BIO-336 Vaccines and MHC

Why is the Tuberculosis vaccine (BCG) considered an "unanswered need"?

Although the vaccine exists, it is not very effective.

Why is the Rabies vaccine considered "unusual"?

It can be given AFTER exposure and still protect because the virus travels slowly up peripheral nerves to the brain.

Why is the BCG vaccine unique regarding testing?

It is a live attenuated M. bovis vaccine for TB that causes a positive PPD skin test.

Why is Peptide Editing necessary?

MHC molecules fall apart without a peptide, but if a viral peptide "falls out" and is picked up by a healthy cell, CTLs might kill that healthy cell (autoimmune damage).

Why is it beneficial that IgM does not cross the placenta?

Blood group antigens (A, B, O) are determined by IgM; if it crossed, it could destroy fetal blood cells of incompatible types.

Why is Hilleman's "conjugate trick" necessary for carbohydrates?

Because IgG almost never recognizes carbohydrates on its own.

Why does MHC restriction cause tissue rejection?

Recipient CTLs see donor MHC as non-self (because they were never tolerized to it) and attack the donor cells.

Why do Live attenuated vaccines have reduced virulence?

1. Grow poorly at body temperature
2. Do not replicate well in human cells
3. Susceptible to normal immunity
4. Replicate at non-disease sites

Why can't self-proteins be used as carriers in conjugate vaccines?

Because central tolerance deleted all T cells that recognize self-peptides, so there would be no CD4 help or class switching.

Why are immunosuppressed patients a concern regarding live vaccines?

They cannot tolerate live vaccines and can also shed the live virus to vulnerable contacts.

Why are CD1 molecules important in specific infections?

They are critical for responses to mycobacterial infections like Tuberculosis and Leprosy.

Why are carbohydrates T-independent antigens?

They only produce IgM, have no memory, and are not boostable.

Who won the 1996 Nobel Prize for discovering MHC restriction?

Zinkernagel and Doherty.

Who is considered the most prolific vaccinologist in history?

Maurice Hilleman (developed more than half of all vaccines used today).

Who developed the live oral polio vaccine?

Albert Sabin.

Who developed the killed polio vaccine?

Jonas Salk.

Which polio vaccine carries a risk of reversion?

Sabin (Oral, live).

Which diseases have vaccines effectively controlled the spread of?

H. influenzae, pneumococcus, measles, mumps, and rubella.

Which company did Maurice Hilleman work for?

Merck Pharmaceuticals.

Which antibody isotype is the only one to cross the placenta?

IgG (never IgM).

Where does T Cell Education take place?

The Thymus (cortex and medulla).

Where are the differences between MHC types primarily located?

In the binding pocket (amino acids that engage the peptide).

Where are CD1 genes located compared to MHC?

Outside the MHC gene complex.

What was the first vaccination ever performed?

Edward Jenner using cowpox to protect against smallpox in the late 1700s.

What was Maurice Hilleman's "neoglycoconjugate" vaccine strategy?

Coupling a carbohydrate to a protein to generate a boostable IgG response to a carbohydrate antigen.

What organisms typically produce superantigens?

Certain strains of Staph and Strep.

What molecule occupies the MHC II binding cleft after synthesis?

Ii (Invariant chain).

What is the status of the Malaria vaccine?

There is no well-developed vaccine yet.

What is the status of the HIV vaccine?

There is still no vaccine, despite more money being spent on it than all other vaccines combined.

What is the risk of using equine-sourced passive vaccines?

Risk of hypersensitivity (serum sickness) on the second exposure.

What is the result of Superantigen activation?

A massive, non-specific population of T cells (up to 20%) is activated, causing a cytokine storm (e.g., Toxic Shock Syndrome).

What is the post-exposure prophylaxis for Rabies?

Antibody + inactivated virus administered together.

What is the physical characteristic of the CD1 binding pocket?

It is a hydrophobic pocket (to fit lipids).

What is the only disease to have been eliminated from the entire planet, and when was the last case?

Smallpox; no cases since 1977.

What is the human-specific name for MHC?

HLA (Human Leukocyte Antigen).

What is the function of AIRE (AutoImmune REgulator)?

It causes thymic cells to express every protein encoded by the genome to ensure self-reactive T cells are identified and deleted.

What is the final result (Step 5 and 6) of Hilleman's Neoglycoconjugate solution?

5. B cell class switches from IgM to IgG.
6. Result: Boostable, memory-generating IgG response to a carbohydrate.

What is the evolutionary benefit of MHC diversity?

It allows the population to display the maximum number of different peptides, ensuring someone survives a new pathogen.

What is the current preference for Polio vaccination in the US?

Salk (injected, killed) is preferred because it is safer (no reversion possible).

What is the "natural progression" of the cellular response triggered by live attenuated vaccines?

TH1 then TH2.

What is Serum Sickness?

A Type 3 hypersensitivity reaction occurring when animal (horse) antibodies are used, specifically on the second exposure.

What is Rhogam and why is it given?

An IgG specific for RhD antigen; given to RhD-negative mothers after delivering RhD-positive babies to prevent immunization/hemolytic disease.

What is Disassortative mating?

The tendency to choose mates with different MHC haplotypes, often mediated by pheromones.

What is CLIP?

Class 2 Associated Invariant Chain Peptide; the remnant of the invariant chain that stays in the MHC II groove until the actual antigen is loaded.

What is alum used for in vaccines?

As an adjuvant to boost the immune response.

What is Alloreactivity?

The failure of negative selection for foreign MHC; T cells react to donor MHC because it was never present during thymic education.

What is a Toxoid?

A denatured toxin that is still immunogenic but no longer toxic (e.g., Tetanus, Diphtheria).

What is a major disadvantage of Killed vaccines compared to Live ones?

1. Shorter duration of immunity
2. Mostly antibody response (TH2) / weak cell-mediated immunity
3. No local IgA response
4. Need for boosters and larger doses

What happened in Experiment 3 of the Zinkernagel/Doherty study?

Strain A CTLs were mixed with Strain B infected cells; no death occurred because the MHC type was wrong, even though the viral peptide was present.

What does MHC stand for and why is it a "misnomer"?

Major Histocompatibility Complex; named because it determines organ/skin graft success, but its real purpose is displaying foreign peptides.

What does it mean for MHC to be polygenic?

You have more than one gene for each class (3 MHC I genes; 3 pairs of MHC II genes).

What does ISG stand for?

Immune Serum Globulin (human-derived IgG shot).

What do CD1 molecules display, and to which cells?

They display glycolipids to NKT cells.

What disease was successfully eliminated from the Western Hemisphere via vaccination?

Polio.

What characterizes the Normal Proteasome?

It has 28 subunits, chops proteins tagged with ubiquitin into 9-12 amino acid peptides.

What are VLPs and why are they used?

Virus-Like Particles; they give a better response than killed whole organisms.

What are the two types of Whole Organism Vaccines?

1. Killed (inactivated)
2. Live attenuated

What are the three sources of MHC Diversity?

1. Polymorphism
2. Polygenic
3. Codominance

What are the sources for passive bacterial vaccines like Diphtheria and Botulism?

Equine (horse) sources.

What are the primary uses for Artificial Passive Immunization?

1. Protect after suspected exposure (Rabies)
2. Reduce symptoms
3. Protect immunosuppressed individuals
4. Block toxin effects

What are the main concerns with Live attenuated vaccines?

Reversion to virulence, danger in pregnancy, spread to immunosuppressed, and maintenance of viability (cold chain).

What are the key characteristics of Passive Immunity?

It is short lived, no memory cells are formed, but it works immediately.

What are the key characteristics of Active Immunity?

It is long lasting because memory cells are formed.

What are the four types of immunity?

1. Natural Active
2. Natural Passive
3. Artificial Active
4. Artificial Passive

What are the consequences of having too many MHC types (more than 12)?

More T cells would interact with MHC during central tolerance and get deleted, reducing T cell diversity and compromising immune function.

What are some general barriers to vaccine development and distribution?

1. Costly development
2. Many serotypes for some organisms
3. Economic, political, and religious barriers

What are Immunological non-responders?

People who are homozygous at certain MHC loci, leading to less diversity and failure to respond to certain vaccines.

What are four major diseases that vaccines have successfully protected us from?

1. Pertussis (whooping cough)
2. Diphtheria
3. Tetanus
4. Rabies

What antibody isotype is usually the result of a T-independent carbohydrate response?

IgM.

What "supercharges" the proteasome during viral infection to form the Immunoproteasome?

Interferon stimulates the addition of a molecule called PA28.

Live attenuated vaccines are especially important for diseases requiring what kind of response?

T-cell responses (especially enveloped viruses).

List the specific genes for MHC I and MHC II.

MHC I: HLA-A, HLA-B, HLA-C.
MHC II: HLA-DR, HLA-DP, HLA-DQ.

List four examples of conjugate vaccines.

HIB, N. meningitidis, S. pneumoniae, S. typhi.

In T cell education, what happens if there is weak but positive MHC interaction?

The cell survives (positive selection).

In T cell education, what happens if there is too strong MHC interaction?

The cell dies (negative selection / clonal deletion) to prevent autoimmunity.

In T cell education, what happens if there is too little MHC interaction?

The cell dies (positive selection failure).

How many total MHC molecules does an average person express?

12 total (6 MHC I + 6 MHC II).

How does HLA-DM function in peptide editing?

It actively removes weakly bound CLIP and facilitates the loading of higher-affinity peptides in MHC II.

How do Superantigens differ from normal antigens?

They are not processed by the proteasome and bind to the outside of the TCR and MHC, crosslinking them non-specifically.

How do DNA/mRNA vaccines work?

They administer genetic instructions so the body produces the antigen itself, triggering an immune response (e.g., Pfizer/Moderna COVID-19).

How are Subunit Vaccines produced?

Harvest a portion of the agent, clone the antigenic gene, and express the protein region (e.g., Hepatitis B produced in yeast).

How are peptides loaded onto MHC I?

Via TAP1 and TAP2 transporter proteins.

How are pathogens in vesicles (like leprosy or TB) processed?

They are cleaved by proteases (not the proteasome) and loaded onto MHC II to activate CD4 cells.

How are Killed/Inactivated vaccines typically "killed"?

With heat or formalin.

Give examples of Live attenuated vaccines.

MMR, Varicella, Oral Polio (Sabin), BCG, Smallpox (vaccinia).

Give examples of Killed (inactivated) vaccines.

Polio (Salk), Rabies, Influenza, Hepatitis A.

From which group of animals did MHC genes first arise?

Jawless vertebrates (agnathans).

Explain the Red Queen Process (Arms Race) in MHC evolution.

Host and pathogen are in a constant race; pathogens evolve to evade immunity, and hosts evolve new MHC types to display pathogen peptides.

Explain Step 3 and 4 of Hilleman's Neoglycoconjugate solution.

3. Inside the B cell, the protein is processed into peptides and displayed on MHC II.
4. CD4 T cell recognizes the peptide, leading to co-stimulation.

Explain Step 1 and 2 of Hilleman's Neoglycoconjugate solution.

1. Covalently couple carbohydrate to a protein (e.g., diphtheria toxoid).
2. B cell with BCR for carbohydrate internalizes the whole complex.

Define reversion in the context of immunization problems.

When live attenuated vaccines mutate back to wild-type virulence.

Define Polymorphism in MHC.

An enormous number of alleles exist; it is the most polymorphic gene in the human genome.

Define Natural Passive Immunity and give an example.

Receiving antibodies naturally from someone else; example: Colostrum (breast milk) or transplacental IgG transfer.

Define Natural Active Immunity and give an example.

Getting sick and recovering from an ordinary infection; stimulates full immune response and memory.

Define MHC Restriction.

The reactivity of a T cell is restricted to/depends on the specific MHC haplotype of the individual it was trained on.

Define interference in the context of immunization problems.

When one vaccine blocks another (e.g., rubella blocking polio) or the immune system fails to respond to multiple stimuli simultaneously.

Define Codominance in MHC expression.

Both maternal and paternal alleles are expressed simultaneously; neither is dominant.

Define Artificial Passive Immunity and give an example.

Being given antibodies from elsewhere via injection; example: Antivenom, Rhogam, Rabies post-exposure shot.

Define Artificial Active Immunity and give an example.

Stimulating your own immune response + memory via injection; example: Flu shot, Hepatitis A/B vaccine, COVID vaccine.

Compare the Sabin and Salk polio vaccines by type and route.

Sabin: Live attenuated, Oral.
Salk: Inactivated (killed), Injection.