Vaccines and Immunological Memory Lecture Notes PDF

Immunology HSCI 3540 Lecture #16 Schedule Today’s Plan Pathogen Overview Viral Infections Other Infections Vaccines  Overview Approximately 25% of deaths worldwide are associated with communicable diseases Kill up to an estimated 12 m...

Immunology HSCI 3540 Lecture #16 Schedule Today’s Plan Pathogen Overview Viral Infections Other Infections Vaccines  Overview Approximately 25% of deaths worldwide are associated with communicable diseases Kill up to an estimated 12 million people annually Vaccines can help cut these numbers Challenges remain  Barriers to Infection Chemical and physical barriers must be breached to cause infection Epithelial linings of skin and gut are important barriers Assisted by normal microbiota of areas, as well as secretions that lower pH and make environment inhospitable to pathogens A breaching pathogen encounters innate mechanisms first Innate mechanisms lead to recruitment and initiation of adaptive mechanisms Pathogens are either cleared or kill the host Often, they survive long enough to spread from one host to another before cleared  Pathogenic-Specific Responses Mucosal or barrier infections are controlled by TH2- type responses Majority of infectious agents enter through mucosal routes Pathogens in intestinal tract encounter antimicrobial peptides (AMPs) and immune cells of the MALT Dimeric IgA’s role in neutralizing pathogens by binding and inhibiting surface attachment maintains barrier integrity TH2-type responses that activate ILC2, release of cytokines, and IgE control pathogens of the body surfaces  Pathogenic-Specific Responses Extracellular pathogens must be recognized and attacked using extracellular tools Extracellular infections can remain localized or spread systemically Immune mediators to these infections vary depending on location and environment but can include phagocytes, complement, AMPs, cytokines, and antibody Pathogenic-Specific Responses Intracellular infections require mechanisms to recognize infected host cells. Pathogens spend some time in intracellular vesicles or endosomal spaces where they activate PRRs and certain TLRs Often requires a vigorous TH1 response Pathogens that enter cytosol can be detected by cytosolic PRRs Pathogenic-Specific Responses Intracellular infections require mechanisms to recognize infected host cells. Pathogens spend some time in intracellular vesicles or endosomal spaces where they activate PRRs and certain TLRs Often requires a vigorous TH1 response Pathogens that enter cytosol can be detected by cytosolic PRRs Often leads to cytokine secretion, inflammasome activation, and induction of cytotoxic NK cells and CTLs Today’s Plan Pathogen Overview Viral Infections Other Infections Vaccines  Viral Infections Viruses typically enter host cells through a cell-surface receptor Once inside, replication can occur Genome replication is often error prone, leading to mutations Viruses are more likely to thrive if they don’t kill the host More chance for replication and spread  Combating Viruses Innate immune functions seek to prevent or eliminate viral infections Complement, AMPs, recognition of PAMPs PRRs induce antiviral type I interferon expression, inflammasome complex assembly (pyroptosis), and NK cell activation. During replication, viruses trigger humoral and cell-mediated adaptive immunity mechanisms Combating Viruses Many viruses are neutralized by antibodies, can prevent it from binding to a target cell receptor This can occur on viruses when they enter a system if the Ab is present, preventing productive infection Can also happen on viruses when they leave a host cell after being formed, protecting adjacent cells Antibody protection can also foster opsonization, complement activation, phagocytosis  Combating Viruses Ab can’t target cells where viral genomes have integrated into host cell chromosomes Cell-mediated immunity is important for viral control and clearance CD4+ helper T cells secrete cytokines that promote antiviral activity IFN-γ directly induces an antiviral state in adjacent cells IL-2 indirectly assists via promotion of CTL differentiation CD8+ CTLs actively find and destroy virally infected host cells Prevents production of more virus particles ADCC and NK cells can identify viral membrane antigens  Viral Immune Evasion Viruses employ several different strategies to evade host defense mechanisms Hepatitis C overcomes interferon antiviral effects by blocking/inhibiting protein kinase R (PKR) that is trying to halt translation HSV inhibits TAP activity, effectively shutting down MHC class I presentation to CD8+ T cells Adenoviruses and cytomegalovirus use a similar strategy Measles virus/HIV inhibit MHC class II expression and presentation to helper T cells Influenza and HIV constantly change their surface Ag Influenza Antigen Modification Influenza has two primary surface proteins, hemagglutinin (HA) and neuraminidase (NA) Its ssRNA(-) genome and RNA polymerase are error prone, resulting in altered HA/NA proteins that antibodies can’t bind It also has a segmented genome, meaning it can recombine when different viruses infect the same cell  Problem of Original Antigenic Sin During primary response, naïve antigens stimulate B cell activation During reinfection, prior antigens stimulate memory cell reactivation However, naïve B cells contain FcR receptors that inhibit activation if antibody is already bound to virus, so new antigens don’t stimulate a response  Problem of Original Antigenic Sin This means that during subsequent infections, the memory response is progressively less effective as mutated antigens are produced Eventually the virus will escape detection entirely, stimulating a new primary response but not be detected by any prior memory response Today’s Plan Pathogen Overview Viral Infections Other Infections Vaccines Bacterial Infections Immune responses to extracellular and intracellular bacteria can differ Ab provides several strong mechanisms for elimination of extracellular bacteria Best combated by TH2-type response Intracellular bacteria aren’t as strongly affected by Ab (except while outside target cells) Can activate NK cells and macrophages for clearance Ultimate effect is TH1-type response Parasitic Infections Malaria (#1 cause of parasite- induced death worldwide) Genus Plasmodium species carried by female Anopheles mosquitoes Maturational changes allow Ag shifting Intracellular phases resist Ab-based responses (no MHC class I in RBC) Short blood circulation time of free parasite stage prevents good immune stimulation Ab responses avoided by outer coat shedding Drug resistance becoming a problem Parasitic Infections African sleeping sickness Caused by two trypanosome species transmitted by tsetse fly bites Protozoan differentiates and divides every six hours in blood Moves from blood to central nervous system Expresses 1 variable surface glycoprotein (VSG) gene at a time Prevents effective immunity Results in waves of parasite multiplication/symptoms  Parasitic Infections A variety of diseases are caused by parasitic worms (helminths) Enter hosts through intestinal tracts Exclusively extracellular Don’t replicate in hosts, limiting immune engagement May decrease external Ag expression or wrap themselves in host proteins to further limit immunity Immunity may proceed via induction of IgE production and recruitment of eosinophils Induction of TH2 responses including ILC2s, and IL-4 production, are effective as protective immunity  Human Eosinophils Attack a C. elegans Nematode Video 3 from Patnode ML, Bando JK, Krummel MF, Locksley RM, Rosen SD. "Leukotriene B4 amplifies eosinophil accumulation in response to nematodes." J Exp Med 2014, June 30; 211(7):1281–8. doi:10.1084/jem.20132336.  Fungal Infections Innate immunity controls most fungal infections PRRs, especially C-type lectin receptors (CLRs), on innate immune cells keep fungi in check Commensal fungal organisms also help “crowd out” pathogenic fungi However, this is why antibacterial medications may result in oral thrush or vulvovaginal candidiasis (yeast infections) Commensal fungi suddenly have no competition for resources and overgrow Induction of phagocytosis helps destroy fungal cells Candida Fungi have evolved evasion mechanisms Capsules that interfere with PRR binding Fungi-induced expulsion from macrophages  Fungal Infections Adaptive immunity can play some role against fungal pathogens Evidence in HIV patients Control/resistance eventually lost, resulting in increase of fungal infections Evidence in B-cell–deficient mice No increased susceptibility to fungal infections Resistance must be mediated by cellular responses Many fungi can survive intracellularly within phagocytes Observations indicate strong TH1 responses Aspergill are effective at controlling fungal infections; us TH2/TREG responses are tied to increased susceptibility to such pathogens  Emerging And Reemerging Infectious Diseases Some noteworthy new infectious diseases have appeared recently Ebola (1976) Legionnaires’ disease (1976) Severe acute respiratory syndrome (SARS, 2002) West Nile virus (1999 in U.S.) Middle East respiratory syndrome (MERS, 2012) Zika (nationally notifiable in US in 2016) COVID-19 (2020) Emerging And Reemerging Infectious Diseases Diseases may reemerge for various reasons Combinations of diseases (HIV and TB) Improper antibiotic use (MDR TB, MRSA) Zoonotic pathogens Ebola primary host is fruit bat Laxity in vaccination program adherence Diphtheria reemergence in the former Soviet Union Whooping cough outbreaks in the United States Measles outbreaks in the United States Today’s Plan Pathogen Overview Viral Infections Other Infections Vaccines  Vaccines Basic research and rational design advance vaccine development Vaccine development begins with basic research to discover immunogens Useful immunogens are those from the pathogen that can be recognized by B and T cells Determination of specific immune targets or correlates of immune protection High circulating concentrations of IgG against a pathogen may be desirable to be effective Other pathogens may be better combatted by a mucosal IgA response Jonas Salk, polio Identify the desirable specific memory response vaccine before encountering real pathogen  Vaccines Passive immunization by delivery of preformed antibody Several conditions still warrant this older method Immune deficiency Toxin or venom exposure with immediate threat to life Exposure to pathogens that can cause death faster than an effective immune response can develop Vaccines Active immunization to induce immunity and memory Immune system activation of B and T cells results in formation of memory cells There are several vaccine strategies, each with unique advantages and challenges Should be safe Should be effective at preventing infection Delivery strategy should be achievable in desired population Attenuated Vaccines Virulence factors There are several vaccine strategies, each with unique advantages and Nutrient challenges pathway s Live, attenuated vaccines Weakened pathogens Pros: Cons: Retain their ability May mutate back (revert) to to replicate, promoting both pathogenic form humoral and cell- mediated responses May have more side-effect Often do NOT need complications boosters May also require a “cold chain” for stability during transport  Killed Vaccines There are several vaccine strategies, each with unique advantages and challenges Inactivated or “killed” vaccines Heated or chemically treated to inactivate Pros: Cons: No reversion to Often require booster shots pathogenic form Don’t replicate in host, don’t induce cell-mediated immunity (humoral Often more only) stable/easy to Possible chemical exposures or store and adjuvants often required transport Potentially dangerous if not all pathogen is killed/inactivated  Subunit Vaccines There are several vaccine strategies, each with unique advantages and challenges Subunit vaccines Use purified macromolecules derived from pathogen Inactivated exotoxins/toxoids, diphtheria and tetanus toxins Inactivated surface glycoproteins (or recombinant protein Ag), glycoprotein-D from HSV-2 Inactivated capsular polysaccharides, pneumococcus capsule Pros/cons: Similar to those of inactivated/killed vaccines  Conjugate Vaccines Conjugate or multivalent vaccines can improve immunogenicity and outcome Some molecules aren’t strong enough antigenically on their own to stimulate a good response Couple with something that is antigenic Vaccine to H. influenzae is a conjugate of capsular polysaccharide with tetanus toxoid Activates TH cells enabling IgM to IgG switch Induces B-cell memory Conjugate Vaccines Simple linking of a weak Ag with a stronger one may still not give the desired outcome Subunits are good at Ab induction, but what if you need a CTL response? You have to deliver Ag into cells for presentation in MHC class I molecules Creation of lipid carriers known as immunostimulating complexes (ISCOMs) for delivery Recombinant Vector Vaccines Non- pathogenic There are several vaccine strategies, host Virulence factors each with unique advantages and challenges Recombinant vector vaccines Use an attenuated pathogen Bacteria – Can be intracellular or extracellular Virus – Produces cytoplasmic antigen Genetically engineer it to carry another pathogen’s genes and express them Pros: Cons: All the benefits of attenuated vaccines Some of the attenuated Fewer risks — not using the actual vaccine problems are still pathogen, but something else entirely present (especially stability issues)  DNA/RNA Vaccines There are several vaccine strategies, each with unique advantages and challenges DNA vaccines Plasmids carrying pathogen genes injected into muscle tissue RNA vaccines mRNA for a pathogen gene is injected instead, often in a liposome Less stable than DNA (cold temps required), but can’t incorporate into genome Host cells take up DNA and express it internally Provides Ag presentation via MHC class I, stimulating CTL production Pros: Induces humoral and cell-mediated immunity Cons: Prolongs expression, enhancing memory Unknown at present…too new! Very stable and customizable Adjuvants Adjuvants are included to enhance the immune response to a weak antigen vaccine Promoting inflammation recruits more immune cells to the area, enhance effectiveness Slowing down Ag release can promote longer interactions, enhancing effectiveness Adjuvants are chemicals that can help Alum — good at stimulating TH2 but not TH1 responses AS04 — alum plus a TLR4 agonist, encourages TH1 responses  Learning Objectives Understand the localizations of pathogens, the best response against each, and what the following helper T subtypes will induce: Mucosal = TH2 (dimeric IgA, ILCs, mast cells, MALT) Extracellular = TH2 or TH17 (mIgA, IgM, IgG, phagocytes) Intracellular = TH1 (NK cells, ADCC, CTLs) Understand the categories of pathogens, how the immune system tries to combat them, and how the pathogens can evade immunity Viruses Bacteria Parasites Fungi  Learning Objectives Understand the difference between passive and active immunization Know the three factors that go into vaccine design Safety, efficacy, delivery Understand the different categories of vaccines and how they fit into the above three design factors Attenuated Killed Subunit Recombinant vector DNA Understand how vaccine conjugates and adjuvants can improve vaccines