Prevention of infection 2 Immuno and chemoprophylaxis

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Prevention of infection 2Immuno- and
chemoprophylaxis

• Mark Pallen
• With help from
• S. Marlowe
• Matthias Maiwald

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History
Mims C et al. Medical Microbiology. 2004.
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Terms

• Immunization conferring immunity by artificial
  means
• Vaccination conferring immunity to a disease
  using a vaccine or special antigenic material to
  stimulate the formation of appropriate antibodies
• Vaccine preparation of antigenic material
  stimulates Ab production confers active
  immunity vs. disease
• Latin vacca cow (from cowpox)

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Immunization

• Using vaccines or antibody-containing
  preparations to provide immune protection vs.
  specific diseases
• Passive
• Preformed antibodies - another host
• Protect individual exposed to disease
• Active (vaccines)
• Modified / purified pathogens or their products
• Stimulate host to produce own specific immunity

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Passive Immunization

• IgG - immediate protection - no memory
• Standard Igs (human, animals) Non-specific
• Pooled plasma from donors
• Igs vs. many common viruses
• Human hyperimmune serum (high titre) Specific
• From donor c. high titre Abs to specific virus
• Against specific (single) virus

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Passive Immunization

• Indications
• Exposure has occurred, or is expected to occur
  soon
• No effective vaccine exists or time reqd too
  short
• Underlying illness prevents admin. vaccine
• E.g. uses
• Standard Ig Congenit./acq. Ig deficiency,
  prevent Hep A
• Rabies Ig (HRIg) post-exposure prophylaxis
• VZ Ig post-exposure prophylaxis if at high risk
• CMV Ig passive imm. renal transplant recipient

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Passive Immunization
Mims C et al. Medical Microbiology. 1998.
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Vaccines - Active

• Injection of viable / non-viable pathogens or
  purified pathogen products
• Response as if being attacked by intact organism
• Live / inactivated / DNA vaccines
• Effective starting after 2 wks to few months
• Prolonged immunity lt-- own antibodies produced

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From Vaccine brochure, SmithKline Beecham
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Antibody-mediated (humoral) immune response
From Vaccine brochure, SmithKline Beecham
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Active immunization
Penetrate cells - intracell. Ag processing to
surface of cells - cytotoxic T cell response

• Formulations
• Live pathogens attenuated
• Killed micro-orgs
• Microbial extracts
• Vaccine conjugates
• Toxoids

Do not enter host cells 1ary B cell-mediated
humoral response
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Primary andsecondary immune response and
Boostereffect
From Vaccine brochure, SmithKline Beecham
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Active vaccine - Live attenuated pathogens

• Multiplies inside human host provides strong
  antigenic stimulation
• Provides prolonged immunity (yrs to life), often
  with single dose
• Vaccine often provides cell-meditated immunity
• Disadvantage can revert to virulent form
• --gt Do not give to immunocomprom., pregnant

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Active - Killed micro-organism

• Does not multiply in human host
• Immune response depends on Ag content of vaccine
• Multiple doses of vaccine required with
  subsequent booster doses
• Provides little cell-mediated immunity
• No possibility of a vaccine-assoc. infection

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Active - Microbial extracts

• Extracted molecules (Ags)
• from pathogen
• from acellular (non-infectious) filtrate of
  culture medium in which org. grown
• recombinant DNA techniques
• Vaccines can be prepared with toxoids
  (derivatives of exotoxins)
• Used when pathogenicity of org. is due to
  secreted toxin
• E.g., tetanus, diphtheria

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Active - Conjugated vaccines

• Covalent binding (conjugation) of an antigenic
  polysaccharide to a protein higher Ab titres
  than unconj. polysacc.
• Esp. children lt 2yrs
• E.g.
• Hib conjugate (polysacc. conjugated to diphtheria
  toxoid protein)
• Meningococcal type C polysaccaride conjugate

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Active - Toxoids

• Derivatives of bacterial exotoxins
• Rendered non-toxic
• But remain immunogenic
• Admin IM, SC
• E.g.
• Tetanus
• Diphtheria

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Vaccine components
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Properties, advantages and disadvantages of live
vs. non-live vaccines
Mims C et al. Medical Microbiology. 1998.
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Vaccines vs. bacterial Diseases

• Pneumococcus (Streptococcus pneumoniae)
• 2 types of vaccines
• Pneumococcal polysaccharide (23-valent, i.e.,
  against 23 bacterial capsule types)
• Pneumococcal polysacc.-protein conjugate
  (7-valent covers children lt 2 yrs)

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Vaccines vs. bacterial diseases

• Meningitis (Neisseria meniningitis)
• Capsular polysaccharide (4 serotypes of Neiss.
  men. A, C, W135, Y)
• --gt Indications Campus, military, outbreak
• Capsular polysacch.-protein conjugate (serotype
  C of Neiss. men.)
• --gt For children

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Vaccines vs. bacterial diseases

• Tetanus (Clostridium tetani)
• Tetanus toxoid
• Indications
• Young child
• Booster (10 yrs)
• Suspected exposure (e.g., dirty wound) -- then
  with immunoglobulin

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Vaccines vs. viral diseases

• Hepatitis A inactivated whole virus
• Hepatitis B recombinant Hep B SAg
• Varicella-Zoster (live)
• Polio
• Inactivated polio virus (Salk vaccine)
• Attenuated live polio virus (Sabin vaccine)
• Influenza inactivated
• MMR (measles/mumps/rubella) live atten.

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Vaccines vs. polio

• Attenuated live (Sabin)
• Advantages
• Admin. PO
• Life-long protection gt95 after 3 doses
• Early GI tract immunity
• Disadvantage
• Risk of infection 1 / 2.4 million doses

• Inactivated virus (Salk)
• Advantages
• Safe in immunocomprom.
• No risk of infection
• Disadvantages
• Administration injection only (IM)
• Less GI immunity ? asympt. infection of GI
  tract c. wild virus

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DNA vaccines

• Gene for protein confers protective resistance -
  cloned into bacterial plasmid
• Plasmid injected enters host cell
• Remains as episome
• Gene expressed
• Translated into antigenic proteins
• Antigenic protein presented to immune response
  Th1 Th2 responses

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DNA vaccines
Gene for antigenic protein
Vaccine plasmid
Host cell
(1)
Antigenic protein
(2)
Free Ag
(4)
mRNA
Nucleus of host cell
Cleavage
(3)
Antigenic peptide
Cellular DNA
MHC 1
Fragment of antigenic peptide
T cell response
Humoral response
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Future combined cloned vaccines?
Mims C et al. Medical Microbiology. 1998.
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Age Immunity

• Passive immunity from mother
• Maternal IgG passes the placenta
• Before and at birth IgG present
• Breast milk secretory Abs (GI resp. tract)
• Active Immunization
• Infant begins to produce Abs in 1st yr
• Start immunization at 2 months (usually)
• Elderly --gt weaker immune response

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Problems with vaccines

• Localized - at site of injection
• Anaphylaxis to Ag or non-microbial content
  vaccine (eggs)
• Contamination with pathogen
• Reversion of attenuation
• Lack of efficacy if another concurrent infection
  (rubella polio vaccine)
• Organisms with lots of serotypes

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Vaccine development

• Properties of good candidate
• Organism causes significant illness
• Organism 1 serotype
• Organism no oncogenic potential
• Antibodies block infection / systemic spread
• Vaccine heat stable

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Success of immunization program

• Composition of vaccine
• Life-long immunity
• Administration
• Timing
• Site
• Conditions

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Immunization - ? When

• Birth - Hep B
• Childhood - DTP, Polio, Hep B (2,4,6/12),
  Hib (2,4,12), MMR (12/12), DT (15 -19yrs)
• Adult - Boosters, 50yrs DT (unless
  booster lt10 yrs)
• Travellers - Yellow fever, Typhoid
• Non-immune ? - MMR
• Risky lifestyle - Hep B, Heb A
• Aboriginal gt50yrs Influenza (yearly),
• or non-Abor gt 65 yrs - Pneumococcus (5-yearly)

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Standard vaccination schedule
For footnotes, see http//www.dh.sa.gov.au/pehs/I
mmunisation/aust-vacc-schedule-web.pdf From
http//www.dh.sa.gov.au/pehs/communicable-diseases
-index.htm
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Other target groups
From Vaccine brochure, SmithKline Beecham
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Challenges

• Predicting the protective ags
• e.g., Influenza (haemagglutinin neuraminidase
  variants)
• Not knowing the virulence determinants
• e.g., Tuberculosis
• Antigenic variation
• Promoting T-cell stimulation

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Chemoprophylaxis

• Aimed at preventing infection
• Primary prophylaxis
• Distinct from early treatment
• Or relapse
• Secondary prophylaxis

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Principles of chemoprophylaxis

• As narrow a specturm as possible
• Choice should be based on known or likely target
• As short as possible
• single dose unless evidence to contrary

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Surgical prophylaxis

• Only if bacterial contamination or spillage of
  normal flora
• e.g. bowel surgery, amputation
• OR
• Implantation of foreign body
• e.g. hip replacment
• Otherwise poor evidence base!
• Timing is important
• Maximum tissue levels during op.
• Avoid post-op. dosing

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Endocarditis prophylaxis

• To prevent endocarditis
• Susceptible people
• Damaged or artificial valves
• Risky procedures
• Dental, GI, GU, resp surgery
• Poor evidence base
• Recommendations in BNF

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Other Chemoprophylaxis

• For contacts of a case
• Meningitis
• meningococcal and H. influenzae
• TB
• Diphtheria
• HIV
• Chickenpox

• In immunocompromised
• Primary chemoprophylaxis
• Pneumocystis, Toxoplasma, Candida, CMV, HSV, gut
  decontamination
• Penicillin in asplenics etc
• Secondary Prophylaxis
• Pneumocystis, Cryptococcus
• In primary immunodeficiency, anti-staph
  prophylaxis