Serotype Replacement in Perspective

Serotype Replacement in Perspective Ron Dagan The Pediatric Infectious Disease Unit Soroka University Medical Center Ben-Gurion University Beer-Sheva, Israel

Pneumococcal Disease Endpoints Invasive infections sepsis meningitis Spread to other individuals Antibiotic resistance Mucosal infections otitis media sinusitis conjunctivitis pneumonia

Impact of Pneumococcal Conjugate Vaccines Against Pneumococcal Nasopharyngeal Carriage Author Conjugate Country Age at vaccination (m) VT Non-VT Dagan Pn OMP 7 Israel 12 18 + - Dagan Pn D 4, Pn T 4 Israel 2, 4, 6 + -/+ Obaro Pn CRM 7 Gambia 2, 3, 4 + + Kristinsson Pn D 8, Pn T 8 Iceland 3, 4, 6 + + Mbelle Pn CRM 9 S. Africa 1.5, 2.5, 3.5 + + Edwards Pn CRM 9 USA 2, 4, 6, 12 + + Dagan Pn D/T 11 Israel 2, 4, 6, 12 + - Dagan Pn CRM 9 Israel 12-35 (DCC) + + O Brien Pn CRM 7 USA (N/WMA) 2, 4, 6, 12 + + Kilpi Pn CRM 7 Finland 2, 4, 6, 12 + +

Evidence for NP replacement after PCV is universal and beyond doubt How does this relate to replacement disease? There is increasing evidence that replacement disease occurs mostly in compromised hosts or situations

Contacts AOM IPD HIV (+) Adults IPD Elderly

Eustachian tube Middle ear Nasopharynx VIRUS

Effect of 7-valent PCVs on AOM by Organism Overall efficacy PCV CRM = 6% ( -4% to 16%) PCV OMPC = -1% (-12 to 10%) Eskola et al, N Engl J Med, 344:406-9, 2001 Kilpi et al Clin Infect Dis 37:1155-64, 2003

Otitis Media: Efficacy of Prevenar in Preventing Ventilation Tube Insertion US 20.1% (1.5-35.2) Black S, et al. Pediatr Infect Dis J. 2000;19:187-195. Finland 39% (4-61) Palmu AA, et al. Abstract presented at: 3 rd International Symposium on Pneumococci and Pneumococcal Diseases; May 2002; Anchorage, Alaska.

Rates of Ambulatory Visits and Antibiotic Prescriptions for AOM and non-aom ARIs, 1997-2004 Overall decrease 42.7% (95% CI 42.7 43.1) X Ambulatory visits for AOM Antibiotic prescription for AOM visits Non-AOM ARI visits Antibiotic prescriptions for non-aom visits Zhou et al, Pediatr. 121;253-260, 2008

Replacement Disease in Children <5 Yrs Children <5 yrs Hick et al, J Infect Dis, 196:1346 54, 2007

Effect in Target Age Group IPD Rates in Children <5 Years, ABCs, 1998-2005 Cases/100,000 population 250 200 150 100 50 0 1 yr <1 yr 2 yrs 3 yrs 4 yrs PCV7 2005 vs baseline - 77% (<1 yr) - 82% (1 yr) - 75% (2 yr) - 61% (3 yr) - 26% (4 yr) 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 Slide Courtesy Cindy Whitney, CDC

Changes of Admissions for All Cause Pneumonia by December 2004 Compared to Expected Rates (Pre- Vaccination Rates) in the US Decline 39% (95% CI 22 to 52) Grijalva CG, et al, Lancet. 2007;369:1179-1186

Changes in Rates of Hospitalizations and Ambulatory Visits for All-Cause Pneumonias among Children <2 Years: 2004 vs 1997-9 52.4% 41.1% This retrospective, population-based study was conducted yo estimate the effect of PCV7 on rates of pneumoniarelated health care utilization and costs in children < 2 years Data were derived from approximately 40 large employers each year, from 1997 to 2004 Error bars indicate 95% confidence intervals. Rates are given for the period of 1997 to 1999 and 2004, respectively. Zhou et al, Arch Pediatr Adolesc Med. 161:1162-1168, 2007

Trends in Pneumococcal Meningitis Hospitalization Rates by Age group, US 1994-2004 Tsai et al, Clin Infect Dis 2008 (In press)

Effect of PCVs on Pneumococcal Transmission Replacement carriage Replacement in contacts

Replacement Disease in Children <5 Yrs vs Elderly (65+ Yrs) Children <5 yrs Adults 65 yrs Hick et al, J Infect Dis, 196:1346 54, 2007

Trends in Pneumococcal Meningitis Hospitalization Rates by Age group, US 1994-2004 Tsai et al, Clin Infect Dis 2008 (In press)

Difference in Serotype-specific Ratio of Cases of IPD Among Persons Living with AIDS in 2001, 2002, and 2003 Compared With Baseline (1998-9 average) Difference in IPD Case-Patients with HIV Infection per 100,000 Persons with AIDS, n 60 40 20 0-20 -40-60 -80-100 -120 4 6B 9V 14 18C 19F 23F 6A 19A 9N 1 3 5 7F 11A 12F 15B 22F 33F VT VT-related Non-VT 2001 2002 2003 Flannery et al, Ann Internal Med, 144:1-9, 2006

Non-vaccine serotype disease, Adults 18-64 years with vs without HIV/AIDS 700 600 HIV/AIDS Vaccine introduction + 43%* 500 400 Cases per 100,000 300 200 100 10 8 6 No HIV/AIDS * P<0.05 compared to baseline - 3% 4 2 0 1998 1999 2000 2001 2002 2003 Source: 7 ABCs sites, preliminary data slide by Cindy Whitney Flannery et al, Ann Internal Med, 144:1-9, 2006

Replacement Disease in Children <5 Yrs vs Elderly (65+ Yrs) <5 yrs Hick et al, J Infect Dis, 196:1346 54, 2007

Replacement Disease in Children <5 Yrs vs Elderly (65+ Yrs) 65 yrs <5 yrs Hick et al, J Infect Dis, 196:1346 54, 2007

Age-Specific Incidence of 19A IPD, 1998-2005 <5 5-17 18-49 50-64 65-79 >80 Cases per 100,000 population 10 9 8 7 6 5 4 3 2 1 0 1998 1999 2000 2001 2002 2003 2004 2005 Year Relative changes in rates represent results of the 2 test comparing rates in 2005 to pre-pcv7 average rates during 1998-1999 Moore et al, JID, (In press)

Proportion of all IPD Isolates of Serotype 19A with Intermediate or Full Pen- R and Nonsusceptibility to 3 Antibiotic Classes in Children <5 years old, Active Bacterial Core Surveillance Sites, July 1999 June 2004 serotype 19A 8.1 3 CDC; Hicks et al, IDSA 2005 Pai et al, JID 192:1988 95, 2005

Single Clonal Expansion of S. pneumoniae Serotype 19A in Korean Children Before PCV7 Introduction % of all IPD in children < 5 yrs 25 20 15 10 5 0 23 8 0 1991-1994 1995-1999 2000-2006 All 19A isolates were MDR All isolates from 2001 exhibited Sequence Type (ST) 320 A dramatic increase in rates of IPD caused by antibiotic-resistant serotype 19A can occur without vaccination Year Choi et al, 45 th IDSA abstract #202, 2007

Serotype 19A AOM in Bedouin Children in Southern Israel 1999-2006 (Pre-PCV7 Era) % of all AOM pneumococcal isolates 16 15 14 13 12 11 10 9 8 7 6 14.9 13.6 12.6 9.5 9.7 10 7.9 7.9 1999 2000 2001 2002 2003 2004 2005 2006 % serotype 19A that were MDR 60 50 40 30 20 10 0 52.9 50 36.7 22.5 24.3 11.4 4.9 0 1999 2000 2001 2002 2003 2004 2005 2006 Year Dagani et al, 47 th ICAAC abstract #1001, 2007

Clonal Distribution of Pn19A Isolated from MEF of Bedouin Children with AOM in Southern Israel, 1998*-2006 MDR ST-172 ST-2927 ST-276 ST-2928 ST-2929 ST-1756 ST-847 ST-2930 ST-2931 ST-199 Yearly clonal distribution (%) 100% 80% 60% 40% 20% 0% n=13* n=35 n=26 n=31 n=39 n=34 n=26 n=16 n=13 98* 99 00 01 02 03 04 05 06 * Isolates from 1998 were obtained before the initiation of the prospective surveillance Year Dagani et al, 47 th ICAAC abstract #1001, 2007

Conclusions Evidence for NP replacement after PCV is universal and beyond doubt In contrast to the NP situation, There is increasing evidence that replacement disease occurs mostly in compromised hosts or situations AOM Elderly HIV (+) young adults Children with underlying conditions? The effect of replacement on overall IPD and pneumonia has been so far small The dramatic increase in serotype 19A is universally related to antibiotic use and resistance and is seen also in nonvaccinating countries PCV7 is ineffective against serotype 19A, but the extent of its contribution to the expansion of this serotype in unclear