Emerging concept sin pneumococcal disease prevention

Emerging Concepts in
Pneumococcal Disease
prevention in India
Dr Gaurav Gupta,
Pediatrician,
Member AAP, IAP,
Charak Clinics, Mohali
1

Brief intro about Pneumococcal Disease
t
India – Scope of IPD – morbidity & mortality
Latest data (Pneumonet) regarding Pneumococcal
Disease in India
u
Data regarding Pneumococcal serotypes &
antimicrobial resistance in India
s Possible Impact of PCV 13 in India
o PCV 13 – Safety & Non-inferiority data from India
&
Various schedules

2

t
Disease in India
u
&
Various schedules

3

Pneumococcal Disease

e
S. pneumoniae first isolated by Pasteur in
1881
b 90 known serotypes
e First U.S. vaccine in 1977 (14 valent PPV)
n
PCV 7 launched in 2000
n
Polysaccharide capsule important virulence
factor
a Type-specific antibody is protective

4

DISEASES CAUSED BY
STREPTOCOCCUS PNEUMONIAE

PNEUMOCOCCAL INFECTION

Non-invasive disease Invasive disease
• Sinusitis • Bacteraemia (blood)
• Otitis media
• Pneumonia
• Meningitis (CNS)
• Endocarditis (heart)
• Peritonitis (body cavity)
• Septic arthritis (bones and joints)
• Others (appendicitis, salpingitis,
soft-tissue infections)

Musher, in Principles and Practice of Infectious
Diseases, 1995 5

Strep Pneumoniae in developing countries

6

t
Disease in India
u
&
Various schedules

7

Child DEATHS Each Dot = 5,000 child deaths

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

8

PNEUMONIA 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; 44:491-496
2. Pneumonia – The forgotten killer of children, WHO, UNICEF, 2006
3. Thacker N. IPD burden - An Indian Perspective. Pediatrics Today 2006; 9(4): 208-213

9

PNEUMOCOCCAL DISEASE BURDEN

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

TOP TEN

O,Brien K, et al. Lancet. 2009;374:893-902. 10

Strep Pneumoniae & Pneumonia –
Indian Disease Burden

u
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
n 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 11

We are missing the target
(Millennium Development Goal 4)

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

U5MR in 2015
85
at current
AAR

38 MDG Target
U5MR in 2015

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

Source: UN Population Division World Population Prospects, 2004. 12

t
Disease in India
u
&
Various schedules

13

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
14

PNUEMONET… (1 year data)

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)

15


OBJECTIVES

•Primary
Estimate - 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

• Secondary
Describe the antibiotic resistance rates of invasive SP isolates
Describe the serotype distribution of resistant SP isolates
 Estimate the incidence rate of clinical pneumonia and chest
radiograph-confirmed pneumonia with or without pneumococcal
bacteremia
16


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

17

• SD – Standard Deviation


RESULTS

1) Demographics
Table 1: Demographics of Enrolled Children
Variable N = 5,249
Age in months (Mean + SD) 19.8±13.9
Age group n (%)
•28 days to <6 months 806 (15.4)
•6 months to <12 months 1,132 (21.6)
•12 months to <24 months 1,551 (29.5)
•24 months to <36 months 1,082 (20.6)
•36 months to <60 months 678 (12.9)
Gender, n (%)
•Male 2,901 (55.3)
•Female 2,348 (44.7)
SD – Standard Deviation 18

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


RESULTS
2) Incidence Rates
Table 2: Incidence Rates of IPD by Age Group
Age Group No. of Cases No. in At-risk Incidence Rate per
Population 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
• 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
19


RESULTS
3) BACTERIOLOGY AND ANTIBIOTIC RESISTANCE
Table 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 20


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

21


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

22

ˆ
t
Disease in India
u
o
PCV 13 – Safety & Non-inferiority data from India
&
Various schedules

Antimicrobial resistance data – Other studies

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

19A Streptococcus 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
• Singleton RJ, et al. JAMA.2007:297:1784-1792. 5. Kaplan SL, et al. Pediatrics. 2010; 125:429-436.
• Pai R, et al. J Infect Dis. 2005;192:1988-1995. • Pichichero ME, Case JR. JAMA. 2007:298:1772-1178.
• Dagan R, et al. Poster presented at . 47th Interscience Conference on Antimicrobial • Harrison CJ, et. J Antimicrob Chemother. 2009:511-519.
Agents and Chemotherapy (CIAAC); September 17-20, 2007; Chicago, IL.
4. PneumoADIP, GSP Summary Report for Sage 2007.

19A S. pneumoniae: INDIA

• 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
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

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

Serogroup distribution in India
IBIS Group. The Lancet 1999; 353: 1216-1221

6A
+ 6B
18 9
23

1
7

5
F
4 +19
14 19A

7V 4 6B 9V 14 18C 19F 23F
10V 4 6B 9V 14 18C 19F 23F 1 5 7F
13V 4 6B 9V 14 18C 19F 23F 1 5 7F 19A 6A 3

Serogroup distribution of SP in India –
Summary of 4 studies

d 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.
s Among 42 pneumococcal strains **, over one-third in children
were serotypes 5, 6 and 7
o 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
7VPNEUMONET – 6 A, 5, 1, 14& 14 were19F 23F
3 18C commonest strains
6
4 6B 9V
10V 4 6B 9V 14 18C 19F 23F 1.0 5.0 7F
13V 4 6B 9V 14 18C 19F 23F 1.0 5.0 7F 19A 6A 3
* Kanungo R. Indian J Med Res. 2001
** John TJ. Indian J Med Res.1996 28

Œ
t
Disease in India
u
o
PCV 13 – Safety & Non-inferiority data from India
&
Various schedules

Impact of Vaccination With PCV7

IPD

Carriage
Indirect Effect

OM
Pneumonia

Office Visits Antibiotic Resistance and Use of Antibiotics

Cost-effectiveness
OM=otitis media.
IPD=invasive pneumococcal disease. 30

Efficacy and Effectiveness of PCV7

Proven Efficacy:
Invasive disease
Pneumonia
OM


Proven Effectiveness:
Invasive disease
Pneumonia
OM
NP colonization
Herd immunity

31

Key Serotypes Worldwide

Serotype Clinical Implications
High prevalence in many regions of the world
Associated with Epidemic outbreaks 1
Serotype 1
Causes complicated pneumonia (with empyema), especially in
children aged 2 -5 years 2
Associated with Epidemic outbreaks
Serotype 5 (along with serotype 1 account for 29 % IPD in India)
Common serotype in Latin America and Africa 3

Increasingly important cause of IPD , particularly in Europe and
Serotype 7F North America
High case-fatality rate compared with other serotypes 4
Among the most common isolates in older children. 5 ,6
Serotype 3 Associated with severe childhood pneumonias & lung necrosis 2
Associated with antibiotic resistance 2
Serotype 6A Commonly found in nasopharyngeal isolates 2

Increasingly important cause of serious pneumococcal disease 7 -9
Most common serotype in nasopharyngeal colonisation 9
Serotype 19A
Increasingly resistant to antibiotics and has been associated with
multidrug resistance 9

• Hausdorff WP. Vaccine. 2007;25:2406-2412. • Rodgers GL, et al. Vaccine. 2009;27:3802-3810.
• Hausdorff WP, et al. Lancet Infect Dis. 2005;5:83-93. • Pichichero ME, Casey JR. JAMA. 2007;298:1772-1778.
• GAVI Pneumococcal AMC TPP, Nov 2008. http://www.vaccineamc.org/ • Rajasingham CR, et al. Pediatr Infect Dis J. 2008;27:771-775.
files/TPP_codebook.pdf. Accessed September 3, 2009. • Kyaw MH, et al. N Engl J Med. 2006;354;1455-1463.
• Ruckinger S, et al. Pediatr Infect Dis J. 2009;28:118-122. • Dagan R, et al. J Infect Dis. 2009;199:776-785. 32

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Disease in India
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&
Various schedules

33

Vaccine Efficacy studies

Cochrane review (2009) – 113,044 children worldwide
(Africa, US, Finland & Philippines)
l IPD by vaccine serotypes – 80 %
e IPD by any serotype – 58 %
y
radiological pneumonia - 27%
u
clinical pneumonia 6%
u
All-cause mortality 11%

Lucero MG, Dulalia VE, Nillos LT, Williams G, Parreño RAN, Nohynek H, et al. Pneumococcal conjugate
vaccines
for preventing vaccine-type invasive pneumococcal disease and X-ray defined pneumonia in children less than 34


Systematic review from developing countries (9 & 11
valent vaccines)
w Radiological pneumonia – 26 %
u Clinical pneumonia 7 %
u
Clinically severe pneumonia 7 %
e
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
35


Systematic review (2009)
w
IPD by vaccine serotypes – 89 %
e
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. 36

S. pneumoniae Conjugate vaccines,
Potential vaccine protection

% Neumococcal disease caused by different serotypes included into the
conjugated
North
Latin
América
Europa America Oceania
Africa (%) Asia (%) (%) (%) (%) (%)

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%

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

37
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. 37

Likely PCV 13 efficacy in India

f
The recently introduced 13-valent PCV is expected to
cover about three quarters of the serotypes
responsible for invasive disease in India,
i
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 38

Vaccine safety profile

42 studies were included to review safety of PCV.
i
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 39

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

a
Phase 3 double blind multi-centre RCT
l
179 children received PCV 13, 176 received PCV 7
e
Responder rates > 80 % for both vaccines for the
common serotypes
>
Responder rates between 80-99 % against additional 6
serotypes
b 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 40

t
Disease in India
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&
Various schedules

41

PCV13: Phase 3 Clinical Program

Non-inferiority studies
Evaluation of different dosing schedules:
6, 10, 14 weeks, and 12 months
3+1 Schedule 2, 3, 4, and 12-15 months
2, 4, 6, and 12-15 months
2, 4, and 12 months
2+1 Schedule 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)

42
42
42

Vaccination schedule for 7-18 years – MMWR 2011

43 43

Vaccination schedule for high-risk children – IAP 2011

PPSV23 should be administered after PCV among HIGH-RISK children
aged 2 –18 years as follows:
s 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
f 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 44

Difference between PCV13 and PPV23

PCV131 PPV232
Valency 13 valent 23 valent
Target population Healthy Children At risk population
Minimum age of vaccination > 6 weeks > 2 years (High Risk)
Immune response
---- at 6 weeks of age Strong Absent to weak
---- at 2 years of age Strong Moderate to Strong
Duration of immunity Long term Short term
Vaccine efficacy- children < 2 Yes None
years
Important reductions in Yes No effect
nasopharyngeal carriage
Indirect protection Reported Unlikely
Important reductions in the Reported Not established
prevalence of antibiotic resistant
isolates
• PCV for childhood immunization – WHO position paper Weekly Epidemiological Record. 2007, 12 (82): 93–104.
• Prevenar13 Prescribing Information Wyeth Limited* 2010 (*A subsidiary of Pfizer Inc.)
45
• 23-valent pneumococcal polysaccharide vaccine - WHO position paper. WHO Weekly Epidemiological Record. 2008; 83(42): 373–384

Summary

Pneumococcal disease is the #1 vaccine-preventable cause of
death worldwide in children aged <5 years1
i Data from India clearly points to vaccine preventable serotypes
being common cause of Pneumococcal Disease !
s PCV13 provides the broadest serotype coverage of any
pneumococcal conjugate vaccine2,3
j
Convenient transition from PCV 7 to PCV13 at any point in the
vaccination schedule4
d Children who have completed vaccination with PCV 7 should be
offered catch-up with PCV 13 5
p
For high risk cases PCV/ PPSV can be given up to 18 years !

1. WHO. http://www.who.int/immunization_monitoring/data/GlobalImmunizationData.pdf. Accessed September 3, 2009.
• 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.
• Prevenar 13. Summary of Product Characteristics. Wyeth Pharmaceuticals.
• Data on file. Pfizer Inc, New York, NY. 46

46

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