Vaccination and Tolerance Dr Alex Strachan (2024-25) PDF

Vaccinat ion and Toleranc e Learning outcomes Contemplate the role that tolerance plays in regulating immune response to antigen Consider the rationale for vaccination Describe the different types of vaccine Explain how vaccines work by stimulating immune responses Relate the p...

Vaccinat ion and Toleranc e Learning outcomes Contemplate the role that tolerance plays in regulating immune response to antigen Consider the rationale for vaccination Describe the different types of vaccine Explain how vaccines work by stimulating immune responses Relate the principles of vaccination to protecting against oral disease To consider emerging issues relating to vaccination What is immunity? Inherited, acquired, or induced res istance to infection by a specific pathogen Why don’t we respond to everything? We know we don’t want to respond to self-antigens…… but; There are many foreign substances (non-self) in our bodies which we don’t want our immune system to respond to; food, commensal bacteria etc. Tolera nce Tolerance is a term used to describe multiple mechanisms: T cells and B cells – central and peripheral tolerance Non reaction to potential antigen Sub optimal response due to repeated exposure (Immunological tolerance) T & B cell tolerance We have discussed the role of central tolerance and peripheral tolerance for B and T cells to prevent recognition of self. Maturing and selection of B cells occurs in the bone marrow, T cells in the thymus. Continuation of this selection can continue in the lymphatic system, MALT, lymph nodes, spleen etc. None reaction to foreign antigen. We have looked at the role of compartmentalisation and how barriers form this function. Key to maintaining the homeostatic system is the regulatory T cells. Tregs produce immunosuppressive cytokines such as IL-10, TGF-β and IL35. Immunological tolerance Immunological tolerance was originally suggested to be a preventative mechanism to limit tissue damage due to unresolved infection/prolonged inflammation. Repetitive exposure to antigen results in a reduced inflammatory response (e.g. TNF). This is not a complete down-regulation, some functions remain unaffected (IL-8). There are some who think that rather than a protective mechanism, it is part of a change in strategy to try and resolve the infection. This response is dependent upon various factors including timing and dosage of antigen. How do we acquire immunity to pathogens? Natural Acquired immunity: immunity: Naturally Active or catching the passive infection Acquired immunity: Passive immunity Examples? Tetan us HBsA Rabi g es Acquired immunity: Active immunity Active immunity Exposure to antigen, either through natural infection or vaccination How can we use immunity to help protect the population? Vaccination Why vaccinate? Vaccination less symptomatic than natural disease Remove Protect against reservoirs of pandemics infection Eradicate More cost particular effective to diseases prevent than treat Protect vulnerable Some diseases people within a have no cure population (herd immunity) Herd immunity (community immunity) Leading causes of death worldwide theoretical – limited clinical Combined success influenza and pneumococcal influenza, vaccine – but not pneumococcal and TB enough evidence vaccines in clinical trials Rotavirus vaccine …and their vaccines Leading causes of death worldwide Many of these disease are vaccine preventable. Infectious diseases have been (almost) eradicated in the past, E.g small-pox and polio myelitis http://www.who.int/mediacentre/factsheets/fs310/en/index1.html Vaccination decreases disease incidence N Engl J Med 2013; 368:551-560 DOI: 10.1056/NEJMra1204186  Poliomyelitis 3 strains of Polio virus: Faeco-oral transmission Most infections (95%) are mild, either asymptomatic or with a mild flu-like illness. 5% acute symptoms (nausea, vomiting, sore throat) 0.5% Invades motor neurones (via gut)  irreversible paralysis (hours) “The strategy to eradicate polio is therefore based on preventing Two types of vaccine… Khan Academy video on Polio disease: infection by immunizing every child https://youtu.be/K9eZTm4TL2c until transmission stops and the world is polio-free”  Polio vaccines …1950’s New York… BBC documentary on polio: https://youtu.be/gE4ef0yQZRU  Polio vaccines Dr. Salk …1950’s New York… Dr. Sabin Oral (live) polio Inactivated polio vaccine vaccine Trivalent – effective against all 3 Inactivated strains of strains of poliovirus polioviruses 1-3. Blood antibodies prevent the Advantage: no risk of spread of wild poliovirus to the vaccine-related polio. nervous system. local, mucosal immune Disadvantage: does not stimulate antibody response  antibodies in the GALT. in the gut, so less effective against wild In poorly sanitised areas, faecal poliovirus. spread of poliovirus  heard Protects only the immunity (passive immunization) immunised person; no https://youtu.be/gE4ef0yQZRU community benefits OPV may mutate back to wild  Polio vaccines …1950’s New York… Oral (live) polio vaccine Trivalent – effective against all 3 strains Albert Sabin of poliovirus Blood antibodies limit the spread of wild poliovirus to the nervous system. local, mucosal immune response  antibodies in the GALT. In poorly sanitised areas, faecal spread of poliovirus  heard immunity (passive immunization) OPV may mutate back to wild type Polio vaccine effectiveness Until 2004, OPV was used for routine immunisation in the UK OPV is no longer available for routine use and will only be available for outbreak control Inactivated polio vaccine (IPV) used in UK as part of 6-in 1 vaccine at 8 List of current vaccine preventable diseases: Anthrax Human Papilloma Pneumococcal Smallpox and virus (HPV) monkeypox Cholera Influenza Polio Tetanus COVID-19 Japanese Rabies Tick-borne encephalitis encephalitis Diphtheria Which Measles of these Respiratory are Tuberculosis in Haemophilus the current Meningococcal Rotavirus UK syncytial virus Typhoid vaccination schedule? influenzae type b (Hib) Hepatitis A Mumps Rubella Varicella Hepatitis B Pertussis Shingles (herpes Yellow fever zoster) https://www.gov.uk/government/collections/immunisation-against-infectious-disease-the-green-book https://www.gov.uk/government/publications/the-complete-routine-immunisation-schedule/the- complete-routine-immunisation-schedule-from-february-2022 UK immunisation schedule 2022 (and where to find it) https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1183106/ UKHSA_12706_complete_immunisation_schedule_September2023.pdf What’s in a vaccine? The aim of a vaccine is to reproduce natural infection as closely as possible, without causing the wild- type disease Antigen: Part or all of the infectious microbe Preservatives and stabilisers: Thimerosal (contains mercury), MSG Adjuvants: Aluminium or lipid A Induce a stronger and more prolonged immune response in subunit vaccines N Engl J Med 2013; 368:551-560 DOI: 10.1056/NEJMra1204186 Subunit vaccines A piece of the virus or bacteria (epitope) is isolated Less chance of adverse reaction Hepatitis B, Pertussis (whooping cough) and some influenza vaccines are produced by this method Toxoid vaccines – Toxins secreted by bacteria are sometimes the key virulence factors (E.g. Tetanus) – Heat or formalin inactivate bacterial toxins (toxoids) – Antibodies produced to toxoid and patient becomes immune Diphtheria and tetanus vaccines are produced using this method. Conjugate vaccines – Some bacteria have a polysaccharide coat, disguising the antigens underneath (E.g. Haemophilus influenzae type B) – Particularly difficult for infant immune systems to recognise – Polysaccharide antigens are conjugated to protein that can be recognised by immature systems, and T cells Hib vaccines are produced using this method. Inactivated whole vaccines Bacteria or viruses that have been killed – (radiation, heat, formalin/formaldehyde) Cannot mutate back to virulent form Easily stored and transported Polio* and Hepatitis A produced by this method Problems with subunit / killed vaccines? Not as similar to natural pathogen as a live vaccine Not as immunogenic, require multiple doses and boosters Polysaccharide antigens need to be conjugated to protein for T cell help MHC class restriction leads to issues generating T cell mediated immunity, leading to problems developing fully effective vaccines for HIV, TB “Boosters” Inactivated vaccines always require multiple doses. first dose does not produce protective immunity A protective immune response develops after the second or third dose. Antibody titers against inactivated antigens diminish with time. Some inactivated vaccines may require periodic supplemental doses to increase, or “boost,” antibody titers. Live attenuated vaccines – Weakened version of the original pathogen: Virulence factors are removed therefore can’t* cause disease – Mimics a natural infection so initiates a robust immune response – Usually results in lifelong immunity with only one or two doses. MMR, chickenpox, measles and polio vaccines are made by this method. The measles virus used as a vaccine today** was isolated from a child with measles in 1954. ~ 10 years of serial passage using tissue culture media was required to transform the wild virus into attenuated vaccine virus Problems with live vaccines? Can mutate back to disease causing form Cannot be given to people with weakened immune systems (e.g. chemotherapy or are HIV+) Need for refrigeration can cause problems with storage and transit (problem for developing countries) Pfizer and Moderna: mRNA https://www.immunology.org/sites/default/files/BSI %20resource_A%20guide%20to%20vaccinations%20for %20COVID19.pdf Oxford/AstraZenica: viral vector Dangers associated with vaccines Vaccines for oral disease Caries (Streptococcus mutans) – Believed cross reactivity with endocardium (whole bacteria) – Antibodies (salivary IgA) targeted to S. mutans glucosyltransfereses, glucan-binding proteins, adhesins under research Periodontal disease – Aetiogenic bacteria identified (red complex and Aa) – Problem that it is host response that is dysregulated Vaccines for oral disease: HPV Approx. 100 types of HPV dsDNA virus Infects squamous epithelia of the upper respiratory and anogenital tracts. Mostly asymptomatic and self-limiting Associated with genital warts and anogenital cancers (men and women) Transmission: sexual contact vertical transmission (mother to baby) HPV and cervical cancer High- or low- risk viruses HPV prevalence extremely low in girls aged 14 years but rises sharply in the mid-teens. Tumour suppresso Viral proteins bind to and inactivate p53 and Rb CIN: Cervical intraepithelial neoplasia HPV16 and HPV18 > 70% cervical cancers (Europe) HPV and Oropharyngeal cancer HPV16: dsDNA virus Base of tongue Back of throat Tonsils The leading cause of oropharyngeal cancer (a very small number of OSCC also occur from HPV) White, non-smoking males age 35 to 55 are most at risk HPV vaccine - Gardasil® (UK) Recombinant subunit quadrivalent vaccine (4 strains) Protects against HPV16, HPV18 and HPV6 and HPV1 Highly effective at preventing infection:  99% effective at preventing pre-cancerous lesions associated with HPV types 16 or 18 in young women > 99% effective at preventing genital warts HPV vaccination routinely recommended for all girls at 11 to 14 years of age (UK, year 8) Update – Gardasil 9 ® (UK) Recombinant subunit vaccine (9 strains) Protects against HPV6, 11, 16, 18, 31, 33, 45, 52 and 58.  Gardasil 9 protects against a further four types of HPV: 31, 33, 45, and 52 which cause an additional 15% of cervical cancers. Issues surrounding HPV vaccine The Joint Committee on Vaccination and Immunisation (JCVI) recommends that the existing HPV vaccination programme for girls should be extended to boys and latterly men under 45 who have sex with men. Vaccine victim and scientist convers Scientific responsibility…… Measles In 1998,vaccine Andrew virus is live and Wakefield andattenuated colleaguesa-published The vaccine virus in a paper probably the the In 2002, replicatesWakefield and coworkers published second paper examining about 15 to 20 times. Measles vaccine virus is likely to be taken up journal Lancet. relationship between measles by specific cells which uptake virus and autism. to the immune system. and presentation Wakefield's hypothesis was that the MMR vaccine caused intestinal The APCs study tested travel intestinal throughout thebiopsy samples for body (including thethe presenceit of intestine), is measles plausiblevirus that a from inflammation, entrance into the bloodstream of proteins harmful to the childchildren immunised withwith andMMR without wouldautism. have measles virus detected in intestinal brain, and consequent development of autism. tissues using a very sensitive assay. Seventy-five of 91 children with autism were found to have measles virus in The study described 12 children with developmental delay — eight had Children with intestinal biopsyor tissue without asautism comparedmustwithbe matched only 5 of for 70 immunization status. patients who didn't This study autism. Also, childrenOn was must subsequently be matched retracted; in scientific terms, have autism. its surface, this for wasthe length of time a concerning between receipt of result. this vaccine MMR means that the paper is not part ofAlthough the scientific record All of these and collection children of biopsy had intestinal specimens. complaints and developedthis information autism because was clearly However………… within it was oneavailable found theto month oftoreceiving beMMR.basedand investigators on critical scientific misconduct. to their hypothesis, itIn wasthis case, the specifically studies omitted from thewerepaper.deemed fraudulent and data About 90% of children in England received MMR at the time this paper was misrepresented. Because natural measles virus is still circulating in England, it would have written. been important to determine whether the measles virus detected in these samples MMR iswas natural measles administered virus at a time or vaccine when virus. Although many children methods are diagnosed are with available autism.to distinguish these two types of virus, the authors chose not to use them. The observation that some children with autism recently received MMR is, The method used therefore, to detect measles virus in these studies was very sensitive. expected. Laboratories that work with natural measles virus are at high risk of getting results However, determination that are of whether false positives. No mentionMMR iscauses madeautism is bestas in the paper made to howby  Vaccine controversy is nothing new! James Gillray, 1802 Major diseases for which there are no vaccines Viruses Disease HIV Problems Antigenic variation; immunosuppression? Herpes Virus Risk of reactivation (varicella-zoster appears safe) Adenoviruses, Multiple serotypes Rhinoviruses Respiratory Syncytial Generation of neutralising antibodies; failure of killed Virus virus vaccine Hepatitis C Antigenic variation; difficult to grow in vitro Dengue Multiple serotype; poor animal models SARS Need for robust T cell response in addition to antibody West Nile Virus Equine vaccine but has caused severe reactions 241 Bacteri Staphylococci million Early vaccines ineffective (antibiotics originally better). a cases, Group A Streptococci 627,000 Early vaccines ineffective (antibiotics originally better). Mycobacterium Lepra (BCG gives some protection) deaths Treponema pallidum Ignorance of effective immunity (WHO Chlamydia spp. Early vaccines ineffective 2020) Fungi Candida spp. Ignorance of effective immunity Affects ~ Pneumocystis spp. Ignorance of effective immunity 70 million Protozo Malaria Antigenic variation people in a Africa and Trypanosomiasis Extreme antigenic variation; immunopathology; autoimmunity Brazil Leishmaniasis Copyright © 2013, Variable 2006, 2001 Saunders, an effectiveness imprint of ofrights Elsevier Ltd. All vaccines in humans reserved. Summary Tolerance is an important regulatory method of controlling how the immune system responds to antigens. Vaccination is the most effective way to protect against some diseases Vaccines can be made in a variety of ways which may induce different immune responses Vaccines for oral disease are under investigation Some diseases have no vaccine and other precautions must be taken. Any questions: [email protected]