Amanda Cohn, MDCDR, US Public Health Service

National Center for Immunization and Respiratory Diseases

April 6, 2011

Epidemiology of Meningococcal Disease in Infants and Young Children and

Vaccine Effectiveness of the Adolescent Program

Background

Meningococcal disease affects all age groups

High case-fatality ratio substantial morbidity among survivors

Adolescent vaccination program may be informative to questions around infant vaccination Initial ACIP recommendation in 2005, preferred age 11-

12 years Booster dose at age 16, January 2011

Infant Burden of Disease: Data Sources

Active Bacterial Core surveillance (ABCs) Active laboratory- and population-based surveillance 10 sites (~13% of U.S. population) Limited to culture confirmed cases

National Notifiable Diseases Surveillance System (NNDSS) Passive surveillance All states and territories Limited serogroup information

Published reports of sequelae and estimates of severity

Meningococcal Disease Incidence, United States

1970

1972

1974

1976

1978

1980

1982

1984

1986

1988

1990

1992

1994

1996

1998

2000

2002

2004

2006

2008

0

0.5

1

1.5

2

Year

Ra

te p

er

10

0,0

00

1921-1996 NNDSS data, 1997-2008 ABCs data projected to U.S. population

MCV4

0

5

10

15

1921

1925

1929

1933

1937

1941

1945

1949

1953

1957

1961

1965

1969

1973

1977

1981

1985

1989

1993

1997

2001

2005

Year

Rat

e p

er 1

00,0

00

Meningococcal Disease Incidence by Year and Serogroup, 1999-2008

1999 2000 2001 2002 2003 2004 2005 2006 2007 20080

0.1

0.2

0.3

0.4

0.5

B C Y

Year

Rat

e p

er 1

00,0

00

ABCs cases from 1999-2008 and projected to the U.S. population

MCV4

Meningococcal Disease Incidence by Age, 1999-2008

0-4

5-9

10-1

4

15-1

9

20-2

4

25-2

9

30-3

4

35-3

9

40-4

4

45-4

9

50-5

4

55-5

9

60-6

4

65-6

9

70-7

4

75-7

9

80-8

485

+0

0.5

1

1.5

2

2.5

Age (years)

Rat

e p

er 1

00,0

00

ABCs cases from 1999-2008 and projected to the U.S. population

Estimated Annual Number of Cases of Meningococcal Disease, United States: Age 0 -

21 years

<1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 210

50

100

150

200

250 Serogroups A,C,Y,W-135 Serogroup B

Age

Nu

mb

er

of

ca

se

s

ABCs cases from 1999-2008 and projected to the U.S. population

Meningococcal Disease Incidence in Children <5 years,

1999-2008

<1 1 2 3 40

1

2

3

4

5

6

Serogroup B Serogroup C Serogroup Y Other*

Age (years)

Rat

e p

er 1

00,0

00

ABCs cases from 1999-2008 and projected to the U.S. population

*Other includes: serogroups W-135, nongroupables, other, and unknown

Average Annual Cases of Meningococcal Disease in Children <5

years, 1999-2008

Age Serogroup C

Serogroup Y

C+Y (incidence)

0-2 months 6 18 24 (2.3)

3-5 months 8 19 27 (2.5)

6-8 months 7 14 21 (2.0)

9-11 months 5 2 7 (0.7)

1 year 11 7 18 (0.4)

2 years 16 6 22 (0.5)

3 years 7 1 8 (0.2)

4 years 7 5 12 (0.3)

0-59 months 67 72 139

ABCs cases from 1999-2008 and estimated to the U.S. population

Cases of Serogroup C + Y Meningococcal Disease in Children

6-59 months, 2000-2009

2000 2001 2002 2003 2004 2005 2006 2007 2008 20090

20

40

60

80

100

120

140

160 6-23 months 24-59 months

2000-2009 NNDSS reports, includes all case statuses; proportion of C+Y disease from ABCs reports

Average Annual Burden of Meningococcal Disease, 6-59 months

vs. 11-19 years

Age NNDSS Average Annual Cases 2005-2009

ABCs Proportion Serogroup C+Y

ABCs Cases 2000-2009 Serogroup C+Y (Incidence)

Estimated Cases of Serogroup C+Y (Incidence) 2005-2009

6-23 months 112 28.2 43 (0.5) 32 (0.3)

24-59 months

72 26.8 37 (0.2) 19 (0.2)

11-19 years 173 61.2 173 (0.4) 106 (0.3)

2005-2009 NNDSS reports, includes all case statuses; proportion of C+Y disease from ABCs reports

Hospitalization of Meningococcal Cases, ABCs,

1999-2008 92% of all cases were hospitalized Median length of hospitalization*:

<1 year: 7 days (0-373) 1-10 years: 6 days (0-61) 11-19 years: 6 days (0-79) ≥20 years: 6 days (0-128)

Does not vary by month of age, serogroup or syndrome

*Limited to hospitalized patients

Meningococcal Cases in Children <2 years by Serogroup and Syndrome,

ABCs, 2000-2009

62%

38%

Serogroup C

Meningitis BacteremiaOther

44%

40%

17%

Serogroup Y

Meningitis BacteremiaOther

U.S. Multicenter Study of Pediatric Meningococcal Disease, 2001-2005

≤5 years

(n=105)

6-10 years

(n=21)

>10 years

(n=33)Mechanical ventilation 16.7% 50.0% 39.4%

Hypotension 12.4% 0% 9.1%

Purpura 34.3% 52.4% 39.4%

Death 3.8% 9.5% 21.2%

≤5 years: 45% serogroup B, 44% serogroup A,C,Y,W135; 6-10 years: 43% serogroup B, 57% serogroup A,C,Y,W135; >10 years: 42% serogroup B, 58% serogroup A,C,Y,W135

Kaplan et al., Pediatrics 2006, 118(4):e979-84.

U.S. Multicenter Study: Sequelae at Hospitalization

≤5 years >5 years

Serogroup B Serogroup C+Y

Serogroup B Serogroup C+Y

Necrosis 5/60 (8.3) 7/50 (14.0) 1/22 (4.5) 2/32 (6.3)

Hearing loss 6/56 (10.7) 6/50 (12.0) 3/17 (17.6) 3/31 (9.7)

Hemiplegia 0/61 (0.0) 1/50 (2.0) 0/19 (0.0) 1/34 (2.9)

Death 4/66 (6.1) 0/20 (0.0) 3/21 (14.3) 4/34 (11.8)

Personal communication, S. Kaplan

Quebec, Canada, 1990-1994: Sequelae from Serogroup C

Disease

Fig 1. Percentage of cases of meningococcal disease in Quebec with major complications (solid bars), minor complications (open bars), or fatal outcome (hatched bars), by age group

Erickson and De Wals. CID 1998, 26:1159-64.

Neurological Sequelae Associated With All Cause Bacterial Meningitis

Long-term neurological sequelae are difficult to measure

More than 2/3 of patients exhibit neurologic or neuropsychological deficits after acute bacterial meningitis (non-pathogen specific)a

Nearly 1/5 of children with meningitis have a permanent severe or moderate severe disability, and subtle deficits are also more prevalent (non-pathogen specific)b

aMerkelback et al., Acta Neurol Scand 2000, 102: 118-123.bBedford et al., BMJ 2001, 323: 533-7.

Average Annual Deaths and Case-Fatality Ratios by Serogroup and Age,

2000-2009Serogroup

B C Y Overall

<2 years 16 (10.5) 5 (22.5) 1 (3.1) 22 (9.9)

2-4 years 7 (16.4) 1 (8.0) 1 (9.7) 9 (12.2)

5-10 years 7 (22.9) 3 (12.6) 1 (9.0) 11 (16.7)

11-19 years 9 (18.3) 12 (17.8) 3 (6.0) 24 (13.3)

20+ years 28 (17.0) 36 (18.0) 44 (16.6) 118 (17.4)

ABCs cases from 2000-2009 and projected to the U.S. population

Summary While infants age <1 year are at greatest

risk, amount of potentially preventable disease in infants is low Current nadir in disease incidence Low proportion of serogroup C+Y disease Declining incidence after first 6-8 months of life

Morbidity and mortality in infants is lower than in other age groups

Preliminary Results: Vaccine Effectiveness of Menactra®

Matched Case-Control Study Design

Enrollment ongoing (January 2006 – present) in 29 health departments Provider verified vaccination record (85%) N. meningitidis serogroup A, C, W-135, Y isolated from a

normally sterile site, or detection by PCR Challenges due to low disease incidence and difficulty

enrolling adolescent age group Matched by age and state (friend and school controls)

Conditional logistic regression Controlling for underlying illness*, smoking VE = 1- Odds Vaccinated vs Unvaccinated

*Complement deficiency, asplenia, HIV, other immune disorder, cancer, diabetes, kidney disease

Cases by serogroup and vaccination status (n=120)

Based on paperwork received by March 23, 2010

Vaccination status Serogroup C(n=63)

Serogroup Y(n=51)

Serogroup W135 (n=6)

Not vaccinated 54 40 5

Vaccinated <1 year 2 2 0

Vaccinated 1<2 years

2 2 1

Vaccinated 2<5 years

5 7 0

Total controls enrolled

100 62 6

Demographics

Eligible Cases(n=207)

Enrolled Cases

(n=120)

Controls (n=168)

Mean Age: 17.9 years (11-24)

18.3 years (11-23)

18.2 years (10-24)

Male: 59% 62% 52%

Race:

White 71% 78% 89%

Black 18% 15% 4%

Other 3% 3% 8%

Unknown 8% 6% 1%

Case fatality ratio

13% 10% Analysis results based on paperwork received by March 23, 2010; excludes cases and controls vaccinated with MPSV4 only

PRELIMINARY RESULTS, SUBJECT TO CHANGE.

Proportion of Cases and Controls Vaccinated with MenACWYD by Year

Based on paperwork received by March 11, 2011; unknown vaccination status excluded

2006 2007 2008 2009 20100

10

20

30

40

50

60

Cases Controls

Year

Perc

en

t V

accin

ate

d

Cases n=23

Controls n=39

Cases n=25

Controls n=35

Cases n=11

Controls n=18

Cases n=26

Controls n=41

Cases n=36

Controls n=43

Preliminary VE, Menactra Effectiveness, (0-5 years)

All Enrolled Cases Controlling for: VE (95% CI)

Serogroups C, Y and W-135 combined 74% (35-90%)

Serogroup C 83% (38, 95%)

Analysis results based on paperwork received by March 23, 2010.Controls for smoking status and underlying condition statusPRELIMINARY RESULTS, SUBJECT TO CHANGE.

Preliminary Menactra VE Estimates: C, Y, and W-135, Duration of Protection*

Analysis results based on paperwork received by March 23, 2010.Controls for smoking status and underlying condition statusPRELIMINARY RESULTS, SUBJECT TO CHANGE.

Cases* VE (95% CI)All cases (n=120)

VE (95% CI)Cases with no underlying illness (n=105)

Vaccinated <1 year 99% (0,100%) 99% (0, 100%)

Vaccinated 1 to 2 years

80% (-3,96%) 89% (5, 99%)

Vaccinated 2 to 5 years

46% (-66, 83%) 56% (-48, 87%)

Evolving Understanding of Protection

Immunologic memory not enough* Boost response takes 5-7 days after exposure, incubation

period of N. meningitidis is 1-4 days. Vaccine failures occur in person in whom immunologic

memory can be demonstrated

Unlikely getting the additional benefits of herd immunity with the current U.S. program Coverage increasing slowly, only now about 60% Adolescent immunity at population level lower than 60%

Need circulating antibody at time of exposure*Snape et al, CID, 2006, Auckland et al, JID, 2006

Menactra SBA-BR % of subjects with brSBA ≥1:128 post-vaccination,

serogroup C

1 mo 3 years 5 years0

102030405060708090

100 98.9

74.6

54.6

44 42.1

MCV4 Age-matched naive

% >

= 1

:128

n= 440 n= 71 n=84 n= 108 n=107

*Data courtesy of sanofi pasteur, 3 year follow-up of MTA02 (11-18 year-olds), 5 year follow-up of 603-02 (2-10 year-olds)

Menveo and Menactra % of subjects with hSBA ≥ 1:8,

Serogroup C Phase III, Persistence/Booster of Bactericidal Antibodies in

Adolescents

1 month 22 months 36 months persistence

0

10

20

30

40

50

60

70

80

90

100

Menveo Menactra

% h

SB

A ≥

1:8

Does Observational Effectiveness Inform Interpretation of Serologic

Data?

Vaccine effectiveness= 1- AR (vacc) x 100 AR (unvacc)

Serologic markers of protection do not incorporate natural protection in unvaccinated

VE is not directly inferred from serologic marker

1 mo0

102030405060708090

100

54.6

42.1

MCV4

Age-matched naive

% >

= 1

:128

Conclusions

Trends in observational data and serologic data are consistent and indicate waning immunity

Serologic markers of protection should be correlated with post-licensure clinical efficacy

For more information please contact Centers for Disease Control and Prevention1600 Clifton Road NE, Atlanta, GA 30333Telephone, 1-800-CDC-INFO (232-4636)/TTY: 1-888-232-6348E-mail: cdcinfo@cdc.gov Web: www.cdc.gov

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Thank you!