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”)