Enfermedad meningocócica • La Enfermedad Meningocócica Invasiva (EMI) por Neisseria
meningitidis, es una patología exclusiva del ser humano y continúa siendo un problema de Salud Pública de distribución mundial, debido a su potencial epidémico y su morbimortalidad.
• Incidencia global: 1 a 1.000/100.000 habitantes según la zona geográfica
• Tasa de letalidad: 8-14%. La incidencia es mayor en niños. • En Chile:
1. Enfermedad de Notificación Obligatoria (ENO) DS. Nº 158.
Neisseria meningitidis:
van Deuren M, et al. Clin Microbiol Rev. 2000;13:144-166 - Broome CV. J Antimicrob Chemother. 1986;18 (suppl A):25–34 Dull PM, et al. J Infect Dis. 2005;191:33-9
Diplococcus encapsulado gram-negativo
Patógeno sólo para el hombre
Prevalencia de portación: 5%–40%
<1% de los portadores llegan a ser sintomáticos
Presenter
Presentation Notes
Key Point: Neisseria meningitidis is strictly a human pathogen that can be carried and transmitted through person-to-person contact. Slide Overview: N meningitidis is a gram-negative diplococcus and can only colonize in the human nasopharyngeal tract.1 Carriage of the bacteria is relatively common. In non-endemic areas, baseline prevalence of carriage is estimated to be 5% to 10%. In contrast, much higher carrier rates are found in household contacts of a case of meningococcal meningitis and in military recruits.2 Transmission occurs through the droplet route by means of respiratory secretions and direct contact.3 The disease has an incubation period of 2 to 10 days and can be fatal within �24 to 48 hours following onset of symptoms.3 References: van Deuren M, Brandtzaeg P, van der Meer JW. Update on meningococcal disease with emphasis on pathogenesis and clinical management. Clin Microbiol Rev. 2000;13(1):144-166. Broome CV. The carrier state: Neisseria meningitidis. J Antimicrob Chemother. 1986;18(suppl A):25–34. World Health Organization. Fact sheet: meningococcal meningitis. 2003. http://www.who.int/mediacentre/factsheets/fs141/en/print.html. Accessed December 4, 2007.
CDC, 2005; National Health and Medical Research Council, 2003
5 serogrupos (A, B, C, Y y W135) reconocidos como causantes de epidemias.
Determinados por diferencias estructurales en PS
Determinados por diferencias en las Proteinas de Membrana Externa (OMP)
Neisseria meningitidis
Modified from Rosenstein NE, et al. N Engl J Med. 2001;344:1378-1388.
Lipooligosaccharide
Outer membrane Periplasmic space Cytoplasmic membrane
Pilus
Polysaccharide capsule
(serogroup)
Phospholipid
Cytoplasmic-membrane proteins
Outer-membrane proteins
(serotype/serosubtype)
Polisacárido capsular: Serogrupos (13) A, B, C, W, Y
Presenter
Presentation Notes
Key Point: The cell surface biology of meningococci has implications for vaccine development. Slide Overview: Serogroups for Neisseria meningitidis are classified by the immunologic reactivity of their capsular polysaccharides. At least 13 serogroups have been identified, but the majority of cases of meningococcal disease are caused by serogroups A, B, C, W-135, and Y.1 The capsular polysaccharides serve as key antigens for the development of vaccines, except in the case of serogroup B.2 However, using capsular polysaccharides from N meningitidis presents some challenges.3 Different approaches are being taken to overcome these challenges. References: Rosenstein NE, Perkins BA, Stephens DS, Popovic T, Hughes JM. Meningococcal disease. N Engl J Med. 2001;344:1378-1388. Girard MP, Preziosi MP, Aguado MT, Kieny MP. A review of vaccine research and development: meningococcal disease. Vaccine. 2006;24:4692-4700. Ravenscoft N, Feavers IM. Conjugate vaccines. In: Frosch M, Maiden MCJ, eds. Handbook of Meningococcal Disease. Weinheim, Germany: Wiley-VCH; 2006:chap 17.
Epidemiología: Grupos de edades
Salisbury et al., 2006
< de 5 años: B
14-19 años C
< 1 año A y B
W 135
Grupos de edad más afectados, depende del serogrupo:
A. Niños menores B. Cualquier edad. Más frecuente
en lactantes. C. Adolescentes y Adultos Jóvenes W135: Cualquier edad
Prevención a través de vacunación programática: clave en el control
B A C W
Y
H. influenzae (1 tipo)
S. pneumoniae (25 serotipos)
N. meningiditis (5 serogrupos)
Enf invasora Enf invasora Enf invasora y fulminante
Vacuna conjugada
Hib
Vacuna conjugada
S. pneumoniae
Vacuna conjugada
Meningococo
Vacuna anti meningococo B
eg, PCV7, PPCV10,CV13 MenC, MenACWY
Bacterias capsuladas como causa de meningitis y sepsis
Presenter
Presentation Notes
Key Point: Primary prevention through routine vaccination is key to controlling IMD. Slide Overview: Capsular approaches to vaccine development have been successful for preventing Hib- and pneumococcal-associated meningitis and sepsis. Capsular approaches have also been successful for 4 of the 5 major meningococcal disease–causing serogroups (ACWY). Vaccines formulated from the polysaccharide capsule of serogroup B are poorly immunogenic.1 A broadly protective vaccine effective against serogroup B remains a significant unmet medical need and a public health priority. Serogroup B is responsible for approximately 70% of meningococcal disease in developed countries.1 Reference: Häyrinen J, Jennings H, Raff HV, et al. Antibodies to polysialic acid and its N-propyl derivative: binding properties and interaction with human embryonal brain glycopeptides. J Infect Dis. 1995;171:1481-1490.
r
• Ag: Polisacárido capsular purificado, N. meningitidis
serogrupo específico 1. Segura y efectiva1
Price. Curr Pharm Des 2007;13:2009-14; 2. Post et al. Infect Immun 2003; 647-55; 3. Modified from Rosenstein et al. N Engl J Med 2001;344:1378-88.
Vacuna Polisacárido capsular3
N. meningitidis 2
Vacunas polisacáridas
Presenter
Presentation Notes
Key Point: Polysaccharide vaccines have a history of safety and efficacy in preventing meningococcal disease. Slide Overview: Polysaccharide vaccines use purified polysaccharides from specific Neisseria meningitidis serogroups as antigens to produce serum antibodies that activate complement-mediated bacteriolysis and phagocytosis.1 The first successful polysaccharide vaccines against meningococcal disease were developed for serogroups A and C approximately 30 years ago to stop epidemics in US military recruits and were tested extensively in Europe, Latin America, and Africa. The vaccine was shown to be safe and effective in preventing epidemics of serogroup C in the US military and in mass campaigns to control epidemics of serogroup A in Africa.2 In addition to a bivalent vaccine against serogroups A and C, a tetravalent vaccine that also includes antigens from serogroups W-135 and Y has been developed.2 Polysaccharide vaccines have a high degree of safety and good short-term efficacy in older children and adults.3 References: Price A. Meningococcal vaccines. Curr Pharm Des. 2007;13:2009-2014. Girard MP, Preziosi M-P, Aguado M-T, Kieny MP. A review of vaccine research and development: meningococcal disease. Vaccine. 2006;24:4692-4700. Stephens DS. Conquering the meningococcus. FEMS Microbiol Rev. 2007;31:�3-14.
Vacunas conjugadas
• Conjugación química de PS de N. meningitidis a proteínas transportadoras1
• Mejoría de la respuesta inmune sobre las vacunas polisacáridas1
1. Harrison. Cl
Conjugación a prot transportadora4
carrier
Polisacárido capsular3
N. meningitidis2 Vacuna
Vacunas conjugadas
Harrison LH. Clin Microbiol Rev. 2006;19:142-164; 2. Post DMB, et al. Infect Immun. 2003:647-655; Modified from Rosenstein NE, et al. N Engl J Med. 2001;344:1378-1388; 4. Ravenscoft N, et al. In: Frosch M, Maiden MCJ, eds. Handbook of Meningococcal Disease. 2006:chap 17.
Presenter
Presentation Notes
Key Point: Polysaccharide-protein conjugate vaccines represent a major advance compared with unconjugated polysaccharide vaccines. Slide Overview: Conjugate vaccines overcome the shortcomings of polysaccharide vaccines by converting the polysaccharide into a T-cell–dependent antigen. This is done by covalently linking the saccharide antigen to a carrier protein that induces a �T-cell response. The carrier proteins used to create conjugate vaccines for meningococcal disease include tetanus toxoid, diphtheria toxoid, and diphtheria cross-reactive material (CRM197).1 A primary advantage of conjugated meningococcal vaccines (versus polysaccharide vaccines) is that these vaccines produce immunity in younger age groups, which have the highest incidence of meningococcal disease.2 The first conjugate vaccines were developed to prevent Haemophilus influenzae type b in the 1980s. The first conjugated meningococcal vaccine for serogroup C was introduced to the United Kingdom in 1999. In 2005, a tetravalent conjugate vaccine for serogroups A, C, W-135, and Y was approved in the United States.1 References: Ravenscoft N, Feavers IM. Conjugate vaccines. In: Frosch M, Maiden MCJ, eds. Handbook of Meningococcal Disease. Weinheim, Germany: Wiley-VCH; 2006:chapter 17. Harrison LH. Prospects for vaccine prevention of meningococcal infection. Clin Microbiol Rev. 2006;19:142-164.
• Polisacáridas - A y C; A/C/W/Y • Conjugadas: - C; A/C/W/Y • Dificultad en serogrupo B
– Similitud del PS capsular con moléculas de adhesión de células neurales humanas.
Vacunas N meningitidis
Lo H, Lancet InfectiousDisease 2009; 9(7): 418-427. Finne J, J Immunol. 1987; 138:4402 -4407
Fabricante Vacuna Componentes Adjuvante Wyeth Vaccines Meningitec™ 10 μg O-acetylated group C
Oligosaccharide conjugated to 11–25 μg CRM197
AlPO4
Novartis Vaccines Menjugate® 10 μg O-acetylated group C Oligosaccharide conjugated to 11–25 μg CRM197
Al(OH)3
Baxter Bioscience NeisVac- C™ 10 μg de-O-acetylated group C Oligosaccharide conjugated to 10–20 μg tetanus toxoid
Al(OH)3
GSK Menitorix™ 5 μg Hib polysaccharide & 5 μg group C polysaccharide each conjugated to ~17.5 μg of tetanus toxoid
None
Granoff DM, Harrison L, Borrow R. Meningococcal vaccines. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. 5th ed. Saunders; 2008.
Vacunas conjugadas meningococo C
Fabricante Vacuna Componentes Adjuvante
Sanofi Pasteur Menactra® 4 μg each of serogroups A, C, Y and W-135 polysaccharides conjugated to
diphtheria toxoid
none
Novartis Vaccines
Menveo™ 10 μg of serogroup A & 5 μg each of serogroups C, W-135 and Y
polysaccharides conjugated to CRM197
none
Composición de las vacunas tetravalentes conjugadas A/C/W/Y
GSK Nimenrix®
5 μg polysaccharide from each of serogroups A, C, Y and W-135 conjugated to ~44 μg of TT
none
A partir de 9 meses A partir de 2 meses A partir de 1 año
Presenter
Presentation Notes
Mutante no tóxico de la toxina diftérica1,2 CRM 197, mutante no tóxico de la toxina diftérica. Difiere en 1 aminoácido en la posición 52 (glicina reemplaza al ac glutámico)
• Vaccinología reversa: Identificación proteínas antigénicas con actividad bactericida
• Lipoproteínas comunes diferentes tipos y subtipos
serogrupo B
• Objetivo: Inmunidad heteróloga
Otras vacunas Meningococo B
Presenter
Presentation Notes
Se implemento dado el aumento de la incidencia una vacuna de 3 dosis a los menores de 20 años en un plazo de 2 años. Vacunaron desde los 6 meses. Efectividad de la vacuna se estimaba de un 72%. Ivonne Galloway hizo un estudio de cohorte con seguimiento de 24 meses despues de completada la vacunación a los niños entre 6 meses y 5 años. Calcularon la efectividad de la vacuna como 1 – RR. RR fue calculado con un 95% IC como el razon entre la enfermedad en vacunados vs no vacunados.
Expresión y
purificación en un vector Proteínas
purificadas
Immunización
Proteínas expresadas en Escherichia coli son purificadas y usadas para
immunizar ratones
Basado en la secuencia genómica de N meningitidis, se identifican
ORFs que potencialmente codifican proteínas antigenicas
Vaccinología reversa
100,000
200,000
300,000
400,000
500,000
600,000
700,000
800,000
900,000 1,000,000
1,100,000 1,200,000 1,300,000
1,400,000
1,500,000
1,600,000
1,700,000
1,800,000
1,900,000
2,000,000
2,100,000 2,200,000
IHT-A
IHT-B
IHT-C
1
Identificación proteínas
antigénicas con actividad
bactericida
Confirmación: presencia de proteínas expresadas
y de acs producidos
ORF = open reading frame (marco de lectura abierto) Based on Rappuoli R. Vaccine. 2001;19:2688-2691; Tettelin H, et al. Science. 2000; 287:1809-1815; Modified from Rosenstein NE, et al. N Engl J Med. 2001;344:1378-1388.
Vaccinología reversa
Presenter
Presentation Notes
Key Point: Reverse vaccinology is a novel approach to identifying potential protein antigens with bactericidal activity that would not have been identified through traditional methods of vaccine development. Slide Overview: Reverse vaccinology capitalizes on the availability of meningococcal genome sequences. A computer program is used to analyze genome sequences and predict antigens that can be used to develop potential vaccines. The advantages to this approach include the ability to evaluate a large number of potential antigens without having to cultivate microorganisms. The pool of potential antigens can also be much larger because this process can include all antigens that a pathogen can express at any time, regardless of whether they are expressed in vivo or in vitro. This process does require a high-throughput system to screen for protective immunity. One challenge is that this screening also requires good correlates for protection, which are currently not well defined. Another challenge is that this system does not identify nonprotein antigens such as polysaccharides. Despite these issues, the process has the potential to relatively quickly and efficiently identify antigens. In summary: To identify potential vaccine candidates, novel surface-exposed proteins were identified based on the complete genome sequence of Neisseria meningitidis. The use of genomics for vaccine development has since been termed reverse vaccinology. After successful expression of identified surface exposed proteins in Escherichia coli, purification of proteins, and immunization in mice, novel surface-exposed protein antigens with bactericidal activity are identified. Reference: Rappuoli R. Reverse vaccinology, a genome-based approach to vaccine development. Vaccine. 2001;19:2688-2691.
16
Tendencia de EMI y Prevalencia por serogrupo. Chile 2006-2013*
Cepas confirmadas de Neisseria meningitidis según serogrupo
