How does the body defend itself?

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1 Prevention of Infection 2 Immunisation 3 rd BDS B. Martin Major World Causes Of Death COUNTRIES Developing Developed Total x10-6 Population 5400 (80%) 1200 (20%) 6600 CAUSE OF DEATH % % % Infectious diseases Circulatory diseases Perinatal Malignancy Injuries Respiratory disease Other Infectious diseases remain serious killers Rank Cause Total deaths (in thousands) % of total 1. Ischaemic heart disease 7, Cerebrovascular disease 5, Lower respiratory infections 3, HIV/AIDS 2, Chronic obstructive pulmonary disease 2, Diarrheal diseases 2, Tuberculosis 1, Childhood diseases 1, Cancer of trachea/bronchus/lung 1, Road traffic accidents 1, Malaria 1, Hypertensive heart disease Other unintentional injuries Stomach cancer Self-inflicted Total approx 60% of causes of death listed, approx 20% due to infections Source: The World Health Report, 2002, The World Health Organization (WHO) Disease is not necessarily the most common outcome from infection Whether an infection becomes a clinically apparent disease depends upon many factors e.g. age, sex, dose, route of infection. Disease is not necessarily the most common outcome from infection Infections becoming disease depends upon many factors Immunity can be sterileclearing- or non-sterile non-clearing-e.g. TB infects 2 bn people but only 10% will go on and develop disease How does the body defend itself? 1

2 Host Defences Outer Skin Secretions Inner Non-specific (innate) immunity Specific (adaptive) Immunity Adaptive immunity faster on re-encounter The induction of adaptive immunity is the aim of vaccination In its simplest form there are 2 types of adaptive immunity Cell mediated immunity where much protection is mediated by T cells Humoral immunity where protection is mediated by B cells and antibody The main initial protective adaptive response to infection is production of antibody by B cells How does adaptive immunity develop? What happens during the development of the adaptive immune response? Dendritic cells chew up lots of antigens into peptides to present to T cells whereas B cells recognise only one antigen Dendritic cells & Macrophages Not specific B cells 2

3 Dendritic cells chew up lots of antigens into peptides to present to T cells, whereas B cells recognise only one antigen To limitthe possibility of autoimmunity,dendritic cells must prime T cells to start adaptive immunity, whereas T cells need to tell B cells to produce antibody. This is done through direct contact Figure 1-21 Dendritic cells & Macrophages B cells Specific To prevent false-starts second or co-stimulatory signals are required to prime T cells; once primed, T cells can expand to make many more clones of themselves Vaccination "Vaccination," was the word Jenner invented for his treatment (from the Latin vacca, a cow) Word adopted by Pasteur for immunisation against any disease. Pasteur advanced work on the attenuation of pathogens He obtained attenuated viruses by passage through animals for the prevention of rabies. What are vaccines? Memory responses and vaccines Immunological memory normally develops during/after infection Vaccines are artificial ways of introducing memory against a pathogen 3

4 What are vaccines? Vaccines are a way of tricking the body into thinking it has seen a pathogen or its parts before This means that when the pathogen is then encountered there are moret cells, moreb cells and moreantibody sooner!!!!!! Instead of 3 days to get small numbers of B cell to expand, takes < 24 hours to get lots of memory B cells to proliferate This means the pathogen can be attacked more rapidly and the magnitude of the response will be much greater This is the benefit of memory and the basis of vaccination An example of the benefits of vaccination and B cell memory DEATH Corynebacterium diphtheriae Response to toxin An example of the benefits of vaccination and B cell memory An example of the benefits of vaccination and B cell memory CLEARANCE Response to toxin Response to vaccine Response to vaccine Vaccine Vaccine Corynebacterium diphtheriae What is the natural progression of a typical infection? The big advantage of vaccines is that they work when the bacterial burden is likely to be at its lowest level, antibiotics at their highest level Vaccines work here!!! Antibiotics are mainly used here!!! 4

5 Features of effective vaccines Vaccines must be: Safe and not cause illness themselves They must be protective against exposure to live pathogen They must provide long-lived protection They must induce neutralising antibody and protective T cells They should be cheap, stable, easy to give and have few side-effects Immunisation may be Passive Pre-made antibodies Active Antigen Types of Vaccine Natural infection (active) Modified (attenuated) pathogen (active) Antigenic components of pathogen (active) Specific (not necessarily pure) antibody or serum (passive) Passive Immunisation Begins to work very quickly, but it is shortlived The antibodies are normally produced in animals and injected into humans Therefore can also result in serum sickness and anaphylaxis Can be naturally acquiredwhen antibodies are being transferred from mother to fetus during pregnancy Normally given by injection Used as an emergency treatment for venom etc. Sometimes used for acute infections (diphtheria, tetanus, hepatitis A, measles, rabies, VZV, etc.) Live Killed Subunit Recombinant DNA Active Immunisation Live vs. Killed Vaccine Safety issues Incomplete inactivation of killed Reversion of live Duration of immunity Live more enduring than killed 5

6 Live Live pathogen attenuated e.g., by passage in culture Killed Inactivated e.g. by treatment with formaldehyde Other Vaccine Strategies Subunit(flu) Components of the virus particle Recombinant(rabies, HBV) Virus antigens made by using recombinant DNA Protective targets in bacteria What are the sources of most vaccines? Vaccines are derived from the bacterium or their products Capsular Polysaccharide cloak of invisibility Toxoid(inactivated protein exotoxins) Killed bacteria Live attenuated bacteria To work they must trigger the immune system using adjuvants. Adjuvants can be intrinsic (killed bacteria) or extrinsic (alum, etc) Adjuvant: A substance that enhances the immune response to an antigen with which it is mixed How do you make a live virus safer? Attenuation by Cell Culture The Impact of Vaccination What good has it been? From: Principles of Virology: Flint 2 nd Ed 6

7 The two public health interventions that have had the greatest impact on the world s health are clean water and vaccines (World Health Organization) A handful of vaccines prevent illness or death for millions of individuals every year. Immunisation, the most cost-effective public health intervention, continues to be under-used. Almost two million children still die each year from diseases for which vaccines are available at low cost. Over 90,000 contract paralytic polio, which could have been prevented by immunisation. What impact have vaccines had on infectious disease? Disease Pre-vaccine Era 2000 % change Diphtheria 31,054 1 >99 Measles 390, >99 Mumps 21, >98 Pertussis 117,998 7,867 >93 Polio (wild) 54, Tetanus 1, Invasive Hib Disease 24, Total 566,706 8, All Vaccine Adverse Events 0 <13,500 (2.4%) Figure 1-33 part 1 of 3 Impact of Polio & Measles Vaccination in USA From: Principles of Virology: Flint 2 nd Ed Impact of Mumps Vaccination in USA Current Vaccinations What happens routinely in the UK? 7

8 UK immunisation schedule 4 months old Diphtheria, tetanus, pertussis, polio and Haemophilus influenzae type b WHEN TO IMMUNISE WHAT IS GIVEN HOW IT IS GIVEN Meningitis C (meningococcal group C) 2 months old Diphtheria, tetanus, pertussis (whooping cough), polio and Haemophilus influenzae type b (Hib) Pneumococcal infection 3 months old Pneumococcal infection (Pneumococcal conjugate vaccine) Diphtheria, tetanus, pertussis, polio and Haemophilus influenzae type b Around 12 months old Haemophilus influenza type b (Hib) and meningitis C Meningitis C (meningococcal group C) Pneumococcal infection Around 13 months old Measles, mumps and rubella (German measles) (MMR) 3 years and 4 months to 5 years old Pneumococcal infection Diphtheria, tetanus, pertussis (whooping cough) and polio What s are the plans worldwide? Measles, mumps and rubella (MMR) 13 to 18 years old Diphtheria, tetanus, polio Polio eradication by the year 2000 In 1988, the World Health Assembly selected Poliomyelitis as the next disease to be targeted for global eradication. Target not reached, but considerable reduction in virus transmission. Globally, by 1995, 78% of children had received three doses of polio vaccine by 12 months Polio immunisation now in 63 countries. The key to polio eradication effective surveillance 107 countries now conducting surveillance specially for cases of paralysis. 8

9 In 1994, the Americas were declared polio-free. Polio-free zones also exist in Western Europe and in the Pacific basin. Dramatic reductions in incidence recorded in countries such as China and Egypt. By 1995, 146 countries reported zero polio cases. In 2008, only fourcountries in the world remain polio-endemic, down from more than 125 in 1988 (the remaining countries are Afghanistan, India, Nigeria and Pakistan). What s the latest? Newer Virus Vaccines Human papillomavirus (HPV16/18) (Cervarix) Vaccines Under Development HIV, dengue, avian (H5N1) and swine (H1N1) influenza Volume 369, 30 June July 2007, Pages Vaccine Approaches Under Development Synthetic peptides Delivery of T cell epitopes within heterologous recombinant polypeptides Immunomodulation (with cytokines, Mab) Targeted delivery Immunization with DNA (DNA from the pathogen inoculated directly) Development of new vaccines A number of new vaccines with major potential for controlling infectious diseases have been licensed or are at advanced stages of development. Among the illnesses targeted are rotavirusdiarrhoea, pneumococcaldisease, and cervical cancer (as caused by human papillomavirus), which together kill more than a million people each year, most of them in developing countries. progress is being made on a vaccine for the regional menace posed by meningococcalmeningitis serogroup A, which causes frequent epidemics and high rates of death and disability in African countries south of the Sahara. Continuing, intensive efforts are under way to develop effective vaccines for AIDS, malaria, tuberculosis, dengue, leishmaniasis, and enteric diseases World Health Organisation,