vaccines midterm

Name one significant symptom/effect of Measles (If death, provide approximate mortality rate)

Death (lethality rate is currently 1-3 per 1000), encephalitis, mental retardation, central nervous system damage/immune amnesia

Name one significant symptom/Effect of Smallpox (If death, provide approximate mortality rate

Death (mortality was about 30%), blistering and pockmarks that scar

Against what disease was the first vaccine?

Smallpox

How was the first vaccine made, and why cant we use the same approach for most other cases?

Jenner’s smallpox vaccine was made using matter from cowpox sores (a related disease) and by inoculating smallpox patients. We can’t use this approach, known today as live-attenuated vaccines, for many reasons, including reversion, immunocompromised risk, transport issues, and cost. While not super common, it is possible for live vaccines to revert to their virulent form inside the body and cause full infection. They are also especially dangerous for immunocompromised individuals whose bodies cannot process the vaccines in the same way. Lastly, live vaccines must remain viable to remain effective, posing challenges for long-distance transport due to the required “cold chain,” which is inefficient and very expensive. “Cant generally use this approach because we don’t have ‘sister’ non-pathogenic viruses akin to Cowpox for our other viruses”

How is an attenuated viral vaccine made?

To attenuate a pathogenic human virus, it is grown in cells from another

animal species. Such conditions select for variant viruses that grow faster in the

non-human cells, which makes them less fit for growth in human cells so as not to infect the patient (weakening the virus in general).

How is the transmission of Polio different from the transmission of Smallpox?

Whereas smallpox is transmitted by face-to-face contact, poliovirus is transmitted by the

fecal–oral route, leading to various disease outbreaks being associated with communal

bathing in public swimming pools.

What is complement, and why is it important?

Complement is a system of plasma proteins that mark pathogens for destruction. They are important because they help to combat pathogens and distinguish between healthy and infected cells.

1. Complement often involves the proteolytic cleavage of the C3 protein into C3a (small) and C3b (large) Complement can “tag” pathogens for destruction (like C3b) by binding covalently through “complement fixation”.

2. C3a and C5a can also cause inflammation at the site of infection which recruits phagocytes. Smaller C3a and C5a fragments are ligands for receptors on phagocytes, endothelial cells, and mast cells. These ligand–receptor interactions increase inflammation at the site of complement activation. Inflammation (see Section 1-4) is a major consequence of the innate immune response to infection, which is also known as the inflammatory response. In some circumstances, C3a and C5a induce anaphylactic shock, an acute and powerful inflammatory reaction that affects tissues throughout the body and can be lethal. In this context, C3a and C5a are described as anaphylatoxins, with C5a being more potent and stable than C3a. These changes facilitate the exit of plasma proteins and cells from the blood and their passage to sites of infection in the tissues

3. The terminal components of the complement cascade comprise the C5, C6, C7, C8, and C9 proteins. These five components cooperate to form the membrane-attack complex (MAC), a large pore that is assembled in the membrane of bacterial and eukaryotic pathogens and kills them by perturbing their structural integrity.

What is a central role of dendritic cells?

The critical function of the dendritic cell is one of decision: to determine whether, and when, the innate immune response needs reinforcement with an adaptive immune response. When adaptive immunity is required, dendritic cells within the infected tissue gather up a cargo of intact and degraded pathogens and take them to lymphoid tissues, where they initiate the adaptive immune response to the pathogen (by interacting with B- and T-cells). Dendritic cells thus provide a link between the innate and adaptive immune responses. Take antigens from site of infection to lymph nodes, to activate the T- and B cells in the Lymph nodes.

What is the main role of B cells?

When a B cell encounters the specific antigen recognized by its B-cell receptor, the B cell is activated to divide and differentiate into antibody-producing plasma cells. The synthesis and secretion of antibody is the principal effector function of B cells.

What are the two types of T cells, and what do they do?

Antigen-activated effector T cells are of different functional types, distinguished by their surface glycoproteins, the cytokines they respond to, the cytokines they secrete, and the type of target cell they interact with. The main subdivision of effector T cells is defined by the cell-surface expression of either the CD4 or CD8 co-receptor protein. (i.e. CD4 or CD8 T cells).

1. T cells expressing the CD8 co-receptor are cytotoxic T cells that kill cells infected with a virus or bacterium. These cytotoxic T cells of adaptive immunity have similar effector functions to the NK cells of innate immunity

2. T cells expressing the CD4 co-receptor are known as helper T cells because they secrete cytokines that enable other cells to become fully activated effector cells.

What is an AMP and why is it useful?

Antimicrobial Peptides (AMPs), often called host defense peptides, are small, naturally occurring protein fragments that destroy pathogens directly by disrupting their membranes, modulate the immune response. The main example is defensins, which are amphipathic peptides with separate regions having charged or hydrophobic residues. This feature allows defensins to interact with the cell membrane's charged surface and insert into the lipid bilayer. This leads to pore formation and consequent loss of membrane integrity. They can also protect against toxins released by bacteria by promoting localized unfolding of the toxin (due to structural plasticity and thermodynamic instability), thereby destabilizing its three-dimensional structure. This has the effect of making the toxin susceptible to attack by human proteases and to physical denaturation and precipitation (anti-chaperone).

What is a phagosome, and how is it useful?

A phagosome is an internal cytoplasmic vesicle that is acidic and contains enzymes that destroy and degrade bacteria. A phagoCYTE is a cell that eats, or engulfs bacteria and brings it to the phagosome for degradation.

What is the impact factor, and why is it useful?

The impact factor is the average number of times a paper in the journal is cited, per year. It can help you determine the credibility of a source and it’s status in a peer-reviewed, reputable journal. A ‘good’ impact factor is 3 or 4. A really good impact factor is 8-12. Some ‘sexy’ journals that are hard to publish in, like PNAS have impact factors in this range. An Amazing impact factor is 20+. Science (47), Nature (50), and Cell (41), as well as the New England Jl. Of Medicine (91) have super high impact factors.

How can you assess if a source is reliable? (2 reasons)

1. If the source is not peer-reviewed/not original research: Do they cite original research to back up any claims, and was that original research peer reviewed, and in a reputable journal? If they are making statements about things that may or may not be true, and are NOT providing citations to back up the statements, you SHOULD NOT TRUST IT.

2. Look at the author's background and qualifications. If they are making statements about medical findings, etc., do they have a PhD? Are they technically well-trained?

Is vaccine hesitancy/opposition to vaccines a relatively new societal problem? Explain

NO, vaccine hesitancy is not a new societal problem; there have always been people distrustful of or afraid of vaccines. For example, when the smallpox vaccine was first formulated, there were many sanitary, religious, scientific, and political concerns. Some felt the method was unhealthy or unchristian, as it used matter from lower creatures. Some disputed that smallpox was transmitted from person to person, but many simply did not like being told what was good for them.

1. People were asking questions about rights, especially working-class rights. There was a sense that the upper classes were trying to take advantage, a feeling of distrust

2. This was a move into an area of people's private lives, their health, which had not been governed before

3. And vaccines were not as safe as they are now - people did become seriously ill and even died

What is R0 and why should we care?

R0 is a measure of how contagious a virus is. It can be affected by:

1. The proportion of susceptible people at the start and the density of the population

2. The infectiousness of the organism

3. The time for which an individual is infective

The denser the population, the more people are susceptible, an the more infective, the larger R0 will be. The faster the rate of removal, the smaller the R0 will be. For example the R0 of measles is about 15 which means you need around 95% vaccination to reach herd immunity (1- 1/15).

What is herd immunity?

Herd immunity makes it possible to protect the population from a disease, including those who can’t be vaccinated, such as newborns or those with compromised immune systems. It is reached when enough people in the population have protective antibodies against future infection. Can be caused by vaccination or sickness/recovery, so we lose herd immunity when vaccination rates go down. If you allow the virus to spread within the community, in a controlled way, you hope to have increasing immunity develop, ultimately reaching so-called herd immunity.

What are the two parts of innate immunity?

1. Physical and chemical barriers (anatomic, physiological, polypeptide mediators)
   anatomic: → skin, mucous, cilia, epithelimum
   physiological → low pH of stomach
   polypeptide → lysozyme in saliva and tears, peptides in the GI tract and on epithelial surfaces

2. Active defense (innate immune cells)

What are the ‘commander’ cells in innate immunity?

The tissue-resident Macrophages

What are the ‘infantry’ cells in innate immunity?

The neutrophils that the macrophages summon to enter the infected tissues

How do these two sets of cells work together?

The macrophages detect the presence of pathogens, and release chemical messengers (cytokines and chemokines) to attract/recruit the neutrophils and other cells such as NK cells.

What are Lymphocytes and why are they called that?

The cells of the adaptive immune system (B and T cells). They are called that because they start out in the lymph nodes, where they are activated by dendritic cells that bring antigens into the lymph nodes.

What are commensal microorganisms?

Bacteria that live in your body that are not harmful; frequently they help protect you from pathogenic bacteria, and may also help you absorb nutrients better.

Name two different classes of pathogens

bacteria, Fungi, viruses, worms

In the innate immune system, what is the effect/role of inflammation?

It is used to bring in helper cells (e.g. neutrophils etc) from other parts of the body to fight infection.

What is a key role of NK cells?

They are cytotoxic, and kill virally infected cells

What are the differences between adaptive versus innate immunity?

1. adaptive: not pre-existing. develops over time. Makes use of B and T cells when the innate immunity cannot stop the infection. Has a slow response, can be variable between people and infections, can be highly specific

2. innate: 1st line of defense. chemical and physical barriers plus a cellular response. The response is rapid (within hours)

Typically how long does adaptive immunity take to respond?

4 days to a few weeks.

What is the difference between the primary and secondary response of adaptive immunity?

The primary response is the first time the body sees the pathogen. It takes ~ 8 days, and makes some antibodies although they are so-so (IGMs). The secondary response is a subsequent time when a previously seen pathogen is detected again. The response is faster (~4 days) and stronger, with more/better (IGG) antibodies.

What are the pathogen receptors on B cells called, and why are they useful?

Immunoglobulins, or attached antibodies. They have high specificity for specific pathogens. When they bind to the antigen( part of the pathogen) they signal the b cells to make clonal copies, many of which turn into plasma cells and release antibodies.

What is the role/importance of the Lymph system?

It is where pathogen fragments are taken by dendritic cells, to bring them into contact with Naïve B and T-cells, to allow activation of those cells to subsequently fight the pathogen.

What are the two roles of antibodies?

To neutralize the pathogen (by coating it with antibodies, and e.g. preventing it from entering cells) and To target the pathogen for destruction by phagocytosis.

What are the two ways to kill pathogens? Broadly, how do these mechanisms work?

Macrophage engulfment: A cellular receptor binds to the pathogen (e.g direct, or via C3b or antibody) and this promotes the macrophage to endocytose the bacterium, which creates a phagosome and with lysosomes it forms a phagolysosome (this delivers toxins that kill and degrade the bacterium) pore formation: Either an AMP directly forms pores in the pathogens surface, or terminal components comprised of proteins cooperate to form the membrane attack complex (which is a large pore that assembles on the pathogen surface and destroys them by destroying their structural integrity)

What is the role of macrophages and neutrophils in sensing and eliminating infection?

Macrophages are resident in tissues, and are the first cells to detect an infection. They respond by secreting a barrage of effector molecules that act together to make the induced innate response. Neutrophils and NK cells respond to these effectors by entering the infected tissue and eliminating bacterial or viral pathogens.

How do these work together to kill bacteria?

The neutrophil can engulf the bacteria, with lysosomes to degrade the bacteria, and when the neutrophil dies by apoptosis, the macrophage can engulf it.

Why is the acute-phase response important?

This increases the effectiveness of innate immunity by increasing the amount of pathogen-recognition receptors, as well as recruiting additional cells like Neutrophils to the site of infection. This can be triggered by the inflammatory cytokines.

How are T cells activated?

When the infection overcomes the innate immune system, the adaptive immune system then needs to take action. This occurs through activation of T cells and B cells. When the antigens are taken up by dendritic cells, the dendritic cells can take move to the lymph nodes and ‘present’ the antigen to the T-cells there. Those T-cells with receptors that bind the antigen well are then activated.

What are long-lived plasma cells and what do they do?

long lived plasma cells and the antibodies they make are an important part of a person’s immunological memory of pathogens. (the other are b and t cells). The plasma cells produce and secrete antibodies, which make up the steady-state level of antibodies circulating in a person’s blood.

What can influence how long a vaccine can protect for? Do we know how long all vaccines last for?

1. rate of viral infection

2. amount of virus produced by infected individuals

3.the infectivity of the virus

4.the number of antibodies produced by the vaccine (& how long they last)

5.the kinetic of infection vs activation of memory b cells

Essentially, we do not know how long all vaccines last for, as there is extreme variation between the vaccines for certain infections . Many do not last long, but there are some that last a lifetime

What are adjuvants and why are they important?

adjuvants help activate the innate immune system, helping attract dendritic cells that then take antigens to the Lymph nodes to activate the B and T cells. Increasing adjuvants in vaccines can help with their effectiveness.