Prevention of infection 2 Immuno and chemoprophylaxis

Prevention of infection 2 Immuno- and chemoprophylaxis Mark Pallen With help from S. Marlowe Matthias Maiwald 1 Mims C et al. Medical Microbiology. 2004. History 2 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) 3 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 4 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 5 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 6 Passive Immunization 7 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 8 From: Vaccine brochure, SmithKline Beecham 9 Antibody-mediated (=humoral) immune response From: Vaccine brochure, SmithKline Beecham 10 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 11 Primary and secondary immune response and Booster effect From: Vaccine brochure, SmithKline Beecham 12 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 13 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 14 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 15 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 16 Active - Toxoids • • • • • Derivatives of bacterial exotoxins Rendered non-toxic But remain immunogenic Admin – IM, SC E.g. – Tetanus – Diphtheria 17 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 18 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. 19 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) 20 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 21 Vaccines vs. bacterial diseases Tetanus (Clostridium tetani) • Tetanus toxoid • Indications – – Young child – Booster (10 yrs) – Suspected exposure (e.g., dirty wound) -- then with immunoglobulin 22 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. 23 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 24 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 25 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 26 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 28 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 29 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 30 Success of immunization program • Composition of vaccine • Life-long immunity • Administration – Timing – Site – Conditions 31 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) 32 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 33 Other target groups 34 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 35 Chemoprophylaxis • Aimed at preventing infection – Primary prophylaxis – Distinct from early treatment • Or relapse – Secondary prophylaxis 36 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 37 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 38 Endocarditis prophylaxis • To prevent endocarditis • Susceptible people – Damaged or artificial valves • Risky procedures – Dental, GI, GU, resp surgery • Poor evidence base • Recommendations in BNF 39 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 40