Prevention of infection 2 Immuno- and chemoprophylaxis by AmnaKhan

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									Prevention of infection 2 Immuno- and chemoprophylaxis
Mark Pallen
With help from S. Marlowe Matthias Maiwald

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Mims C et al. Medical Microbiology. 2004.

History

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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 req’d 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

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Mims C et al. Medical Microbiology. 1998.

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 <-- 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
Formulations: 1. Live pathogens – attenuated 2. Killed micro-orgs 3. Microbial extracts 4. Vaccine conjugates 5. Toxoids
Penetrate cells - intracell. Ag processing to surface of cells - cytotoxic T cell response

Do not enter host cells: 1ary B cell-mediated humoral response
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Primary and secondary immune response and

Booster effect

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
--> 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 < 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
Attenuated pathogen Bacterial Diseases
Typhoid (PO) BCG (M. bovis) (Salmonella)

Killed pathogen
Typhoid fever Cholera Pertussis Plague (Y. pestis) Anthrax Polio (Salk) Hep. A Influenza Rabies Japanese encephalitis

Microbial extract / product
B. pertussis Ag *Hib Diphtheria (Tox.) *Meningococcal *Pneumococcal Tetanus (Tox.) Hep. B

Viral Diseases

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Measles Mumps Rubella Chickenpox Polio (Sabin - PO) Yellow fever

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 < 2 yrs)

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Vaccines vs. bacterial diseases
Meningitis (Neisseria meniningitis) • Capsular polysaccharide (4 serotypes of Neiss. men. – A, C, W135, Y)
--> Indications: Campus, military, outbreak

• Capsular polysacch.-protein conjugate (serotype C of Neiss. men.)
--> 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
Inactivated virus (Salk) • Advantages:
– Safe in immunocomprom. – No risk of infection

Attenuated live (Sabin) • Advantages:
– Admin. PO – Life-long protection >95% after 3 doses – Early GI tract immunity

• Disadvantages:
– Administration – injection only (IM) – Less GI immunity – ? asympt. infection of GI tract c. wild virus

• Disadvantage:
– Risk of infection ~ 1 / 2.4 million doses

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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) (2)
Nucleus of host cell mRNA Cleavage

Antigenic protein

(4)

Free Ag

(3)

Cellular DNA
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Fragment of antigenic peptide

MHC 1

Antigenic peptide Humoral response

T cell response

Future: combined cloned vaccines?

Mims C et al. Medical Microbiology. 1998. 27

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 --> 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 • Childhood Hep B DTP, Polio, Hep B (2,4,6/12), Hib (2,4,12), MMR (12/12), DT (15 -19yrs) • Adult Boosters, 50yrs – DT (unless booster <10 yrs) • Travellers Yellow fever, Typhoid • Non-immune ♀ MMR • Risky lifestyle Hep B, Heb A • Aboriginal & >50yrs – Influenza (yearly), or non-Abor & > 65 yrs - Pneumococcus (5-yearly)
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Standard vaccination schedule

For footnotes, see: http://www.dh.sa.gov.au/pehs/Immunisation/aust-vacc-schedule-web.pdf From: http://www.dh.sa.gov.au/pehs/communicable-diseases-index.htm
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Other target groups

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From: Vaccine brochure, SmithKline Beecham

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 • In immunocompromised
– Meningitis
• meningococcal and H. influenzae – Primary chemoprophylaxis
• Pneumocystis, Toxoplasma, Candida, CMV, HSV, gut decontamination • Penicillin in asplenics etc

– – – –

TB Diphtheria HIV Chickenpox

– Secondary Prophylaxis
• Pneumocystis, Cryptococcus • In primary immunodeficiency, antistaph prophylaxis

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