Pneumococcal vaccines Marco Aurélio Sáfadi, MD, PhD FCM da Santa Casa de São Paulo
Challenges in establishing the baseline burden of disease, before implementing a vaccination program
S. pneumoniae disease Endpoints: • Mucosal infections (AOM, sinusitis, pneumonia) • Invasive infections (sepsis, meningitis, bacteremic pneumonia) Dagan R, et al. Pneumococcal infections. In: Feigin RD, Cherry JD, Demmler GJ, Kaplan S, eds. Textbook of pediatric infectious diseases. Philadelphia: Saunders; 2004:1204-58.
Global mortality rates of pneumococcal disease Pneumococcal disease caused around 476,000 (333,000 – 529,000) deaths in children aged 1 – 59 months in 2008 1 61% of all deaths in ten countries from Africa and Asia 2 Deaths per 100,000 children < 5 years Pneumococcal meningitis • Incidence rates of 17/100,000 in 2000 • 103,000 cases with 60,500 deaths • CFR 59% (27 – 80%) • Most cases and deaths in developing countries • High proportion (up to 50%) of survivors are left with disability 1. Wkly Epidemiol Rec. 2012;14:129 – 144 2. O’Brien K, et al. Lancet 2009; 374: 893 – 902; 3.Goetghebuer T et al. Trop Med Int Health 2000 Mar;5:207 – 13
Incidence of invasive pneumococcal disease - US (meningitis, bacteremia, sepsis, bacteremic pneumonia) 180 160 140 120 100 80 60 40 20 0 <2 2 a 4 5 a 17 18 a 34 35 a 49 50 a 64 65 a 79 >80 Robinson et al. JAMA 2001;285:1729 5
Risk Factors for Pneumococcal Diseases or Complications • Immunocompetent children – Chronic heart disease – Chronic lung disease – Diabetes mellitus – Cerebrospinal fluid leaks – Cochlear implant • Children with functional or anatomic asplenia – Sickle cell disease and other hemoglobinopathies – Congenital or acquired asplenia, or splenic dysfunction • Children with immunocompromising conditions – HIV infection – Chronic renal failure and nephrotic syndrome – Diseases associated with treatment with immunosuppressive drugs or radiation therapy; or solid organ transplantation – Congenital immunodeficiency CDC. MMWR Recomm Rep . 2010;59(RR-11):1-18.
What have we learned with the use of pneumococcal conjugate vaccines...
Changes in overall invasive pneumococcal disease, 1998 – 2007 (US) PCV7 introduced Age group 2007 vs baseline 120 Cases/100,000 population (years) (% reduction) <5 76 100 5 – 17 43 18 – 49 40 50 – 64 18 80 ≥ 65 37 60 40 20 0 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 Year Pilishvili T, et al. J Infect Dis . 2010;201:32 – 41
Herd Immunity: Invasive Pneumococcal Disease in Infants 0 to 90 days,1997 – 2004 Poehling K, et al. JAMA . 2006;295:1668-1674.
Incidence rates of pneumococcal meningitis by PCV7 serotype over time in US • The absolute increase in non- PCV7 serotype disease in this population was smaller than the decrease in PCV7 ST disease Hsu et al. N Eng J Med 2009;360:244
Estimate reduction in pneumonia episodes according to vaccine efficacy PCV efficacy VAR 80 200 • VAR (cases/100,000 child-yrs) 172 67 180 70 160 • PCV Efficacy (%) 60 140 50 100 120 40 100 80 30 20 60 20 40 14 7 10 20 0 0 Clinical LRTI CXR-confirmed Vaccine-type Bacteremic pneumonia pneumonia • Despite the lower efficacy against clinical pneumonia, the number of episodes prevented is 12 times higher than the number of severe bacteremic pneumonia cases prevented. • Madhi, et al, CID 40: 1511-8 , 2005
• Observational database studies showed that OM visit rates decreased 19% on average following 7vCRM introduction, with estimates ranging widely (+7% to −48%). Before 7vCRM introduction, OM visit rates were already declining in all but one study
New pneumococcal conjugate vaccines currently in use 1, 5, 7F 4, 6B, 9V, 14, 18C, 19F, 23F • PCV-10 T D • NTHi protein D • NTHi protein D • PCV-13 1, 5, 7F 4, 6B, 9V, 14, 18C, 19F, 23F 3, 6A, 19A • CRM 197 Diphtheria carrier protein
Efficacy of PCV10 against IPD. Finland and LA. Number of episodes Vaccine effectiveness PHiD-CV Control VE point group group estimate 95% CI FinIP 100% Vaccine-type IPD: 3+1 schedule 0 12 83-100 92% Vaccine-type IPD: 2+1 schedule 1* 12 58-100 93% Overall IPD: 3+1 & 2+1 combined 2 14 75-99 100% Overall IPD: catch up children 7-18 mo 0 7 86-100 COMPAS (LA) 100% Vaccine-type IPD: 3+1 schedule 0 18 77-100 67% Overall IPD: 3+1 schedule 7 21 22-85 • 10 May, 2012 • ESPID 2012 • Palmu et al, Lancet 2013 Tregnaghi ISAAR 2013
Evaluating the impact of a vaccination program:
Brazil: demographic characteristics • Population: 190 million, with a 3 million children birth cohort • PCV10 was introduced into the Brazilian Immunization Program in a 3+1 schedule for children <2 years of age in mid 2010 • Coverage for the primary three doses schedule of the vaccine among infants was 50% in early 2011 and reached 80 – 85% in late 2011 1,2 São Paulo is the most populated State with 42 million inhabitants 1. http://www.cve.saude.sp.gov.br/htm/imuni/imu_shmenor1.htm [accessed April 2012] 2. http://tabnet.datasus.gov.br/cgi/deftohtm.exe?pni/cnv/DPniuf.def [accessed April 2012]
Invasive pneumococcal disease cases by serotype before PCV10 . SIREVA Children <2 years, Brazil 100 Number of cases 90 80 2007 – 2009 (Annual average) 70 60 80% of the cases were due to PCV10 50 40 30 20 10 0 SIREVA. http://new.paho.org/hq/index.php?option=com_content&task=blogcategory&id=3609&Itemid=3953 [accessed April 2012] 14 6B 23F 18C 19F 7F 5 9V 4 1 19A 3 6A/6C Others
- Population-based Surveillance Data
Methods • We analyzed population-based surveillance data to evaluate trends in the burden of PM before and after the introduction of PCV10 • Changes in the incidence of PM in 2011 and 2012 were assessed against baseline values from 2001 – 2009, considering 2010 as a transition year • Isolation of S. pneumoniae from cerebrospinal fluid or the clinical diagnosis of meningitis with pneumococcus isolated from the blood (culture or PCR) Adapted from Liphaus et al. ISPPD 8 Iguaçu Falls, Brazil from 11-15 March2012. Abstract
Trends in pneumococcal meningitis rates in children <2 years after introduction of PCV10 São Paulo, 2001 – 2012 N = 1,390 cases in children aged <2 years 14 Introduction of 12 PCV10 10 I.R. cases/100.000 8 6 • The rates of PM in children aged <2 years declined from an average of 4 10.2/100,000 persons in the pre-vaccination baseline period to 5.4/100,000 in the post-vaccination period 2 • Reduction of 47% (p<0.01) in incidence rates of children <2 years 0 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Adapted from Liphaus et al. ISPPD 8 Iguaçu Falls, Brazil from 11-15 March2012. Abstract
Cumulative number of cases of pneumococcal meningitis in children <2 years, Brazil 2008 – 2012 N = 1,220 cases reported in children < 2 years PCV10 introduced in mid 2010 for children <2 y (3 + 1) Reduction of ~43% in the number of cases reported http://portal.saude.gov.br/portal/arquivos/pdf/graficompmenores2anos.pdf [accessed september 2013]
−40.3% -37.6% -23.5% p<0.001 p<0.001 p = 0.052 Post-vaccine period: pneumonia hospitalization rates −49.3 13.4% p<0.001 p = 0.074
- Sentinel Hospital-based Surveillance Data
Hospital-based surveillance in São Paulo (50,000 emergency department consultations and 3,200 admissions/ year in children <5 years), including all children <2 years admitted due to pneumococcal invasive disease (2004 – 2011) A unique opportunity to assess the impact of the introduction of PCV10 on pneumococcal invasive disease Berezin et al. ISPPD 8 Iguaçu Falls, Brazil from 11 – 15 March 2012. Abstract
Distribution of IPD cases according to PCV10 types. Santa Casa, 2004 – 2011. N = 91 cases in children <2 years Average annual number of IPD cases N 16 • Reduction of 95% in the number of 14 annual vaccine-type IPD cases in 12 children < 2 y 10 Vaccine-type 8 cases 6 Non vaccine- type cases 4 2 0 2004-2009 (Pre- 2010-2011 (post- vaccine) vaccine) Adapted from Berezin et al. ISPPD 8 Iguaçu Falls, Brazil from 11 – 15 March 2012. Abstract
Invasive pneumococcal disease cases by serotype before and after PCV10 . São Paulo, Brazil . 2006 – 2010 (pre-vaccine) Reduction of 80% and 97% in the incidence rates of all IPD and vaccine-type IPD, respectively, in children < 2 years. 2010-2012 (post-vaccine) 25 No increase in overall non-PCV10 type incidence rates. All IPD cases Incidence rates (cases/1000) 20 PCV10 serotype cases 15 80% reduction 97% reduction (p < 0.0001) (p < 0.002) 10 Non-PCV10 serotype cases 5 NS NS NS NS NS NS NS NS NS NS 0 Overall < 2 y 2 - 15 y > 15 y Overall < 2 y 2 - 15 y > 15 y Overall < 2 y 2 - 15 y > 15 y Santos SR et al. Vaccine 2013 (http://dx.doi.org/10.1016/j.vaccine.2013.05.042 )
- Effectiveness Data
Effectiveness of PCV10 against invasive pneumococcal disease. Brazil N = 135 cases of invasive pneumococcal disease (IPD); 66 (49%) meningitis 100 85% 90 % (64 – 94) 71% 80 (48 – 83) Effectiveness of 70 PCV10 (≥ one 60 50 dose) 40 30 20 10 0 All types IPD Vaccine-types IPD Domingues C et al. Abstract No 320. ISPPD 2012
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