Vaccines PDF

Microbes and the Immune System Vaccination: design and mechanisms. James Brewer [email protected]  Key Learning Objective Explain key principles of immunological memory and it’s importance for vaccine success.  Intended Learning Objectives Understand the cellul...

Microbes and the Immune System Vaccination: design and mechanisms. James Brewer [email protected]  Key Learning Objective Explain key principles of immunological memory and it’s importance for vaccine success.  Intended Learning Objectives Understand the cellular basis of immunological memory Why does immunological memory provide immunity to infection? How do vaccines exploit memory and eliminate infectious diseases? Describe the strategies used to make vaccines  Vaccination A means of producing immunity against pathogens, such as viruses and bacteria, by the introduction of live, killed, or altered antigens that stimulate the body to produce antibodies against more dangerous forms  You don’t get measles twice i.e. one infection with measles is suf cient to provide life-long protection against disease fi  Vaccination - Edward Jenner Jenner was a Gloucester GP Routinely practiced variolation (and was variolated himself) 1765 - The potential for cowpox (vaccinia) to protect against smallpox (variola) was known (Fewster) 1796 - Performed the rst protection trial with James Phipps fi  Public Reaction The single greatest health intervention in history  Public Reaction The single greatest health intervention in history Understand the cellular basis of immunological memory Vaccines induce memory Why does immunological memory provide immunity to infection?  Memory vs Naïve B Lymphocytes Long Lived Increased frequency Rapid proliferation Produce more Ab Produce higher af nity Ab Class switching – IgG & IgA have better effector functions than IgM fi  Secondary Ab responses Faster Higher Isotype Switched Higher Af nity fi  Why are secondary responses better? The Germinal Centre reaction drives af nity maturation and class switching of Memory B cells and Long Lived Plasma Class fi  Most vaccines work by inducing long lived plasma cells and plasma antibody responses Serum Ab titre Age  Memory vs Naïve T Lymphocytes Long Lived Increased frequency Rapid proliferation Lower activation threshold Better effector functions T cell vaccines T cell vaccines Target CTL How do vaccines exploit memory and eliminate infectious diseases?  Routine UK immunisations (2023-24) Live, attenuated Measles, Mumps, Rubella (MMR) Rotavirus In uenza (LAIV 2014) Shingles (Zostavax 2015) https://www.gov.uk/government/publications/the-complete-routine-immunisation-schedule-201314 fl  Routine UK immunisations (2023-24) Live, attenuated Measles, Mumps, Rubella (MMR) Rotavirus In uenza (LAIV 2014) Shingles (Zostavax 2015) Killed Inactivated Polio (Salk) In uenza (split virion) https://www.gov.uk/government/publications/the-complete-routine-immunisation-schedule-201314 fl fl  Routine UK immunisations (2023-24) Live, attenuated Subunit Measles, Mumps, Rubella (MMR) Diphtheria,Tetanus, Pertussis Rotavirus (DTP) In uenza (LAIV 2014) In uenza surface antigen Shingles (Zostavax 2015) Pneumococcal Killed Inactivated Polio (Salk) In uenza (split virion) https://www.gov.uk/government/publications/the-complete-routine-immunisation-schedule-201314 fl fl fl  Routine UK immunisations (2023-24) Live, attenuated Subunit Measles, Mumps, Rubella (MMR) Diphtheria,Tetanus, Pertussis Rotavirus (DTP) In uenza (LAIV 2014) In uenza surface antigen Shingles (Zostavax 2015) Pneumococcal Subunit (conjugate) Haemophilus In uenzae B Meningicoccal C Killed Inactivated Polio (Salk) Meningicoccal ACWY (2015) In uenza (split virion) https://www.gov.uk/government/publications/the-complete-routine-immunisation-schedule-201314 fl fl fl fl  Routine UK immunisations (2023-24) Live, attenuated Subunit Measles, Mumps, Rubella (MMR) Diphtheria,Tetanus, Pertussis Rotavirus (DTP) In uenza (LAIV 2014) In uenza surface antigen Shingles (Zostavax 2015) Pneumococcal Subunit (conjugate) Haemophilus In uenzae B Meningicoccal C Killed Inactivated Polio (Salk) Meningicoccal ACWY (2015) In uenza (split virion) Recombinant Subunit Human Papilloma Virus Meningococcal B (Bexsero) Shingles (Shingrix; 2019) Respiratory Syncytial Virus (2024) https://www.gov.uk/government/publications/the-complete-routine-immunisation-schedule-201314 fl fl fl fl https://www.theguardian.com/society/ng-interactive/2015/feb/05/-s spreads-when-kids-get-vaccinated Vaccine induced Herd Immunity https://pubmed.ncbi.nlm.nih.gov/ 34495822/ Describe the strategies used to make vaccines  Example of Virus Attenuation (Sabin Polio Vaccine) 1. Pathogenic virus is isolated and cultured on host (e.g human) cells.  Example of Virus Attenuation (Sabin Polio Vaccine) 1. Pathogenic virus is isolated and cultured on 2.Virus is incubated on cells from another host (e.g human) cells. host (eg.Monkey).  Example of Virus Attenuation (Sabin Polio Vaccine) 1. Pathogenic virus is isolated and cultured on 2.Virus is incubated on cells from another host (e.g human) cells. host (eg.Monkey). 3.Virus spontaneously mutates and grows on monkey cells.  Example of Virus Attenuation (Sabin Polio Vaccine) 1. Pathogenic virus is isolated and cultured on 2.Virus is incubated on cells from another host (e.g human) cells. host (eg.Monkey). 3.Virus spontaneously mutates and grows 4.Virus can be used as a vaccine as it cannot grow on monkey cells. on human cells.  Noti ed cases of Polio (England and Wales 1912 -2006) fi  Vaccine associated poliomyelitis Last case of natural polio infection acquired in the UK was in 1984. Between 1985 and 2002, a total of 40 cases of paralytic polio were reported in the UK – Thirty cases were VAPP; – six cases had wild virus infection acquired overseas; – four cases unknown but wild virus was not detected. 2004 - killed (Salk) vaccine introduced Global Polio Eradication 35,000 700 https://econ.st/3215uix  Killed and Subunit Vaccines Killed vaccines Usually use chemicals or heat These kill the organism and render it completely uninfective Killed organism can still induce immunity e.g. whole cell pertussis vaccine Subunit vaccines Toxins are the pathogenic fragments of bacteria Antibodies to toxins can protect from infection Chemically inactivated toxins are called toxoids e.g. acellular pertussis vaccine  Recombinant subunit vaccines Certain viruses/bacteria/parasites are very hard to grow – e.g. they grow in host cells that are not readily cultivated – e.g. Human Papilloma Virus The Journal of Clinical Investigation 2004 Vol 114 (4) August  Recombinant subunit vaccines Human Papilloma Virus Vaccination and the Risk of Invasive Cervical Cancer Lei et al. N Engl J Med 2020; 383:1340-1348  Live Attenuated In uenza Viruses (LAIV) Fluenz (AstraZeneca/MedImmune) Uses multiple attenuated master virus (ca - cold-adapted only replicate ef ciently at 25°C; ts - restricts replication at 37°C or 39°C; att - doesn’t produce illness) Virus RNA Isolate genes for Multiply attenuated virus 4 seasonal virus surface proteins (HA/ A/Ann Arbor/6/60 and B/Ann Arbor/1/66 NA) fl fi  Live Attenuated In uenza Viruses (LAIV) Effective in children over 2 years Well-tolerated in children and adults Ease of administration Known limitations: – ineffective in over 50s – issues with safety in children with asthma/wheezing – not for immunocompromised fl  UK immunisations (2023) Live, attenuated Subunit Measles, Mumps, Rubella (MMR) Diphtheria,Tetanus, Pertussis (DTP) Rotavirus In uenza surface antigen In uenza (LAIV) Pneumococcal Shingles (herpes zoster; Sept 2015) Subunit (conjugate) Killed Haemophilus In uenzae B Inactivated Polio (Salk) Meningicoccal C In uenza (split virion) Meningicoccal Quadrivalent (ACWY) Recombinant Subunit Human Papilloma Virus Meningicoccal B https://www.gov.uk/government/publications/the-complete-routine-immunisation-schedule-201314 fl fl fl fl Global Mortality 2020 Global Mortality 2020  Vaccine Design Process Antigen Identi cation fi  Vaccine Design Process Antigen Identi cation Vaccine Delivery fi  Vaccine Design Process Antigen Identi cation Vaccine Delivery Immune activation fi  SARS-CoV-2: Antigen fi identi cation SARS-CoV-2:Vaccine Platform Technologies (2023) https://vac-lshtm.shinyapps.io/ncov_vaccine_landscape/  SARS-CoV-2:Vaccine Delivery/ Immune Activation Nucleic Acids Viral (DNA/RNA) vector Protein Inactivated subunit/ Virus Adjuvant Callaway, E. Nature 2020, 580 (7805), 576–577.  What is an Adjuvant?.... “Agents which act non-speci cally to increase the speci c immune response or responses to an antigen” The Dictionary of Immunology “the immunolgists dirty little secret” Charles Janeway fi fi  How to make vaccines Clinical 1. Attenuated - nd or make an attenuated pathogen using culture methods 2. Killed - Kill the pathogen ± Adjuvant 3. Subunit - Kill the pathogen and isolate its protective antigens (toxoids) + Adjuvant 4. Recombinant Subunit - clone genes for protective antigen, express in (e.g. yeast). Isolate antigen + Adjuvant 5. Live Recombinant - clone genes for protective antigen, express in vaccine vector (e.g. LAIV) 6. Nucleic Acid vaccine - Inject DNA or RNA construct to induce protein expression in host Experimental 6. Genetically attenuated - knock out virulence genes with recombinant technology fi  Intended Learning Objectives Understand the cellular basis of immunological memory Why does immunological memory provide immunity to infection? How do vaccines exploit memory and eliminate infectious diseases? Describe the strategies used to make http://www.docbastard.net/2016/05/124- vaccines papers-that-do-not-prove-vaccines.html