(4.2) VACCINES

BMS 545 Immunology - November 6, 2024

• Course content spans November 6, 2024, to December 6, 2024

• Exam 3 scheduled for November 8, at 2:30 PM.

• Asynchronous modules on PBS vaccine documentary (Nov 11), Secondary Immunodeficiency (Nov 15), Hypersensitivity (Nov 25), covering Research days Nov 15-18

• Modules on: Transplantation & Immune Pharmacotherapy (Nov 18), Transplantation & Immune Pharmacotherapy & Cancer (Nov 20), Cancer & Tumor Immunity (Nov 22).

• Thanksgiving break from November 27 to 29

• A Case Study, "What's Wrong with Me?" is scheduled for December 4.

• A final Immunology debrief: The Well Patient is scheduled for December 6..

Why Vaccination Saves Lives

• Vaccination saves lives.
• Smallpox, polio, diphtheria, pertussis, tetanus, measles, mumps, rubella, rotavirus, H. influenzae, varicella, and hepatitis are 99 problems.
• Vaccination is the only infectious disease of humans that has been eradicated worldwide.

Class Objectives

• Relate B & T cell immunity and memory to vaccination.
• Identify, compare, and contrast different types of memory cells (e.g., B, plasma, TCM, TEM, TRM).
• Describe why memory cells are better at being activated (e.g., FcyRIIBI, CD45RA/RO).
• Describe the asymmetric division of naïve T cells, and differentiate naïve, effector, or memory cells.
• Understand and describe why vaccines are important.
• Differentiate inoculation and vaccination.
• Define different types of vaccines and their characteristics and pros/cons.
• Define adjuvants and identify examples.
• Have a discussion concerning vaccinations, debunking common vaccine myths and with anti-vaccine/on-the-fence individuals.
• Learn more about vaccines (where to find information).

Immunological Memory & Secondary Immune Response

• Immunological memory is essential for the survival of human populations.
• Specific anti-vaccinia antibodies remain for ~75 years after initial exposure.
• CD4 & CD8 memory T-cells are retained.
• Antibody response is measured in International Units (IU).

Antibodies (primary & secondary response)

• Antibodies made in the primary response persist to prevent reinfection.
• Secondary responses have a low steady-state level.
• Memory B cells—major participants in B cell memory.

Immunological Memory & Secondary Immune Response -- B-Cell Memory

• Long-lived plasma cells mediate B-cell memory.
• Short-lived plasma cells are followed by long-lived ones.

Complexes of IgG and Polymeric Antigen

• IgG and polymeric antigens prevent naive B cell activation by cross-linking to the inhibitory FcyRIIB1 receptor.
• Naive B cells do not become activated when BCR and FcyRIIB1 are cross-linked.
• Memory B cells do not express FcyRIIB1 but are capable of activation.

Antigen Activation of Naive T Cells

• Antigen-mediated activation of naive T-cells generates effector and memory T cells.
• Naive T cells become metabolically reprogrammed and divide asymmetrically into an effector T cell (TE) and memory T cell (TM) after activation.

Naive, Effector, & Memory T Cells

• Naive, effector, and memory T cells differ in cell-surface phenotypes.
• CD44, CD45RO, and CD45RA are cell adhesion and tyrosine phosphatase markers.
• CD69 is an activation marker.

Different Isoforms of CD45

• CD45 isoforms (CD45RA & CD45R0) differentiate memory T cells from naive T cells.
• CD45RA is larger than CD45R0 and interacts less with T-cell receptors, making memory T cells easier to activate than naive T cells.
• Three memory T cell subtypes exist based on location: TCM, TEM, and TRM.

Central & Effector Memory T Cells

• Central memory T cells (TCM) prefer secondary lymphoid tissues and mature into effector T cells after encountering antigens in those tissues.
• Effector memory T cells (TEM) prefer inflamed tissues and rapidly mature into effector T cells.

Resident Memory T Cells

• Resident memory T cells (TRM) are long-lived memory T cells produced during adaptive immune responses.
• TRM cells enter infected non-lymphoid tissue and reside there permanently.

Primary & Secondary Immune Responses

• Primary responses involve a small number of pathogen-specific cells with IgM antibodies of low to medium affinity, a high activation threshold, and a delay in effector T-cell activation.
• Secondary responses involve a large number of pathogen-specific cells with isotype-switched antibodies of high affinity, rapid activation, and the presence of effector T cells in infected tissue.
• Close cooperation between innate adaptive immunity happens from the start of infection.

How Vaccines Are Generally Made

• Vaccines use premises from both primary and secondary responses to pathogens.

Vaccination to Prevent Infectious Disease

• Protection from smallpox is achieved by immunization with cowpox.
• Cowpox and smallpox share surface antigens.
• Vaccination with cowpox elicits neutralizing antibodies against smallpox virus epitopes.
• Smallpox is the only human infectious disease to have been eradicated by vaccination.

Childhood Vaccination Schedules

• Vaccination schedules are based on CDC Prevention immunization schedules.

Antibody Amount & Affinity

• Antibody amount and affinity increase after successive immunizations with the same antigen
• Antibody concentration and affinity increase significantly over time.

Best Immune Response

• Live-attenuated vaccines and inactivated vaccines result in the best immune responses.
• Replication of organisms leads to good immune responses.
• Vaccine safety may not be proportional to effectiveness.

Vaccine Preparation

• Live-attenuated vaccines use whole living organisms with reduced virulence and replication ability.
• Inactivated vaccines use killed or inactivated organisms (virus, bacteria), rendering them incapable of infection or reproduction.

Additional Vaccine Preparations

• Subunit, recombinant, polysaccharide, and conjugate vaccines use parts of pathogens (proteins, sugars, capsids).

Conjugate Vaccines

• Conjugate vaccines enable high-affinity antibodies targeting carbohydrate antigens..

Macromolecular Complexes

• Macromolecular complexes, with separate epitopes, are important for generating effective vaccines.

TFH Cell Recognition & Activation

• A TFH cell receptor recognizes the p:MHC complex, activating the T cell and cytokines' secretion.
• Activated B cells differentiate into plasma cells, producing protective antibodies against polysaccharides (e.g., Haemophilus).

Vaccine Testing & Safety

• Vaccines are rigorously tested through multiple phases of clinical trials, including randomized double-blind placebo trials, to ensure safety and efficacy.
• Vaccines' safety and effectiveness are constantly monitored after being included in the recommended immunization schedule.

Monitoring Vaccine Safety

• FDA/CDC closely monitor vaccine safety.
• Systems like VAERS, VSD, and PRISM gather, analyze, and monitor adverse events after vaccinations.
• Clinical Immunization Safety Assessment Project (CISA) conducts research on complex vaccine safety questions.

Addressing Arguments Against Simultaneous Vaccine Administration

• Multiple vaccines are often given simultaneously, and their safety is thoroughly evaluated in clinical trials.

Vaccine Development & Procedures

• Vaccine development follows a multi-phased process from basic research through regulatory approvals (e.g., FDA review).
• Volunteers are used in clinical trials to evaluate vaccine safety and effectiveness to ensure it's safe for use.
• Information and transparency are promoted by entities like the FDA to increase trust in vaccination.

Vaccines Not Currently Available

• Vaccines are not yet available for diseases such as malaria, schistosomiasis, tuberculosis, diarrheal diseases, HIV/AIDS, measles, and hepatitis C.

Timeline of mRNA Vaccine Development

• The timeline of mRNA vaccine development traces research and advancements from the 1960s to recent development in 2020 of COVID-19.

Andrew Wakefield's Paper

• Wakefield's research paper about a link between the MMR vaccine and autism was retracted due to falsification of data and bias.

Vaccine Development Process

• Vaccine development is a rigorous process taking multiple years. It involves extensive lab testing and multiple clinical phases to ensure safety and efficacy.

Public Scrutiny of Vaccines

• Vaccine development is scrutinized more than drug development in many cases due to public health concerns and safety implications.

Vaccine Uptake & Measles Incidence

• Vaccine uptake decline, after unfounded assertions about MMR causing autism, has led to increased measles infections.

Additional Points

• Data regarding mortality and vaccination coverage has been collected.
• The importance and challenges in vaccine development are highlighted.
• The value of scientific methodology in ensuring vaccine safety is emphasized.