MIIM30011_L12_Vaccination_NW_2024.pdf

Vaccination Nancy Wang, PhD [email protected] MIIM30011 Medical Microbiology: Bacteriology 22nd March 2024  Learning objectives At the end of this lecture, students should be able to: - Understand vaccines can induce protective immunity - Explain the role of antigens and adjuvan...

Vaccination Nancy Wang, PhD [email protected] MIIM30011 Medical Microbiology: Bacteriology 22nd March 2024  Learning objectives At the end of this lecture, students should be able to: - Understand vaccines can induce protective immunity - Explain the role of antigens and adjuvants in vaccine design - Give examples of different types of vaccines currently in use (e.g. live- attenuated, killed, toxoid, subunit, conjugated, etc) and discuss their main strengths and weaknesses - Discuss the importance of population-wide implementation for vaccine effectiveness 3  What is a vaccine? - Upon encounter with a pathogen, our body can develop immunity, which enable us to mount stronger and quicker immune responses against the same pathogen subsequently ⇒ natural immunisation - An immunised individual is considered to be protected when they experience: - Shortened course of pathogen growth Individual benefit - Reduced or no disease symptoms - Reduced chance for passing on the pathogen Impact at the population level - A vaccine is a reduced and safer form of the pathogen that, when given to the individual, can induce protective immunity without causing disease 4 I. How does prior infection or vaccination give rise to protective immunity? An antibody-focused view  Antibodies (Abs) are produced by B cells and bind directly to conformational epitopes An antigen may be a protein, LPS, polysaccharide, carbohydrate, PTM (e.g. glycosylation site) or other chemical structures. An epitope is a binding site that interacts directly with the Ab. An antigen may harbour one or more immunogenic epitopes. 6 Janeway, Figures 1.14 d of Bothto the activation affinity of B cells maturation andand antibody class switching occur only in B cells and require macrophage bacterium can 2. T-cell provoke antibody production with- help. In the second part of the chapter, we introduce the distributions B cells by antigens usuallyclasses involves help toxin o functions and of various of antibody, in particular those secreted into ee Section n, mucosal nlasma region cells 9-20). sites. and Antibodies mediate protection in most vaccines Activated In the third part memory B B cells of the cells. then Most chapter, we discuss in detail how the Fc of the antibody engages various effector mechanisms to contain and called h et e affinity eliminate infections. antigen are that are currently available maturation, produced in which Like the by the T-cellanti- somatic response, the humoral immune response produces immunological memory, and this is discussed in Chapter 11. Fc receptor egion (V-region) genes. We examine the ermutation and its immunological con- h process that generates Neutralization Opsonization Complement activation —a Fig. 10.1 Antibodies mediate the thehumoral different immune response through neutralization, y diversity on the antibody response. onal opsonization, and complement activation. After being secreted by plasma cells, h- macrophage bacterium C1q tching occur antibodies protectonly the in B from host cellsinfection and require toxin in three (or main ways. virus) They can inhibit the toxic p effects chapter, or infectivity of pathogens we introduce or their products by binding to them, a process called the distributions n neutralization (top panel). When tibody, in particular those secreted bound to pathogens, into the antibody’s Fc region can bind to membrane- attack complex st Fc receptors on accessory cells, such as macrophages and neutrophils, helping these cells chapter, we discuss in detail how the Fc o ingest and kill the pathogen. This process is called opsonization (middle panel). Antibodies i- us can effector mechanisms to contain and trigger complement by activating C1, the first step in the classical complement pathway. c sponse, the humoral immune response Deposition of complement proteins enhances opsonization and can also directly kill certain Fc receptor bacterial membrane d ethis is discussed in Chapter 11. bacterial cells by activating the membrane-attack complex (bottom panel). n- Opsonization nt Immunobiology | chapter 10 | 10_100 e. - Antibodies are effective in the extracellular space: Complement activation Murphy et al | Ninth edition immune response through neutralization, © Garland Science design by blink studio limited.eAfter being - Bind macrophage secreted by directly bacterium plasma to toxins or viruses to prevent access to host cells (neutralisation) cells, C1q nsree main ways.- They Tagcan inhibit the bacteria toxic for phagocytosis via the Fc receptor (opsonisation) ucts o by399binding to them, a process called 0.indd 24/02/2016 hogens, Fc - TagFcbacteria the antibody’s region can forbind direct to lysis or phagocytosis via the complement membrane- system (complement activation) rophages and neutrophils, helping these cells attack complex d s called -opsonization B cell development and antibody production require T cell help – more later (middle panel). Antibodies e Fc receptor first step in the classical complement pathway. - Vaccines opsonization not and can also effective directly kill certain bacterial if antibodies alonemembrane is not enough for immunity against the pathogen ack complex (bottom panel). - E.g. malaria, Complement HIV, tuberculosis and intracellular bacterial pathogens activation Immunobiology | chapter 10 | 10_100 - T cell-based vaccine strategies highly Murphy et al |desired Ninth editionbut under-developed C1q © Garland Science design by blink studio limited 7 membrane- Janeway, Figure 10.1 attack complex 24/02/2016 15:48  The typical Ab response is quicker and more effective upon second exposure to the antigen Ab level in blood 8 Janeway, Figure 1.25 II. Vaccine strategies Antigen | Adjuvant | Design  How do we make a vaccine work? Adjuvant Activation signals Antigen(s) Immune memory Pathogen-specific targets Specific and sustained Key considerations Choice of antigen and adjuvant Vaccine type (formulation) Route, dosing and schedule (primary vs boosters) Terminology - An immunogenic antigen triggers good immune responses - A reactogenic vaccine induces unwanted side effects (e.g. inflammatory responses to PAMPs) that can be at the injection site or systemic, mild or serious - An efficacious (or effective) vaccine is protective, i.e. it ‘works’ 10  Licensed vaccines Type of vaccine using this technology First introduced Measles, mumps, rubella, Live attenuated yellow fever, influenza, oral (weakened or polio, typhoid, Japanese 1798 (smallpox) inactivated) encephalitis, rotavirus, BCG, varicella zoster Types of Whole-cell pertussis, Killed whole polio, influenza, organism Japanese encephalitis, 1896 (typhoid) hepatitis A, rabies vaccines Toxoid Diphtheria, tetanus 1923 (diphtheria) Pertussis, influenza, Subunit (purified protein, hepatitis B, meningococcal, recombinant protein, 1970 (anthrax) pneumococcal, typhoid, polysaccharide, peptide) hepatitis A Virus-like Human papillomavirus 1986 (hepatitis B) particle Outer Pathogen 1987 membrane antigen Gram-negative bacterial outer Group B meningococcal (group B vesicle meningococcal) membrane Polysaccharide Protein–polysaccharide Haemophilus influenzae 1987 (H. influenzae conjugate type B, pneumococcal, type b) meningococcal, typhoid Carrier protein Viral vector Pathogen gene Viral Ebola 2019 (Ebola) vectored Viral vector genes RNA Nucleic acid DNA whole-cell acellular vaccine SARS-CoV-2 2020 (SARS-CoV-2) 11 Lipid coat Adapted from Pollard & Bijker, Nature Reviews Immunology, 2021. Pathogen gene  Licensed vaccines Type of vaccine using this technology First introduced Measles, mumps, rubella, Live attenuated yellow fever, influenza, oral (weakened or polio, typhoid, Japanese 1798 (smallpox) inactivated) encephalitis, rotavirus, BCG, varicella zoster Types of Whole-cell pertussis, Killed whole polio, influenza, organism Japanese encephalitis, 1896 (typhoid) hepatitis A, rabies vaccines Toxoid Diphtheria, tetanus 1923 (diphtheria) Pertussis, influenza, Subunit (purified protein, hepatitis B, meningococcal, recombinant protein, 1970 (anthrax) pneumococcal, typhoid, polysaccharide, peptide) hepatitis A Virus-like Human papillomavirus 1986 (hepatitis B) particle Outer Pathogen 1987 membrane antigen Gram-negative bacterial outer Group B meningococcal (group B vesicle meningococcal) membrane Polysaccharide Protein–polysaccharide Haemophilus influenzae 1987 (H. influenzae conjugate type B, pneumococcal, type b) meningococcal, typhoid Carrier protein Viral vector Pathogen gene Viral Ebola 2019 (Ebola) vectored Viral vector genes RNA Nucleic acid DNA SARS-CoV-2 2020 (SARS-CoV-2) vaccine Lipid coat 12 Pathogen gene  whole-cell Live-attenuated vaccines (LAVs) - LAVs show limited replication in vivo but induce very similar immune responses - resemble expression of genes required for growth and immune evasion in the host - antigens are delivered with infection-specific PAMPs in the right cellular space - one of the most effective methods for generating T cell-based immunity - Common methods for attenuation: - using closely related species causing milder disease, e.g. Smallpox (Cowpox) - long cultivating or passaging method, e.g. tuberculosis (BCG), Measles - chemically induced multi-site mutagenesis, e.g. typhoid fever (Ty21a) - gene-specific engineering > largely experimental 13  whole-cell Live-attenuated vaccines (LAVs) - LAVs show limited replication in vivo but induce very similar immune responses - resemble expression of genes required for growth and immune evasion in the host - antigens are delivered with infection-specific PAMPs in the right cellular space - one of the most effective methods for generating T cell-based immunity - Common methods for attenuation: - using closely related species causing milder disease, e.g. Smallpox (Cowpox) - long cultivating or passaging method, e.g. tuberculosis (BCG), Measles - chemically induced multi-site mutagenesis, e.g. typhoid fever (Ty21a) - gene-specific engineering ⇒ largely experimental - Main risks and weaknesses: - reactogenic LAVs are still widely used in experimental - disease (e.g. in immunocompromised) systems for understanding correlates of or transmission (e.g. during pregnancy) protection, but new development of - reversion (e.g. oral polio) vaccines for complex pathogen has been - maintaining viability in storage can be tricky moving away from LAVs and towards (e.g. cold-chain transport) purer, acellular formats 14  whole-cell Killed whole-cell vaccines - Almroth Wright first prepared heat-killed S. Typhi to vaccinate British soldiers against typhoid fever in 1896 - today both bacteria and viruses can be killed by physical or chemical processes - Killed whole-cell vaccines cannot replicate to cause disease - shorter development time and can respond to seasonal strain changes, e.g. influenza - retains endogenous PAMPs - induces good antibody response 15  whole-cell Killed whole-cell vaccines - Almroth Wright first prepared heat-killed S. Typhi to vaccinate British soldiers against typhoid fever in 1896 - today both bacteria and viruses can be killed by physical or chemical processes - Killed whole-cell vaccines cannot replicate to cause disease - shorter development time and can respond to seasonal strain changes, e.g. influenza - retains endogenous PAMPs - induces good antibody response - Main risks and weaknesses: - Reactogenic (especially bacteria) - antigen expression depends on growth conditions, e.g. internal protein antigens - immunity tends to be short-lived and requires repeated booster doses - poor induction of T cell immunity Killed whole-cell vaccines are still in common use for viral pathogens, but like LAVs, their use is becoming increasingly more limited for bacterial pathogens 16  Licensed vaccines Type of vaccine using this technology First introduced Measles, mumps, rubella, Live attenuated yellow fever, influenza, oral (weakened or polio, typhoid, Japanese 1798 (smallpox) inactivated) encephalitis, rotavirus, BCG, varicella zoster Types of Whole-cell pertussis, Killed whole polio, influenza, organism Japanese encephalitis, 1896 (typhoid) hepatitis A, rabies vaccines Toxoid Diphtheria, tetanus 1923 (diphtheria) Pertussis, influenza, Subunit (purified protein, hepatitis B, meningococcal, recombinant protein, 1970 (anthrax) pneumococcal, typhoid, polysaccharide, peptide) hepatitis A Virus-like Human papillomavirus 1986 (hepatitis B) particle Outer Pathogen 1987 membrane antigen Gram-negative bacterial outer Group B meningococcal (group B vesicle meningococcal) membrane Polysaccharide Protein–polysaccharide Haemophilus influenzae 1987 (H. influenzae conjugate type B, pneumococcal, type b) meningococcal, typhoid Carrier protein Viral vector Pathogen gene Viral Ebola 2019 (Ebola) vectored Viral vector genes RNA Nucleic acid DNA SARS-CoV-2 2020 (SARS-CoV-2) vaccine Lipid coat 17 Pathogen gene  acellular Toxoid vaccines - Some pathogenic bacteria can produce toxins (in this case exotoxins) - Where toxins are the main virulence mechanism leading to disease symptoms, neutralisation of toxins can stop disease - purified toxins are detoxified by heating or chemical inactivation ⇒ toxoid vaccine - toxoid protein is highly immunogenic but antibody response is short-lived without active infection ⇒ multiple boosters over lifetime - Two licensed toxoid vaccines to date, several more preclinical - Clostridium tentani (Tetanus toxin, TT) - Corynebacterium diphtheriae (Diphtheria toxin, DT) 18  acellular Toxoid vaccines - Some pathogenic bacteria can produce toxins (in this case exotoxins) - Where toxins are the main virulence mechanism leading to disease symptoms, neutralisation of toxins can stop disease - purified toxins are detoxified by heating or chemical inactivation ⇒ toxoid vaccine - toxoid protein is highly immunogenic but antibody response is short-lived without active infection ⇒ multiple boosters over lifetime - Two licensed toxoid vaccines to date, several more preclinical - Clostridium tentani (Tetanus toxin, TT) - Corynebacterium diphtheriae (Diphtheria toxin, DT) - Main risks and weaknesses: - must produce toxin! - bacterial replication is not directly affected Much effort was devoted to - little transmission control (if at all) testing a variety of toxin- - require repeated booster doses to maintain producing bacteria over the immunity over lifetime decades, but it is not a focal area for vaccine development now 19  Licensed vaccines Type of vaccine using this technology First introduced Measles, mumps, rubella, Live attenuated yellow fever, influenza, oral (weakened or polio, typhoid, Japanese 1798 (smallpox) inactivated) encephalitis, rotavirus, BCG, varicella zoster Types of Whole-cell pertussis, Killed whole polio, influenza, organism Japanese encephalitis, 1896 (typhoid) hepatitis A, rabies vaccines Toxoid Diphtheria, tetanus 1923 (diphtheria) Pertussis, influenza, Subunit (purified protein, hepatitis B, meningococcal, recombinant protein, 1970 (anthrax) pneumococcal, typhoid, polysaccharide, peptide) hepatitis A Virus-like Activating T cell help to particle Human papillomavirus 1986 (hepatitis B) enhance the quality of antibody response to Outer Pathogen Gram-negative 1987 non-protein antigens membrane vesicle antigen bacterial outer Group B meningococcal (group B membrane meningococcal) Polysaccharide Protein–polysaccharide Haemophilus influenzae 1987 (H. influenzae conjugate type B, pneumococcal, type b) meningococcal, typhoid Carrier protein Viral vector Pathogen gene Viral Ebola 2019 (Ebola) vectored Viral vector genes RNA Nucleic acid DNA SARS-CoV-2 2020 (SARS-CoV-2) vaccine Lipid coat 20 Pathogen gene  B cells present BCR-imported antigens to T helper cells for activation signals - Activation of naïve B cells requires (1) BCR stimulation AND (2) co-stimulatory signals - Non-proteins (e.g. LPS, polysaccharide): via PAMP or other danger signals (T-independent); IgM (primary) 21  B cells present BCR-imported antigens to T helper cells for activation signals - Activation of naïve B cells requires (1) BCR stimulation AND (2) co-stimulatory signals - Non-proteins (e.g. LPS, polysaccharide): via PAMP or other danger signals (T-independent); - Proteins: via CD40 ligand and cytokine stimulation from helper T cells (T-dependent). IgM (primary) IgG (high-affinity) 22 DNA flanking the rearranged V gene, but does not generally extend into th Janeway, Figure 11.25 per 1010 base pairs per cell division. Somatic hypermutation also affects23 som tions in the rest of the cell’s DNA is much lower: around one base pair chang Class switch one base pair change per 103 base pairs per cell division, while the rate of mut The immunoglobulin V-region genes accumulate mutations at a rate of abo 9 24/02/2016 15:49 IMM9 chapter 10.indd 410 15:4 16 2/20 24/0 can improve antibody affinity. complementarity-determining regions, which determine antibody specificity we first present a general overview of this process in which random mutation is evident in the accumulation of numerous amino acid replacements in the c m- le an increased survival rate compared with low-affinity cells. Positive selection s, d ly B- n Fig. 10.15) because the cells expressing receptors with such mutations will have io center B cells. Before describing the enzymatic mechanisms initiated by AID r e the cell g receptor for antigen, and these mutations will be selectively expanded (see c o l s h p ents phoid tissues. Less frequently, mutations may improve the affinity of a B-cell e is im v n - helm m a n dividing B cells from expanding to numbers that would overwhelm the lym- isru , induced cytidine deaminase, or AID, which is expressed only by germin g o n e of ti in e s pre are critical for immunoglobulin V-region folding. This process prevents rapidly l s g c ntal either tr il blo u reflecting the loss of cells that had mutated any one of the many residues that y thu e e ants ld ges. ime roce. De These mutations in the V genes are initiated by an enzyme called activation by the relative scarcity of amino acid replacements in the framework regions, d.7 or b imenta t n ha ut end 0.14). dark-staining nuclear debris in their cytoplasm. Negative selection is implied n of th s pha le - e ta MOVIE 10.1 n h r e u ts igin 0 giving rise to the characteristic tingible body macrophages. These contain r n desc g f abo - B-cell clones that differ subtly in specificity and antigen affinity (Fig. 10.13 n engu u o are filled with apoptotic B cells that are quickly engulfed by macrophages, lo y on g olec c affec into the s, an the es (Fig. 1 s will ly om a cannot take up antigen as well as sibling B cells (Fig. 10.15). Germinal centers 0.13 er k y 0 eme d w d e c 6 th because they can no longer make a functional B-cell receptor or because they st also a rate muta