HOST IMMUNITY

AND VACCINES AGAINST

BACTERIALMENINGITIS

• 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

• 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.

• 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

• 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

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)

Pathogenesis of Bacterial Meningitis

BACTERIAL FACTORS

• Lipopolysaccharide (capsule)

• Cell wall components Teichoic and lipoteichoic acid Peptidoglycan Outer membrane proteins

• Bacterial proteins IgA protease Pneumolysin

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

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

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)

Time(Hours

postinfection)

Pathophysiologic events Clinical symptoms

0 Bacteria and bacterial products accumulate in CSF

None

4 Release of inflammatory mediators and cytokines

Fever

8–24 Blood-brain barrier disruption; development of cerebral edema;transendothelial migration of leukocytes; more proinflammatoryand toxic mediators; followed by impaired cerebralblood flow, elevated intracranial pressure, and vasculitis

Elevated CSF protein; meningism/neck stiffness;elevated CSF leukocytosis; systemiccomplications; altered mental status,focal symptoms, and seizures

24–48 Neuronal injury Focal symptoms; hearing loss; paralysis; cognitiveimpairment; death

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

PATHOGENIC EVENT

BACTERIAL FACTORS HOST FACTORS

Mucosal colonization

•Fimbriae•Polysaccharide capsule•IgA protease•Bacteriocin

•Mucosal epithelium•Secretory IgA •Ciliary activity•Anticapsular antibodies

Intravascular survival

Polysaccharide capsule •Complement activation•Organism specific antibodies

Meningeal invasion •Fimbriae •Association with monocytes•Platelet activating factor receptor•Pneumococcal choline binding receptor A

Blood brain barrier

Survival in subarachnoid space

Polysaccharide capsule Poor opsonic activity

MUCOSAL COLONIZATIONFimbriae

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

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

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.)

MENINGEAL INVASIONGoverned by

High levels of bacteria in blood

Sites of CNS invasion

Dural venous sinuses

Cribriform plate

Choroid plexus

Adherence through fimbriae

Ascent of the bacteria through monocytes “TROJAN HORSE HYPOTHESIS”

Transcytosis through microvascular endothelial cells

Bacterial components Lipopolysaccharide

Outer membrane proteins

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

BLOOD BRAIN BARRIER

• Adjacent endothelial cells are fused together by tight junctions that prevent intracellular transport

• Rare or absent pinocytotic vacuoles

• Abundant mitochondria

• 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

Features of BBB

RAISED INTRACRANIAL PRESSURE

Vasogenic edema Interstitial edema

Cytotoxic edema

Increased permeability of BBB

Swelling of cellular elements of brain by the release of toxic mediators from bacteria or neutrophils

Obstruction to the flow of CSF

Alteration in cerebral blood flow and ischaemia

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

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

VACCINES FOR MENINGITIS!!!!

Choice of vaccine: Polysaccharide or protein

conjugate??

TYPE OF VACCINE POLYSACCHARIDE PROTEIN CONJUGATE

T-cell dependent immunological function X

Effect on young children and infants X

Immunological memory and long term protection X

Reduction of nasopharyngeal

colonization

X

Herd immunity X

Haemophilus influenzae Type 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.

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

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.

PCV 7 PCV 13

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)

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)

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)

MENINGOCOCCAL VACCINES

Meningococcal polysaccharide

vaccine (MENOMUNE)

Meningococcal conjugate vaccine (MENACTRA and MENVEO)

(www.cdc.gov)

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)

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)

• 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)

• 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)

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

2

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

Potential vaccine candidates for Grp BPROTEIN FUNCTION

Neiserrial surface protein A (NspA) Immunogenic surface protein

PorA (class 1 protein) Cation porin

PorB (class 2/3 protein) Anion porin, induces immunity

Adhesion penetration protein (App) Autotransporter, induces antibodies after infection

Ferric binding protein (FbpA) Iron binding

Lactoferrin binding protein (LbpA) Lactoferrin binding

Opacity associated protein (OpA; class 5)

Adhesion, invasion

OpcA (Opc; class 5c) Invasion, adhesion

Transferrin binding protein A&B(TbpA, TbpB)

Iron acquisition from transferrin,

Pilin Adhesion

(Segal S, Pollard AJ. British Medical Bulletin 2004;72:65–81)

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)

• 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

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