"Non-invasive Pneumococcal Diseases dynamics & the Host Age" Roman Prymula Ministry of Health, the Czech Republic

"Non-invasive Pneumococcal Diseases dynamics & the Host Age" Roman Prymula Ministry of Health, the Czech Republic

Disease Caused by S. pneumoniae S. pneumoniae Eustachian Tube Nasopharynx Pharynx Nasal Cavity Trachea Larynx Primary Bronchi Lungs Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Diseases. Atkinson W, et al, eds. 11th ed. Washington DC: Public Health Foundation, 2009. Chapter 15: Pneumococcal Disease. Dagan R, Klugman KP. Chapter 25: Impact of Conjugate Pneumococcal Vaccine on Antibiotic Resistance. In: Pneumococcal Vaccines: the Impact of Conjugate Vaccine. Siber G, et al (eds). ASM Press, Washington DC (2008). pp374.

Disease Caused by S. pneumoniae S. pneumoniae Bacterial respiratory pathogens Eustachian Tube Nasopharynx Pharynx Nasal Cavity Trachea Larynx Primary Bronchi Lungs Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Diseases. Atkinson W, et al, eds. 11th ed. Washington DC: Public Health Foundation, 2009. Chapter 15: Pneumococcal Disease. Dagan R, Klugman KP. Chapter 25: Impact of Conjugate Pneumococcal Vaccine on Antibiotic Resistance. In: Pneumococcal Vaccines: the Impact of Conjugate Vaccine. Siber G, et al (eds). ASM Press, Washington DC (2008). pp374.

Disease Caused by S. pneumoniae S. pneumoniae Bacterial respiratory pathogens Upper Respiratory Tract Infections Sinusitis Otitis media Eustachian Tube Nasopharynx Pharynx Nasal Cavity Trachea Larynx Primary Bronchi Lungs Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Diseases. Atkinson W, et al, eds. 11th ed. Washington DC: Public Health Foundation, 2009. Chapter 15: Pneumococcal Disease. Dagan R, Klugman KP. Chapter 25: Impact of Conjugate Pneumococcal Vaccine on Antibiotic Resistance. In: Pneumococcal Vaccines: the Impact of Conjugate Vaccine. Siber G, et al (eds). ASM Press, Washington DC (2008). pp374.

Disease Caused by S. pneumoniae S. pneumoniae Bacterial respiratory pathogens Upper Respiratory Tract Infections Sinusitis Otitis media Eustachian Tube Nasopharynx Pharynx Nasal Cavity Trachea Larynx Lower Respiratory Tract Infections Pneumonia Primary Bronchi Lungs Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Diseases. Atkinson W, et al, eds. 11th ed. Washington DC: Public Health Foundation, 2009. Chapter 15: Pneumococcal Disease. Dagan R, Klugman KP. Chapter 25: Impact of Conjugate Pneumococcal Vaccine on Antibiotic Resistance. In: Pneumococcal Vaccines: the Impact of Conjugate Vaccine. Siber G, et al (eds). ASM Press, Washington DC (2008). pp374.

Disease Caused by S. pneumoniae S. pneumoniae Bacterial respiratory pathogens Meningitis Upper Respiratory Tract Infections Sinusitis Otitis media Eustachian Tube Nasopharynx Pharynx Nasal Cavity Invasive Diseases Trachea Larynx Lower Respiratory Tract Infections Pneumonia Primary Bronchi Bacteraemia/ Sepsis Lungs Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Diseases. Atkinson W, et al, eds. 11th ed. Washington DC: Public Health Foundation, 2009. Chapter 15: Pneumococcal Disease. Dagan R, Klugman KP. Chapter 25: Impact of Conjugate Pneumococcal Vaccine on Antibiotic Resistance. In: Pneumococcal Vaccines: the Impact of Conjugate Vaccine. Siber G, et al (eds). ASM Press, Washington DC (2008). pp374.

Disease Caused by S. pneumoniae S. pneumoniae Bacterial respiratory pathogens Meningitis Upper Respiratory Tract Infections Sinusitis Otitis media Treatment with antibiotics Trachea Eustachian Tube Nasopharynx Pharynx Larynx Nasal Cavity Invasive Diseases Lower Respiratory Tract Infections Pneumonia Primary Bronchi Lungs Bacteraemia/ Sepsis Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Diseases. Atkinson W, et al, eds. 11th ed. Washington DC: Public Health Foundation, 2009. Chapter 15: Pneumococcal Disease. Dagan R, Klugman KP. Chapter 25: Impact of Conjugate Pneumococcal Vaccine on Antibiotic Resistance. In: Pneumococcal Vaccines: the Impact of Conjugate Vaccine. Siber G, et al (eds). ASM Press, Washington DC (2008). pp374.

Disease Caused by S. pneumoniae S. pneumoniae Bacterial respiratory pathogens Meningitis Upper Respiratory Tract Infections Sinusitis Otitis media Treatment with antibiotics Trachea Nasal Cavity Eustachian Tube Nasopharynx Pharynx Antibiotics Larynx resistance! Invasive Diseases Lower Respiratory Tract Infections Pneumonia Primary Bronchi Lungs Bacteraemia/ Sepsis Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Diseases. Atkinson W, et al, eds. 11th ed. Washington DC: Public Health Foundation, 2009. Chapter 15: Pneumococcal Disease. Dagan R, Klugman KP. Chapter 25: Impact of Conjugate Pneumococcal Vaccine on Antibiotic Resistance. In: Pneumococcal Vaccines: the Impact of Conjugate Vaccine. Siber G, et al (eds). ASM Press, Washington DC (2008). pp374.

High burden childhood pneumococcal disease has driven the search for adequate paediatric vaccines Vaccination drivers Meningitis Bacteraemia Pneumonia Severity Deaths Transmission Hospitalization Cost Non-invasive diseases (Otitis media) Volume of cases Cost ATB use & resist. CDC MMWR 1997 & 2000; Dagan R, Textbook of Pediatric Infectious Diseases. 5th ed.; 2004 ; Melegaro J. Infection 2006; Ziebold Acta Pædiatr 2000; Valenzuela MT PAHO J. 2007; Leimkugel J Infect Dis 2005; NTHi: non-typeable Haemophilus influenzae

High burden childhood pneumococcal disease has driven the search for adequate paediatric vaccines CDC MMWR 1997 & 2000; Dagan R, Textbook of Pediatric Infectious Diseases. 5th ed.; 2004 ; Melegaro J. Infection 2006; Ziebold Acta Pædiatr 2000; Valenzuela MT PAHO J. 2007; Leimkugel J Infect Dis 2005; NTHi: non-typeable Haemophilus influenzae

Non-invasive pneumococcal diseases These may be less serious than invasive pneumococcal disease and occur outside the major organs or the blood. S. pneumoniae can spread from the nasopharynx (nose and throat) to the upper and lower respiratory tract and can cause: Otitis media - middle ear infection. Inflammation of the middle ear, typically with accumulation of fluid in the middle ear, swelling of the eardrum, earache. If the eardrum is perforated drainage of pus into the ear canal. Streptococcus pneumoniae conjunctivitis is a characteristically acute and painless infection with occasional pruritus. On inspection, the conjunctiva is thickened and injected and there is purulent, sometimes profuse, discharge. The infection is often self-limiting but topical antibiotic treatment may be required. Non-bacteremic pneumonia - infection of the lower respiratory tract without detectable spread of organisms to the blood stream CDC, ECDC, 2018

Colonization and Carrier State I Torres, A. CAI, 2014

Colonization and Carrier State II Torres, A. CAI, 2014

Carriage prevalence and serotype distribution of Streptococcus pneumoniae prior to 10-valent pneumococcal vaccine introduction: A population-based cross-sectional study in South Western Uganda, 2014 14 Neckars F., et al. Vaccine 2017.

Effect of PHiD-CV on pneumococcal nasopharyngeal carriage Open, controlled, not randomized trial in Czech Republic PHiD-CV + DTPa-HBV-IPV/Hib + HRV* (N=414) with or without prophylactic paracetamol (PP) Dose 1 3 months of age Dose 2 4 months of age Dose 3 5 months of age Booster 12 15 months of age *HRV only co-administered with the 1 st and 2 nd PHiD-CV dose Prymula et al. Lancet 2009; 374: 1339 50; Prymula et al. WSPID Buenos Aires, 18 22 Nov 2009 (Abstract 1113); Prymula et al. ISPPD-7 Tel Aviv, 14 18 March 2010 (Abstract 530)

Swab Swab Swab Swab Swab Effect of PHiD-CV on pneumococcal nasopharyngeal carriage Open, controlled, not randomized trial in Czech Republic PHiD-CV + DTPa-HBV-IPV/Hib + HRV* (N=414) with or without prophylactic paracetamol (PP) MenACWY-TT control + DTPa-HBV-IPV/Hib (N=336) Dose 1 3 months of age Dose 2 4 months of age Dose 3 5 months of age Booster 12 15 months of age *HRV only co-administered with the 1 st and 2 nd PHiD-CV dose Prymula et al. Lancet 2009; 374: 1339 50; Prymula et al. WSPID Buenos Aires, 18 22 Nov 2009 (Abstract 1113); Prymula et al. ISPPD-7 Tel Aviv, 14 18 March 2010 (Abstract 530) 0 1 3 7 12 Months post-vaccination

% colonization 20 Effect of PHiD-CV on pneumococcal nasopharyngeal carriage Booster dose Pneumococcal vaccine serotypes (VT) 15 10-28% (ns) -34%* -22% (ns) -31% (ns) -35%* 5 Control Synflorix Study Month M0 M1 M3 M7 M12 Age (months) 12 15 13 16 15 18 19 22 24 27 0 Prymula et al. WSPID Buenos Aires, 18 22 Nov 2009 (Abstract 1113) * statistically significant difference based on non-overlapping 95% confidence intervals; ns = not statistically significant

% colonization 20 Effect of PHiD-CV on pneumococcal nasopharyngeal carriage Booster dose Pneumococcal vaccine serotypes (VT) 15 10 5 Synflorix with PP Control Synflorix without PP Study Month M0 M1 M3 M7 M12 Age (months) 12 15 13 16 15 18 19 22 24 27 0 Prymula et al. WSPID Buenos Aires, 18 22 Nov 2009 (Abstract 1113)

% colonization Effect of PHiD-CV on pneumococcal nasopharyngeal carriage Pneumococcal non-vaccine serotypes (NVT), non-cross-reactive 20 serotypes Booster dose 15 10 +14% (ns) +14% (ns) +19% (ns) +45% (ns) 5-16% (ns) Control Synflorix Study Month M0 M1 M3 M7 M12 Age (months) 12 15 13 16 15 18 19 22 24 27 0 Prymula et al. WSPID Buenos Aires, 18 22 Nov 2009 (Abstract 1113) ns=not statistically significant

% colonization Effect of PHiD-CV on pneumococcal nasopharyngeal carriage Pneumococcal non-vaccine serotypes (NVT), non-cross-reactive 20 serotypes Booster dose 15 10 5 Synflorix with PP Control Synflorix without PP Study Month M0 M1 M3 M7 M12 Age (months) 12 15 13 16 15 18 19 22 24 27 0 Prymula et al. WSPID Buenos Aires, 18 22 Nov 2009 (Abstract 1113)

Impact of the 13-valent Pneumococcal Conjugate Vaccine on Chronic Sinusitis Associated With Streptococcus pneumoniae in Children (Texas, Houston) Olarte Liset, PIDJ, 2014 Despite effectiveness of pneumococcal conjugate vaccines, Streptococcus pneumoniae is still an important pathogen in chronic sinusitis among children younger than 5 years. Overall, - 14% of participants had a positive sinus culture for S. pneumoniae; - 22% were in the pre-vaccine period - 9% were in the post-vaccine period (P<.0001). Year Cases 2009 2010 2011 2012 2013 19 26 11 20 5. - Chronic nasal congestion/drainage and chronic cough were present in all patients. Before surgery, information on antibiotic therapy was available in 43 patients and 40 had received an antibiotic within 4 weeks before surgery. Chronic otitis media (67%) was the most common comorbid condition, followed by allergic rhinitis (37%), reactive airway disease/asthma (30%) and gastroesophageal reflux (15%).

The complexity of acute otitis media Bacterial pathogen(s) C. Deriez

The complexity of acute otitis media Bacterial pathogen(s) AOM (Acute Otitis Media) C. Deriez

The complexity of acute otitis media Bacterial pathogen(s) AOM (Acute Otitis Media) or watchful waiting C. Deriez

The complexity of acute otitis media Bacterial pathogen(s) AOM (Acute Otitis Media) or watchful waiting OME (Otitis Media with Effusion) C. Deriez

The complexity of acute otitis media Bacterial pathogen(s) AOM (Acute Otitis Media) or watchful waiting Rare, severe complications (Mastoiditis, meningitis) OME (Otitis Media with Effusion) C. Deriez

The complexity of acute otitis media Bacterial pathogen(s) RECURRENT AOM AOM (Acute Otitis Media) SURGERY (Tympanostomy tubes) or watchful waiting Rare, severe complications (Mastoiditis, meningitis) OME (Otitis Media with Effusion) OME (hearing, learning disability) C. Deriez

The Otitis Media Spectrum Recurrence and persistence are the hallmarks of OM 1,2 Terms Acute OM (AOM) Initial AOM episode Recurrent OM (ROM) 3 episodes in 6 months or 4 episodes in 12 months 3 Chronic OM (COM) 6 episodes in 6 months Chronic Suppurative OM (CSOM) COM or chronic OME with perforation OM spectrum Symptoms Pain, fever 4 Draining ears OM with effusion (OME) 5 Tympanic perforation OM with tympanic perforation Chronic perforation Suppurative complications 1 Mastoiditis, hearing loss, brain abscess, meningitis 1. Available at. www.who.int/childadolescenthealth/new_publications/child_health/isbn_92_4_159158_7.pdf (accessed Nov 2007) 2. Teele DW, et al. J Infect Dis 1989;160:83 94. 3. Pichichero ME. Pediatr Infect Dis J 2000;19:911 916. 4. Kenna M. Otitis media and its complications. In: Behrmann RE et al, editors. Nelson Textbook of Pediatrics 16th ed. Philadelphia, PA: W.B Saunders 2000. p1951. 5. Daly KA, et al. Pediatr Rev 1999;20:85 93.

29 POET Study Design Czech and Slovak Republics Double blind, randomized (1:1) study Protein D conjugate vaccine prototype 11 Pneumococcal serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, 23F* 1 µg of every serotype conjugated individually to protein D Control vaccine Hepatitis A vaccine (Havrix TM -720 ELISA units) of inactivated virus antigen Three doses at 3, 4 and 5 months* + booster at 12-15 months Concomitant EPI vaccine DTPa-HBV-Hib/IPV (Infanrix hexa TM ) administered in both groups at 3.4 and 5 months of age. Booster followed at 15-18 months of age ~ 5 000 infants, with 24 months follow-up 3 4 5 12-15 24-27 m Prymula R, et al. Lancet 2006;367:740-748.

30 Vaccine efficacy (VE)- Bacterial AOM Total = 306 164 No of bacterial AOM 25 68 34 V-Pn serotypes+crossr serotypes Non-vaccine Pn serotypes H. influenzae M. catarrhalis 36 Control group (N=2452) Prymula R, et al. Lancet 2006;367:740-748. Vaccine group (N=2455) Others

31 Vaccine efficacy (VE)- Bacterial AOM Total = 306 164 VE against bacterial AOM = 42% No of bacterial AOM 25 VE = 58% 68 V-Pn serotypes+crossr serotypes Non-vaccine Pn serotypes 68 34 36 Control group (N=2452) Prymula R, et al. Lancet 2006;367:740-748. VE = 36% 23 44 31 30 Vaccine group (N=2455) H. influenzae M. catarrhalis Others

32 Serotype Specific Efficacy Control 11Pn-PD (N=2452) (N=2455) VE (%) 95%CI Clinical 499 333 33.6 20.8 44.3 4 3 0 100.0-27.8 100.0 6B 24 3 87.6 58.4 96.3 9V 8 3 62.6-40.8 90.1 14 22 1 95.5 66.0 99.4 18C 5 3 40.1-176.6 87.0 19F 43 24 44.4 8.3 66.3 23F 18 5 72.3 24.8 89.8 1 1 1 0.2-1495.0 93.8 3 17 20-17.1-126.5 39.5 5 0 0-7F 1 0 100.0-283.6 100.0 Any VT 141 60 57.6 41.4 69.3 6A 11 4 63.7-13.9 88.4 19A 3 1 67.4-208.7 96.6 NTHi 63 41 35.3 1.8 57.4 Prymula et al. Lancet 2006;367:740-8

No protection against serotype 3 AOM in POET: why? Polysaccharide capsules known to protect bacteria against immune system Serotype 3 pneumococci are abundantly capsulated Polysaccharide capsule Hammerschmidt et al. IAI 2005; 73:4653 Serotype 3 Serotype 19F

Seasonality of AOM cases in the US, 2008 2014 10/8/2018 34 Tong S., et al. BMC Health Serv Res. 2018.

Community-acquired pneumonia (CAP) Community-acquired pneumonia (CAP) is defined as pneumonia acquired outside of hospital or healthcare facilities. Clinical diagnosis is based on a group of signs and symptoms related to lower respiratory tract infection with presence of fever >100ºF (>38ºC), cough, expectoration, chest pain, dyspnea, and signs of invasion of the alveolar space. However, older patients in particular are often afebrile and may present with confusion and worsening of underlying diseases. Is one of the most common infectious diseases and is an important cause of mortality and morbidity worldwide. Typical bacterial pathogens that cause CAP include Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis The most common viral pathogens recovered from hospitalized patients admitted with CAP include human rhinovirus and influenza.

Woodhad, 1998

Study CAPITA (Community-Acquired Pneumonia Immunization Trial in Adults) Netherland 84 496 healthy volunteers Age 65 let Prevenar 13 vs. Placebo Primary objective: Efficacy of PCV13 in prevention of the first CAP (community-acquired pneumonia) episode caused by vaccine serotypes Secondary objectives: Efficacy of PCV13 in prevention of the first non-bacteremic (noninvasive) episode caused by vaccine serotypes Efficacy of PCV13 in prevention of the first IPO episode caused by vaccine serotypes Hak E, Grobbee DE, Sanders EAM, et al. Netherlands J Med. 2008;66:378-383

Microbiological Definitions for Primary and Secondary Endpoints Endpoint Definition Confirmed VT pneumococcal CAP Confirmed NB/NI VT pneumococcal CAP (1) Presence of 2 or more specified clinical findings consistent with CAP AND (2) Chest x-ray consistent with CAP AND (3) Culture of VT S pneumoniae from blood, pleural fluid or other sterile site and/or positive VT SSUAD Confirmed VT pneumococcal CAP for which a blood culture result is available and is negative and for which any other culture results from pleural fluid or other sterile site are negative for S pneumoniae VT-IPD VT S pneumoniae in blood, pleural fluid or other sterile site, If no serotype was determined from the S pneumoniae culture isolate and a serotype was determined by SSUAD for the same case, the SSUAD serotype was assigned to the case. Bonten, N

60 1st Episode VT-CAP Cumulative Case Counts 30 1st Episode VT-IPD Days since vaccination Days since vaccination 60 1st Episode NB/NI VT- CAP Days since vaccination Days since vaccination plots from post hoc analysis 39

60 1st Episode VT-CAP Cumulative Case Counts 30 1st Episode VT-IPD Days since vaccination Days since vaccination 60 1st Episode NB/NI VT- CAP Interim analyses (1 st episode VT-CAP, n=74) PCV13 Placebo VE 99.48% CI p-value 25 49 49.0-2.4, 75.9 0.007 Final analyses (1 st episode VT-CAP, n=139) 95.2% CI 49 90 45.56 21.82,62.49 0.0006 Days since vaccination Days since vaccination plots from post hoc analysis 40

Study CAPITA (Community-Acquired Pneumonia Immunization Trial in Adults) Study confirmed both primary and secondary objectives efficacy against community pneumonia and IPO in persons 65 years and older Objective Prevenar 13 (n=42,240) Placebo (n=42,256) VE (%) 95.2% CI P-value First CAP episode caused by vaccine serotypes 49 90 45.56 (21.82,62.49) 0.0006 First non-bacteremic (noninvasive) episode caused by vaccine serotypes 33 60 45.00 (14.21, 65.31) 0.0067 First IPO episode caused by vaccine serotypes 7 28 75.00 (41.43, 90.78)* 0.0005 Presented at ISPPD-9, March 9-14, 2014, Hyderabad, India * 95% CI

Serotype Distribution 42

Serotype Distribution 43

Serotype Distribution 44

Figure 1. Serotype distribution of the isolates causing non-invasive pneumococcal pneumonia in adults in Portugal (1999 2011). Horácio AN, Lopes JP, Ramirez M, Melo-Cristino J, for the Portuguese Group for the Study of Streptococcal Infections (2014) Non-Invasive Pneumococcal Pneumonia in Portugal Serotype Distribution and Antimicrobial Resistance. PLOS ONE 9(7): e103092. https://doi.org/10.1371/journal.pone.0103092 http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0103092

Figure 2. Proportion of isolates expressing serotypes included in pneumococcal vaccines causing noninvasive pneumococcal pneumonia in adults in Portugal (1999 2011). Horácio AN, Lopes JP, Ramirez M, Melo-Cristino J, for the Portuguese Group for the Study of Streptococcal Infections (2014) Non-Invasive Pneumococcal Pneumonia in Portugal Serotype Distribution and Antimicrobial Resistance. PLOS ONE 9(7): e103092. https://doi.org/10.1371/journal.pone.0103092 http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0103092

VT serotypes in pneumococcal CAP, UK Chalmers, BMC Pulm Dis, 2016

Take home message The most recent available data suggests that VT pneumococcal disease continues to have a high burden in UK adults despite the impact of childhood PCV13. vaccination. IPD estimates represent only a fraction of the total burden of pneumococcal disease. Universal problem: underestimation of non-ipds. Different risk based on age. Chalmers, BMC Pulm Dis, 2016