Meningococcal infections in the United StatesF M LaForce, The Meningitis Vaccine Project, Ferney, France

GIM Conference, Denver - December 16, 2008

22

Neisseria meningitidis

• Gram-negative diplococcus• Enveloped by

polysaccharide capsule Determines serogroup Determinant of immunity

• Common disease-causing serogroups A B C Y W-135

33

Carriage and transmission of N. meningitidis

• Carried in human nasopharynx• Transmission occurs through direct

contact • 5-10% of the population are carriers• Proportion of carriers in population does

not predict outbreaks

44

Flow of Neisseria meningitidis through a population

Invasion

Colonisation'Recovery'

Acquisition

Transmission

Release Disease

Invasion

Courtesy Drs. Maiden and McLennan

Courtesy Dr. Martin Maiden

Reservoir

55

Nasopharyngeal carriage, by Age

66

• Meningitis: most common presentation

• About half of all cases• Secondary result of hematogenous

dissemination• Clinical findings

• fever• headache • stiff neck

• Cerebrospinal fluid: pleocytosis, N. meningitidis

Clinical forms of meningococcal disease

77

• Meningococcemia: fulminant presentation

• About 40% of cases• Case-fatality of 15-30%, death often in 12-48

hours• Result of substantial endotoxemia• Clinical findings

• petechial/purpuric rash• hypotension• disseminated intravascular coagulopathy• Multi-organ failure

Clinical forms of meningococcal disease

88

99

1010

11

Incidence and Case-Fatality, U.S., 1920-2005*

0

2

4

6

8

10

12

14

Year

Rate

per

100

,000

po

pula

tion

01020304050607080

Case

fata

lity

ratio

(%

)

Incidence Case-fatality ratio

*NETSS data

12

Meningococcal Disease Incidence United States 1970-2005

00.20.40.60.8

11.21.41.61.8

Year

Rat

e pe

r 10

0,00

0 po

pula

tion

NETSS data

1313

Cross-sectional View of the Cell Membrane

Capsular polysaccharide (serogroup)

Outer-membrane proteinsserotype/subserotype

14

Proportion of N. meningitidis Isolates by Serogroup, 1991–2005*

NG4%

Y27%

W-1352%

Other1%

C29%

B37%

*ABCs, n=3176 serogroup results (89.7% of total)

1515

The Goldschneider papers, J Exp Med 1969

• Considered to be the definitive papers on human immunity against meningococci

The setting and the problem - High attack rates of meningococcal meningitis in military recruits undergoing basic training

Pressing need to develop an effective preventive approach (vaccine)

1616

Serum bactericidal activity was an accurate measure of susceptibility

• Using randomly collected sera they established that the age-related incidence of meningococcal meningitis in the US is inversely related to serum bactericidal activity against serogroups A, B and C

Susceptibility was a function of the absence of serum bactericidal activity

1717

Goldschneider et al. J. Exp. Med. 1969;129,1327-48.

Age-specific meningococcal incidence and prevalence of SBA

1818

.........

.........

Heat inactivatesera

Complement

BactericidalBuffer

Overnight growth oftarget strain

4 hours incubation -exponential growth

phase

bacterialsuspension

Tilt Method COUNT

overnightincubation, CO2

37oC

.........

.........

Incubate 37oC

Serum bactericidal antibody assay

1919

Membrane attack complex

2020

First prospective study• 14,744 recruits were bled during week 1 of basic training (12/67 to

3/68 – base line serum)

• There were 60 cases of meningococcal meningitis in this group (all serogroup C) Baseline serum tested against individual infecting strain Ten control sera randomly chosen from same platoon

Bactericidal titer 1:4 or greater Cases Controls

3/54 (6%) 444/540 (82%) (sera from cases lacked bactericidal activity to disease producing strain)

(bactericidal activity reconstituted with addition of gamma globulin)

Conclusion: Absent bactericidal activity related to lack of antibody to infecting strain

2121

Second prospective study• What happens to recruits who acquired the epidemic strain in

the absence of bactericidal antibody • 492 men in three companies followed for 7 weeks NP cultures and serum at weeks 1, 3, 5 and 7• Five men developed meningitis due to serogroup C

ResultsSera without NP pos Cidal activ Incidence ofcidal activ Tot Men C to acq strain disease 54/492 44/54 24 11/24 5/13 (38%)

(Conclusion: of the initial 54 susceptibles only 13 were exposed to the epidemic strain in the absence of bactericidal antibody; five developed meningitis – an incidence rate of 38%)

2222

Conclusions from the Goldschneider and Gotschlich papers• Susceptibility to meningococcal disease in man is

related to a selective deficiency of antibody to the offending organism

• Even during an epidemic meningococcal disease occurs in a fraction of susceptibles because the majority of susceptibles are not exposed to the epidemic strain

• These studies established a clear path that led to the development of PS meningococcal vaccines

• Introduction of PS meningococcal vaccines eliminated meningococcal meningitis as a threat to US military forces

2323

Development and testing of meningococcal vaccines

• US Army led in the development of Men A/C polysaccharide vaccineTest results for Men C PS vaccine were

dramatically positive in military recruits One case/13,733 vaccinees 38 cases/68,072 non-vaccinees

(87% reduction)

• Finnish studies showed Men A PS vaccine effective from 3 months to 5 years

2424

Quadrivalent Polyaccharide Vaccine (Menommune, Sanofi Pasteur)

• SQ - Safe with mild adverse reactions• Good efficacy (>85%) in older children &

adults• Poorly immunogenic (C>A) in children <18-

24 mo• Immunity of limited duration• Possible immunological tolerance

2525

Quadrivalent Conjugate Vaccine (MCV4) (Menactra, Sanofi Pasteur)

• Jan 2005, licensed for IM use in 11-55yo• October 2007, license extension for 2-10yo • 0.5cc dose contains 4ug of capsular polysaccharide

from serogroups A, C, Y, W-135• Conjugated to 48ug of diptheria toxoid • Similar to conjugated Hib, S. pneumonia and

serogroup C meningococcal vaccines Conjugation changes immune response to T-cell

dependent, increasing response in infants & anamnestic response at re-exposure

26

GBS cases among 11-19 year-olds within 6 weeks of receipt of MCV4, by month of onset, 1/05-7/07 (n=22)*

0

1

2

3

4

5

Date of GBS Onset

# C

ases

*October 2007

MCV4 Licensed2nd MMWR

1st MMWR 3rd MMWR

2727

Size of Association of GBS with MCV4

Expected Cases

Cases Observed

IRR(95% CI)

Excess Risk per Million Doses

11-19 Year Olds 18 221.3

(0.8-1.9)0.4

15-19 Year Olds 12 201.7

(1.0-2.5)1.3

•Excess risk comparable to some prior seasonal influenza vaccines•In decision analysis, vaccination favored, even with larger magnitude of risk

2828

Duration of Protection, MCV4, 11-18yo

• MPSV4 in adults > 3-5 years protection• Conjugate vaccines induce memory and

higher antibody levels which should provide longer protection

• UK studies =90% VE at 3 yrs in 11-18 yo• Therefore, ACIP assumed MCV4 will

provide protection of >8 yrs in adolescents

2929

Summary of Cost Effectiveness Analyses, MCV4 Adolescent Strategy

• High cost per case prevented ($100Ks)• Compared to infant or toddler strategy

• Least expensive• Fewer cases and deaths prevented

• Greater impact on disease could be achieved at lower cost with herd immunity

3030

Revised ACIP Recs, Menactra – 2/2008

• Adolescents aged 11-18 years recommended for routine MCV4 vaccination

• AND high-risk people aged 2-54 years

3131

Future Prospects: Control & Prevention of Meningococcal Disease in U.S.

• Conjugate A/C/Y/W135 vaccine offer substantive opportunity to reduce disease• Effect on carriage and herd immunity?• Implementation?

• Other meningococcal conjugate vaccines• Age groups, formulations, combinations

• Availability of serogroup B vaccines?

3232

Public health impact after introduction of the Men C conjugate vaccine • Complete success of the Men C conjugate

vaccine in the UK Catch-up strategy (single dose for 1-25 year olds –

80% coverage) plus immunizing birth cohorts Strong herd immunity with clear protection of the

unvaccinated Disappearance of the disease

• The Men C conjugate vaccines significantly decreased Group C N mening colonization

3333

Laboratory-confirmed Cases of Meningococcal Disease England & WalesFive Weekly Moving Averages: 1997 to 2008

0

20

40

60

80

100

120

140

160

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Laboratory confirmed Serogroup B Laboratory confirmed Serogroup C Laboratory confirmed Total

Health Protection Agency Meningococcal Reference Unit unpublished data

3434

Invasion

Colonisation'Recovery'

Acquisition

Transmission

Release Disease

Invasion

X

?X

X

X

X

Population effects of MCC vaccinesPopulation effects of MCC vaccinesHerd immmunity or vaccine escapeHerd immmunity or vaccine escape

Courtesy Dr.Martin Maiden

Population Effects of Men C Conjugate Vaccines:

The development of herd immunity

reservoir

3535

Herd Immunity After Conjugate Vaccine Use(Mening, pneumo and H influenzae)

• Comprehensive use of conjugate polysaccharide vaccines against encapsulated pathogenic bacteria spread by “respiratory droplets” has resulted in a major fall in colonization rates (carriage) in the general population with resultant protection of the unimmunized (so-called “herd immunity”)