7: Infectious Diseases & Vaccines

How pathogens enter the body? What is the response controlled by?

Mucosal routes or digestive system (b/c most commonly exposed to pathogens)

Mucosal & barrier infections controlled by TH2 responses

• IL-4, IL-13, IgE

• dimeric IgA neutralizes pathogens → makes sure they don’t leave intestinal tract

Immune response to extracellular infections (infect cells, interstitial fluid, bloodstream)

Innate immune response: targeted by PRRs on phagocytic cells, complements, antimicrobial compounds, cytokines, antibodies (IgM, IgA, IgG)

TH2, TH17, TFH cells activate B cells (need antibodies for neutralization)

Immune response to intracellular infections

(intracellular bacteria & parasites, all viruses)

Trigger endosomal TLRs, cytosolic PRRs

TH1 response (IFN-gamma):

• causes DTH response → macrophage activation

• license DCs for cross-presentation → CD8 T-cell activation

(TLDR: cell-mediated immunity, activated DCs, TH1 cells activating CD8 cells)

How do viral infections work?

Rely on host cells for replication:

viruses (nucleic acids w/ protein/lipoprotein coat) enter through mucosal tissues or punctured skin → bind to surface receptors → use error-prone polymerases (inducing mutation to avoid T-cell recognition) to replicate

(better immune system evasion = dominant strain)

How do bacterial infections work?

enter via mucosal routes, breaks in mucous membrane or skin → induce local inflammatory response (triggered by immunogenic toxins on cells or secreted toxic proteins)

How are bacterial infections cleared?

(humoral immunity = main protective response)

1. Memory B cells bind + neutralize bacterial endo/exotoxins

2. Complement-mediated lysis

3. Opsonization → phagocytosis

4. Mast-cell degranulation → induces inflammation

5. Neutrophils, macrophages → quick killing

How are vaccines developed?

Identify immunogens (important features of pathogens) & epitopes on pathogens that can be recognized by B & T cells

immunization

eliciting a state of protective immunity against a pathogen (memory response)

(either naturally or vaccination)

natural immunization

infection and recovery

immunization via vaccination

exposure to modified form of pathogen that doesn’t cause disease; generates memory cells to provide long-lived protection

types of vaccines

1. liva attenuated

2. inactivated/killed

3. toxoid

4. subunit

5. conjugate

6. recombinant vector

7. DNA

What is a live attenuated vaccine?

bacteria/viruses mutated so they don’t cause significant disease (don’t grow well in host but grow well in abnormal culture condition) → slow and transient growth in host

Attenuated vaccine advantages

• Most similar to real pathogen → increased immunogenicity & memory cell production

• Slow growth in host (and mimic growth patterns of real pathogen)→ prolonged exposure to immunogens on attenuated pathogen; induce cell-mediated response

Attenuated vaccine disadvantages

• Can revert back to virulent form in host (may not always induce disease but could pass this to immunocompromised/unvaccinated person)

• May have complications similar to those seen in natural disease

What is an inactivated/killed vaccine?

Pathogen treated with heat/chemicals (chemicals safer) and dies → incapable of replication, but still induces immune response to immunogens

induce humoral/Ab repsonse (b/c can’t get inside cell and activate T cells)

Inactivated/killed vaccine disadvantages

• Heat inactivation may damage epitopes needed to activate immune system

• Generally require boosters

• Less T-cell response

Inactivated/killed vaccine advantages

• chemical inactivation more successful, don’t have to use heat (risk damaging epitopes)

• don’t replicate in host

What is a subunit vaccine?

Using part of a pathogen:

1. Toxoids (inactivated pathogen exotoxins)

2. Capsular polysaccharides (surface glycoproteins)

3. Recombinant protein antigens

Subunit vaccine disadvantages

• Poor activation of TH cells b/c activates B-cells in T-dependent manner

• Produces IgM w/ limited class switching, no affinity maturation, few memory cells

Subunit vaccine advantages

• Less risks

• Can be improved by conjugating polysaccharide antigen to protein carrier (induce TH-cell response)

What is a recombinant vector vaccine?

• Genes that encode important antigens of virulent pathogens introduced into safe attenuated viruses or bacteria (live carriers)

• Attenuated vector replicates in host → expresses pathogen genes

(gets rid of parts of pathogen that would allow reversion, unlike attenuated vaccines)

Vaccine Conjugates

Fusion of highly immunogenic protein to weak vaccine immunogens to enhance immunogenicity to vaccine

(if there’s no live component in vaccine)

(allows T-cell response)

Liposomes and Immunostimulating Complexes (ISCOM)

multivalent vaccine that delivers antigen INTO cells by incorporating into lipid vesicles; activates T-cell response

Liposomes

proteins + phospholipids → lipid bilayer vesicles w/ protein incorporations

increased immunogenicity

immunostimulating complexes (ISCOMs)

phospholipid monolayers that carry antigenic proteins

increased immunogenicity

Adjuvants

triggers for innate immune response that are added to vaccines to enhance immunogenicity

Main adjuvant in human vaccines, what does it do?

Alum (aluminum salts)

Enhances TH2 responses, but weak stimulator of TH1

Creates slow-release of antigen at the injection site for sustained immune stimulation

Primary immunodeficiencies

inherited; genetic defects in the immune system (present at birth)

Secondary immunodeficiency

acquired; loss of immune function due to exposure to external agent (diseases, infections, immunosuppressive drugs, malnutrition)

immunodeficiencies

primary (inherited) or secondary (acquired)

most are monogenic & rare

Effects innate or adaptive immunity (B, T, or both; phagocytes; complement)

Earlier mutation in developmental pathway results in what?

More severe primary immunodeficiencies

SCID

severe combined immunodeficiencies; absence/impairment of T cells and some defects of antibody responses

T-cell defects affect humoral system → impair B-cell activation, Ab production, class switching, affinity maturation

What does SCID / T-cell impairment lead to?

reduction in DTH responses & cell-mediated cytotoxicity → more susceptible to infectious agents (even rarely pathogenic viruses)

What are two B cell immunodeficiencies?

1. X-linked agammaglobulinemia (X-LA): few Abs, almost no B-cells → frequent extracellular/bacterial infections

2. Selective IgA deficiency: IgA-expressing B cells can’t differentiate into plasma cells, but normal levels of other antibodies → susceptible to mucosal tissue infections

Treatments for primary immunodeficiencies, define them (3)

1. Protein Replacement Therapy: administer Abs

2. IV immunoglobulin (IVIG): inject pooled human gammaglobulin (Abs from healthy pt) to protect against concurrent infection

3. Cell Replacement Therapy: Transfer HSCs from immunocompetent donor to develop into T/B cells (required high degree/haploidentical HLA; T-cell depletion to avoid GvHD)

Causes of Secondary Immunodeficiencies

1. Agent-induced: chemical agents, immunosuppressive drugs (steroids, cytotoxic drugs, radiation/chemo)

2. Extremes of age: immune system either hasn’t developed fully or # T cells decreases

3. Severe malnutrition: low protein-calorie diets reduce T cell #/function; insufficient nutrients

How does HIV infect CD4 T-cells?

1. HIV fusion protein binds to CD4 & chemokine receptor (CXCR4 or CCR5)

2. HIV membrane fuses w/ cell membrane, releases viral genome & reverse transcriptase into cell

3. reverse transcriptase synthesizes dsDNA from RNA

4. Integrase allows dsDNA into nucleus

5. RNA produced → forms precursor proteins or new genome

6. Precursor proteins cleaved by protease

7. Proteins + genome packaged and shed from plasma membrane

What does antiretroviral therapy target to treat HIV?

1. chemokine receptors (chemokine antagonists)

2. fusion (fusion/attachment inhibitors)

3. reverse transcription (NRTI: azidothymidine; NNRTI: nevirapine)

4. integrase (integrase inhibitors)

5. protease (Saquinivir)

Nucleoside reverse transcriptase inhibitors (NRTIs)

Competitive inhibitors of normal nucleosides, inhibits reverse transcription

Azidothymidine → non-selective (also used by DNA polymerase; prevents production of RNA in normal cells)

Nonnucleoside reverse transcriptase inhibitors (NNRTIs)

noncompetitive inhibitors of normal nucleotides (inhibit allosteric site), inhibits reverse transcription

Nevirapine → more selective than azidothymidine (NRTI)

Protease inhibitor

Saquinivir

Inhibit HIV protease so precursors cannot become mature proteins → prevents assembly of new visions

Fusion/attachment inhibitors as ART

gp1 inhibitor

blocks fusion of virus w/ host cell membrane → prevents infection

Chemokine antagonists as ART

Blocks access to CCR5 for viral entry

Integrase inhibitors

prevent incorporation of virus into host genome

How is ART given?

2 NRTIs + 3rd ART (NNRTI, integrase inhibitor, protease inhibitor) → fewer resistance variants; inhibits multiple steps in HIV life cycle

Begin treatment immediately following diagnosis (less mutations = more effective)