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Vaccination and Immunisation Simon Powis History • Infectious diseases have shaped human populations throughout history • European Plague of mid 1300’s probably killed one-third of human population, biggest epidemic ever recorded • Measles and Smallpox introduced into South America by Europeans co...

Vaccination and Immunisation Simon Powis History • Infectious diseases have shaped human populations throughout history • European Plague of mid 1300’s probably killed one-third of human population, biggest epidemic ever recorded • Measles and Smallpox introduced into South America by Europeans contributed to disappearance of Aztec civilisation History • Modern Immunology attributed to work of Edward Jenner in 1790’s. • Jenner showed that Cowpox (Vaccinia), a mild infection in humans, protected exposed individuals from smallpox. Hence ‘Vaccination’. • Long before this, evidence for ancient Chinese and Egyptians exposing infants to extracts of pustular material of smallpox infected people, significantly reducing mortality rate. • 19th Century before disease-pathogen link. • Vaccination and Immunisation is probably the most single effective healthcare initiative in history Success of smallpox vaccination Polio: Two billion children vaccinated, reducing global incidence by over 99% from 350,000/yr to around 800/yr cases (1998-2002) Pasteur Principle • 1880’s, Pasteur devised vaccine against cholera in chickens, then rabies vaccine for humans • ISOLATE • INACTIVATE • INJECT Vaccine development • 1775 to 1925: 3 in 150 years • 1925 to 1990: 16 in 65 years • 1990 to 2000: 1 per year. • In next ten years? Meningitis, Papilloma, Avian Flu, HIV, SARS Essential characteristics of vaccines • Must provide effective protection without risk of causing disease or severe side effects • Protection should be long-lived • Should stimulate correct arm of immune response, ie antibodies or effector T cells • Stimulate neutralising antibodies to prevent reinfection • Stable for long-term storage and transport • Economically affordable for widespread use Types of vaccines • Live: organisms capable of normal infection and replication. Not used against pathogens that can cause severe disease • Attenuated: Organism is live, but ability to replicate and cause disease reduced by chemical treatment or growth-adaptation in non-human cell lines. (measles, mumps, rubella) Types of vaccines • Killed: organism killed by physical or chemical treatment. Incapable of infection or replication, but still able to provoke strong immune response (B.pertussis, typhoid) • Extract: materials derived from disrupted or lysed organism, eg capsular polysaccharides. Used when risk of organism surviving inactivation steps (flu, pneumococcal, diptheria, tetanus) Types of vaccines • Recombinant: genetically engineered to alter critical genes. Often can infect and replicate but does not induce associated disease • DNA : naked DNA injected. Host cells pick up DNA and express pathogen proteins that stimulate immune response What vaccine is best? • In general the most effective vaccines have been live or attenuated • Paradoxically, the safer the vaccine, the less effective some have been • Living or attenuated organisms express proteins and stimulate the immune response in a manner which most closely resembles normal infection Herd Immunity • Beneficial impact of vaccination so clear that some people no longer are aware of dangers of disease • Vaccination rates have fallen, for above reason, and also public debate on whether side-effects occur, eg MMR • A pool of unimmunised individuals is created that can become victim to disease. Measles has increased probably because of this. • Possibly not everyone needs to immunised. If enough are vaccinated then the chances of an unprotected person meeting a pathogen becomes small. The population remain essentially resistant Current UK Vaccinations: Definitions DTaP/IPV/Hib: Diptheria, tetanus, pertussis, inactivated Polio vaccine, haemophilus influenzae type B Men C: meningococcal C conjugate DTaP/IPV: booster vaccine for diptheria, tetanus, pertussis, Polio. Td/IPV: booster vaccine for tetanus, diptheria, polio UK vaccination schedule When? What? How? 2, 3 & 4 months old DTaP/IPV/Hib One injection MenC One injection Around 13 months MMR One injection 3yr 4mo, to 5yr DTaP/IPV One injection MMR One injection Td/IPV One injection 13 to 18yr BCG: usually given at 10-14yr, now targeted to at-risk individuals Other UK vaccinations • Pneumococcal: offered to 65yr and over individuals • Flu: offered to elderly and at-risk individuals. In region of 11 million plus people in recommended groups, 14 million doses available. Travel vaccination • Constantly changing advice. Check latest updates. • 2005 advice includes: Avian Flu, West Nile Virus (USA, Canada and Portugal), Marburg Virus (Angola), Poliomyelitis (Nigeria) • www.dh.gov.uk/PolicyAndGuidance/HealthA dviceForTravellers/fs/en The changing face of vaccination • Meningococcus B • The capsular polysaccharide antigen that would normally be a good target looks almost identical to a sugar on NCAM, an important neuronal membrane protein. Antibodies could cause autoimmunity • Molecular biological advances now allow ‘Reverse Vaccinology’. Reverse Vaccinology for MenB • Whole bacterial genome sequenced • 600 candidate genes identified • 350 expressed in E.coli bacteria in lab • 344 proteins purified and used to generate antisera in mice • 91 novel surface molecules identified • 28 bactericidal sera identified • 5 vaccine candidates in clinical trials • Total time: 24-36 months. The emerging challenges • 1918: Spanish Flu, 20-40 million dead • 1957: Asian Flu, 1-4 m dead • 1968: Hong Kong, 4m dead • Latest potential threat is H5N1. First reappeared HK 1997, infected 18, killed 6. Multiple cases in Far East. www.who.int/csr/disease/avian_influenza/en/ • 100 million fowl culled to prevent spread. • SARS coronavirus: Feb to July 2003, infected 8,098 people, killed 774. • West Nile Virus: NY 1999, within 4 years spread across most of USA, infected 9,862 people, 264 deaths in 2003 Origins of new challenges • HIV: nonhuman primate origin • Ebola: handling of gorilla, chimp, duikers (bush meat) • SARS: palm civets and racoon dogs (animal markets) • vCJD: food chain, rendering. Infectious diseases over last decade Dendritic cells in vaccination DC also express Pattern Recognition Receptors (PRR), members of the Toll-like receptor Family (TLR) Toll-like receptors on DC • TLR1 &2: lipopeptides • TLR3: dsRNA • TLR4: Lipopolysaccharide, heat shock proteins • TLR5: flagellin • TLR6: lipoproteins • TLR7: ? • TLR8: ssRNA • TLR9: CpG (cytosine-phosphate-guanosine, bacterial DNA • TLR10: ? • TLR11: bacterial components. Dendritic cells Encounters antigen in periphery, becomes activated Migrates to lymph node Activates T cells to become effector cells • DC sit at the interface between innate immunity and specific immunity • Activation of DC’s vastly increases their ability to capture and process antigen and immunogens, and also attract and activate T cells. • When CpG is included with HepB or flu vaccines the result is increased antibody or IFN-! secretion