Ch 11 Memory & Vax PDF

IMMUNOLOGIC MEMORY & VACCINATION Chapter 11 Learning Objectives Explain the differences in primary and secondary immune responses (LO11.1) Describe differences between naive, effector, and memory lymphocytes (LO11.2) Understand the basis of vaccination and explain how different vaccines...

IMMUNOLOGIC MEMORY & VACCINATION Chapter 11 Learning Objectives Explain the differences in primary and secondary immune responses (LO11.1) Describe differences between naive, effector, and memory lymphocytes (LO11.2) Understand the basis of vaccination and explain how different vaccines work (LO11.3) Course of a typical infection Stages of infection & host response Immunological Memory Primary immune response Clears the pathogen Builds immunological memory Adaptive response only – B & T cells Secondary immune response Faster and more robust than the primary response due to the presence of memory B and T cells Immunological Memory Memory cells persist because of changes in metabolism Immunologic Memory is long-lasting Ag-specific Ab is maintained for years CD4+ T cells decrease compared to CD8+ T cells, but a population of memory T cells survives several years However, protective immunity varies for different pathogens Vaccination with vaccinia virus Blue – one vaccination Pink – two vaccinations Maintenance of Immunologic Memory Not dependent upon antigen Long-lived B and T cells in the absence of any pathogen demonstrates that antigen is not necessary for survival of the memory cells Most memory cells are quiescent, but a small fraction are dividing, renewing the population (T cells) Perhaps the presence of cytokines such as IL-7 and IL- 15 stimulate survival and proliferation Memory T cells For both CD4 and CD8 T cells, ~5-10% of the T cells activated during a response survive the downregulation mechanisms  memory T Important features Found in peripheral tissues and inflammatory sites, not just lymphoid tissue Minimal to no co-stimulation is required for activation Upon antigen encounter- Less than 24 hrs versus 4-5 days Exist in a resting state, but undergo self-renewal to maintain long-term survival Memory T cells do not need co-stimulation  3 populations of Memory T cells Central Memory T cells Effector Memory T cells Resident Memory T cells EXLCUDED from secondary lymph tissue ** CD8, Th1, Th2, & ** persist in tissue even ** can re-enter T cell zones Th17 after infection cleared of secondary lymph tissue  Memory B cells do not use IgM as the BCR Memory B cells Activated B cells that isotype switched and went through somatic hypermutation. Morphologically similar to naïve B cells and very different than plasma cells. In a secondary response, memory B cells are activated efficiently 1. Enhanced adhesion molecules, move more quickly to LNs 2. BCR has increased affinity for antigen 3. Large #s of memory B cells and increase co-stim molecule expression can activate Th cells 4. Progeny of memory B differentiate into additional plasma cells Plasma B Cells Short-lived effector plasma cells Made during primary immune response Stress/speed of Ab production leads to cellular damage and genomic mutation Immune complexes binding to FcgRIIBI on the plasma cell induce apoptosis Long-lived plasma cells Survive in absence of antigen Protected in bone marrow Provide maintenance levels of Ab Depend on IL-6 from stromal cells for survival No BCR Plasma B cells * Do not divide Memory B cell Response Memory B cell responses The activation of naïve pathogen-specific B cells is suppressed by the binding of antibodies present from the primary response. FcɣRIIB1 Memory B cell responses For pathogens that are highly mutable and for which new strains are constantly emerging, it is problematic that memory B cells prevent the activation of naïve B cells Original antigenic sin Tendency of individuals to make antibodies to epitopes expressed by the pathogenic strain of first exposure even when subsequently exposed to variants with more immunogenic epitopes Example: influenza Original Antigenic Sin Summary - Memory Vaccination Clinical application of immunization designed to artificially help the body to defend itself Preventative therapy Modified form of a natural immunogen (antigen) Whole pathogen Components of a pathogen Toxin The principle of vaccination Vaccine mounts primary response* Second dose induces secondary response Passive immunization – Antibodies via placenta or breastmilk Most vaccines require multiple doses Elicit primary and secondary response Long-lived antibody levels*  Generating Vaccines Type of pathogen Location of infection Mutagenic capacity of pathogen Chronic versus short- term infection Risk of infection and/or serious illness Antibody response might not be enough —> need T cells Challenge to RNA vaccine development Recombination in segmented genomes Occurs at a higher frequency than recombination Effect on virus  huge variations Lead to influenza pandemic in humans RNA Viruses The first vaccine- smallpox (vaccinia virus) Types of vaccines Antibody protection from vaccines Attenuated Vaccines Mutant live virus Grows poorly in humans and can’t cause disease Great job at mimicking real infection Conjugate vaccines Leads to activation of both CD4 T cells and B cells Produces complement- fixing antibodies Toxoid is inactivated toxins from pathogen Available vaccines Adjuvants Innate immune response activation is necessary Adjuvants bind TLRs Adjuvants are approved in these combinations, not individually. Coronavirus Cause common cold SARS MERS Vertebrate hosts 4 structural proteins, enveloped virus, S protein  cell attachment via ACE2  Boopathi et al., 2020 J Biomol Struct Dyn Coronavirus  COVID-19 Vaccine: mRNA vaccines mRNA encodes for S protein mRNA degrades ~48 hours after injection Lipids that contain mRNA induce innate immune response Does not require actual virus to generate vaccine Technology could be used for HIV, RSV, and Influenza HIV- entry via co-receptors HIV Vaccine- Germline Targeting Goal is to elicit broadly neutralizing antibodies (bnAb) These are rare (bnAb precursor cells are even more rare) bnAb will recognize several epitopes on the envelope protein Phase 1 clinical trial showed proof of vaccination concept Vaccine development and hesitancy  Vaccine development Knipe et al., 2020 Science