Vaccines S21 Notes-2.pdf

4/12/21 The Immune System 1 Vaccines Textbook: Chapter 8 2 1 4/12/21 History of Vaccines The origin of vaccines is attributed to the English Physician, Edward Jenner who discovered in 1769 the cowpox induced protection against human smallpox (a fatal disease) https://www.pinterest.com/pin/3787950186...

4/12/21 The Immune System 1 Vaccines Textbook: Chapter 8 2 1 4/12/21 History of Vaccines The origin of vaccines is attributed to the English Physician, Edward Jenner who discovered in 1769 the cowpox induced protection against human smallpox (a fatal disease) https://www.pinterest.com/pin/378795018631755005/ http://carrington.edu/blog/medical/vaccines/smallpox-and-smallpox-vaccine/ 3 History of Vaccines Edward Jenner noticed that milkmaids who had recovered from cowpox never contracted smallpox Based on this observation, he injected the material from a cowpox pustule into the arm of an 8-year-old boy The disease did not develop when the boy was later intentionally inoculated with smallpox Jenner called this procedure vaccination and this term is still used to describe the inoculation of healthy individuals with weekend or attenuated strains of disease-causing agents to provide protection from disease 4 2 4/12/21 History of Vaccines It took almost two centuries for smallpox vaccination to become universal until the World Health Organization announced in 1979 that smallpox had been eradicated https://www.lib.umich.edu/online-exhibits/exhibits/show/smallpox-eradication-india/item/5404?exhibit=143&page=1235 5 Antigens and Immunogens Antigen A molecule that is capable of specifically binding to the lymphocytes receptors Immunogen A molecule that is capable of eliciting an immune response by an organism's immune system An immunogen is necessarily an antigen, but an antigen may not necessarily be an immunogen 6 3 4/12/21 Types of Immunity Passive immunity Active immunity Exposure to a microbial antigen mounts an active immune response to eradicate the infection and develops resistance to later infection by that microbe (memory) A naive individual receives antibodies or immune cells from another individual already immune to an infection Passive immunity does not induce long-lived resistance to the infection Newborns are protected against infections by acquiring antibodies from their mothers through the placenta and breast milk Clinically, passive immunity is limited to treatment of some immunodeficiency diseases with antibodies pooled from multiple donors, and for emergency treatment of some viral infections and snakebites using serum from immunized donors 7 Vaccines Vaccination is the process of stimulating protective adaptive immune responses against microbes by exposure to nonpathogenic forms or components of the microbes The development of vaccines against infections has been one of the great successes of immunology Many diseases have been largely controlled by vaccination Several types of vaccines are in use and being developed Effective protective immunity against some organisms requires the presence of pre-existing antibody at the time of infection (memory) The ideal vaccination provides host defense at the point of entry of the infectious agent Stimulation of mucosal immunity is an important goal of vaccination 8 4 4/12/21 Types of Vaccines Based on the route of admistration Oral Intranasal Injection Ø The majority of vaccines are given by injection Ø Injection is not the usual route of entry of the majority of pathogens against which the vaccination is directed Based on the immunogenic components of the vaccine What should contain? the vaccine Remember that Vaccines should actively stimulate your immune responses and develop memory 9 https://media.springernature.com/original/springer-static/image/chp%3A10.1007%2F978-1-4614-6486-0_22/MediaObjects/273058_4_En_22_Fig3_HTML.gif 10 5 4/12/21 The Route of Vaccine Is an Important Determinant of Success The ideal vaccination provides host defense at the point of entry of the infectious agent Stimulation of mucosal immunity is an important goal of vaccination Many important pathogens infect mucosal surfaces or enter the body through mucosal surfaces It is therefore important to understand how these organisms stimulate mucosal immunity and to develop vaccines that can be administered to the mucosa orally or by nasal inhalation The power of this approach is illustrated by the effectiveness of live attenuated polio vaccines 11 Types of Vaccines (Immunogenic Components) Live attenuated Microorganisms are treated to reduce the virulence of the pathogen such as BCG and polio vaccines Conjugate Viral vectors and nucleic acid vaccines killed (inactivated) Microorganisms are killed with chemicals, heat, etc. Example is polio Subunit Recombinant protein subunit 12 6 4/12/21 Whole Cell Vaccines Live attenuated viruses Inactivated or killed viruses They are more potent because they elicit cytotoxic T cells Attenuation takes place by culturing the virus on human cells then successively on cells of a different species. This will cause several mutations which make the new virus grow poorly on human cells Therefore, the attenuated virus can induce immunity without causing disease Attenuated organisms may also pose particular risks to immunodeficient recipients Viruses are treated so that they are unable to replicate They can not produce proteins in the cytosol , no MHCI presentation and consequently no cytotoxic T cells activation 13 Polio Polio is caused by a virus that lives in the throat and intestinal tract and spread through the stool of an infected individual or through oral/nasal secretions It may cause no symptoms; however, for the less than 1% who develop paralysis it may result in permanent disability and even death 14 7 4/12/21 Polio Vaccine Polio is an infectious disease caused by a virus that lives in the throat and intestinal tract It is most often spread through person-to-person contact with the stool of an infected person or through oral/nasal secretions Polio used to be very common in the United States and caused severe illness in thousands of people each year before polio vaccine was introduced in 1955 Most people infected with the polio virus have no symptoms; however, for the less than 1% who develop paralysis it may result in permanent disability and even death 15 Polio Vaccine Oral Poliovirus (OPV) (Live attenuated) Inactivated Poliovirus Vaccine (IPV) IPV is given as an injection in the leg or arm, depending on the patient's age OPV has not been used in the United States since 2000 but is still used in many parts of the world Just as polio itself can be transmitted by fecal contamination of public swimming pools and other failures of hygiene, the vaccine can be transmitted from one individual to another 16 8 4/12/21 What if killed or attenuated whole bacterial or viral vaccine is unsafe? 17 The History of Vaccination Against Bordetella pertussis The history of vaccination against the agent that causes whooping cough Bordetella pertussis, provides a good example of the challenges of developing an effective vaccine At the turn of 20th century, whooping cough killed approximately 0.5% of American children under the age of 5 years Pertussis can cause violent and rapid coughing, over and over, until the air is gone from your lungs. When there is no more air in the lungs, you are forced to inhale with a loud “whooping” sound In the early 1930, a trial of a killed whole bacterial cell vaccine provided evidence of protective effect Whole cell pertussis vaccine causes unwanted side effects 18 9 4/12/21 The History of Vaccination Against Bordetella pertussis During 1970s, widespread concern developed following several observations that encephalitis leading to irreversible brain damage might follow pertussis vaccination very rarely Study of the natural immunity responses to B. pertussis showed that infection induced antibodies to 4 different pure components of the bacterium Acellular vaccines are safer than vaccines based on whole organisms 19 Types of Vaccines (Immunogenic Components) Live attenuated Microorganisms treated to reduce virulence of pathogen such as vaccine are the the BCG Viral vectors and nucleic acid vaccines Killed (inactivated) Conjugate Microorganisms are killed with chemicals, heat, etc. Example is polio Subunit (toxoid) Made from Inactivated toxic compounds (toxoid) that cause illness such as tetanus and diphtheria Recombinant protein subunit Microbial proteins synthesized in the lab using the recombinant DNA technology (such as Hepatitis virus) 20 10 4/12/21 Acellular Vaccines (Subunits and Recombinant Proteins) Acellular vaccines are safer than vaccines based on whole organisms such as acellular Bordetella pertussis vaccine Corynbacterium diphtheria and Clostridium tetani produce very powerful toxins Pre-existing antibodies to the bacterial exotoxin is necessary to defend against the disease 21 Types of Vaccines (Immunogenic Components) Live attenuated Microorganisms are treated to reduce the virulence of the pathogen such as BCG vaccine Conjugate Killed (inactivated) Microorganisms are killed with chemicals, heat, etc. Example is polio Subunit (toxoid) Made from Inactivated toxic compounds (toxoid) that cause illness such as tetanus and diphtheria Viral vectors and DNA vaccines Poorly immunogenic bacterial polysaccharides could be linked to a proteins such as Haemophilus influenza type B vaccine Recombinant protein subunit Microbial proteins synthesized in the lab using the recombinant DNA technology (such as Hepatitis virus) 22 11 4/12/21 Conjugate Vaccines A fully effective vaccine can not normally be made from a single isolated constituent of a microorganism because of the need to activate more than one cell type to initiate an immune response One consequence of this insight has been the development of conjugate vaccines Many bacteria including Meningococcus and Haemophilus spp. have an outer capsule composed of polysaccharides that are species and type specific for particular strains of bacteria The aim of vaccination is to produce antibodies against the polysaccharide coat required for opsonization Capsular polysaccharide can be harvested from bacterial growth media (T independent antigen) An efficient mean of inducing a T cell response, is to chemically conjugate bacterial polysaccharides to a protein carrier 23 Conjugate Vaccines Conjugate vaccines are created by covalently attaching a poor antigen to a strong antigen to elicit a stronger immunological response to the poor antigen Most commonly, the poor antigen is a polysaccharide that is attached to strong protein antigen 24 12 4/12/21 Conjugate Vaccines Sugar antigen can not be displayed on MHC molecules T-independent B cell activation 25 Haptens Haptens are low-molecular-weight molecules that can not crosslink the B cell receptors and do not recruit T cell help These small molecules can elicit an immune response only when attached to a large carrier such as a protein; the carrier typically does not elicit an immune response by itself Haptens themselves are nonimmunogenic and they cannot evoke an immune response until they bind with a larger carrier immunogenic molecule 26 13 4/12/21 Haptens and Conjugate Vaccines B cells recognize one epitope of the antigen and display different epitopes (peptides) for recognition by helper T cells A hapten is a small chemical that is recognized by B cells but stimulates strong antibody responses only if it is attached to a carrier protein B cell binds the hapten portion, ingests the conjugate, and displays peptides derived from the carrier to helper T cells Bacteria with polysaccharide-rich capsules stimulate T-independent antibody responses, which are weak in infants and young children Coupling the polysaccharide to a carrier protein will induce a T-dependent responses against the polysaccharide Such conjugate vaccines induce protective immunity against bacteria such as Haemophilus influenzae, especially in infants 27 What if the antigenic component of the vaccine is not immunogenic (does not activate DCs and costimulation)? 28 14 4/12/21 Conjugate Vaccines with Adjuvants Even conjugate vaccines are not usually strongly immunogenic on their own, most require the addition of adjuvants Adjuvants act on APCs to enhance the immunogenicity of the antigen Polysaccharide + protein + adjuvant Main antigen (antibody production) + protein (to activate T cells required for T dependent B cell activation) + adjuvant (to activate APCs) 29 Adjuvants An adjuvant is a substance that is added to a vaccine to increase the body's immune response to the vaccine Adjuvants can, for example, stimulate the immune response to the antigen in the vaccine or stabilize the vaccine formulation 30 15 4/12/21 Conclusion A fully effective vaccine can not normally be made from a single isolated constituent of a microorganism because of the need to activate more than one cell type to initiate an immune response 32 Types of Vaccines (Immunogenic Components) Live attenuated Microorganisms are treated to reduce the virulence of the pathogen such as BCG vaccine Conjugate Killed (inactivated) Microorganisms are killed with chemicals, heat, etc. Example is polio Subunit (toxoid) Made from Inactivated toxic compounds (toxoid) that cause illness such as tetanus and diphtheria Viral vectors and nucleic acid vaccines Poorly immunogenic bacterial polysaccharides could be linked to a proteins such as Haemophilus influenza type B vaccine Recombinant protein subunit Microbial proteins synthesized in the lab using the recombinant DNA technology (such as Hepatitis virus) 33 16 4/12/21 Vaccines for Intracellular Microbes One of the continuing challenges in vaccination is to develop vaccines that stimulate cell-mediated immunity against intracellular microbes 34 Vaccines for Intracellular Microbes Using viral vectors The genetic material of the microbial antigens are incorporated into viral vectors, which will infect host cells and produce the antigens inside the cells (in the cytosol) Bacterial plasmids (DNA) Individuals are immunized with DNA encoding a microbial antigen in a bacterial plasmid which is ingested by host APCs, and the antigen is produced inside the cells (in the cytosol) mRNA The mRNA is engineered to resemble fully processed mature mRNA molecules as they occur naturally in the cytoplasm of eukaryotic cells Non-replicating mRNA which encode the antigen of interest and contain 5ʹ and 3ʹ untranslated regions (UTRs) All of the above 3 types should produce the antigens in the cytosol which can activate the MHCI pathway and lead to the activation of the cytotoxic T cells Self-amplifying RNAs encode not only the antigen but also the viral replication machinery that enables intracellular RNA amplification and protein expression 35 17 4/12/21 Types of Vaccines Killed whole bacterial cell vaccine was developed against Bordetella pertussis (whooping cough) Live attenuated could be also used in some cases It caused side effects and rarely caused brain damage Studies showed that 4 components of the bacterium induced antibodies The acellular vaccine of B. pertussis and other pathogens are safer than whole organism vaccines (subunit or recombinant) A fully effective vaccine may require more than a single constituent in order to activate more than one cell type Many bacteria have a polysaccharide capsule. A mean of inducing a T cell response, is to chemically conjugate bacterial polysaccharides to a protein carrier Even conjugate vaccines are not usually strongly immunogenic on their own, most require the addition of adjuvants which act on APCs to enhance the immunogenicity of the antigen None of the above (except live attenuated) can trigger a cytotoxic T cell response. Viral vectors and nucleic acid vaccines may overcome this problem as they introduce the antigen to the cytosol of the host 36 Valence of Vaccines Monovalent (Univalent) Designed to immunize against a single antigen or microorganism Multivalent (Polyvalent) Designed to immunize against two or more strains of the same organism or against two or more microorganisms DTaP Diphtheria Tetanus Acelular B. pertussis 38 18 4/12/21 Why are Repeated doses sometimes required? A goal of vaccination is to induce the humoral adaptive immune responses and stimulate the development of long-lived plasma cells and memory cells The progressive increase in antibody affinity with repeated stimulation of B cells is one of the reasons for the recommended practice of giving multiple rounds of immunizations with the same antigen for generating protective immunity 39 Why are new flu vaccines released every year? Because Flu viruses evolve so quickly 40 19 4/12/21 Genome Reassortment (The Emergence of New Viruses) 41 Genome Reassortment (The Emergence of New Viruses) The exchange of RNA segments between mammalian and avian influenza viruses can give rise to pandemic influenza. The 2009 H1N1 pandemic strain is a reassortment of avian, human, and swine influenza viruses https://4.bp.blogspot.com/-6MV6Q8eo6iI/WNzvbOz1nMI/AAAAAAAAkvA/YNzLQtSi2dUwm2TqtqG0QfJdpT2azGnNwCLcB/s1600/Triple%2BReassortment%2BIn%2BSwine%2BHost.jpg 42 20 4/12/21 Genome Reassortment (The Emergence of New Viruses) The segmented nature of the influenza virus genome allows reassortment between coinfecting viruses This process of genetic exchange vastly increases the diversity of circulating influenza viruses It is a major mechanism underlying the rapid evolution of influenza viruses 43 This will affect: Antiviral drugs Vaccines Immune memory cells 44 21