Exam 3 Flashcards
microbiota
the collection of commensal microbes/ the actual microbes
microbiome
the collective activities and genetic potential of microbes in their environment/ the microbes and their genes
barrier epithelial cells function
they separate the barrier organs from the external environment/ provide a physical barrier, help provide an immune response to microbiota
3 innate immune cells that help regulate the microbiota response
epithelial cells, dendritic cells, macrophages, innate lymphoid cells
3 adaptive immune cels that help regulate the microbiota response
IgA producing B cells, conventional and invariant T cells (like CD8, Treg, Th17, Tfh, delta game T cells), intraepithelial lymphocytes (IELs, like Trm), mucosa-associated invariant T cells
innate lymphoid cells
abundant in healthy barrier tissue, don’t make antigen-specific receptors, and respond to cytokines produced by epithelial cells, DCs, and macrophages in a type 1,2, or 3 manner
skin immune system
has a multi-layer barrier (epidermis, dermis, hypodermis), keratinocytes help form the barrier and recognize pathogens, unique dendritic cells, lots of tissue resident CD8+ T cells
iSALT (induced skin-associated lymphoid tissue)
during inflammation, follicles in the epidermis of the skin can form a loosely organized immune structure to help dermal immune responses (rather than producing mucus or having an organized secondary lymphoid tissue)
microbial load rank
large intestine>small intestine>stomach
small intestine has the most digestion/absorption
lamina propria
the connective tissue layer just under the gut epithelial layer that is the site of most immune cell activity
how epithelial cells help defend mucosal tissue
- provides a barrier between gut lumen and gut tissue
- first responders to invading microorganisms
-detect invaders and initiate the immune response by secreting cytokines/chemokines so neutrophils/monocytes come from the blood
epithelial cells characteristics
-main ones in the gut are enterocytes
-absorb water and food and can recognize pathogens with PRRs
-epithelial cells in the gut turn over every 2 days, so the inflammatory responses are tightly controlled/ only persist during infection
role specialized epithelial cells in mucosal immunity
-between enterocytes and goblet cells
-secrete a protective layer of mucus
-produce/secrete antimicrobial peptides
-transport antigen
Paneth cells
-in between villi
-secrete defensins, lysozyme, antimicrobial factors
-help sustain stem cells
M cells
-over Peyer’s patches
-provide portals to transport microorganisms/their antigens from gut lumen to secondary lymphoid tissue in membrane vesicles
commensal bacteria in intestinal immune response
-help maintain tolerance in the intestine
-tune the immune system so it can protect against pathogenic organisms by making anti-inflammatory cells like Treg, IgA+B cells
immune systems of mice in germ-free conditions
-skinnier
-need 30% more calories to maintain weight
-decreased # of immune cells in mucosa/secondary lymph organs
-decreased IgA secretion/Th17 cells
-less anxious
-decreased cognitive/memory capacity
2 ways intestinal microbiota and immune cells communicate with the brain
-gut has its own nervous system (enteric nervous system)
-coordinates with peripheral nervous sys. (vagus nerve etc)
-convey info between brain, gut, immune syst.
-enteric nerves express proinflammatory receptors
-can respond to immune cell activity
-neurons generate neuropeptides that effect immune cells
psychobiotics
-microbes/microbial products that may influence our mood/behavior
-correlational = changes in intestinal microbiota could help ppl. with mental health issues like depression, schizophrenia, bipolar disorder
How do microbial communities differ in the upper and lower respiratory tracts and what type of immune responses are that generated?
The upper respiratory tract is populated by communities of microbes, but not the lower. Macrophages in the upper and lower respiratory tracts cooperate with the epithelium and other immune cells to mount type 1, 2, and 3 immune responses.
Naïve lymphocytes circulate between secondary and tertiary lymphoid tissue scanning antigen, what percent initially go to the spleen, lymph node, and barrier organs?
Thirty minutes after entering the blood stream, nearly 50% of all mature naïve lymphocytes travel directly to the spleen where they remain for five hours, about 40% travel to the lymph nodes where they spend 12-18 hours, and about 10% go to barrier immune tissues.
critical portal for lymphocytes to extravasate into lymph nodes
lymphocytes leave the blood stream through high-endothelial venules, which are in all secondary lymphoid organs except the spleen
CD62L, CCR7, addressins, chemokines
-CD62L & CCR7 from lymphocytes bind to addressing, and cytokines expressed by the high-endothelial venues
-L-selectin (CD62L) = activated by chemokines from CCR7 selectin for naive T/B cells to bind to GlyCAM on lymph node endothelial cells to slow down
L-selectin (CD62L)
activated by chemokines from CCR7 selectin for naive T/B cells to bind to GlyCAM on lymph node endothelial cells to slow down
CCR7 chemokines
upregulates the high affinity form of integral LFA-1 to make cells stop
PE-CAM1 and chemokine gradients
controls the crawling of lymphocytes between the epithelial cells
locations T/B cells go towards in the lymph nodes
enter the lymph node cortex, then chemokines help show them where to go so they end up in different microenvironments.
T cells = surfaces of APCs in paracortex
B cells = follicular DC networks in follicles
fibroblast reticular cells/follicular DCs importance for immune response
- the fibroblast reticular network helps the T cells to interact with them so that they can move along the paracortex
- follicular DCs provide a network so that B cells can look for antigens in the follicles
-both increase the odds of T and B cells being able to interact with the antigen
steps of healthy innate immune response to viral SARS-CoV-2 lung infection a few days after infection
Innate immune cells such as alveolar epithelial cells or macrophages could bind the viral pathogen via PRRs within minutes, initiating cell activation and generation of chemokines and cytokines. This would recruit additional innate immune cells such as neutrophils, monocytes, ILCs, and NK cells which may clear or contain the infection in the first few days.
steps of healthy adaptive immune response to viral SARS-CoV-2 lung infection a few days after infection
Activated APCs such as DCs process antigen and migrate to the local lymph nodes via CCR7 chemokine gradients with the first 6-24 hours and then initiate activation of antigen specific effector and memory T and B cells in the lymph node. The antigen specific adaptive effector immune cell numbers peak within two weeks whereas plasma and memory cell last for months to years in the bone marrow or tissues such as the lung (via CXCR6 or CXCR3 chemokine gradients) or stay in the lymphoid tissue.
how does processed and unprocessed antigen get to T and B cells in the lymph nodes
Once alerted to pathogen, APCs migrate to the T cell zone of lymph nodes (paracortex) to present processed Ag to lymphocytes. DCs enter lymph nodes via afferent lymphatics within hours on infection while small soluble Ag gains access to the B cell zone of lymph nodes (follicles) within minutes. Larger unprocessed Ag bound by opsonized complement are collected by subcapsular sinus macrophages (SCSMs) that line the lymph node sinus and relayed to follicular DCs often via B cells.
after being activated, how to B cells traffic to find T cell help
After being activated by antigen, B cells upregulate CCR7 and travel to the follicle and paracortex border for T cell help (T follicular helper cells upregulate CXCR5 and migrate to the border). After receiving T cell help, activated B cells travel to the outer edges of the follicle and proliferate and differentiate into plasma cells or return to the germinal center for additional rounds of proliferation and somatic hypermutation.
how do T cells help after the B cells are activated and come find them
Upon forming a stable connection, the B and T cell migrate together, form an immunological synapse, and the T cell delivers cytokines that stimulate B cell differentiation. The synapse is the site of the interactions between CD40L (T cell) and CD40 (B cell).
how do B and T cells behave differently in germinal centers
- Germinal B cells are unusually motile and morphologically distinct (more like DCs) and some B cells go from the dark zone to the light zone to sample antigen and interact a little with T helper cells
- germinal T cells are also more mobile.
- Germinal centers are initiated by several B cell clones, but the clones with the highest affinity for antigen are the ones in charge of the center
how do CD4 T cells provide help to CD8 T cells when they do not directly interact
- CD8+ T cells are activated in the lymph nodes via a multicellular interaction.
- need help from CD4+ helper subsets to complete differentiation which is a 3-cell interaction between an APC that is binding to CD8+ and CD4+ T cells simultaneously (or sequential licensing of the DC).
- facilitated by chemokine gradients and receptor upregulation.
what is the timing of an effector and memory primary response
after antigen exposure naïve lymphocytes differentiate into effector and memory cells over the first 4-7 days of the response.
- Pathogen specific antibodies are evident within 10 days and the type of effector cells (helper T cells, cytotoxic T cells, plasma cells) depends on environmental cues that naïve T cells receive from DCs and their neighbors.
Where do central, effector, and resident memory cells originate from and reside
During the first 7 days a population of central memory cells is formed with the effector cells, and they stay in the secondary lymphoid organs.
- There may be multiple origins of effector and resident memory cells
- effector memory cells reside in the periphery
- resident memory in tissue.
how does effector and memory cell homing to a specific tissue site occur
- effector and memory lymphocyte homing is regulated by interactions between cell-adhesion molecules and chemokine/chemokine receptor interactions.
- Effector T cells home to the tissue where their stimulating APCs originated from.
- Long lived plasma cells home to the bone marrow and
- some antibody producing cells stay in the lymph nodes while others traffic to the tissue.
- Memory T cells take up residence in the secondary lymphoid tissue (central memory cells) and peripheral tissues (effector memory cells).
- Activated cells upregulate S1P1 to leave the lymph node and effector cells downregulate CD62L to avoid homing to lymph nodes and adhesion molecules and chemokine receptors home them to sites of infection.
how do effector and memory cells help clear infections in tissues and undergo contraction
-after infection B and T cells expand -1,000-fold and leave the secondary lymph organs
-home to different tissues
-assist the innate immune system by clearing the infection
-2-4 weeks after infection they contract/leave 5% of the lymphocyte pool is left (central, effector, and resident memory cells)
how do memory cells position themselves to respond to reinfection
- the memory cells after infection continue to divide and respond to exposures if they happen again
- resident memory cells present in high concentrations in barrier organs like skin, lungs, intestines, etc.
- become first responders to re-infection
- memory cells are more dominant lymphocytes in older people
type I hypersensitivity reaction
mediated by IgE antibodies and include many of the most common respiratory allergens such as pollen and dust mites (e.g., hay fever)
Type II hypersensivity reactions
caused by IgG or IgM antibodies binding to host cells that are destroyed by complement or cell mediated mechanisms (e.g., blood transfusions).
Type III hypersensivity reactions
due to antigen-antibody complexes depositing on host cells and inducing complement fixation and inflammation (e.g., rheumatoid arthritis)
Type IV hypersensivity reactions
(Delayed type hypersensitivity - DTH) result from inappropriate T cell activation (e.g., contact dermatitis).
what does IgE normally protect against
parasitic worms
how does IgE cause type I hypersensitivity symptoms
- cross-linking Fcε receptors on the surfaces of innate immune cells.
- binding of IgE to FceRs activates granulocytes and causes degranulation.
- Granule contents released include histamine, heparin, proteases, leukotrienes, prostaglandins, and chemokines which act on surrounding tissues/cells to cause symptoms.
how do the high and low affinity Fc regulators on mast cells regulate the response?
- high-affinity IgE receptor (FcεRI) is highly expressed on mast cells, basophils, and eosinophils and causes most allergy symptoms
- It is a tetrameric protein and has a 10-10 M binding affinity for the IgE Fc region.
- low-affinity IgE receptor (FcεRII) has a 10-6 M binding affinity for the IgE Fc region, has membrane bound and soluble forms, and regulates production of IgE by B cells.
how do FcyRIIB Ig receptors regulate the antibody response?
Mast cells express both FcεR1 (activating) and FcγRIIB (inhibiting) Ig receptors. If a cell binds IgE and IgG, the inhibiting signal induced by IgG binding wins out. This is partially why inducing IgG in atopic individuals (usually through “allergy shots”) helps treat their allergies.
what is the purpose and mechanism for allergy skin testing?
- is commonly used/inexpensive/safe way to screen a wide range of antigens
- Small quantities of known allergens are introduced by injection or applying to a scratch at specific skin sites on the forearm or back.15-30 minutes later the sites are reexamined and swelling and redness (resulting from local mast cell degranulation) indicate allergic response. A histamine controls is also run, and each response is scored based on the area of the wheal and flare.
what is the mechanism underlying hyposensitization treatment for type I allergy?
Repeated exposures via ingestion or injection to increasing doses of allergen may induce an increase in regulatory T cells and their anti-inflammatory cytokines (IL-10 and TGF-b).
- May also cause competitive IgG subtypes that block antigen binding or bind to inhibitory Fc receptors.
- most effective way to manage allergies b/c it can reduce or even eliminate symptoms for months or years after the desensitization course is complete
describe how early exposure to endotoxins could be protective to asthma?
- hygiene hypothesis = early exposure to microorganisms inhibits the development of allergy by preventing Th2 mediated responses that induce IgE antibodies. Exposure to pathogens early in life provides development of better T-cell balance. May explain why countries with improved hygiene are experiencing increases in asthma and allergy rates.
How are blood transfusion reactions an example of type II hypersensitivity?
Several proteins and glycoproteins on the membrane of red blood cells are encoded by genes with several allelic forms. Blood group Ag are carbohydrates (A, B, or H) rather than proteins and all blood types have H antigen. Adults possess antibodies to the blood antigen they do NOT have. If they receive a transfusion of the “wrong” type of blood, their antibodies will quickly attach to the donor blood cells and trigger complement proteins. The degraded RBC components can build to toxic levels. Many other cell types also have these antigens.
Many diseases can result from immune complex mediated (Type III) hypersensitivity reactions, list the three main types (categories) of diseases.
1) Autoimmune: Lupus, arthritis, MS
2) Drug reactions: allergies to penicillin and sulfonamides
3) Infectious disease: nephritis, meningitis, hepatitis, mononucleosis, malaria, trypanosomiasis
Describe how the initiation of delayed-type (type IV) hypersensitivity (DTH) response involves sensitization by an antigen.
Initial exposure triggers a T-cell response (Th1 or Th17) via Langerhans cells (skin DCs) or other APCs. Takes 1–2 weeks of time. The effector phase of a classical DTH response is induced by second exposure to a sensitizing Ag. Second exposure induces production of inflammatory cytokines from sensitized Th1 or Th17 cells that recruit and activate macrophages. Inflammatory symptoms noticeable after 24 hours and peak 48-72 hours after 2nd exposure.
What is the relationship between Type II diabetes, obesity, and inflammation?
Obesity is associated with chronic inflammation. Visceral adipocytes are secretors of proinflammatory cytokines (TNF-α, IL-6, IL-1). Greater obesity linked to greater Type 2 diabetes. Chronic inflammation can cause systemic disease and insulin resistance. Aspirin can help improve insulin function. Patients with HIV or RA had worse insulin resistance that was improved with anti- inflammatory drugs. TNF-α/IL-6 induce signaling cascades that inhibit ability of insulin receptors to function. JNK blocks the signaling of the insulin receptor signaling pathway by phosphorylating a serine residue on the insulin receptor substrate (IRS) protein that prevents the insulin signal from being sent, resulting in deficiency in insulin function. Macrophages, mast cells, NKT cells, CD8 cells, and adipocytes release of proinflammatory cytokines in diabetes.
tolerance
prevention of an immune response against self
central tolerance
deletion of lymphocytes before they mature and occurs in the thymus and bone marrow
peripheral tolerance
occurs outside of the bone marrow and thymus and can make self-reactive lymphocytes nonresponse or actively generate inhibiting lymphocytes (like Tregs)
identification of T regulatory cells
- have high levels of CD25 (IL2Ralpha), CTLA4, FoxP3 (transcription factor)
- prevent autoimmune diseases such as diabetes
- CD4+ T regulatory cells help suppress responses against non-self antigens like commensal microbes
- deficiency = higher levels of inflammatory bowel disease
how the gut microbiome affects the development of the immune system
- lots of cross talk
- EX: germ-free mice have defects in their humoral/adaptive immune systems & there is increase in severity of autoimmune disease
- Intestinal epithelial cells (IECs) and mucosal dendritic cells play a key role in communicating between the microbiome and adaptive immune cells
- what we eat can affect the immune cells
- EX: Sodium chloride can
drive the development of CD4+ T cells to the TH17 phenotype.
Dependent mechanisms of T regulatory cells to inhibit the immune response
TREG cells express high levels of inhibitory CTLA-4 molecules. Can kill
APCs or CD8 T cells via granzyme/perforin or cause APCs to have reduced costimulatory molecules,
pro-inflammatory cytokines, and increased anti-inflammatory molecules
Independent mechanisms of T regulatory cells to inhibit the immune response
Rely upon secretion of anti-inflammatory cytokines (IL-10, TGF-β, IL-35) into the
surrounding area, shutting down nearby cells’ responses. They can also act as a sponge to soak up IL-2 since they have lots of non-signaling IL-2Ra
cause of Hashimoto’s thyroiditis
Auto-ab and sensitized TH1 cells specific for thyroid Ag are produced. Ab interfere with iodine uptake. Decreases thyroid function leads to goiter & hypothyroidism.
cause of Myasthenia gravis
Auto-ab bind acetylcholine receptors on motor end plates of muscles. Block the normal binding of acetylcholine, induce complement-mediated lysis of cells. Result is a progressive weakening of the skeletal muscles and can effect the ability to move and eat.
Why are women more susceptible than men to autoimmunity?
Evidence suggests that women mount a more robust humoral and cellular immune response than men. They have higher CD4 T cell levels, higher antibody titers in primary and secondary responses, and increased levels of graph rejection. Males are more prone to infections than women. It is
believed that estrogen enhances immunity whereas testosterone decreases it. Females are more likely to mount a proinflammatory TH1 response than men.
Why is autoimmunity induced in some genetically similar individuals and not in others?
- Induction may be multifactorial
- a series of triggering events that cross an individual’s systems of tolerance over a threshold
- Infections and molecular mimicry may activate cross reactive lymphocyte
- Damage/stress events may expose sequestered Ag. Foods that alter gut microbial balance, promoting chronic inflammation and
hypersensitivity reactions.
Autograft
self-tissue grafted to another self area (skin grafts, blood vessels)
Allograft
tissue transferred between genetically different members of the same species (majority
of transplant cases).
main steps for screening for a histocompatible organ donor
1) Test for blood group match (blood typing)
2) Find full or partial HLA match (tissue typing)
3) Look for anti-HLA antibodies in serum (cross matching)
sensitization stage of graft rejection
where CD4+ and CD8+ T cells recognize alloantigens
expressed on foreign graft cells (MHC only or pepMHC).
effector stage of graft rejection
where the cell mediated response infiltrates and rejects the graft tissues.
Hyperacute rejection
occurs by preexisting antibodies occurs before grafted tissue revascularizes (in as few
as 24 hours)
Acute rejection
mediated by T-cell responses. Begin 7–10 days post-transplantation. Induce massive infiltration of lymphocytes and macrophages.
Chronic rejection
develops months or years after acute rejection reactions have subsided.
Antigen specific immunotherapies hold great promise for aiding in long term success after
organ transplantation, describe how these therapies work.
Monoclonal antibodies can achieve some of this desired effect. mAb to CD3 (OKT3) depletes T cells prior to transplant. Can also use anti-CD20 antibodies to deplete B cells or antibodies against cytokines to slow down the immune response. Soluble CTLA-4 fusion proteins (belatacept) can induce T-cell anergy by blocking co stimulation and are showing promise.
outbreak
When a pathogen infects many people in one area over a short window of time
endemic
If that outbreak remains constant and predictable over time
epidemic
When a pathogen unexpectedly begins to infect large numbers of people in a community or region
pandemic
an epidemic, and if that spreads over multiple countries
Chain of infection
Infectious agents -Reservoirs Portals of exit - Modes of transmission - Portals of entry - Susceptible hosts
infectious agents
microbes that can cause disease or illness
Reservoirs
places where infectious agents live, grow, and reproduce
Portals of exit
ways infectious agents leave human or animal reservoirs
Modes of transmission
ways infectious agents can encounter a susceptible host.
Portals of entry
places where infectious agents can enter a susceptible host
Susceptible hosts
characteristics that influence in individuals’ susceptibility to infection
three known ways transmission of respiratory infections occur
small-aerosolized nuclei, larger droplets, and contact with contaminated surfaces (fomites)
the best way to prevent disease transmission with respiratory diseases
can be best prevented by masks (small-aereolized nuclei), distancing (large droplets), and
regular cleaning of fomites/hands respectively (contaminated surfaces).
How are mosquitoes, flies, ticks, snails, and fleas involved with infectious diseases? What are two examples of host factors that increase susceptibility to infectious disease?
Vector borne infections account for one out of every six instances of human infectious disease. Susceptibility to infectious disease is determined by a combination of host factors which include health
status, genetics, and the immune response. Malaria and HIV susceptibility/resistance factors (hemoglobin
structure and CXCR5 Δ32 allele) are examples of genetic factors.
characteristics of a cytokine release syndrome/cytokine storm
CRS can cause a hyperinflammatory conditions (acute phase responses caused by hyperactive immune cells) that when occurring throughout the body (such as with sepsis), it can drop blood pressure and cause organ failure and death.
acute respiratory distress syndrome (ARDS) and why are they a health concern
When CRS occurs in the respiratory tract it can cause acute respiratory distress syndrome (ARDS), which is a
life-threatening condition where the alveolar-capillary barrier is injured, and fluid can accumulate cause
patients to be unable to breathe (likely a major cause of death with Spanish flu).
R0
the reproduction rate of a virus and since viruses need hosts to replicate
- is the average number of
people that one virally infected individual will infect. This also helps us understand what percentage of the
population will need to be immune to develop herd immunity
- is calculated assuming that no one in the population is immune and that host behavior or pathogen infectivity do not change. As these change over
time then the original R0 is obsolete
Models of the effective reproductive rate (Re)
account for changes in
immune status, host behavior, and viral mutations over time but even when using Re, the effective reproductive rate and herd immunity thresholds must be constantly updated based on changing conditions.
Trained immunity
when engagement of the innate immune system results in epigenetic and metabolic
changes like adaptive memory that result in a future shift in innate responses to the same or different subsequent stimuli. Sequence matters since prior exposures can shape future innate responses, even to newly
encountered infectious agents. We know that microbial exposures can alter innate responses, but it is also
likely that other stimuli like diet, stress, pollution, allergens etc. also have a similar effect.
Type 1 immune responses
dominate during intracellular infections
type 2 responses
important for barrier surface control of infections that arise at the epithelial surfaces (particularly anti-helminth
immunity)
type 3 immune responses
target extracellular pathogens.
Infections of the blood
can cause sepsis (many white blood cells, fever, rapid heart rate, elevated breathing,
and weakness). If not controlled sepsis can lead to septic shock, a powerful and disseminated immune
response that can lead to circulatory collapse, respiratory collapse, and a 50% mortality rate.
strategies do viruses employ to enter cells and evade the immune system
express immune inhibiting or immune blocking compounds, suppress MHC class I expression,
and regularly change surface antigens to misdirect the immune response
Antigenic drift
due to high mutation potential of RNA genome. RNA polymerase lacks proofreading capability. Reason for changing flu vaccine formulation every year
Antigenic shift
occurs when different
virus types infect a single cell. RNA genome segments can be swapped in new virus. Can create new HA/NA
combinations. A population may have little to no resistance against new combination.
Original antigenic sin
occurs because once we have an effective response, we won’t initiate a new one until the original one is no longer effective. This results in an inability to mount a new response against the epitopes that have been mutated and are not bound by current antibodies
How are extracellular and intracellular bacterial infections primarily resolved?
Immunity to bacterial infections is achieved by antibodies for extracellular bacteria and via cell mediated
immunity for intracellular bacteria
What makes immune detection of parasitic infections so difficult?
Parasites are a broad category and include unicellular protozoan eukaryotes living in or outside cells and macroscopic worms that live exclusively outside cells. Most protozoan parasites undergo multiple life cycle changes making immune detection difficult. Natural immunity to worms is generally weak.
Which branch of the
immune system primarily resolves fungal infections?
Most fungal infections are controlled by the innate immune system in health individuals, although humoral
and adaptive immune responses are engaged by fungal infections.
Passive immunization
achieved by delivery of preformed antibody but does not confer long lived protection or memory. Several conditions warrant using this method such as immune deficiency, toxin, or venom
exposure with immediate threat to life, or exposure to pathogens that cause death faster than an effective
immune response can develop
- occurs naturally between mother and her newborn.
Active immunization
exposure to a pathogen epitope to elicit long-lived protective immunity. This is useful for protection from infection and the generation of long-lasting memory to future live pathogen exposures.
Describe how vaccines activate different cells and immune response pathways.
Successful vaccination initiates activation of specific innate and adaptive response elements. Antigen presenting cells like DCs recognize adjuvants via PRRs and engulf and present the antigenic components. These activated DCs traffic to the draining lymph node where they initiate lymphocyte activation. The vaccine modality, pathogen-specific antigenic components, and the delivery route help determine the type of adaptive response (type 1, 2, or 3) and site of memory cell deposition. Type 1 responses involve CD8 T cells
(and CD4 T cell help), type 2 responses involve B cells (and CD4 T cell help), and a type 3 response involves
Th17 cells, IgA, and neutrophils.
empirical vaccine approach
involves growth of the pathogen, extraction of the antigen or inactivation of the whole pathogen, and then injection.
rational vaccine design
scientists employ
predictive powers of nucleic acid sequences, protein structures, immune response pathways, and molecular
level interactions to design a vaccine with more precise objectives
antigen
any substance that binds to a B-cell receptor or T cell receptor
epitope
the specific biochemical moiety on the antigen that contacts these receptor binding sites. Some, but not all, foreign antigens elicit good humoral and cellular immunity
Immunogens
antigens that elicit specific, strong humoral and/or cellular immune responses. All immunogens are antigens, but not all antigens are good
immunogens; identifying good immunogens and epitopes are key steps in designing a good vaccine.
Why are “correlates of immune protection” essential for vaccine development?
An essential step in the path to a new vaccine is to define specific immune targets as measurable immunological signs that the host has antigen-specific adaptive responses likely to protect against disease with the live pathogen. This may include specific antibody isotype titers or CD8 or CD4 effector or memory cell numbers. Pathogen characteristics such as incubation period, mutation rates, and key surface structures
must be considered in establishing these immune markers.
phase I of clinical trials
measures safety in a small number of closely monitored volunteers
phase II of clinical trials
evaluates efficacy of the
vaccines in a larger group of humans
phase III
measures the vaccine effectiveness against a previously established clinical benchmark in a large group of people and may include a non-treatment control before it can undergo FDA approval
phase IV of clinical trials
a closely monitored phase after vaccines are distributed.
Adjuvants
separate molecules from the antigenic protein
how do adjuvants/conjugates work
When combined with an antigen, the goal of using an adjuvant or conjugate is to increase immunogenicity (the strength of the immune response) and they usually target the innate response which then amplifies the adaptive response
innate response to adjuvants
- swelling/redness
Adjuvants work by stimulating innate microbial and danger signals, slowing antigen release, facilitating
phagocytosis, and creating a local pro-inflammatory microenvironment which helps to instruct the
transition to an adaptive response.
conjugates
covalently linked to the
antigenic protein
advantages of whole pathogen vaccines (attenuated live or
inactivated microbes)
- live attenuated vaccines trigger a robust adaptive immune response after a single dose
- Killed inactivated vaccines contain the entire pathogen in a non-infectious form and there is no risk of reversion or storage issues
disadvantages of whole pathogen vaccines (attenuated live or
inactivated microbes)
- attenuated live could potentially revert to a virulent form that can cause disease
- inactivated produce lower
immunogenicity, poor cell mediated immune response, manufacturing risks, and the need for booster shots
advantages of subunit vaccines (protein, polysaccharide, and
toxoid)
- Subunit vaccines use a piece of infectious agent (protein, polysaccharide, or a conjugate of the two) or an inactivated version of a secreted exotoxin (toxoid)
- improved production safety and storage and
transportation advantages
disadvantages of subunit vaccines (protein, polysaccharide, and
toxoid)
produce weaker immune responses than attenuated vaccines. Most subunit
vaccines (except toxoids) do not trigger innate responses and require multiple doses, innate stimulating
additives, and/or conjugation.
outer membrane particle/vesicle or virus-like particle
Outer membrane/vesicle vaccines use vesicles from the outer membranes of bacteria that contain pathogen-
derived proteins whereas virus-like particle vaccines are made from viral structure proteins that self-assemble into empty virions containing pathogen-specific structures.
advantages of particle-based vaccines (outer membrane particle/vesicle or virus-like particle)
These are newer approaches that should provide a good boost to the innate and adaptive immune systems
disadvantages of particle-based vaccines (outer membrane particle/vesicle or virus-like particle)
No bacterial vesicles have been approved to date and the virus like particle vaccines have worked okay but have required boosters.
vectored vaccines (viral or bacterial vectors)
Attenuated, benign, recombinant viruses, and bacteria can be used as live vehicles for the delivery of
heterologous antigens or nucleic acids to host cells. This is often done by adding pathogen antigen genes to
the vector of an already licensed live attenuated vaccine.
advantages and disadvantages of vectored vaccines (viral or bacterial vectors)
Replication competent microbial vectors retain
many of the advantages of attenuated vaccines (prolong delivery, strong cell mediated responses, long lived
immunity, no reversion potential) with fewer disadvantages
disadvantages of vectored vaccines (viral or bacterial vectors)
(Requires effort to clone in gene and make sure
that it generates strong immunity and requires production process). Replication deficient versions are good at delivering antigen but provide weaker immune protection.
nucleic acid vaccines (DNA or mRNA)
Nucleic acid-based vaccines deliver genetic material with instructions for the host cell to make pathogen-associated antigens, which activate a pathogen-specific immune response. DNA based vaccines deliver their information to the nucleus and RNA based vaccines to the cytosol, where host cell machinery takes over
expression.
advantages of nucleic acid vaccines (DNA or mRNA)
include potential to activate strong adaptive responses and short
production times
disadvantages of nucleic acid vaccines (DNA or mRNA)
The major disadvantage of DNA based vaccines centers on lower protein expression that can lower immune activation levels whereas RNA vaccines suffer mainly from cold-chain storage limitations.
