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Bacterial Meningitis:

Addressing the missing link

Etiology Of Meningococcal
Meningitis
(Children <13 years of age, Israel study)
Meningococcus
22%
Pneumococcus
20%

Haemophilus influenzae type b


58%
Dagan R. et al. J Inf Dis 1994; 169: 912-916

Overview
Infection

with N. meningitidis common although the majority of


infections are transient and asymptomatic
10% of healthy population carrier of N. meningitidis contributing to
circulation of bacteria in communities via air-borne or direct
transmission
Gram-negative, diplococcal bacterium enveloped in a
polysaccharide capsule
Serogroups (n=13, such as A, B, C, Y, and W-135) defined by
capsular specificity
Capsule composed of T-cellindependent antigens that do not
induce long-term immunologic memory

At Risk Populations
Infants, children < 5, adolescents
High density populations
Hostellers
Military
Hajj pilgrims

Caregivers and household contacts of infected patients


Travelers to endemic areas
Lab workers dealing with N. meningitidis
Immuno-compromised persons

Cushing A. In VPD surveillance manual 4th Ed 2008; MMWR 2005;54; Bilukha O. Ped Inf Dis J 2007.26(5)

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11

12

13

14

15

16

17

18

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Seriousness of
Meningococcal
Disease
Onset often rapid and life-threatening, sometimes causing death

with in 24 hours of initial symptoms


Despite treatment with appropriate antimicrobial agents and
optimal medical care, the overall case fatality rates is 9 to 12%,
with a rate of up to 40 % among patients with meningococcal
sepsis
11 to 19% of survivors of meningococcal disease have sequelae,
such as hearing loss, neurological disability, or loss of a limb.

D. Sinclair et al. Tropical Medicine and International Health 2010;15(12):1421-35


V Manchanda et al. Indian J Med Microbiol 2006;24(1): 7-19

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Diseases with High Case


Fatality Rates in India,
2011
4th

* Non-neonatal
National Health Profile, India 2011

Clinical presentation

Meningococcal meningitis clinically indistinguishable from meningitis due to other


bacteria. Non-blanching petechial rash is present in only a few cases. 1.
In a study of 110 cases of IMD from a tertiary care hospital in Meghalaya from Jan 08
June 09 during an outbreak 2

In the same study, meningococcal meningitis was seen in 61.8% of cases,


meningococcemia in 20 %. 18.2% had both.

1. Nelson text book of Pediatrics. 19th Ed.


2. Hazarika RD et al, Indian J Pediatr 2012 doi:10.1007/s12098-012-0855-0

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Obstacles in Microbiological
Diagnosis

N.meningitidis is fastidious, susceptible to cold and drying, and


culture frequently unsuccessful.
Antibiotics given prior to cerebrospinal fluid (CSF) collection
significantly increase the number of negative cultures.
Economic constraints, lack of after-hours laboratory facilities, lack
of laboratory expertise in detecting N. meningitidis and lack of
available techniques aside from Gram stain and culture also
obstacles to successful N. meningitidis identification
Use of PCR increases the sensitivity of detection of N.
meningitidis, particularly in patients who have received antibiotics,
but largely unavailable on a routine basis in much of Asia.

Vyse A. Epidemiol. Infect 2011:139:967-85

Epidemiology in India

Out of 13 serogroups, 90% of the disease caused by 5 serogroups


(A, B, C W-135 and Y)
Serogroup A majorly responsible for both endemic disease and
epidemics in India
Some prevalence of disease due to Serogroup C also reported.
Disease occurs in dry season
Disease is endemic in India and several major epidemics reported
across India especially from Delhi and surrounding districts

D. Sinclair et al. Tropical Medicine and International Health 2010;15(12):1421-35


V Manchanda et al. Indian J Med Microbiol 2006;24(1): 7-19

Bacterial Meningitis in hospitalized


patients:
Number of culture confirmed cases

An IJP Survey in 6 Indian tertiary care


hospitals
No organism identified in
720/852 cases
nd

Indian J Pediatr 1991; 58 : 505-511

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Meningococcal Meningitis in India


National Health Profile (2006 2011)

0.54

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WHO recommendations
In high (>10 cases/100,000 population/year) or intermediate

endemic (2-10/100,000/year) and countries with frequent


epidemics should introduce meningococcal vaccine
In countries with low endemic (<2/100000/year)-recommended for
high risk groups

India most likely is moderately or highly


endemic for meningococcal disease

Weekly epidemiological record no 47,2011,86,521-540

Prevalence & Distribution of Neisseria


meningitidis isolates during endemic
periods
The proportion of Neisseria meningitidis isolates in case
series of endemic bacterial meningitis

CHANDIGARH
Ayyagari et al. (1980): 0.6%
Singhi et al. (2002b): 4.3%
Singhi et al. (2004): 1.1%

DELHI
Paul (1963): 6.3%
Bhaumik (1998): 20%
Jain et al (2000): 18.8%

UTTAR PRADESH
Srivastava et al (1968): 3%
Kalra and Dayal (1977): 5.1%

MADHYA PRADESH
Tamaskar and Bhandari (1976): 14.3%

GUJARAT
Gandhi (1969): 16.7%
Javadekar et al. (1997): 8%
Deivanayagam (1993): 1%
MAHARASHTRA
Pal and Sant (1982): 23.4%
Chinchankar et al. (2002): 1.9%

KARNATAKA
Shivaprakash et al (2004): 1%
Mani et al. (2007): 1%
Shameem et al. (2008): 7.6%

KERALA
Vincent et al. (1987): 15.7%

ORISSA
Suvarna Devi et al (1982): 4.3%

ANDHRA PRADESH
Achar & Rao (1953): 12.2%
Ahmed et al (1964): 2%
Deivanayagam (1993): 1%

During non-epidemic periods,


pyogenic meningitis has been
reported as the main diagnosis in up
to 3.3% of acute admissions to
tertiary paediatric hospitals in India.
All these studies had variable
sample size (n=30-385) and
involved children < 12 years of age.
Their was no organism identified in
a large proportion of patients (often
with significant mortality).
Their was a huge variability among
different studies in isolation of N
meningitidis (0.6-23.4%)

TAMIL NADU
Achar & Rao (1953): 12.2%
Ahmed et al (1964): 2%
Deivanayagam (1993): 1%

D. Sinclair et al. Epidemiology of meningococcal disease in India. Tropical Medicine and International Health. 2010

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Prevalence and Distribution of


Neisseria meningitidis isolates
during epidemics

Year

Location

Suspected cases

Deaths

1966-67

Delhi

616

129

1985-88

Delhi

6133

799

1985-88

Maharashtra

1573

1985-87

Surat

197

34

2005-09

Delhi

1725

2008

Meghalaya

~2000

~ 200

2009

Tripura

~ 200

~ 50

D. Sinclair et al. Tropical Medicine and International Health 2010;15(12):1421-35; V Manchanda et al. Indian J Med Microbiol 2006;24(1): 719; CD Alert. NCDC.DGHS.November 2009.13(3)

Age & Serotype Distribution of


Meningococcal Meningitidis in India
The demographic shift in pyogenic meningitis presentations associated with epidemics
18.4% 30.4%

All-cause bacterial meningitis in India is predominantly a disease of young children with a male
preponderance.
During epidemics, there is a marked shift in the age profile of cases of meningitis, with an increasing
proportion of cases occurring in adults.
Group A meningococcus has caused all major, investigated Indian epidemics with Group C in small
numbers during the 1985 epidemic in Chandigarh

D. Sinclair et al. Epidemiology of meningococcal disease in India. Tropical Medicine and International Health. 2010

The temporal occurrence of epidemics

Without
vaccination

7000

Vaccination with
WHO guidelines

Actual

6000
Cases

5000

Vaccination
starts

4000
3000

not preventable

2000
1000
0

2
9

Dec.

1 1
2 9
January

2
6

1 2
6 3
February

1 2
6 3
March

3
0

Date
Eningitis Enviromental Risk Information Technologies

1 2
3 0
April

2
7

11 1
8
May

2
5

Prevention against
Meningococcal
Disease

Rationale for Meningococcal


Immunization

Invasive meningococcal disease is1:


Potentially fatal
Rapidly progressive, leaving little time for diagnosis and treatment

Much of invasive meningococcal disease is vaccine-preventable2

Hib and S. pneumoniae are already preventable by conjugate vaccines.


Conjugate meningococcal vaccine launched in India and the disease can be
preventable.

Branco RG, et al. J Pediatr (Rio J). 2007;83(2 suppl):S46; 2Keyserling H, et al. Arch Pediatr Adolesc Med. 2005;159(10):907.

Types of Vaccines

Polysacharide vaccines
Bivalent (containing A and C serogroups)
Quadrivalent (A/C/W-135/Y)

Conjugated vaccines
Quadrivalent ((A/C/W-135/Y)
First licensed in the US in 2005 and now in 27 countries.

Polysaccharide vs Conjugate
Vaccines
Characteris Polysaccha Conjugate
tic
ride
T Cell dependent No
primary response

Yes

Immune memory

No

Yes

Lack of
No
hyporesponsivene
ss

Yes

Booster effect

No

Yes

Reduction of
carriage

No

Yes

Herd effect

No

Yes

Hyporesponsiveness to Repeat Doses of


Polysaccharide Vaccine Among 2053
Year Olds
P<0.006
P<0.001

Relative to conjugate vaccine recipients, individuals previously


vaccinated with polysaccharide formulations exhibit reduced immune
responsiveness to booster doses
Granoff DM, et al. J Infect Dis. 1998;178(3):870.

Long-lasting Immunity With ACWY-DT


Menomune

Menactra

51
2
10
24
20
48
40
96
81
92
16
38
4
32
76
8
65
53
>6 6
55
36

25
6

64
12
8

32

Serogroup Y

Serogroup W-135

25
6

64
12
8

32

16

51
2
10
24
20
48
40
96
81
92
16
38
4
32
76
8
65
53
>6 6
55
36

SBA-BR Antibody Titer

10
090
80
70
60
50
40
30
20
10
0
8

51
2
10
24
20
48
40
96
81
92
16
38
4
32
76
8
65
53
>6 6
55
36

Subjects Achieving Titer, %

SBA-BR Antibody Titer

25
6

64
12
8

32

51
2
10
24
20
48
40
96
81
92
16
38
4
32
76
8
65
53
>6 6
55
36

25
6

64
12
8

32

16
16

16

Subjects Achieving Titer, %

Serogroup C
10
090
80
70
60
50
40
30
20
10
0

SBA-BR Antibody Titer


10
090
80
70
60
50
40
30
20
10
0
8

Subjects Achieving Titer, %

Subjects Achieving Titer, %

Serogroup A
10
090
80
70
60
50
40
30
20
10
0

SBA-BR Antibody Titer

Antibody titers 3 years post-immunization are higher for recipients of MCV-4 than MPSV-4
Keyserling H, et al. Arch Pediatr Adolesc Med. 2005;159(10):907.

ACWY-DT Global Overview

Over 28 clinical studies conducted globally involving


approximately 46,000 subjects including Adults, Adolescents,
Children and Infants-toddler age groups.
Licensed since 2005 (US) in 41 countries, 59 million doses
Indications and Usage
Menactra is indicated for active immunization to prevent
invasive meningococcal disease caused by N
meningitidis serogroups A, C, Y and W-135 in 2-55 yrs of
age.
Approved for use in individuals 9 months through 55
years of age in US, Argentina, Philippines & Guatemala.

Menactra induces significantly higher


antibody titers, especially in children 2-5 &
6-10 years when compared to a plain
polysaccharide
Immune Response by Age Group (28 days post-vaccination)
SEROGROUP A

SEROGROUP Y

SEROGROUP C

SEROGROUP W-135

Keyserling H, et al. Poster presented at the 2003 Meeting of the Pediatric Infectious
Diseases Society; Keyserling H, et al. Arch Pediatr Adolesc Med. 2005;159(10):907.

ACWY-DT Clinical Development in


India

Title
Safety and Immunogenicity Study for Use of Meningococcal (Groups A, C, Y and W-135)
Polysaccharide Diphtheria Toxoid Conjugate Vaccine (Menactra) in Healthy Subjects 255 Years of Age in India (MTA51)

Design
A Phase III, open-label, single dose, multi-center study for the primary vaccination against
meningococcal disease in 300 subjects in India.

Objectives
Immunogenicity for serogroups A, C, Y, and W-135
To describe the SBA-BR (serum bactericidal assay-baby rabbit complement)
titers prior to and 30 days after a single dose of Menactra vaccine.
Safety
To describe the safety profile of subjects after 1 dose of Menactra vaccine.

Subject Enrollment (June-Nov 2010)


Age Groups

2-11 years (n=100)

12-17 years (n=100)

18-55 years (n=100)

MAMC, Delhi

50

50

Sion Hospital, Mumbai

50

50

KIMS, Bangalore

100

ACWY-DT: Indian Study

Subjects with a protective SBA-BR titers 128 (1/dil) was over 94% for all age groups

and serogroups, except for serogroup C in children (80%).


Percentage of subjects with a 4-fold rise in SBA-BR titers was high for all serogroups and
in all age groups.

Sanofi Pasteur. Data on File 2012

ACWY-DT: Indian Study


(cont.)

Grade 2 and 3

The vaccine was safe and well tolerated in 2-11 year-old children, 1217 year-old-adolescents, and 18-55 year-old adults.
Sanofi Pasteur. Data on File 2012

PIDJ, in press

Menactra
Post-Licensure Safety
Experience
Seven years of post-marketing safety experience

More than 54 million doses distributed worldwide


Safety profile for most commonly reported AEs consistent with prelicensure data
Overall evaluation: no new safety concerns
Reports of Guillain-Barr syndrome (GBS) within 6 weeks of
Menactra vaccination
Initially observed during the first year of distribution
Assessed in a very large epidemiological study (Harvard Pilgrim Study*)
Results showed no evidence of increased risk of GBS associated with Menactra
vaccine

Study** from the Vaccine Safety Datalink project, a collaborative effort between
the Centers for Disease Control and Prevention and several Managed Care
Organizations in the US reached the same conclusion
* P. Velentgas; Pharmacoepidemiology and Drug Safety 2012 Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/pds.3321** Presented at ACIP 23 June 2010

Recommendations for
meningococcal vaccination

ACIP Recommendations: Always


prefer conjugated meningococcal
vaccine if available
All persons 11-18 years of age
Persons aged 2 through 55 years with persistent

complement component deficiency or asplenia


Persons aged 2 through 55 years with prolonged
increased risk for exposure
Microbiologists routinely working with Neisseria
meningitidis
Travelers to or residents of countries where
meningococcal disease is hyperendemic or epidemic.
ACIP recommended use of MCV-4 for 9m-23m in 2011
MMWR 2011;60(No. 3):72-6.

ACIP Recommendations (contd)

Age-Specific Incidence (1991


2002)
In the United States, infection is most common among infants and
adolescents

C, Y
B

Bilukha O et al.
al. Pediatr Infect Dis J.
J. 2007;26(5):371.

Europe and other countries


Conjugate C Vaccine routinely used in infants in:

UK
The Netherlands
Belgium
Spain
Iceland
Ireland
France

Germany
Luxembourg
Portugal
Switzerland
Brazil
Australia

IAP recommendations: High


risk situations

During disease outbreaks, if caused by serogroups included in the


vaccine
Children with terminal complement component deficiencies.
Children with functional/ anatomic asplenia/ hyposplenia
Laboratory personnel and healthcare workers who are exposed
routinely to Neisseria meningitides
Travelers to Saudi Arabia for Haj, Africa
Students going abroad for higher studies
Adjunct to chemotherapy in close contacts. HCW in contact with
secretions, household contacts, day care contacts
Considering seriousness of IMD, vaccine should be at least
offered to all for individual protection.
IAPCOI Guidebook on Immunization 2011.

Conclusions

Meningococcal disease, a serious disease with high case fatality rate, may
lead to death within 24 hours of initial symptoms.
Difficulties in diagnosis and atypical presentations pose specific
challenges in management and could potentially lead to underestimation.
Data on epidemiology in India scanty due to absence of established
surveillance system and obstacles in microbiological identification.
Quadrivalent conjugate meningococcal vaccine has excellent efficacy and
offers good option to address the missing link in prevention of bacterial
meningitis
Considering the prevalence and seriousness of IMD, vaccine should be at
least offered to all for individual protection.

THANK YOU

The windshield is bigger than the rearview


mirror
-- Tom Daschle

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