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Meningococcal infections in the United StatesF M LaForce, The Meningitis Vaccine Project, Ferney, France
GIM Conference, Denver - December 16, 2008
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Neisseria meningitidis• Gram-negative diplococcus• Enveloped by
polysaccharide capsule Determines serogroup Determinant of immunity
• Common disease-causing serogroups A B C Y W-135
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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
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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
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Nasopharyngeal carriage, by Age
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• 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
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• 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
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Incidence and Case-Fatality, U.S., 1920-2005*
02468
101214
Year
Rat
e pe
r 100
,000
po
pula
tion
01020304050607080
Cas
e fa
talit
y ra
tio
(%)
Incidence Case-fatality ratio
*NETSS data
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Meningococcal Disease Incidence United States 1970-2005
00.20.40.60.8
11.21.41.61.8
Year
Rat
e pe
r 100
,000
pop
ulat
ion
NETSS data
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Cross-sectional View of the Cell Membrane
Capsular polysaccharide (serogroup)
Outer-membrane proteinsserotype/subserotype
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Proportion of N. meningitidis Isolates by Serogroup, 1991–2005*
NG4%
Y27%
W-1352%
Other1% C
29%
B37%
*ABCs, n=3176 serogroup results (89.7% of total)
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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)
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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
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Goldschneider et al. J. Exp. Med. 1969;129,1327-48.
Age-specific meningococcal incidence and prevalence of SBA
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.........
.........
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
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Membrane attack complex
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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
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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%)
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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
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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
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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
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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
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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
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Size of Association of GBS with MCV4
Expected Cases
Cases Observed
IRR(95% CI)
Excess Risk per Million Doses
11-19 Year Olds 18 22 1.3(0.8-1.9) 0.4
15-19 Year Olds 12 20 1.7(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
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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
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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
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Revised ACIP Recs, Menactra – 2/2008
• Adolescents aged 11-18 years recommended for routine MCV4 vaccination
• AND high-risk people aged 2-54 years
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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?
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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
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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
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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
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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”)