjugate Vaccines

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1 Pneumococcal Disease Trends after Pneumococcal Conjugate Vaccines Dr. Jim Kellner Professor & Head Department of Pediatrics University of Calgary & Calgary Zone, Alberta Health Services

2 Tendencias de la enfermedad neumocócica después de las vacunas conjugadas neumocócicas Dr. Jim Kellner Professor & Head Department of Pediatrics University of Calgary & Calgary Zone, Alberta Health Services

3 Objectives Review impact of pneumococcal conjugate vaccines on burden of pneumococcal disease in Canada and globally (including Chile) Invasive pneumococcal disease (IPD), particularly in era of PCV13 and PHiD-CV Primarily pediatric focus Describe the importance of reducing nasopharyngeal carriage of S. pneumoniae Carriage precedes all disease Impact of conjugate vaccines Describe trends in clinical features of IPD

4 Background information

5 Pneumococcal Vaccines Pneumococcal conjugate vaccines First generation vaccine valent (PCV7, Prevnar ) (4, 6B, 9V, 14, 18C, 19F, 23F) Second generation vaccines 10-valent (PHiD-CV, Synflorix ) 2008 (4, 6B, 9V, 14, 18C, 19F, 23F, 1, 5, 7F)» Also active vs NTHi (protein D conjugate) 13-valent (PCV13, Prevnar 13 ) 2010 (4, 6B, 9V, 14, 18C, 19F, 23F, 1, 5, 7F, 3, 6A, 19A) Pneumococcal plain polysaccharide vaccine 23-valent (PPSV23, Pneumovax 23) 1983 (4, 6B, 9V, 14, 18C, 19F, 23F, 1, 5, 7F, 3, 19A, 2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, 33F) Includes all PCV13 serotypes except 6A

6 Herd Effect vs Herd Immunity PCVs reduce nasopharyngeal colonization leading to reduced transmission and reduced disease through herd effect Herd Immunity John TJ, Samuel R. Eur J Epidemiol. 2000;16(7):601-6 Herd Immunity (Direct): the proportion of subjects with immunity in a given population Herd Effect (Indirect): indirect protection is observed in the un-immunized segment of a population in which a large proportion is immunized Immunizing most children (the main reservoir) protects most adults through reduced asymptomatic transmission of vaccine serotype strains

7 All Pneumococcal Infections Death Meningitis/Sepsis Pneumonia Otitis Media Asymptomatic Nasopharyngeal Colonization

8 Invasive Pneumococcal Disease (IPD): Primary Diagnosis & Mortality by Age Groups 100% 90% 80% 70% 60% Meningitis Pneumonia/Empyema Bactermia/Other Invasive Mortality 50% 40% 30% 20% 10% 0% 0-5 m 6-23 m 2-4 y 5-15 y y 85 y Updated from Ricketson et al. 10 th Canadian Immunization Conference, Vancouver CASPER IPD Study & Leal et al. PIDJ 2012;31(9):e169

9 How well have PCVs worked to prevent IPD?

10 Rate Ratio (RR) for PCV7 Vaccine-Type (VT) IPD, Risk Ratio Immediate direct benefit to children Gradual indirect benefit to adults over 5-7 yrs 16 Countries Year after introduction of PCV7 <5 y y y 65 y Solid marker = significant Open marker = NS Feikin DR et al for Serotype Replacement Study Group. PLoS Medicine 2013;10(9):e

11 Trends in PCV7 serotype IPD (cases/100,000/yr) in Calgary, , by age groups Incidence per 100,000 people PCV7 (3+1) Overall 0-23 months 2-4 years 5-15 years years 65+ years PCV13 (2+1) From Ricketson et al, ISPPD 2016, Glasgow (Calgary S. pneumoniae Epidemiology Research (CASPER) Study)

12 Trends in PCV13 (lesspcv7) serotype IPD (n/100,000/yr) in Calgary, , by age groups Incidence per 100,000 people PCV7 PCV Year Overall 0-23 months 2-4 years 5-15 years years 65+ years From Ricketson et al, ISPPD 2016, Glasgow (Calgary S. pneumoniae Epidemiology Research (CASPER) Study)

13 Serotype-specific IPD (cases/100,000/yr) in Calgary , all ages Incidence per 100,000 people PCV7 serotypes PCV13(-PCV7) Serotypes Non-Vaccine Serotypes 8 12F 20 22F (37%) 19A 3 (15%) 4 (13%) Adapted from Ricketson et al, ISPPD 2016, Glasgow

14 Post-PCV13 Data from Other Countries

15 USA ABCs ABCs (Active Bacterial Core surveillance) 10 regions, pop ~29 million, started 1995 Started 1998, measure IPD ( cases/yr) PCV7 introduced 2000 (4-dose) By 2007, for all ages, PCV7 ST IPD 94%, all IPD 45%, 19A 253% (Pilishvili JID 2010;201:32) PCV13 introduced 2010 (children); and (with PPSV23) in 2012 (adults at risk), 2014 (adults 65) Recent reports of data to end of 2015 (Pilishvili et al, 10 th ISPPD, Glasgow 2016 & IDWeek 2016, New Orleans)

16 Pilishvili et al, 10 th ISPPD, Glasgow 2016 USA ABCs

17 USA ABCs Is PCV13 effective against ST3? Decline since PCV13 introduction mainly driven by declines in 19A and 7F; declines in 3 and other ST have been more modest Serotype Children <5 y Adults 65 y % Change vs (95% CI) PCV7 ST -4 (-56, +110) -74 (-82, -63) 19A -91 (-95, -86) -85 (-89, -78) 7F -98 (-99, -89) -92 (-95, -86) 3-42 (-73, +25) -22 (-39, -1) Pilishvili et al. IDWeek 2016, New Orleans

18 England & Wales PHE PHE (Public Health England) Pop ~56 million, started 2000, measure IPD (~5200 cases/yr) PPSV 2003, PCV (3-dose), PCV

19 Children England & Wales PHE Adults Overall IPD trends: - PCV7 ST 97% from pre-pcv7 baseline - PCV13 ST 65% from pre-pcv13 baseline - Non-PCV13 ST 60% from PCV7 baseline - in related to slight in PCV13 ST (esp 3, 19A in elderly) from 1.40->1.57/100,000 and more notable in non-pcv13 ST (esp 8, 9N, 10A, 12F) from 5.25->6.45/100,000 -? Related to active influenza season Collins et al, 10 th ISPPD, Glasgow 2016

20 Canada Toronto (TIBDN) PCV13 ST-specific IPD since , 6A, 7F, 19A (1, 5 rare) only ST3 not McGeer et al. IDWeek 2017, San Diego

21 PCV13 vs PHiD-CV Both contain same 10 serotypes: 4, 6B, 9V, 14, 18C, 19F, 23F, 1, 5, 7F PCV13 also has 3, 6A, 19A Important difference because of emergence of 19A as replacement serotype Is PHiD-CV active against 19A IPD (through cross protection from 19F component)? The clinical and immunologic evidence is unclear at this time More evidence needed

22 PHiD-CV may be cross-protective vs 19A Quebec Deceuninck Vaccine 2015;33(23):2684 PCV7 2004; PHiD-CV 2009; PCV ; case-control study of 516 IPD cases/1767 controls Vaccine efficacy (VE) vs Vaccine serotypes (VTs) 90% for PCV7, 97% for PHiD-CV, 86% for PCV13 VE vs 19A 71% for PHiD-CV, 74% for PCV13 Finland Jokinen PLoS ONE 2015 DOI: /journal.pone PHiD-CV from 2010; cohort study to 2013 All IPD 80%, VTs 92%, 19A 62%, 6A 100% Brazil Dominigues Lancet Resp Med 2014:2(6):464 PHiD-CV from 2010; case control study of 316 IPD cases/1219 controls via PAHO s SIREVA network VTs 84%, 19A 82%

23 PHiD-CV may not be cross-protective vs 19A Finland 2015 public health report ( 81% in IPD in vaccine eligible children 19A cases (<5 yr) (av. 11 cases, 41% of all IPD) vs (av. 6 cases, 10% of all IPD) Brazil Adrade et al. Humm Vacc Immuno 2016:12(2):285 PHiD-CV from 2010; national reference lab surveillance study of ~9800 cases (SINAN) : 44%v in all IPD, 41% in VTs (2-23 mos), but 63% in additional PCV13 STs (3, 6A, 19A) (<5 yrs) New Zealand 2014 public health report ( PCV7 from 2008, PHID-CV from % in vaccine ST IPD (<5 yr) 19A from 4 to 10/100,000/yr (<2 yr) since PHiD-CV, unchanged or in all other age groups

24 Chile Statement from Immunization Advisory Committee of Chilean Infectious Diseases Society PCV10 (PHiD-CV) introduced for children schedule initially, then 2+1, no catchup Decrease in hospital admissions and pneumoniarelated deaths in children From Potin M et al. Rev Chilena Infectol 2016 Jun;33(3):304-6

25 Chile Increase in serotype 19A documented by Institute of Public Health surveillance from <5% of all cases before 2010 to 12-23% in Children <2 yr, 19A from 4-8% in pre-vaccine era to 25% during 2014 Antibiotic resistance in ST 19A (<5 yr) Non-meningitis: 25% Meningitis: 100% Genetic analysis 48% of ST 19A strains belong to clonal complex 320 (pandemic potential and high antimicrobial resistance., Most ST 19A cases have occurred in children fully vaccinated with PCV10 From Potin M et al. Rev Chilena Infectol 2016 Jun;33(3):304-6

26 Asymptomatic nasopharyngeal colonization precedes disease caused by typical colonizing bacteria

27 Pathogenesis Non-Invasive Sinuses Meninges Nasopharynx Tympanic membrane Blood vessel Lung Lung Bone Invasive

28 Bacterial Nasopharyngeal Colonization Pneumococcus Other routinely cultured flora (H. influenzae, Neisseria, S. aureus, etc) Respiratory Microbiome

29 Epidemiology of Pneumococcal Colonization Prevalence of colonization highest in children > adults with children > adults without children Colonizing serotypes α host age, time period, geographical region Colonizing serotypes invasive serotypes, but in different proportions Some are more or less likely to invade Antibiotic resistance tends to be higher in colonizing strains vs invasive strains Early PCV trials anticipated that PCV would colonization with vaccine STs and non-vaccine STs would

30 What happened after introduction Early post-pcv7 findings of universal PCV7 vaccination?

31 Trends in Pneumococcal NP Colonization % 20% 15% 10% 5% 0% Survey 1 - Jun 03 Survey 2 - Nov 03 Survey 3 - May 04 Survey 4 - Nov 04 Survey 5 - May 05 Survey 6 - Nov 05 Overall Colonization PCV7 Col Non-PCV7 Col Kellner et al PIDJ 2008;27:526. CASPER NP study of healthy children <5 yrs

32 What happened after introduction of universal PCV7 vaccination? Early post-pcv7 findings Later post-pcv7 findings Post-PCV13 findings

33 Later Post-PCV Trends in Pneumococcal NP Colonization % Colonized 25.0% 20.0% 19% ( ) vs 13% ( ), P< % 10.0% 5.0% 0.0% Ricketson et al. PIDJ 2014;33(7):724 & unpublished data from CASPER NP study of healthy children <5 yrs

34 Trends in Pneumococcal NP Colonization Serotypes % Percent of S. pneumoniae colonization 90% 80% 70% 60% 50% 40% 30% 20% 23% 9% 68% 30% 21% 49% 40% 14% 46% 59% 14% 67% 69% 12% 21% 86% 94% 96% Other serotypes PCV13-only serotypes PCV7 serotypes Top NP 15B 15C 21 22F 23B 35B (63%) 10% 0% 2003 pre- PCV7 (1) 2003 post- PCV7 (2) 2004 (3 & 4) 27% 2005 (5 & 6) 21% 10% 10% 5% 5% 3% 1% 1% 2006 (7) (8) 2011 (9) 2012 (10) 2016 (12) Year (Survey #) Ricketson et al. PIDJ 2014;33(7):724 & unpublished data from CASPER NP study of healthy children <5 yrs

35 Clinical Features of IPD

36 Changes in IPD in Children (<18 y) Feature Pre-PCV7 Post-PCV7 Post-PCV13 P-value Cases (n) n/a Incidence (per/100,000/yr) Median Age 2.0 yr 2.7 yr 3.9 yr Underlying comorbidity 20% 25% 21% Indigenous 6% 6% 8% (37%) children had received 2 doses of a PCV when their episode of IPD occurred - 7 with 2 doses PCV7 had vaccine type IPD (6B, 14, 18C, 19F (3 cases), 23F) - 4 with 2 doses PCV13 had vaccine type IPD (3, 19A (2 cases), 19F) - 15 (5%) had received a dose of PPSV23 Ricketson, Conradi, Vanderkooi, Kellner. PIDJ 2017 July 20 Epub ahead of print

37 Changes in IPD in Children (<18 y) Feature Pre-PCV7 Post-PCV7 Post-PCV13 P-Value Focal infection* 45% 64% 61% Hospitalization 60% 79% 82% PICU admission 16% 21% 23% Death 2% 3% 2% *Meningitis, pneumonia +/- empyema, peritonitis vs bacteremia Ricketson, Conradi, Vanderkooi, Kellner. PIDJ 2017 July 20 Epub ahead of print

38 Changes in IPD in Children (<18 y) Feature Pre-PCV7 Post-PCV7 Post-PCV13 P-Value Meningitis Penicillin non-suspectible (PNSP) 0% 5.4% 2.9% - PCV7 serotype 77% 42% 6% <0.001 PCV13 only serotype 12% 35% 32% Non-vaccine serotype 11% 23% 62% <0.001 *Meningitis, pneumonia +/- empyema, peritonitis vs bacteremia Ricketson, Conradi, Vanderkooi, Kellner. PIDJ 2017 July 20 Epub ahead of print

39 Feature Changes in IPD in Children (<18 y) Multivariate Analyses Model 1: Predictors of Hospital Admission Odds Ratio (95% CI) P-Value Model 2: Predictors of PICU Admission Odds Ratio (95% CI) P-Value Post-PCV7 period 2.0 (1.0, 3.9) (0.4, 2.2) Post-PCV13 period 2.9 (1.4, 3.6) (0.5, 2.7) Focal infection 2.8 (1.6, 5.1) < (6.9, 124) <0.001 Underlying comorbidity 3.3 (1.4, 7.7) Ricketson, Conradi, Vanderkooi, Kellner. PIDJ 2017 July 20 Epub ahead of print

40 IPD in Children Feature PCV13 IPD ( ) Non-PCV13 IPD ( ) P-Value Focal disease 58% 56% Underlying comorbidity 19% 28% Hospitalization 75% 75% PICU admission 21% 17% Ricketson, Conradi, Vanderkooi, Kellner. PIDJ 2017 July 20 Epub ahead of print

41 Conclusions PCVs highly effective to reduce vaccine-serotype IPD (and related disease) through both direct and indirect (herd) effects PCVs reduce overall IPD in children, with limited replacement disease; the overall indirect effect in adults is variable but the largest studies (USA, UK) describe overall IPD reduction PCV13 effectiveness against ST3 limited PHiD-CV effectiveness against ST19A unclear 3 dose schedules (2+1) for healthy children now routine PCVs have nearly eliminated NP colonization with vaccine serotypes; in some populations PCVs have also reduced overall colonization rates

42 What is next for pneumoccocal vaccines? No perfect vaccine yet to ensure global control of disease Under development Increased valency conjugate vaccines Universal protein vaccines Combined conjugate and protein vaccines Whole cell vaccines

43 CASPER & ACHIEVE 1998 CASPER Calgary S. pneumoniae Epidemiology Research Team Population-based surveillance of IPD Epidemiologic trends, antibiotic resistance, risk factors, clinical features, outcome, unique clinical observations Nasopharyngeal colonization Surveys in Public Health community health centres Collaborations TIBDN (McGeer, Low) IMPACT (Immunization Monitoring Program, ACTive) Cross-Canada epi studies, meningitis case-control study, serotype 19A study, etc National Labortatory of Microbiology (Winnipeg, Demczuk, Martin) SPAT (S. pneumoniae Alberta Team, Marrie, Tyrrell) AHFMR/AI-HS Vaccine Design & Implementation Team Contract studies PCV13 clinical trial WHO Serotype Technical Advisory Group PICNIC (Pediatric Investigators Collaborative Network on Infections in Canada) Empyema study CIHR Microbiome study (Surette) CIHR Innate immunity study (Turvey) CIHR/JPIAMR Antimicrobial Resistance (Bentley, Fittipaldi et al) 2009 ACHIEVE Alberta Children s Hospital Infectious Diseases Epidemiology & Vaccine Evaluation Influenza epidemiology studies and clinical trials PCIRN (PHAC/CIHR Influenza Research Network) CIRN Contract studies Other vaccine preventable diseases CIHR Meningococcus C long term immunogenicity study CIRN RCTs PCV, meningococcal vaccine Contract studies Maternal Pertussis RCT Funding ACH Foundation / ACH Research Institute AHFMR/AI-HS CIHR PHAC Pfizer (formerly Wyeth) GSK Shire Aventis

44 CASPER & ACHIEVE Team Investigators Calgary Jim Kellner Otto Vanderkooi Judy MacDonald Susan Kuhn Current Collaborators Julie Bettinger UBC Manish Sadarangani UBC Allison McGeer Mt. Sinai, U of T Walter Demczuk NLM, Winnipeg Irene Martin NLM, Winnipeg Tony Schryvers U of C Scott Gray-Owen U of T Joenel Alcantara U of C Nahuel Fittipaldi - PHO, U of T Staff Joslyn Gray Shannon Pyra Leah Ricketson Nicole McMillan ~15 part-time research nurses and research assistants Tracie Lloyd CLS Current & Past Trainees Paul Adamiak Aditi Amin Jason Cabaj Rupesh Chawla Tara Chobotuk Shalini Desai HiuYee Kwok Jenine Leal Shannon MacDonald Athena McConnell Leah Ricketson Loreto Twele Joseph Vayalumkal Andrew Wong Melissa Wood Franziska Zukol Lauren Zwicker

45 Mount Rundle near Banff, Alberta