HOST IMMUNITY AND VACCINES AGAINST BACTERIAL MENINGITIS

1. HOST IMMUNITY AND VACCINES AGAINSTBACTERIALMENINGITIS

2. Pathophysiology of bacterial meningitis • Host factors • Agent factors • Host immunity (humoral, cell-mediated) • Vaccines for • Hemophilus influenzae • Streptococcus pneumoniae • Neiserria meningitidis • Streptococcus agalactiae • Future insights

3. MENINGITIS: one of the major causes of infection-related deaths worldwide. • 30–50% of the survivors sustain neurological sequelae. (Pomeroy et al. N Eng J Med 1990;320:1651-56) • Major morbidity and mortality: neonates and children • Pathogenesis depends on complex bacterial-host interactions. • The correct understanding of the disease pathogenesis and host immunity may be of help to formulate therapeutic strategies and vaccines.

4. Major bacterial pathogens: Account for >80% of the cases • Hemophilus influenzae • Streptococcus pneumoniae • Neisseria meningitidis • H. influenzae: incidence decreasing since the introduction of Hib vaccine in late 1980

5. S. pneumoniae: • Peak rates of infection in extremes of age: <2 years and elderly • High rates associated with basilar skull fracture, immunocompromised state (e.g. splenectomy, multiple myeloma) • 90 serotypes recognized, with a limited number accounting for a majority of invasive pneumococcal disease

6. N.meningitidis: • Only bacterium capable of generating epidemics of meningitis • 13 serotypes defined on the basis of capsular antigens (A, B, C, W-135 and Y are responsible for severe cases) A: Africa (Meningitis belt) B,C and Y: endemic meningitis in industrialized countries B: severe persistent meningitis in Latin America (Cuba, Columbia, Chile, Brazil) and New Zealand W-135: In Haji pilgrims and outbreaks in Burkina Faso (2002-03) (www.meningvax.org)

7. Pathogenesis of Bacterial Meningitis

8. BACTERIAL FACTORS • Lipopolysaccharide (capsule) • Cell wall components • Teichoic and lipoteichoic acid • Peptidoglycan • Outer membrane proteins • Bacterial proteins • IgA protease • Pneumolysin

9. HOST FACTORS • Humoral immune response • Secretory IgA • Anticapsular antibodies • Cell mediated immune response • Activation of macrophages • Release of inflammatory mediators (e.g. cytokines, interferons) • Apoptosis and necrosis • Complement pathway • Alternate complement pathway • Role of membrane attack complex

10. (Tunkel AR, Scheld W. Clin Micro Rev 1993;6:118-36)

11. Mucosal colonization Survival and multiplication in blood Pleocytosis and cytokine release Penetration of BBB Neuronal death (Kim KS. Nat Rev Neurosci 2003;4:376-85)

12. (van der Flier et al. Clin Micro Rev 2003;16:415-429)

14. MUCOSAL COLONIZATION Fimbriae • N. meningitidis adhere to nasopharyngeal epithelial cells and then transported across within a phagocytic vacuole • Two types of fimbriae in H. influenzae (a- anterior nasopharynx, b-posterior nasopharynx) and transport through breakdown in tight junction between epithelial cells) Capsule • H. influenzae type B: the most virulent serotype • S. pneumoniae : in-vivo capsular transformation enhances the infection

15. Antibodies • Natural mucosal antibodies e.g. IgA may decrease the rate of nasopharyngeal colonization • IgA protease by Neisseria Hemophilus S. pneumoniae Role of other bacterial components • Lipopolysaccharide • Peptidoglycan • Teichoic acid

16. INTRAVASCULAR SURVIVAL • Capsule : inhibition of neutrophil phagocytosis and resistance to complement- mediated bactericidal activity • S. pneumoniae: Lysed by activation of alternate complement pathway by C3 • N. meningitidis: Susceptible to attack by membrane attack complexes C5b-9 (Kuby Immunology 5th ed.)

17. High levels of bacteria in blood Dural venous sinuses MENINGEAL INVASION Governed by Cribriform plate Sites of CNS invasion Choroid plexus Adherence through fimbriae Ascent of the bacteria through monocytes “TROJAN HORSE HYPOTHESIS” Transcytosis through microvascular endothelial cells Lipopolysaccharide Bacterial components Outer membrane proteins

18. BACTERIAL SURVIVAL IN SUBARACHNOID SPACE AND ITS INFLAMMATION • Prostaglandins (PGE2, prostacyclin) • Interleukins (IL1b, IL6, IL8, IL12, IL16) • Interferon-g • TNF-a • Platelet activating factor • Macrophage inflammatory products 1 & 2 • Leukocyte integrins • Leukocyte selectins • ICAM 1 • Endothelial leukocyte adhesion molecule 1 • Reactive nitrogen intermediates • Peroxynitrite

19. BLOOD BRAIN BARRIER

20. Features of BBB • Separation of tight junctions • Increase in pinocytotic vesicle formation • Inflammatory cytokines (IL-1 and TNF) • Matrix metalloproteinases induce alterations in BBB by their endopeptidase activity • Adjacent endothelial cells are fused together by tight junctions that prevent intracellular transport • Rare or absent pinocytotic vacuoles • Abundant mitochondria

21. RAISED INTRACRANIAL PRESSURE Swelling of cellular elements of brain by the release of toxic mediators from bacteria or neutrophils Increased permeability of BBB Obstruction to the flow of CSF Interstitial edema Vasogenic edema Cytotoxic edema Alteration in cerebral blood flow and ischaemia

22. NEURONAL INJURY • Cell necrosis and damage to cell membrane through free O2 radicals • Apoptosis • Apoptosis inducing factor (AIF) • Pneumolysin • Activation of PARP, poly (ADP-ribose) polymerase • Caspase-3 • Reactive N2 intermediates • Nitric oxide • Excitatory amino acids (glutamate, aspartate, glycine, taurine, alanine) • Peroxynitrite

25. (Koedel U. Lancet Infect Dis 2002;2:721–36)

26. VACCINES FOR MENINGITIS!!!!

27. Choice of vaccine: Polysaccharide or protein conjugate??

28. HaemophilusinfluenzaeType b (Hib) Vaccine • Conjugated vaccines where the Hib capsular polysaccharide (polyribosyl ribitol phosphate or PRP) is conjugated with CRM197 • Universal immunization for children aged <5 years • High-risk indications for children aged ≥5 years • Immune system disorders (HIV/AIDS) • treatment with drugs such as long-term steroids • cancer treatment with x-rays or drugs • bone marrow or organ transplant • damaged spleen or no spleen.

29. PNEUMOCOCCAL VACCINES Pneumococcal polysaccharide vaccine (23-valent) PNEUMOVAX Serotypes covered: 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, 33F. Dosing:0.5mL IM Pneumococcal conjugate vaccine PCV 7: 4, 6B, 9V, 14, 18C, 19F and 23 linked to CRM 197 Dosing: 0.5mL IM PCV 13:1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F conjugated to CRM197

30. PPV23 • 70% efficacy against prevention of invasive pneumococcal disease in the high-risk population but offers no protection against non-bacteremic pneumonia/otitis media. • Not more than two life time doses are recommended as repeated doses may cause immunologic hyporesponsiveness.

31. PCV 7 PCV 13

32. Healthy children • PCV 7 is routinely given to infants as a series of 4 doses, one dose at each of these ages: 6 weeks, 10 weeks, 14 weeks, and a booster at 15-18 months. • Catch up vaccination • 6-12 months: 2 doses 4-8 weeks apart and 1 booster at 15-18 months • 12-23 months: 2 doses 8 weeks apart • 24-59 months: single dose (www.iapcoi.com)

33. High risk children • sickle cell disease, • a damaged spleen or no spleen, • cochlear implants, • cerebrospinal fluid (CSF) leaks, • HIV/AIDS or other diseases that affect the immune system (such as diabetes, cancer, or liver disease), or • chronic heart or lung disease • or children who take medications that affect the immune system, such as chemotherapy or steroids. • Chronic renal/cardiac/hepatic failure (www.iapcoi.com)

34. New antigens being identified…… • Cbp (Choline binding protein) • Ply (Pneumolysin) • LytA (Autolysin) • PsaA (Pneumococcal surface adhesin A) • PspA (Pneumococcal surface protein A) (Kadioglu A. Nat Rev Microbiol 2008;6:288-301)

35. MENINGOCOCCAL VACCINES

36. Meningococcal polysaccharide vaccine (MENOMUNE) Meningococcal conjugate vaccine (MENACTRA and MENVEO) (www.cdc.gov)

37. Meningococcal PolysaccharideVaccine (MPSV) - Menomune • Quadrivalent (serogroups A, C, Y, W-135) • Approved for persons 2 years of age and older • Administered by subcutaneous injection • Recommendations for use: • Individuals who are at elevated risk aged over 55 years • Persons aged 2-55 years if there is a contraindication or precaution to receiving MCV, such as persons with a history of Guillian-Barre syndrome. (www.cdc.gov)

38. Meningococcal ConjugateVaccine (MCV) • Quadrivalent (serogroups A, C, Y, W-135) conjugated to diphtheria toxoid • MENACTRA approved for persons 2 through 55 years of age • MENVEO approved for persons 11 through 55 years of age • Administered by intramuscular injection • Recommendations: • Adolescents aged 13-18 years receive 1 dose of MCV4 • Young adolescents at the pre-adolescent visit (11–12 years old) • All persons aged 13-18 years at the earliest opportunity (www.cdc.gov)

39. Groups that have elevated risk of meningococcal disease • College freshmen living in dormitories • Microbiologists who are routinely exposed to isolates of N. meningitidis • Military recruits • Persons who travel to, or reside in countries in which N. meningitidis is hyperendemic or epidemic, particularly if contact with the local population will be prolonged • Persons who have anatomic or functional asplenia or terminal complement component deficiencies (www.cdc.gov)

40. Initiatives by Meningitis Vaccine Project (MVP) and WHO to launch meningococcus group A vaccine, MenAfriVac in meningitis belt, Africa for 1 to 29 yrs old and produced by Serum Institute of India, Ltd. (www.meningovax.org)

41. Vaccines for Group B meningococcus • Failure as the group B capsular polysaccharide resembles human neural cellular adhesion molecules • Focus of attention has been • Cell surface protein antigens contained in OUTER MEMBRANE VESICLES • Identification of new antigens as candidate vaccines by REVERSE VACCINOLOGY

42. 2

43. (Fraser CM. A genomics-based approach to biodefence preparedness. Nat Rev Gen 2004:5:23-33)

44. Potential vaccine candidates for Grp B (Segal S, Pollard AJ. British Medical Bulletin 2004;72:65–81)

45. Vaccines for Streptococcus agalactiae • Predominant cause of neonatal meningitis • Prophylactic antenatal antibiotic therapy is the main preventive strategy • Nine serotypes • Conjugate vaccines have been prepared against the most prevalent GBS serotypes in the USA (types Ia, Ib,II, III and V) and Japan (types VI and VIII) • Whole-genome sequencing of serotypes Ia, III and V has offered new insights into GBS virulence, with potential vaccine candidates including capsular polysaccharide, β-haemolysin, C5a peptidase, adhesins and immunogenic surface proteins (Maione D et al. Science 2005;309:148-150)

47. Adequate infrastructure for vaccine delivery and production in resource-poor countries with the highest meningitis burden • Development of effective vaccination against group B meningococcus remains a considerable challenge • Implementation of Hib vaccine in many resource-poor countries where disease burden is highest • Tackling complete serotype representation and serotype replacement in pneumococcal vaccines • Advances in the vaccine development through the development of genome-based strategies

49. References • Barocchi MA, Censini S, Rappuoli R. Vaccines in the era of genomics: The pneumococcal challenge. Vaccine 2007;25:2963–73. • Bogaert D, Hermans PWM, Adrian PV, Rümke HC, de Groot R. Pneumococcal vaccines: an update on current strategies. Vaccine 2004;22:2209–20. • Fraser CM. A genomics-based approach to biodefence preparedness. Nat Rev Gen 2004;5:23-33. • Girard MP, Preziosi MP, Aguado MT, Kieny MP. A review of vaccine research and development: meningococcal disease. Vaccine 2006;24:4692-700. • Kadioglu A, Weisser JN, Paton JC, Andrew PW. The role of Streptococcus pneumoniae virulence factors in host respiratory colonization and disease. Nat Rev Microbiol 2008;6:288-301. • Kim KS. Pathogenesis of bacterial meningitis: from bacteraemia to neuronal injury. Nat Rev Neurosci 2003;4:376-85. • Koedel U, Scheld WM, Pfister HW. Pathogenesis and pathophysiology of pneumococcal meningitis. Lancet Infect Dis 2002;2:721–36. • Maione D, Margarit I, Rinaudo CD, Masignani V, Mora M, Scarselli M et al. Identification of a universal group B streptococcus vaccine by multiple genome screen. Science 2005;309:148-50. • Pomeroy SL, Holmes SJ, Dodge PR, Feigin RD. Seizures and neurological sequelae of bacterial meningitis in children. N Eng J Med 1990;324:1651-56. • Segal S, Pollard AJ. Vaccines against bacterial meningitis. British Medical Bulletin 2004;72:65–81. • Tunkel AR, Scheld W. Pathogenesis and pathophysiology of bacterial meningitis. Clin Micro Rev 1993;6:118-36. • van der Flier M, Geelen M, Kimpen JLL, Hoepelman IM, Tuomanen EI. Reprogramming the host response in bacterial meningitis: how best to improve outcome. Clin Micro Rev 2003;16:415-29. • www.cdc.gov • www.iapcoi.com • www.meningvax.org