emerging concepts in pneumococcal disease prevention in india sept 2011

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Emerging Concepts in Pneumococcal Disease prevention in India

Dr Gaurav Gupta,Pediatrician,Member AAP, IAP,Charak Clinics, Mohali

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Brief intro about Pneumococcal Disease India – Scope of IPD – morbidity & mortality Latest data (Pneumonet) regarding Pneumococcal

Disease in India Data regarding Pneumococcal serotypes &

antimicrobial resistance in India Possible Impact of PCV 13 in India PCV 13 – Safety & Non-inferiority data from India Various schedules

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Pneumococcal Disease

S. pneumoniae first isolated by Pasteur in 1881

90 known serotypes First U.S. vaccine in 1977 (14 valent PPV) PCV 7 launched in 2000 Polysaccharide capsule important virulence

factor Type-specific antibody is protective

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DISEASES CAUSED BY STREPTOCOCCUS PNEUMONIAE

Non-invasive disease• Sinusitis • Otitis media • Pneumonia

Musher, in Principles and Practice of Infectious Diseases, 1995

Invasive disease

• Bacteraemia (blood)

• Meningitis (CNS)• Endocarditis (heart)• Peritonitis (body cavity)• Septic arthritis (bones and joints)• Others (appendicitis, salpingitis,

soft-tissue infections)

PNEUMOCOCCAL INFECTION

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Strep Pneumoniae in developing countries

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Child DEATHS Each Dot = 5,000 child deaths

Black RE. The Lancet 2003; 361: 2226-2234We are No. 1

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PNEUMONIA AND INDIAPNEUMONIA AND INDIA

Pneumonia remains the leading killer of children1

410,000 children < 5 die of pneumonia every year1,2

25% of all child deaths are due to pneumonia3

Meta-analysis of 4 CTs suggest 30-40% of all severe pneumonia in children is pneumococcal.

In Indian context, around 123,000 to 164,000 children <5 years die annually from pneumococcal pneumonia1

1. Levine OS et al Indian Pediatrics 2007; 44:491-4962. Pneumonia – The forgotten killer of children, WHO, UNICEF, 20063. Thacker N. IPD burden - An Indian Perspective. Pediatrics Today 2006; 9(4): 208-213

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Countries with the greatest number of pneumococcal deaths among children under 5

years

O,Brien K, et al. Lancet. 2009;374:893-902.

PNEUMOCOCCAL DISEASE BURDEN

TOP TEN

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Strep Pneumoniae & Pneumonia – Indian Disease Burden

In India, Pneumonia is the single most important cause of death among children in the postneonatal period, contributing as much as 27.5% of total under-five mortality

It appears that about 10-15% of childhood pneumonias are caused by H. influenzae and RSV each; and 12-35% by pneumococcus. *

* Mathew J et al. ARI & Pneumonia in India – A systematic review . Indian Pediatrics, March 2011

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We are missing the target(Millennium Development Goal 4)

AAR =average annual rate of reduction MDG=millennium development goal

U5MR in 2015 at current AAR

MDG Target U5MR in 2015

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Under-five mortality ratio (U5MR) projections 60 priority countries

Source: UN Population Division World Population Prospects, 2004.

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PneumoNET

Pan Asia Epidemiologic surveillance network to assess the burden of invasive pneumococcal disease (IPD)

Nisarga RG, Balter I, Premalatha R et al, Prospective, Multinational, Active, Hospital-Based Epidemiologic Surveillance for IPD and Pneumonia Burden Among Children in Bangalore South Zone, Bangalore, India. Poster presented at the 29th Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID), 7–11 June 2011, The Hague, Netherlands

PNUEMONET… (1 year data)

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BACKGROUND •S. pneumoniae - key cause of meningitis, pneumonia and other invasive diseases leading to high morbidity/mortality in children worldwide

• Information in countries varies between countries not robust, and usually coming from passive microbiology surveillance data

• Study done at 3 hospitals in Bangalore South Zone (Kempegowda Institute of Medical Sciences Hospital, Vanivilas Hospital, and Indira Gandhi Institute of Child Health)

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OBJECTIVES

•PrimaryEstimate - Incidence rates of IPD and pneumonia, Serotype distribution and antibiotic susceptibility of SP

in children aged 28 days to <60 months in a defined target population in India

• SecondaryDescribe the antibiotic resistance rates of invasive SP isolatesDescribe the serotype distribution of resistant SP isolates Estimate the incidence rate of clinical pneumonia and chest radiograph-confirmed pneumonia with or without pneumococcal bacteremia

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DESIGN OF THE STUDY • Two -year active, prospective, hospital-based surveillance study of IPD and pneumonia • Children aged 28 days to <60 months• History taken• Blood sample• Cerebrospinal fluid (CSF) was collected for culture with suspected meningitis• Specimens from other sterile sites (e.g. pleural fluid) were collected as per routine medical practice• All samples underwent bacterial culture for identification of pathogens • SP isolates were sub-cultured, serotyped and tested for antibiotic susceptibility • Chest radiograph (CXR) was obtained for children with clinically suspected pneumonia

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RESULTS

1) Demographics Table 1: Demographics of Enrolled Children

Variable N = 5,249Age in months (Mean + SD) 19.8±13.9Age group n (%)28 days to <6 months 6 months to <12 months 12 months to <24 months 24 months to <36 months 36 months to <60 months

806 (15.4)1,132 (21.6)1,551 (29.5)1,082 (20.6)678 (12.9)

Gender, n (%)Male Female

2,901 (55.3)2,348 (44.7)

• SD – Standard Deviation

SD – Standard Deviation

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RESULTS

2) Incidence Rates

Table 2: Incidence Rates of IPD by Age GroupAge Group No. of Cases No. in At-risk

PopulationIncidence Rate per 100,000 children*

(95% CI)28 days to <6 months 3 8,186 36.65 (7.56–107.10)6 months to <12 months 6 13,040 46.01 (16.89–100.15)12 months to <24 months 3 22,777 13.17 (2.72–38.49)24 months to <36 months 4 22,470 17.80 (4.85–45.58)36 months to <60 months 1 46,010 2.17 (0.06–12.11)Overall 17 112,483 15.11 (8.80–24.20)

* Calculated using number of cases divided by number in At-risk population

* Calculated using number of cases divided by number in At-risk population

• Final IPD cases observed were pneumonia (n=12), meningitis (n=3), bacteraemia (n=2) • Overall estimated incidence rates for pneumonia, meningitis, and bacteraemia were 10.67, 2.67, and 1.78 per 100,000 children, respectively

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RESULTS

3) BACTERIOLOGY AND ANTIBIOTIC RESISTANCETable 3: Serotype Distribution and Antibiotic Resistance of IPD Isolates From Children

Aged 28 Days to <60 Months (18 Isolatesa)Serotype N (%) Antibiotic Resistanceb

6A 5 (27.78%) Erythromycin (2 isolates)Ceftriaxone (1 isolate)

5 3 (16.67%)1 2 (11.11%) Trimethoprim/Sulfamethoxazole (1 isolate)3 2 (11.11%) Trimethoprim/Sulfamethoxazole (1 isolate)

14 2 (11.11%) Erythromycin (1 isolate)Trimethoprim/Sulfamethoxazole (1 isolate)

9V 1 (5.56%)19F 1 (5.56%)18C 1 (5.56%)19A 1 (5.56%) Trimethoprim/Sulfamethoxazole (1 isolate)a – In 1 subject 2 different serotypes were obtained from blood and CSF (6A in CSF and 3 in blood)b – Antibiotic susceptibility was determined for 17 isolates only

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RESULTS

4) BACTERIOLOGY AND ANTIBIOTIC RESISTANCE

• Serotypes 6A and 5 were seen most frequently.

• The serotype coverage offered by PCV7, PCV10, and PCV13 was 27.77%, 55.55%, and 100%, respectively.

• Four of the 18 isolates were resistant to trimethoprim/ sulfamethoxazole, 3 to erythromycin, and 1 to ceftriaxone


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KEY MESSAGES• IPD and Pneumonia - important causes of morbidity in the children <5 years

• Most common IPD was pneumonia – 12/17 subjects (10.67 per 100,000)

• Highest incidence of ClinPn and CXR+Pn was in children < 6 months

• Antibiotic resistance observed for serotypes 6A, 14, 1, 3 and 19A

• Second year results awaited

Antimicrobial resistance data – Other studies

IBIS (Lancet.1999) 56% cotrimoxazole resistance.

Resistance to penicillin rare (1.3%),

No resistance to third generation cephalosporins.

ISCAP trial (BMJ. 2004) Cotrimoxazole 66.3%,

Chloramphenicol 9.0%,

Oxacillin 15.9%

Erythromycin 2.8%.

Conclusion - Variable resistance to common antibiotics; penicillin resistance is uniformly low and cotrimoxazole resistance high. *

24* Mathew J et al. ARI & Pneumonia in India – A systematic review . Indian Pediatrics, March 2011

19A 19A Streptococcus pneumoniaeStreptococcus pneumoniae

• Recently there has been an increase in the number of infections caused by serotype 19A in countries that have incorporated PCV7 into national schedules as well as those that have not1-3

• Globally serotype 19A represents ~5% of all isolates and in the U.S. represents the most common non-vaccine serotype4-5

IPD infections: 301% increase in children <5 years of age

173% increase in adults >80 years of age

OM infections: Reports of multidrug resistant cases6

• Usually serotype 19A is penicillin resistant

1. Singleton RJ, et al. JAMA.2007:297:1784-1792.2. Pai R, et al. J Infect Dis. 2005;192:1988-1995.3. Dagan R, et al. Poster presented at . 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (CIAAC); September 17-20, 2007; Chicago, IL.4. PneumoADIP, GSP Summary Report for Sage 2007.

5. Kaplan SL, et al. Pediatrics. 2010; 125:429-436.6. Pichichero ME, Case JR. JAMA. 2007:298:1772-1178.7. Harrison CJ, et. J Antimicrob Chemother. 2009:511-519.

• Serotype 19A - key emerging problem in 10 Asian countries including India• Of invasive S. pneumoniae isolates 91/1637 (5.6%) were serotype 19A• Prevalence was high in India (13.0%), Japan (11.1%), Korea (9.9%), Malaysia (9.1%), and Saudi Arabia (9.0%), but low in Hong Kong (3.1%) Taiwan (4.8%), Thailand (5.2%), the Philippines (1.7%), and Vietnam (0.4%)• ST320 as the most prevalent clone among 19A was identified (MDR) – a global emerging problem• ST320 isolates were evident in Hong Kong, India, Korea, Malaysia, Saudia, Taiwan• In India ST 320 was present in 66.6% of 19A• First published article that documents 19A incidence in India

19A S. pneumoniae: INDIA

Juyoun S, Jin YB, So HK et al. Predominance of ST320 among Streptococcus pneumoniae serotype 19A isolates from 10 Asian countries. Journal of Antimicrobial Chemotherapy Advance 2011; 66: 1001–1004

Serogroup distribution in India

Prospective multicentre hospital surveillance of Streptococcus pneumoniae disease in India IBIS Group. The Lancet 1999; 353: 1216-1221

6A+6B

19A+19F14

4

5

7

1

2318

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7V 4 6B 9V 14 18C 19F 23F10V 4 6B 9V 14 18C 19F 23F 1 5 7F13V 4 6B 9V 14 18C 19F 23F 1 5 7F 19A 6A 3

IBIS Group. The Lancet 1999; 353: 1216-1221

Serogroup distribution of SP in India – Summary of 4 studies

Among 150 clinical isolates * from invasive pneumococcal infections, 59.3% belonged to serotypes 1, 6, 19, 5, 23 and 7.

Serotype 1 was the commonest isolate in meningitis and empyema.

Among 42 pneumococcal strains **, over one-third in children were serotypes 5, 6 and 7

ANSORP Study - 1105 isolates from 4963 children across 11 countries Nasopharyngeal carriage

Prevalence was 22.3%; highest in India (43.2%) and lowest in Singapore (9%)

Most common were 6, 23, 19 and 14 which comprised 60% of the isolates PNEUMONET – 6 A, 5, 1, 3 & 14 were commonest strains

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* Kanungo R. Indian J Med Res. 2001** John TJ. Indian J Med Res.1996

7V 4 6B 9V 14 18C 19F 23F10V 4 6B 9V 14 18C 19F 23F 1.0 5.0 7F13V 4 6B 9V 14 18C 19F 23F 1.0 5.0 7F 19A 6A 3

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IPD

Pneumonia

Antibiotic Resistance and Use of Antibiotics

OM

CarriageIndirect Effect

Office Visits

Impact of Vaccination With PCV7

IPD=invasive pneumococcal disease.

Cost-effectiveness

OM=otitis media.

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Efficacy and Effectiveness of PCV7

Proven Efficacy: Invasive disease

Pneumonia

OM

Proven Effectiveness: Invasive disease

Pneumonia

OM

NP colonization

Herd immunity

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Key Serotypes Worldwide

Serotype Clinical Implications

Serotype 1

High prevalence in many regions of the worldAssociated with Epidemic outbreaks1

Causes complicated pneumonia (with empyema), especially in children aged 2 -5 years2

Serotype 5Associated with Epidemic outbreaks (along with serotype 1 account for 29 % IPD in India) Common serotype in Latin America and Africa3

Serotype 7FIncreasingly important cause of IPD , particularly in Europe and North America

High case-fatality rate compared with other serotypes4

Serotype 3Among the most common isolates in older children. 5,6

Associated with severe childhood pneumonias & lung necrosis2

Serotype 6AAssociated with antibiotic resistance 2

Commonly found in nasopharyngeal isolates2

Serotype 19A

Increasingly important cause of serious pneumococcal disease 7-9

Most common serotype in nasopharyngeal colonisation 9

Increasingly resistant to antibiotics and has been associated with multidrug resistance9

1. Hausdorff WP. Vaccine. 2007;25:2406-2412. 2. Hausdorff WP, et al. Lancet Infect Dis. 2005;5:83-93. 3. GAVI Pneumococcal AMC TPP, Nov 2008. http://www.vaccineamc.org/

files/TPP_codebook.pdf. Accessed September 3, 2009. 4. Ruckinger S, et al. Pediatr Infect Dis J. 2009;28:118-122.

5. Rodgers GL, et al. Vaccine. 2009;27:3802-3810. 6. Pichichero ME, Casey JR. JAMA. 2007;298:1772-1778. 7. Rajasingham CR, et al. Pediatr Infect Dis J. 2008;27:771-775. 8. Kyaw MH, et al. N Engl J Med. 2006;354;1455-1463. 9. Dagan R, et al. J Infect Dis. 2009;199:776-785.

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Vaccine Efficacy studies

Cochrane review (2009) – 113,044 children worldwide (Africa, US, Finland & Philippines)

IPD by vaccine serotypes – 80 % IPD by any serotype – 58 % radiological pneumonia - 27% clinical pneumonia 6% All-cause mortality 11%

Lucero MG, Dulalia VE, Nillos LT, Williams G, Parreño RAN, Nohynek H, et al. Pneumococcal conjugate vaccinesfor preventing vaccine-type invasive pneumococcal disease and X-ray defined pneumonia in children less thantwo years of age. Cochrane Database Syst Rev. 2009;4:CD004977.

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Systematic review from developing countries (9 & 11 valent vaccines)

Radiological pneumonia – 26 % Clinical pneumonia 7 % Clinically severe pneumonia 7 % All-cause mortality 15 %

Theodoratou E, Johnson S, Jhass A, Madhi SA, Clark A, Boschi-Pinto C, et al. The effect of Haemophilus influenzae type b and pneumococcal conjugate vaccines on childhood pneumonia incidence, severe morbidity and mortality. Int J Epidemio.l 2010;39 Suppl 1:i172-85

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Systematic review (2009) IPD by vaccine serotypes – 89 % IPD by any serotype – 63% to 74%

Pavia M, Bianco A, Nobile CG, Marinelli P, Angelillo IF. Efficacy of pneumococcal vaccination in children younger than 24 months: a meta-analysis. Pediatrics. 2009;123:e1103-10.

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S. pneumoniae Conjugate vaccines, Potential vaccine protection

Cobertura de serotipos calculada a partir de datos del Global Serotype Project (GSP) 1980 - Jun 2007.

Dinleyici E, et al. Expert Rev Vaccines. 2009;8:977-986.GAVI Pneumococcal AMC TPP, Nov 2008. http://www.vaccineamc.org/files/TPP_codebook.pdf. Accessed September 3, 2009.

% Neumococcal disease caused by different serotypes included into the conjugated

Africa (%) Asia (%) Europa

(%)

Latin America

(%)

North

América

(%)Oceania

(%)

PCV7 39.3% 48% 67.1% 54.4% 78.1% 64.5%

PCV10 62.5% 66.2% 76.2% 73.6% 80.6% 71.1%

PCV13 76.9% 73.9% 88% 83.4% 88% 79.1%

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Likely PCV 13 efficacy in India

The recently introduced 13-valent PCV is expected to cover about three quarters of the serotypes responsible for invasive disease in India,

PCV are efficacious in reducing disease caused by vaccine-serotypes

Mathew J et al. Acute Respiratory Infection and Pneumonia in India: A Systematic Review of Literature for Advocacy and Action: UNICEF-PHFI Series on Newborn and Child Health, India. Indian Pediatrics 2011, 48, pp 191-218

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Vaccine safety profile

42 studies were included to review safety of PCV. Reactogenicity data from some trials suggested that

PCV-7 may result in more mild, self-limiting local reactions and fever than control vaccines; although severe adverse events were not increased.

Destefano F, Pfeifer D, Nohynek H. Safety profile of pneumococcal conjugate vaccines: systematic review of pre- and post-licensure data. Bull WHO. 2008;86:373-80

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Safety & immunogenicity study of PCV 13 from India – non-inferiority

Phase 3 double blind multi-centre RCT 179 children received PCV 13, 176 received PCV 7 Responder rates > 80 % for both vaccines for the

common serotypes Responder rates between 80-99 % against additional 6

serotypes Incidence of both local & systemic reactions were

similar, and mild

Amdekar Y, et al. Safety and Immunogenicity of a 13-valent Pneumococcal Conjugate Vaccine in Healthy Infants Given With Routine Vaccines in India. 7th International Symposium on Antimicrobial Agents and Resistance, Bangkok, Thailand, March 18-20, 2009

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PCV13: Phase 3 Clinical Program

Non-inferiority studies

Evaluation of different dosing schedules:

3+1 Schedule6, 10, 14 weeks, and 12 months2, 3, 4, and 12-15 months 2, 4, 6, and 12-15 months

2+1 Schedule 2, 4, and 12 months 3, 5, and 11 months

3+0 Schedule 6, 10, and 14 weeks

PCV 13 can be substituted for PCV 7 at any point in the vaccination schedule

New serotype catch-up ( Single dose of PCV13 in children previously vaccinated with PCV7)

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4343

Vaccination schedule for 7-18 years – MMWR 2011

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Vaccination schedule for high-risk children – IAP 2011

PPSV23 should be administered after PCV among HIGH-RISK children aged 2 –18 years as follows:

When elective splenectomy, immuno-suppressive therapy, or cochlear implant placement is being planned; PCV and/or PPSV23 vaccination should be completed at least 2 weeks before surgery or initiation of therapy

Children aged ≥ 2 years with underlying medical conditions should receive PPSV23 after completing all recommended doses of PCV13

1 dose of PPSV23 at age ≥ 2 years and at least 8 weeks after the most recent dose of PCV.

Children who have received PPSV23 previously also should receive recommended PCV doses

1. IAP Guidebook on Immunization 2011

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Difference between PCV13 and PPV23

PCV131 PPV232

Valency 13 valent 23 valentTarget population Healthy Children At risk populationMinimum age of vaccination > 6 weeks > 2 years (High Risk)Immune response ---- at 6 weeks of age ---- at 2 years of age

StrongStrong

Absent to weakModerate to Strong

Duration of immunity Long term Short termVaccine efficacy- children < 2 years

Yes None

Important reductions in nasopharyngeal carriage

Yes No effect

Indirect protection Reported UnlikelyImportant reductions in the prevalence of antibiotic resistant isolates

Reported Not established

1. PCV for childhood immunization – WHO position paper Weekly Epidemiological Record. 2007, 12 (82): 93–104.2. Prevenar13 Prescribing Information Wyeth Limited* 2010 (*A subsidiary of Pfizer Inc.)3. 23-valent pneumococcal polysaccharide vaccine - WHO position paper. WHO Weekly Epidemiological Record. 2008; 83(42): 373–384

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Summary

Pneumococcal disease is the #1 vaccine-preventable cause of death worldwide in children aged <5 years1

Data from India clearly points to vaccine preventable serotypes being common cause of Pneumococcal Disease !

PCV13 provides the broadest serotype coverage of any pneumococcal conjugate vaccine2,3

Convenient transition from PCV 7 to PCV13 at any point in the vaccination schedule4

Children who have completed vaccination with PCV 7 should be offered catch-up with PCV 13 5

For high risk cases PCV/ PPSV can be given up to 18 years !

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1. WHO. http://www.who.int/immunization_monitoring/data/GlobalImmunizationData.pdf. Accessed September 3, 2009.2. Dinleyici E, et al. Expert Rev Vaccines. 2009;8:977-986.3. GAVI Pneumococcal AMC TPP, Nov 2008. http://www.vaccineamc.org/files/TPP_codebook.pdf. Accessed September 3, 2009.4. Prevenar 13. Summary of Product Characteristics. Wyeth Pharmaceuticals. 5. Data on file. Pfizer Inc, New York, NY.

emerging concepts in pneumococcal disease prevention in india sept 2011

Health & Medicine

india data

india pcv

india pneumonia

india various schedules

india possible impact

india dr gaurav gupta

safety noninferiority

severe pneumonia